Breast cancer, HER2-positive

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Note: these are regimens tested in biomarker-specific populations, please see the main breast cancer page for other regimens.

123 regimens on this page 201 variants on this page

Guidelines

ASCO

• 2021: Korde et al. Neoadjuvant Chemotherapy, Endocrine Therapy, and Targeted Therapy for Breast Cancer: ASCO Guideline
• 2020: Denduluri et al. Selection of Optimal Adjuvant Chemotherapy and Targeted Therapy for Early Breast Cancer: ASCO Guideline Update
• 2018: Ramakrishna et al. Recommendations on disease management for patients with advanced human epidermal growth factor receptor 2-positive breast cancer and brain metastases: American Society of Clinical Oncology clinical practice guideline update PubMed
• 2018: Giordano et al. Systemic therapy for patients with advanced human epidermal growth factor receptor 2–positive breast cancer: ASCO Clinical Practice Guideline update PubMed

Older

• 2018: Denduluri et al. Selection of optimal adjuvant chemotherapy and targeted therapy for early breast cancer: ASCO clinical practice guideline focused update PubMed
• 2016: Harris et al. Use of biomarkers to guide decisions on adjuvant systemic therapy for women with early-stage invasive breast cancer: American Society of Clinical Oncology Clinical Practice Guideline
• 2015: Van Poznak et al. Use of biomarkers to guide decisions on systemic therapy for women with metastatic breast cancer: American Society of Clinical Oncology Clinical Practice Guideline
• 2014: Giordano et al. Systemic therapy for patients with advanced human epidermal growth factor receptor 2-positive breast cancer: American Society of Clinical Oncology clinical practice guideline PubMed
• 2014: Ramakrishna et al. Recommendations on disease management for patients with advanced human epidermal growth factor receptor 2-positive breast cancer and brain metastases: American Society of Clinical Oncology clinical practice guideline PubMed

ESMO

• 2017: Cardoso et al. 3rd ESO-ESMO International Consensus Guidelines for Advanced Breast Cancer (ABC 3). PubMed
• 2015: Senkus et al. Primary breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. PubMed

NCCN

• NCCN Guidelines - Breast Cancer

St Gallen Breast Guidelines

• 2019: Burstein et al. Estimating the benefits of therapy for early-stage breast cancer: the St. Gallen International Consensus Guidelines for the primary therapy of early breast cancer 2019

Older

• 2017: Curigliano et al. St. Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2017
• 2015: Coates et al. Tailoring therapies—improving the management of early breast cancer: St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2015

Neoadjuvant chemotherapy

Cyclophosphamide & Doxorubicin (AC)

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AC: Adriamycin (Doxorubicin) & Cyclophosphamide

Regimen variant #1, 4 cycles

Study	Years of enrollment	Evidence
Robidoux et al. 2013 (NSABP B-41)	2007-2011	Non-randomized portion of RCT
Park et al. 2016 (I-SPY 2)	2010-2013	Non-randomized portion of RCT

Preceding treatment

• I-SPY 2: Neratinib & Paclitaxel x 12 wk versus TH x 12 wk

Chemotherapy

• Doxorubicin (Adriamycin) 60 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 600 mg/m² IV once on day 1

21-day cycle for 4 cycles

Subsequent treatment

• NSABP B-41: TH versus THL versus TL, then surgery
• I-SPY 2: Surgery

References

1. NSABP B-41: Robidoux A, Tang G, Rastogi P, Geyer CE Jr, Azar CA, Atkins JN, Fehrenbacher L, Bear HD, Baez-Diaz L, Sarwar S, Margolese RG, Farrar WB, Brufsky AM, Shibata HR, Bandos H, Paik S, Costantino JP, Swain SM, Mamounas EP, Wolmark N. Lapatinib as a component of neoadjuvant therapy for HER2-positive operable breast cancer (NSABP protocol B-41): an open-label, randomised phase 3 trial. Lancet Oncol. 2013 Nov;14(12):1183-92. Epub 2013 Oct 4. link to original article contains protocol PubMed NCT00486668
2. I-SPY 2: Park JW, Liu MC, Yee D, Yau C, van 't Veer LJ, Symmans WF, Paoloni M, Perlmutter J, Hylton NM, Hogarth M, DeMichele A, Buxton MB, Chien AJ, Wallace AM, Boughey JC, Haddad TC, Chui SY, Kemmer KA, Kaplan HG, Isaacs C, Nanda R, Tripathy D, Albain KS, Edmiston KK, Elias AD, Northfelt DW, Pusztai L, Moulder SL, Lang JE, Viscusi RK, Euhus DM, Haley BB, Khan QJ, Wood WC, Melisko M, Schwab R, Helsten T, Lyandres J, Davis SE, Hirst GL, Sanil A, Esserman LJ, Berry DA; I-SPY 2 Investigators. Adaptive randomization of neratinib in early breast cancer. N Engl J Med. 2016 Jul 7;375(1):11-22. link to original article contains verified protocol link to PMC article PubMed NCT01042379

Dose-dense Cyclophosphamide & Doxorubicin (ddAC)

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ddAC: dose-dense Adriamycin (Doxorubicin) and Cyclophosphamide

Regimen

Study	Evidence
Park et al. 2016 (I-SPY 2)	Non-randomized portion of RCT

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Preceding treatment

• Neratinib & Paclitaxel x 12 wk versus TH x 12 wk

Chemotherapy

• Doxorubicin (Adriamycin) 60 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 600 mg/m² IV once on day 1

Supportive medications

• Pegfilgrastim (Neulasta) 6 mg SC once on day 2, given 24 hours after chemotherapy

14-day cycle for 4 cycles

Subsequent treatment

• Surgery

References

1. I-SPY 2: Park JW, Liu MC, Yee D, Yau C, van 't Veer LJ, Symmans WF, Paoloni M, Perlmutter J, Hylton NM, Hogarth M, DeMichele A, Buxton MB, Chien AJ, Wallace AM, Boughey JC, Haddad TC, Chui SY, Kemmer KA, Kaplan HG, Isaacs C, Nanda R, Tripathy D, Albain KS, Edmiston KK, Elias AD, Northfelt DW, Pusztai L, Moulder SL, Lang JE, Viscusi RK, Euhus DM, Haley BB, Khan QJ, Wood WC, Melisko M, Schwab R, Helsten T, Lyandres J, Davis SE, Hirst GL, Sanil A, Esserman LJ, Berry DA; I-SPY 2 Investigators. Adaptive randomization of neratinib in early breast cancer. N Engl J Med. 2016 Jul 7;375(1):11-22. link to original article contains verified protocol link to PMC article PubMed NCT01042379

ECH

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ECH: Epirubicin, Cyclophosphamide, Herceptin (Trastuzumab)

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Untch et al. 2012 (GeparQuinto)	2007-2010	Phase III (C)	See link	See link

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Chemotherapy

• Epirubicin (Ellence) 90 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 600 mg/m² IV once on day 1

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV once on day 1
  • Cycles 2 to 4: 6 mg/kg IV once on day 1

21-day cycle for 4 cycles

Subsequent treatment

• TH (Taxotere) x 4, then surgery

References

1. GeparQuinto: Untch M, Loibl S, Bischoff J, Eidtmann H, Kaufmann M, Blohmer JU, Hilfrich J, Strumberg D, Fasching PA, Kreienberg R, Tesch H, Hanusch C, Gerber B, Rezai M, Jackisch C, Huober J, Kühn T, Nekljudova V, von Minckwitz G; German Breast Group; Arbeitsgemeinschaft Gynäkologische Onkologie-Breast Study Group. Lapatinib versus trastuzumab in combination with neoadjuvant anthracycline-taxane-based chemotherapy (GeparQuinto, GBG 44): a randomised phase 3 trial. Lancet Oncol. 2012 Feb;13(2):135-44. Epub 2012 Jan 17. link to original article contains verified protocol PubMed NCT00567554
   1. Update: Untch M, von Minckwitz G, Gerber B, Schem C, Rezai M, Fasching PA, Tesch H, Eggemann H, Hanusch C, Huober J, Solbach C, Jackisch C, Kunz G, Blohmer JU, Hauschild M, Fehm T, Nekljudova V, Loibl S; GBG; AGO-B Study Group. Survival analysis after neoadjuvant chemotherapy with trastuzumab or lapatinib in patients with human epidermal growth factor receptor 2-positive breast cancer in the GeparQuinto (G5) study (GBG 44). J Clin Oncol. 2018 May 1;36(13):1308-1316. Epub 2018 Mar 15. link to original article PubMed

FEC

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FEC: Fluorouracil, Epirubicin, Cyclophosphamide

Regimen variant #1, 500/75/500 ("FEC-75")

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Buzdar et al. 2013 (ACOSOG Z1041)	2007-2011	Phase III (C)	See link	See link

Note: This is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Chemotherapy

• Fluorouracil (5-FU) 500 mg/m² IV once on day 1
• Epirubicin (Ellence) 75 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 mg/m² IV once on day 1

21-day cycle for 4 cycles

Subsequent treatment

• TH (Taxol) x 12 wk, then surgery

Regimen variant #2, 500/100/600 x 3

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Schneeweiss et al. 2013 (TRYPHAENA)	2009-2011	Randomized Phase II (C)	See link	Not reported

Note: This is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Chemotherapy

• Fluorouracil (5-FU) 500 mg/m² IV once on day 1
• Epirubicin (Ellence) 100 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 600 mg/m² IV once on day 1

21-day cycle for 3 cycles

Subsequent treatment

• THP x 3, then surgery

Regimen variant #3, 1000/75/500 x 4

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Buzdar et al. 2005	2001-2003	Randomized (C)	See link	See link

Note: This is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Preceding treatment

• CI paclitaxel x 4

Chemotherapy

• Fluorouracil (5-FU) 500 mg/m² IV once per day on days 1 & 4
• Epirubicin (Ellence) 75 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 mg/m² IV once on day 1

21-day cycle for 4 cycles

Subsequent treatment

• Surgery

References

1. Buzdar AU, Ibrahim NK, Francis D, Booser DJ, Thomas ES, Theriault RL, Pusztai L, Green MC, Arun BK, Giordano SH, Cristofanilli M, Frye DK, Smith TL, Hunt KK, Singletary SE, Sahin AA, Ewer MS, Buchholz TA, Berry D, Hortobagyi GN. Significantly higher pathologic complete remission rate after neoadjuvant therapy with trastuzumab, paclitaxel, and epirubicin chemotherapy: results of a randomized trial in human epidermal growth factor receptor 2-positive operable breast cancer. J Clin Oncol. 2005 Jun 1;23(16):3676-85. Epub 2005 Feb 28. link to original article contains verified protocol PubMed
   1. Update: Buzdar AU, Valero V, Ibrahim NK, Francis D, Broglio KR, Theriault RL, Pusztai L, Green MC, Singletary SE, Hunt KK, Sahin AA, Esteva F, Symmans WF, Ewer MS, Buchholz TA, Hortobagyi GN. Neoadjuvant therapy with paclitaxel followed by 5-fluorouracil, epirubicin, and cyclophosphamide chemotherapy and concurrent trastuzumab in human epidermal growth factor receptor 2-positive operable breast cancer: an update of the initial randomized study population and data of additional patients treated with the same regimen. Clin Cancer Res. 2007 Jan 1;13(1):228-33. link to original article PubMed
2. TRYPHAENA: Schneeweiss A, Chia S, Hickish T, Harvey V, Eniu A, Hegg R, Tausch C, Seo JH, Tsai YF, Ratnayake J, McNally V, Ross G, Cortés J. Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA). Ann Oncol. 2013 Sep;24(9):2278-84. Epub 2013 May 22. link to original article contains verified protocol PubMed NCT00976989
3. ACOSOG Z1041: Buzdar AU, Suman VJ, Meric-Bernstam F, Leitch AM, Ellis MJ, Boughey JC, Unzeitig G, Royce M, McCall LM, Ewer MS, Hunt KK; American College of Surgeons Oncology Group. Fluorouracil, epirubicin, and cyclophosphamide (FEC-75) followed by paclitaxel plus trastuzumab versus paclitaxel plus trastuzumab followed by FEC-75 plus trastuzumab as neoadjuvant treatment for patients with HER2-positive breast cancer (Z1041): a randomised, controlled, phase 3 trial. Lancet Oncol. 2013 Dec;14(13):1317-25. Epub 2013 Nov 13. link to original article link to PMC article contains verified protocol PubMed NCT00513292
   1. Update: Buzdar AU, Suman VJ, Meric-Bernstam F, Leitch AM, Ellis MJ, Boughey JC, Unzeitig GW, Royce ME, Hunt KK. Disease-Free and Overall Survival Among Patients With Operable HER2-Positive Breast Cancer Treated With Sequential vs Concurrent Chemotherapy: The ACOSOG Z1041 (Alliance) Randomized Clinical Trial. JAMA Oncol. 2019 Jan 1;5(1):45-50. link to original article link to PMC article PubMed

FEC & H

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FEC & H: Fluorouracil, Epirubicin, Cyclophosphamide, Herceptin (Trastuzumab)

Regimen variant #1, q3wk trastuzumab

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Ismael et al. 2012 (HannaH)	2009-2010	Phase III (C)	See link	See link
Pivot et al. 2018 (SB3-G31-BC)	2014-2015	Phase III (C)	See link	See link

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Preceding treatment

• TH (IV) x 4

Chemotherapy

• Fluorouracil (5-FU) 500 mg/m² IV once on day 1
• Epirubicin (Ellence) 75 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 mg/m² IV once on day 1

Targeted therapy

• Trastuzumab (Herceptin) 6 mg/kg IV once on day 1

21-day cycle for 4 cycles

Subsequent treatment

• HannaH: Surgery
• SB3-G31-BC: Surgery, then adjuvant trastuzumab x 30 wk

Regimen variant #2, weekly trastuzumab

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Buzdar et al. 2005	2001-2003	Phase III (E-esc)	See link	See link

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Preceding treatment

• TH x 4

Chemotherapy

• Fluorouracil (5-FU) 500 mg/m² IV once per day on days 1 & 4
• Epirubicin (Ellence) 75 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 mg/m² IV once on day 1

Targeted therapy

• Trastuzumab (Herceptin) 2 mg/kg IV once per day on days 1, 8, 15

21-day cycle for 4 cycles

Subsequent treatment

• Surgery

References

1. Buzdar AU, Ibrahim NK, Francis D, Booser DJ, Thomas ES, Theriault RL, Pusztai L, Green MC, Arun BK, Giordano SH, Cristofanilli M, Frye DK, Smith TL, Hunt KK, Singletary SE, Sahin AA, Ewer MS, Buchholz TA, Berry D, Hortobagyi GN. Significantly higher pathologic complete remission rate after neoadjuvant therapy with trastuzumab, paclitaxel, and epirubicin chemotherapy: results of a randomized trial in human epidermal growth factor receptor 2-positive operable breast cancer. J Clin Oncol. 2005 Jun 1;23(16):3676-85. Epub 2005 Feb 28. link to original article PubMed
   1. Update: Buzdar AU, Valero V, Ibrahim NK, Francis D, Broglio KR, Theriault RL, Pusztai L, Green MC, Singletary SE, Hunt KK, Sahin AA, Esteva F, Symmans WF, Ewer MS, Buchholz TA, Hortobagyi GN. Neoadjuvant therapy with paclitaxel followed by 5-fluorouracil, epirubicin, and cyclophosphamide chemotherapy and concurrent trastuzumab in human epidermal growth factor receptor 2-positive operable breast cancer: an update of the initial randomized study population and data of additional patients treated with the same regimen. Clin Cancer Res. 2007 Jan 1;13(1):228-33. link to original article PubMed
2. HannaH: Ismael G, Hegg R, Muehlbauer S, Heinzmann D, Lum B, Kim SB, Pienkowski T, Lichinitser M, Semiglazov V, Melichar B, Jackisch C. Subcutaneous versus intravenous administration of (neo)adjuvant trastuzumab in patients with HER2-positive, clinical stage I-III breast cancer (HannaH study): a phase 3, open-label, multicentre, randomised trial. Lancet Oncol. 2012 Sep;13(9):869-78. Epub 2012 Aug 9. link to original article contains verified protocol PubMed NCT00950300
   1. Update: Jackisch C, Kim SB, Semiglazov V, Melichar B, Pivot X, Hillenbach C, Stroyakovskiy D, Lum BL, Elliott R, Weber HA, Ismael G. Subcutaneous versus intravenous formulation of trastuzumab for HER2-positive early breast cancer: updated results from the phase III HannaH study. Ann Oncol. 2015 Feb;26(2):320-5. Epub 2014 Nov 17. link to original article PubMed
   2. Update: Jackisch C, Stroyakovskiy D, Pivot X, Ahn JS, Melichar B, Chen SC, Meyenberg C, Al-Sakaff N, Heinzmann D, Hegg R. Subcutaneous vs intravenous trastuzumab for patients with ERBB2-positive early breast cancer: final analysis of the HannaH phase 3 randomized clinical trial. JAMA Oncol. 2019 May 1;5(5):e190339. Epub 2019 May 9. link to original article link to PMC article PubMed
3. SB3-G31-BC: Pivot X, Bondarenko I, Nowecki Z, Dvorkin M, Trishkina E, Ahn JH, Vinnyk Y, Im SA, Sarosiek T, Chatterjee S, Wojtukiewicz MZ, Moiseyenko V, Shparyk Y, Bello M 3rd, Semiglazov V, Song S, Lim J. Phase III, randomized, double-blind study comparing the efficacy, safety, and immunogenicity of SB3 (trastuzumab biosimilar) and reference trastuzumab in patients treated with neoadjuvant therapy for human epidermal growth factor receptor 2-positive early breast cancer. J Clin Oncol. 2018 Apr 1;36(10):968-974. Epub 2018 Jan 26. link to original article contains verified protocol PubMed

FEC & H (SC)

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FEC & H: Fluorouracil, Epirubicin, Cyclophosphamide, Herceptin Hylecta (Trastuzumab and hyaluronidase)

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Ismael et al. 2012 (HannaH)	2009-2010	Phase III (E-RT-switch-ic)	See link	See link

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Preceding treatment

• TH (SC) x 4

Chemotherapy

• Fluorouracil (5-FU) 500 mg/m² IV once on day 1
• Epirubicin (Ellence) 75 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 mg/m² IV once on day 1

Targeted therapy

• Trastuzumab and hyaluronidase (Herceptin Hylecta) 600 mg/10,000 units SC once on day 1

21-day cycle for 4 cycles

Subsequent treatment

• Surgery

References

1. HannaH: Ismael G, Hegg R, Muehlbauer S, Heinzmann D, Lum B, Kim SB, Pienkowski T, Lichinitser M, Semiglazov V, Melichar B, Jackisch C. Subcutaneous versus intravenous administration of (neo)adjuvant trastuzumab in patients with HER2-positive, clinical stage I-III breast cancer (HannaH study): a phase 3, open-label, multicentre, randomised trial. Lancet Oncol. 2012 Sep;13(9):869-78. Epub 2012 Aug 9. link to original article contains verified protocol PubMed NCT00950300
   1. Update: Jackisch C, Kim SB, Semiglazov V, Melichar B, Pivot X, Hillenbach C, Stroyakovskiy D, Lum BL, Elliott R, Weber HA, Ismael G. Subcutaneous versus intravenous formulation of trastuzumab for HER2-positive early breast cancer: updated results from the phase III HannaH study. Ann Oncol. 2015 Feb;26(2):320-5. Epub 2014 Nov 17. link to original article PubMed
   2. Update: Jackisch C, Stroyakovskiy D, Pivot X, Ahn JS, Melichar B, Chen SC, Meyenberg C, Al-Sakaff N, Heinzmann D, Hegg R. Subcutaneous vs intravenous trastuzumab for patients with ERBB2-positive early breast cancer: final analysis of the HannaH phase 3 randomized clinical trial. JAMA Oncol. 2019 May 1;5(5):e190339. Epub 2019 May 9. link to original article link to PMC article PubMed

Lapatinib & Trastuzumab

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Baselga et al. 2012 (NeoALTTO)	2008-2010	Phase III (E-esc)	See link	See link

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Targeted therapy

• Lapatinib (Tykerb) 1000 mg PO once per day
• Trastuzumab (Herceptin) 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8, 15, 22, 29, 36

6-week course

Subsequent treatment

• THL (Taxol) x 12 wk, then surgery

References

1. NeoALTTO: Baselga J, Bradbury I, Eidtmann H, Di Cosimo S, de Azambuja E, Aura C, Gómez H, Dinh P, Fauria K, Van Dooren V, Aktan G, Goldhirsch A, Chang TW, Horváth Z, Coccia-Portugal M, Domont J, Tseng LM, Kunz G, Sohn JH, Semiglazov V, Lerzo G, Palacova M, Probachai V, Pusztai L, Untch M, Gelber RD, Piccart-Gebhart M; NeoALTTO Study Team. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet. 2012 Feb 18;379(9816):633-40. Epub 2012 Jan 17. Erratum in: Lancet. 2012 Feb 18;379(9816):616. Dosage error in published abstract; MEDLINE/PubMed abstract corrected. link to original article link to PMC article contains verified protocol PubMed NCT00553358
   1. Update: de Azambuja E, Holmes AP, Piccart-Gebhart M, Holmes E, Di Cosimo S, Swaby RF, Untch M, Jackisch C, Lang I, Smith I, Boyle F, Xu B, Barrios CH, Perez EA, Azim HA Jr, Kim SB, Kuemmel S, Huang CS, Vuylsteke P, Hsieh RK, Gorbunova V, Eniu A, Dreosti L, Tavartkiladze N, Gelber RD, Eidtmann H, Baselga J. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): survival outcomes of a randomised, open-label, multicentre, phase 3 trial and their association with pathological complete response. Lancet Oncol. 2014 Sep;15(10):1137-46. Epub 2014 Aug 14. link to original article PubMed
   2. Update: Huober J, Holmes E, Baselga J, de Azambuja E, Untch M, Fumagalli D, Sarp S, Lang I, Smith I, Boyle F, Xu B, Lecocq C, Wildiers H, Jouannaud C, Hackman J, Dasappa L, Ciruelos E, Toral Pena JC, Adamchuk H, Hickish T, de la Pena L, Jackisch C, Gelber RD, Piccart-Gebhart M, Di Cosimo S. Survival outcomes of the NeoALTTO study (BIG 1-06): updated results of a randomised multicenter phase III neoadjuvant clinical trial in patients with HER2-positive primary breast cancer. Eur J Cancer. 2019 Sep;118:169-177. Epub 2019 Aug 1. link to original article PubMed

Neratinib & Paclitaxel

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Park et al. 2016 (I-SPY 2)	2010-2013	Adaptively Randomized Phase II (E-switch-ic)	TH	Seems to have superior pCR rate

Targeted therapy

• Neratinib (Nerlynx) 240 mg PO once per day

Chemotherapy

• Paclitaxel (Taxol) 80 mg/m² IV once per day on days 1, 8, 15

Supportive medications

• Loperamide (Imodium) 4 mg PO once on day 1, then 2 mg PO once 8 hours later, then 2 mg PO twice per day for two weeks, then decreased per patient choice, started on day 1 of Neratinib (Nerlynx)

21-day cycle for 4 cycles

Subsequent treatment

• AC or ddAC, then surgery

References

1. I-SPY 2: Park JW, Liu MC, Yee D, Yau C, van 't Veer LJ, Symmans WF, Paoloni M, Perlmutter J, Hylton NM, Hogarth M, DeMichele A, Buxton MB, Chien AJ, Wallace AM, Boughey JC, Haddad TC, Chui SY, Kemmer KA, Kaplan HG, Isaacs C, Nanda R, Tripathy D, Albain KS, Edmiston KK, Elias AD, Northfelt DW, Pusztai L, Moulder SL, Lang JE, Viscusi RK, Euhus DM, Haley BB, Khan QJ, Wood WC, Melisko M, Schwab R, Helsten T, Lyandres J, Davis SE, Hirst GL, Sanil A, Esserman LJ, Berry DA; I-SPY 2 Investigators. Adaptive randomization of neratinib in early breast cancer. N Engl J Med. 2016 Jul 7;375(1):11-22. link to original article contains verified protocol link to PMC article PubMed NCT01042379

TCHP (Taxol)

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TCHP: Taxol (Paclitaxel), Carboplatin, Herceptin (Trastuzumab), Pertuzumab

Regimen variant #1, standard carboplatin

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
van Ramshorst et al. 2018 (TRAIN-2)	2013-2016	Phase III (E-switch-ic)	FEC & HP x 3, then TCHP x 6	Did not meet primary endpoint of pCR rate

Chemotherapy

• Paclitaxel (Taxol) 80 mg/m² IV once per day on days 1 & 8
• Carboplatin (Paraplatin) AUC 6 IV once on day 1

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV once on day 1
  • Cycles 2 to 9: 6 mg/kg IV once on day 1
• Pertuzumab (Perjeta) as follows:
  • Cycle 1: 840 mg IV once on day 1
  • Cycles 2 to 9: 420 mg IV once on day 1

21-day cycle for 9 cycles

Subsequent treatment

• Surgery

Regimen variant #2, split carboplatin

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
van Ramshorst et al. 2018 (TRAIN-2)	2013-2016	Phase III (E-switch-ic)	FEC & HP x 3, then TCHP x 6	Did not meet primary endpoint of pCR rate

Chemotherapy

• Paclitaxel (Taxol) 80 mg/m² IV once per day on days 1 & 8
• Carboplatin (Paraplatin) AUC 3 IV once per day on days 1 & 8

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV once on day 1
  • Cycles 2 to 9: 6 mg/kg IV once on day 1
• Pertuzumab (Perjeta) as follows:
  • Cycle 1: 840 mg IV once on day 1
  • Cycles 2 to 9: 420 mg IV once on day 1

21-day cycle for 9 cycles

Subsequent treatment

• Surgery

References

1. TRAIN-2: van Ramshorst MS, van der Voort A, van Werkhoven ED, Mandjes IA, Kemper I, Dezentjé VO, Oving IM, Honkoop AH, Tick LW, van de Wouw AJ, Mandigers CM, van Warmerdam LJ, Wesseling J, Vrancken Peeters MT, Linn SC, Sonke GS; Dutch Breast Cancer Research Group. Neoadjuvant chemotherapy with or without anthracyclines in the presence of dual HER2 blockade for HER2-positive breast cancer (TRAIN-2): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2018 Dec;19(12):1630-1640. Epub 2018 Nov 6. link to original article contains protocol PubMed NCT01996267

TCHP (Taxotere)

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TCHP: Taxotere (Docetaxel), Carboplatin, Herceptin (Trastuzumab), Pertuzumab

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Schneeweiss et al. 2013 (TRYPHAENA)	2009-2011	Randomized Phase II (E-RT-switch-ic)	See link	Not reported
Hurvitz et al. 2017 (KRISTINE)	2014-2015	Phase III (C)	Pertuzumab & T-DM1	Superior EFS1 (HR 0.38, 95% CI 0.20-0.74)

¹Reported efficacy for KRISTINE is based on the 2019 update. EFS was a secondary endpoint.

Chemotherapy

• Docetaxel (Taxotere) 75 mg/m² IV once on day 1
• Carboplatin (Paraplatin) AUC 6 IV once on day 1

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV once on day 1
  • Cycles 2 to 6: 6 mg/kg IV once on day 1
• Pertuzumab (Perjeta) as follows:
  • Cycle 1: 840 mg IV once on day 1
  • Cycles 2 to 6: 420 mg IV once on day 1

21-day cycle for 6 cycles

Subsequent treatment

• TRYPHAENA: Surgery, then further adjuvant treatment (radiotherapy, chemotherapy, hormonal treatment) according to local guidelines (a total of 1 year of trastuzumab was given)
• KRISTINE: Surgery

References

1. TRYPHAENA: Schneeweiss A, Chia S, Hickish T, Harvey V, Eniu A, Hegg R, Tausch C, Seo JH, Tsai YF, Ratnayake J, McNally V, Ross G, Cortés J. Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA). Ann Oncol. 2013 Sep;24(9):2278-84. Epub 2013 May 22. link to original article contains verified protocol PubMed NCT00976989
2. KRISTINE: Hurvitz SA, Martin M, Symmans WF, Jung KH, Huang CS, Thompson AM, Harbeck N, Valero V, Stroyakovskiy D, Wildiers H, Campone M, Boileau JF, Beckmann MW, Afenjar K, Fresco R, Helms HJ, Xu J, Lin YG, Sparano J, Slamon D. Neoadjuvant trastuzumab, pertuzumab, and chemotherapy versus trastuzumab emtansine plus pertuzumab in patients with HER2-positive breast cancer (KRISTINE): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol. 2018 Jan;19(1):115-126. Epub 2017 Nov 23. link to original article contains protocol PubMed NCT02131064
   1. Update: Hurvitz SA, Martin M, Jung KH, Huang CS, Harbeck N, Valero V, Stroyakovskiy D, Wildiers H, Campone M, Boileau JF, Fasching PA, Afenjar K, Spera G, Lopez-Valverde V, Song C, Trask P, Boulet T, Sparano JA, Symmans WF, Thompson AM, Slamon D. Neoadjuvant trastuzumab emtansine and pertuzumab in human epidermal growth factor receptor 2-positive breast cancer: three-year outcomes from the phase III KRISTINE Study. J Clin Oncol. 2019 Sep 1;37(25):2206-2216. Epub 2019 Jun 3. link to original article link to PMC article PubMed

TH (Taxol)

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TH: Taxol (Paclitaxel) & Herceptin (Trastuzumab)
T-T: Taxol (Paclitaxel) & Trastuzumab

Regimen variant #1, weekly paclitaxel x 12, weekly trastuzumab

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Buzdar et al. 2013 (ACOSOG Z1041)	2007-2011	Phase III	See link	See link
Baselga et al. 2012 (NeoALTTO)	2008-2010	Phase III (C)	See link	See link
Park et al. 2016 (I-SPY 2)	2010-2013	Adaptively Randomized Phase II (C)	Neratinib & Paclitaxel	Seems to have inferior pCR rate

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment. Patients in NeoALTTO had already undergone trastuzumab loading so would continue at the 2 mg/kg weekly dose. In ACOSOG Z1041, this portion of the regimen was used in both the control and experimental arms.

Preceding treatment

• NeoALTTO: Trastuzumab x 6 wk
• ACOSOG Z1041: FEC x 4

Chemotherapy

• Paclitaxel (Taxol) 80 mg/m² IV once per day on days 1, 8, 15

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8 & 15
  • Cycles 2 to 4: 2 mg/kg IV once per day on days 1, 8, 15

21-day cycle for 4 cycles

Subsequent treatment

• NeoALTTO: Surgery, then adjuvant FEC x 3
• ACOSOG Z1041: Surgery
• I-SPY 2: AC or ddAC, then surgery

Regimen variant #2, weekly paclitaxel x 12, q3wk trastuzumab

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
von Minckwitz et al. 2018 (LILAC)	2013-2015	Phase III (C)	Paclitaxel & ABP 980	Inconclusive whether equivalent pCR rate

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Preceding treatment

• Anthracycline-containing chemotherapy x 4

Chemotherapy

• Paclitaxel (Taxol) 80 mg/m² IV once per day on days 1, 8, 15

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV once on day 1
  • Cycles 2 to 4: 6 mg/kg IV once on day 1

21-day cycle for 4 cycles

Subsequent treatment

• Surgery

Regimen variant #3, weekly paclitaxel x 16

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Carey et al. 2015 (CALGB 40601)	2008-2012	Phase III (C)	1. THL	Did not meet primary endpoint of pCR rate
			2. TL	Not reported

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Chemotherapy

• Paclitaxel (Taxol) 80 mg/m² IV once per day on days 1, 8, 15, 22

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8, 15, 22
  • Cycles 2 to 4: 2 mg/kg IV once per day on days 1, 8, 15, 22

28-day cycle for 4 cycles

Subsequent treatment

• Surgery, then adjuvant AC x 4 or ddAC x 4, then trastuzumab for 36 weeks was recommended but not mandated

Regimen variant #4, paclitaxel 3 out of 4 weeks

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Robidoux et al. 2013 (NSABP B-41)	2007-2011	Phase III (C)	1. THL	Might have inferior pCR rate
			2. TL	Did not meet primary endpoint of pCR rate

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Preceding treatment

• AC x 4

Chemotherapy

• Paclitaxel (Taxol) 80 mg/m² IV once per day on days 1, 8, 15

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8, 15, 22
  • Cycles 2 to 4: 2 mg/kg IV once per day on days 1, 8, 15, 22

28-day cycle for 4 cycles

Subsequent treatment

• Surgery, then adjuvant trastuzumab for a total of 52 weeks of therapy.

Regimen variant #5, q3wk, paclitaxel 175 mg/m²

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
von Minckwitz et al. 2018 (LILAC)	2013-2015	Phase III (C)	Paclitaxel & ABP 980	Inconclusive whether equivalent pCR rate

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Preceding treatment

• Anthracycline-containing chemotherapy x 4

Chemotherapy

• Paclitaxel (Taxol) 175 mg/m² IV once on day 1

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV once
  • Cycles 2 to 4: 6 mg/kg IV once on day 1

21-day cycle for 4 cycles

Subsequent treatment

• Surgery

Regimen variant #6, q3wk, paclitaxel 225 mg/m²

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Buzdar et al. 2005	2001-2003	Phase III (E-esc)	See link	See link

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Chemotherapy

• Paclitaxel (Taxol) 225 mg/m² IV continuous infusion over 24 hours on day 1

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 4 mg/kg IV once on day 1 prior to first dose of paclitaxel, then 2 mg/kg IV once per day on days 8 & 15
  • Cycles 2 to 4: 2 mg/kg IV once per day on days 1, 8, 15

21-day cycle for 4 cycles

Subsequent treatment

• FEC & H

References

1. Buzdar AU, Ibrahim NK, Francis D, Booser DJ, Thomas ES, Theriault RL, Pusztai L, Green MC, Arun BK, Giordano SH, Cristofanilli M, Frye DK, Smith TL, Hunt KK, Singletary SE, Sahin AA, Ewer MS, Buchholz TA, Berry D, Hortobagyi GN. Significantly higher pathologic complete remission rate after neoadjuvant therapy with trastuzumab, paclitaxel, and epirubicin chemotherapy: results of a randomized trial in human epidermal growth factor receptor 2-positive operable breast cancer. J Clin Oncol. 2005 Jun 1;23(16):3676-85. Epub 2005 Feb 28. link to original article PubMed
   1. Update: Buzdar AU, Valero V, Ibrahim NK, Francis D, Broglio KR, Theriault RL, Pusztai L, Green MC, Singletary SE, Hunt KK, Sahin AA, Esteva F, Symmans WF, Ewer MS, Buchholz TA, Hortobagyi GN. Neoadjuvant therapy with paclitaxel followed by 5-fluorouracil, epirubicin, and cyclophosphamide chemotherapy and concurrent trastuzumab in human epidermal growth factor receptor 2-positive operable breast cancer: an update of the initial randomized study population and data of additional patients treated with the same regimen. Clin Cancer Res. 2007 Jan 1;13(1):228-33. link to original article PubMed
2. NeoALTTO: Baselga J, Bradbury I, Eidtmann H, Di Cosimo S, de Azambuja E, Aura C, Gómez H, Dinh P, Fauria K, Van Dooren V, Aktan G, Goldhirsch A, Chang TW, Horváth Z, Coccia-Portugal M, Domont J, Tseng LM, Kunz G, Sohn JH, Semiglazov V, Lerzo G, Palacova M, Probachai V, Pusztai L, Untch M, Gelber RD, Piccart-Gebhart M; NeoALTTO Study Team. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet. 2012 Feb 18;379(9816):633-40. Epub 2012 Jan 17. Erratum in: Lancet. 2012 Feb 18;379(9816):616. Dosage error in published abstract; MEDLINE/PubMed abstract corrected. link to original article link to PMC article contains verified protocol PubMed NCT00553358
   1. Update: de Azambuja E, Holmes AP, Piccart-Gebhart M, Holmes E, Di Cosimo S, Swaby RF, Untch M, Jackisch C, Lang I, Smith I, Boyle F, Xu B, Barrios CH, Perez EA, Azim HA Jr, Kim SB, Kuemmel S, Huang CS, Vuylsteke P, Hsieh RK, Gorbunova V, Eniu A, Dreosti L, Tavartkiladze N, Gelber RD, Eidtmann H, Baselga J. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): survival outcomes of a randomised, open-label, multicentre, phase 3 trial and their association with pathological complete response. Lancet Oncol. 2014 Sep;15(10):1137-46. Epub 2014 Aug 14. link to original article PubMed
   2. Update: Huober J, Holmes E, Baselga J, de Azambuja E, Untch M, Fumagalli D, Sarp S, Lang I, Smith I, Boyle F, Xu B, Lecocq C, Wildiers H, Jouannaud C, Hackman J, Dasappa L, Ciruelos E, Toral Pena JC, Adamchuk H, Hickish T, de la Pena L, Jackisch C, Gelber RD, Piccart-Gebhart M, Di Cosimo S. Survival outcomes of the NeoALTTO study (BIG 1-06): updated results of a randomised multicenter phase III neoadjuvant clinical trial in patients with HER2-positive primary breast cancer. Eur J Cancer. 2019 Sep;118:169-177. Epub 2019 Aug 1. link to original article PubMed
3. NSABP B-41: Robidoux A, Tang G, Rastogi P, Geyer CE Jr, Azar CA, Atkins JN, Fehrenbacher L, Bear HD, Baez-Diaz L, Sarwar S, Margolese RG, Farrar WB, Brufsky AM, Shibata HR, Bandos H, Paik S, Costantino JP, Swain SM, Mamounas EP, Wolmark N. Lapatinib as a component of neoadjuvant therapy for HER2-positive operable breast cancer (NSABP protocol B-41): an open-label, randomised phase 3 trial. Lancet Oncol. 2013 Nov;14(12):1183-92. Epub 2013 Oct 4. link to original article contains protocol PubMed NCT00486668
4. ACOSOG Z1041: Buzdar AU, Suman VJ, Meric-Bernstam F, Leitch AM, Ellis MJ, Boughey JC, Unzeitig G, Royce M, McCall LM, Ewer MS, Hunt KK; American College of Surgeons Oncology Group. Fluorouracil, epirubicin, and cyclophosphamide (FEC-75) followed by paclitaxel plus trastuzumab versus paclitaxel plus trastuzumab followed by FEC-75 plus trastuzumab as neoadjuvant treatment for patients with HER2-positive breast cancer (Z1041): a randomised, controlled, phase 3 trial. Lancet Oncol. 2013 Dec;14(13):1317-25. Epub 2013 Nov 13. link to original article link to PMC article contains verified protocol PubMed NCT00513292
   1. Update: Buzdar AU, Suman VJ, Meric-Bernstam F, Leitch AM, Ellis MJ, Boughey JC, Unzeitig GW, Royce ME, Hunt KK. Disease-Free and Overall Survival Among Patients With Operable HER2-Positive Breast Cancer Treated With Sequential vs Concurrent Chemotherapy: The ACOSOG Z1041 (Alliance) Randomized Clinical Trial. JAMA Oncol. 2019 Jan 1;5(1):45-50. link to original article link to PMC article PubMed
5. CALGB 40601: Carey LA, Berry DA, Cirrincione CT, Barry WT, Pitcher BN, Harris LN, Ollila DW, Krop IE, Henry NL, Weckstein DJ, Anders CK, Singh B, Hoadley KA, Iglesia M, Cheang MC, Perou CM, Winer EP, Hudis CA. Molecular heterogeneity and response to neoadjuvant human epidermal growth factor receptor 2 targeting in CALGB 40601, a randomized phase III trial of paclitaxel plus trastuzumab with or without lapatinib. J Clin Oncol. 2016 Feb 20;34(6):542-9. Epub 2015 Nov 2. link to original article contains verified protocol link to PMC article PubMed NCT00770809
   1. Update: Fernandez-Martinez A, Krop IE, Hillman DW, Polley MY, Parker JS, Huebner L, Hoadley KA, Shepherd J, Tolaney S, Henry NL, Dang C, Harris L, Berry D, Hahn O, Hudis C, Winer E, Partridge A, Perou CM, Carey LA. Survival, Pathologic Response, and Genomics in CALGB 40601 (Alliance), a Neoadjuvant Phase III Trial of Paclitaxel-Trastuzumab With or Without Lapatinib in HER2-Positive Breast Cancer. J Clin Oncol. 2020 Dec 10;38(35):4184-4193. Epub 2020 Oct 23. link to original article link to PMC article PubMed
6. I-SPY 2: Park JW, Liu MC, Yee D, Yau C, van 't Veer LJ, Symmans WF, Paoloni M, Perlmutter J, Hylton NM, Hogarth M, DeMichele A, Buxton MB, Chien AJ, Wallace AM, Boughey JC, Haddad TC, Chui SY, Kemmer KA, Kaplan HG, Isaacs C, Nanda R, Tripathy D, Albain KS, Edmiston KK, Elias AD, Northfelt DW, Pusztai L, Moulder SL, Lang JE, Viscusi RK, Euhus DM, Haley BB, Khan QJ, Wood WC, Melisko M, Schwab R, Helsten T, Lyandres J, Davis SE, Hirst GL, Sanil A, Esserman LJ, Berry DA; I-SPY 2 Investigators. Adaptive randomization of neratinib in early breast cancer. N Engl J Med. 2016 Jul 7;375(1):11-22. link to original article contains verified protocol link to PMC article PubMed NCT01042379
7. LILAC: von Minckwitz G, Colleoni M, Kolberg HC, Morales S, Santi P, Tomasevic Z, Zhang N, Hanes V. Efficacy and safety of ABP 980 compared with reference trastuzumab in women with HER2-positive early breast cancer (LILAC study): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2018 Jul;19(7):987-998.Epub 2018 Jun 4. link to original article contains protocol PubMed NCT01901146

TH (Taxotere)

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TH: Taxotere (Docetaxel) & Herceptin (Trastuzumab)
DH: Docetaxel & Herceptin (Trastuzumab)

Regimen variant #1, 75 mg/m² q3wk docetaxel, q3wk trastuzumab

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Ismael et al. 2012 (HannaH)	2009-2010	Phase III (C)	See link	See link
Pivot et al. 2018 (SB3-G31-BC)	2014-2015	Randomized (C)	See link	See link

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Chemotherapy

• Docetaxel (Taxotere) 75 mg/m² IV once on day 1

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV once on day 1
  • Cycles 2 to 4: 6 mg/kg IV once on day 1

21-day cycle for 4 cycles

Subsequent treatment

• FEC & H (IV)

Regimen variant #2, 100 mg/m² q3wk docetaxel, weekly trastuzumab

Study	Evidence	Efficacy
Van Pelt et al. 2003	Phase II	OCR: 77%

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Chemotherapy

• Docetaxel (Taxotere) as follows:
  • Cycles 2 to 5: 100 mg/m² IV once on day 1

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8 & 15
  • Cycles 2 to 5: 2 mg/kg IV once per day on days 1, 8, 15

21-day cycle for 5 cycles

Subsequent treatment

• Surgery, then AC x 4, then H x 52 wk

Regimen variant #3, 100 mg/m² q3wk docetaxel, q3wk trastuzumab

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Untch et al. 2012 (GeparQuinto)	2007-2010	Phase III (C)	See link	See link
Alba et al. 2014 (GEICAM 2006-14)	2009-2010	Phase III (C)	TL (Taxotere)	Superior pCR rate

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment. No loading dose was used for trastuzumab in GeparQuinto because the load occurred during the ECH part of the regimen.

Preceding treatment

• GeparQuinto: ECH x 4
• GEICAM 2006-14: EC x 4

Chemotherapy

• Docetaxel (Taxotere) 100 mg/m² IV once on day 1

Targeted therapy

• Trastuzumab (Herceptin) 6 mg/kg IV once on day 1
  • GEICAM 2006-14 used a loading dose of 8 mg/kg in cycle 1

21-day cycle for 4 cycles

Subsequent treatment

• GeparQuinto: Surgery, then adjuvant trastuzumab for 1 year total
• GEICAM 2006-14: Surgery

References

1. Van Pelt AE, Mohsin S, Elledge RM, Hilsenbeck SG, Gutierrez MC, Lucci A Jr, Kalidas M, Granchi T, Scott BG, Allred DC, Chang JC. Neoadjuvant trastuzumab and docetaxel in breast cancer: preliminary results. Clin Breast Cancer. 2003 Dec;4(5):348-53. link to original article contains protocol PubMed
2. GeparQuinto: Untch M, Loibl S, Bischoff J, Eidtmann H, Kaufmann M, Blohmer JU, Hilfrich J, Strumberg D, Fasching PA, Kreienberg R, Tesch H, Hanusch C, Gerber B, Rezai M, Jackisch C, Huober J, Kühn T, Nekljudova V, von Minckwitz G; German Breast Group; Arbeitsgemeinschaft Gynäkologische Onkologie-Breast Study Group. Lapatinib versus trastuzumab in combination with neoadjuvant anthracycline-taxane-based chemotherapy (GeparQuinto, GBG 44): a randomised phase 3 trial. Lancet Oncol. 2012 Feb;13(2):135-44. Epub 2012 Jan 17. link to original article contains verified protocol PubMed NCT00567554
   1. Update: Untch M, von Minckwitz G, Gerber B, Schem C, Rezai M, Fasching PA, Tesch H, Eggemann H, Hanusch C, Huober J, Solbach C, Jackisch C, Kunz G, Blohmer JU, Hauschild M, Fehm T, Nekljudova V, Loibl S; GBG; AGO-B Study Group. Survival analysis after neoadjuvant chemotherapy with trastuzumab or lapatinib in patients with human epidermal growth factor receptor 2-positive breast cancer in the GeparQuinto (G5) study (GBG 44). J Clin Oncol. 2018 May 1;36(13):1308-1316. Epub 2018 Mar 15. link to original article PubMed
3. HannaH: Ismael G, Hegg R, Muehlbauer S, Heinzmann D, Lum B, Kim SB, Pienkowski T, Lichinitser M, Semiglazov V, Melichar B, Jackisch C. Subcutaneous versus intravenous administration of (neo)adjuvant trastuzumab in patients with HER2-positive, clinical stage I-III breast cancer (HannaH study): a phase 3, open-label, multicentre, randomised trial. Lancet Oncol. 2012 Sep;13(9):869-78. Epub 2012 Aug 9. link to original article contains verified protocol PubMed NCT00950300
   1. Update: Jackisch C, Kim SB, Semiglazov V, Melichar B, Pivot X, Hillenbach C, Stroyakovskiy D, Lum BL, Elliott R, Weber HA, Ismael G. Subcutaneous versus intravenous formulation of trastuzumab for HER2-positive early breast cancer: updated results from the phase III HannaH study. Ann Oncol. 2015 Feb;26(2):320-5. Epub 2014 Nov 17. link to original article PubMed
   2. Update: Jackisch C, Stroyakovskiy D, Pivot X, Ahn JS, Melichar B, Chen SC, Meyenberg C, Al-Sakaff N, Heinzmann D, Hegg R. Subcutaneous vs intravenous trastuzumab for patients with ERBB2-positive early breast cancer: final analysis of the HannaH phase 3 randomized clinical trial. JAMA Oncol. 2019 May 1;5(5):e190339. Epub 2019 May 9. link to original article link to PMC article PubMed
4. GEICAM 2006-14: Alba E, Albanell J, de la Haba J, Barnadas A, Calvo L, Sánchez-Rovira P, Ramos M, Rojo F, Burgués O, Carrasco E, Caballero R, Porras I, Tibau A, Cámara MC, Lluch A. Trastuzumab or lapatinib with standard chemotherapy for HER2-positive breast cancer: results from the GEICAM/2006-14 trial. Br J Cancer. 2014 Mar 4;110(5):1139-47. Epub 2014 Jan 23. link to original article link to PMC article PubMed NCT00841828
5. SB3-G31-BC: Pivot X, Bondarenko I, Nowecki Z, Dvorkin M, Trishkina E, Ahn JH, Vinnyk Y, Im SA, Sarosiek T, Chatterjee S, Wojtukiewicz MZ, Moiseyenko V, Shparyk Y, Bello M 3rd, Semiglazov V, Song S, Lim J. Phase III, randomized, double-blind study comparing the efficacy, safety, and immunogenicity of SB3 (trastuzumab biosimilar) and reference trastuzumab in patients treated with neoadjuvant therapy for human epidermal growth factor receptor 2-positive early breast cancer. J Clin Oncol. 2018 Apr 1;36(10):968-974. Epub 2018 Jan 26. link to original article contains verified protocol PubMed

TH (Taxotere/SC)

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TH: Taxotere (Docetaxel) & Herceptin Hylecta (Trastuzumab and hyaluronidase)

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Ismael et al. 2012 (HannaH)	2009-2010	Phase III (E-RT-switch-ic)	See link	See link

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Chemotherapy

• Docetaxel (Taxotere) 75 mg/m² IV once on day 1

Targeted therapy

• Trastuzumab and hyaluronidase (Herceptin Hylecta) 600 mg/10,000 units SC once on day 1

21-day cycle for 4 cycles

Subsequent treatment

• FEC & H (SC)

References

1. HannaH: Ismael G, Hegg R, Muehlbauer S, Heinzmann D, Lum B, Kim SB, Pienkowski T, Lichinitser M, Semiglazov V, Melichar B, Jackisch C. Subcutaneous versus intravenous administration of (neo)adjuvant trastuzumab in patients with HER2-positive, clinical stage I-III breast cancer (HannaH study): a phase 3, open-label, multicentre, randomised trial. Lancet Oncol. 2012 Sep;13(9):869-78. Epub 2012 Aug 9. link to original article contains verified protocol PubMed NCT00950300
   1. Update: Jackisch C, Kim SB, Semiglazov V, Melichar B, Pivot X, Hillenbach C, Stroyakovskiy D, Lum BL, Elliott R, Weber HA, Ismael G. Subcutaneous versus intravenous formulation of trastuzumab for HER2-positive early breast cancer: updated results from the phase III HannaH study. Ann Oncol. 2015 Feb;26(2):320-5. Epub 2014 Nov 17. link to original article PubMed
   2. Update: Jackisch C, Stroyakovskiy D, Pivot X, Ahn JS, Melichar B, Chen SC, Meyenberg C, Al-Sakaff N, Heinzmann D, Hegg R. Subcutaneous vs intravenous trastuzumab for patients with ERBB2-positive early breast cancer: final analysis of the HannaH phase 3 randomized clinical trial. JAMA Oncol. 2019 May 1;5(5):e190339. Epub 2019 May 9. link to original article link to PMC article PubMed

THL (Taxol)

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THL: Taxol (Paclitaxel), Herceptin (Trastuzumab), Lapatinib

Regimen variant #1, weekly paclitaxel x 12

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Baselga et al. 2012 (NeoALTTO)	2008-2010	Phase III (E-esc)	See link	See link

Preceding treatment

• Lapatinib & Trastuzumab x 6 wk

Chemotherapy

• Paclitaxel (Taxol) 80 mg/m² IV once per day on days 1, 8, 15, 22

Targeted therapy

• Trastuzumab (Herceptin) 2 mg/kg IV once per day on days 1, 8, 15, 22
• Lapatinib (Tykerb) 1000 mg PO once per day

28-day cycle for 3 cycles

Subsequent treatment

• Surgery, then adjuvant FEC x 3

Regimen variant #2, weekly paclitaxel x 16

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Carey et al. 2015 (CALGB 40601)	2008-2012	Phase III (E-esc)	1. TH	Did not meet primary endpoint of pCR rate
			2. TL	Not reported

Chemotherapy

• Paclitaxel (Taxol) 80 mg/m² IV once per day on days 1, 8, 15, 22

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8, 15, 22
  • Cycles 2 to 4: 2 mg/kg IV once per day on days 1, 8, 15, 22
• Lapatinib (Tykerb) 750 mg PO once per day

28-day cycle for 4 cycles

Subsequent treatment

• Surgery; adjuvant AC x 4 or ddAC x 4, then trastuzumab for 36 weeks was recommended but not mandated

Regimen variant #3, paclitaxel 3 out of 4 weeks

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Robidoux et al. 2013 (NSABP B-41)	2007-2011	Phase III (E-esc)	1. TH	Might have superior pCR rate
			2. TL	Might have superior pCR rate

Preceding treatment

• AC x 4

Chemotherapy

• Paclitaxel (Taxol) 80 mg/m² IV once per day on days 1, 8, 15

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8, 15, 22
  • Cycles 2 to 4: 2 mg/kg IV once per day on days 1, 8, 15, 22
• Lapatinib (Tykerb) 750 mg PO once per day

28-day cycle for 4 cycles

Subsequent treatment

• Surgery, then adjuvant trastuzumab for a total of 52 weeks of therapy

References

1. NeoALTTO: Baselga J, Bradbury I, Eidtmann H, Di Cosimo S, de Azambuja E, Aura C, Gómez H, Dinh P, Fauria K, Van Dooren V, Aktan G, Goldhirsch A, Chang TW, Horváth Z, Coccia-Portugal M, Domont J, Tseng LM, Kunz G, Sohn JH, Semiglazov V, Lerzo G, Palacova M, Probachai V, Pusztai L, Untch M, Gelber RD, Piccart-Gebhart M; NeoALTTO Study Team. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet. 2012 Feb 18;379(9816):633-40. Epub 2012 Jan 17. Erratum in: Lancet. 2012 Feb 18;379(9816):616. Dosage error in published abstract; MEDLINE/PubMed abstract corrected. link to original article link to PMC article contains verified protocol PubMed NCT00553358
   1. Update: de Azambuja E, Holmes AP, Piccart-Gebhart M, Holmes E, Di Cosimo S, Swaby RF, Untch M, Jackisch C, Lang I, Smith I, Boyle F, Xu B, Barrios CH, Perez EA, Azim HA Jr, Kim SB, Kuemmel S, Huang CS, Vuylsteke P, Hsieh RK, Gorbunova V, Eniu A, Dreosti L, Tavartkiladze N, Gelber RD, Eidtmann H, Baselga J. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): survival outcomes of a randomised, open-label, multicentre, phase 3 trial and their association with pathological complete response. Lancet Oncol. 2014 Sep;15(10):1137-46. Epub 2014 Aug 14. link to original article PubMed
   2. Update: Huober J, Holmes E, Baselga J, de Azambuja E, Untch M, Fumagalli D, Sarp S, Lang I, Smith I, Boyle F, Xu B, Lecocq C, Wildiers H, Jouannaud C, Hackman J, Dasappa L, Ciruelos E, Toral Pena JC, Adamchuk H, Hickish T, de la Pena L, Jackisch C, Gelber RD, Piccart-Gebhart M, Di Cosimo S. Survival outcomes of the NeoALTTO study (BIG 1-06): updated results of a randomised multicenter phase III neoadjuvant clinical trial in patients with HER2-positive primary breast cancer. Eur J Cancer. 2019 Sep;118:169-177. Epub 2019 Aug 1. link to original article PubMed
2. NSABP B-41: Robidoux A, Tang G, Rastogi P, Geyer CE Jr, Azar CA, Atkins JN, Fehrenbacher L, Bear HD, Baez-Diaz L, Sarwar S, Margolese RG, Farrar WB, Brufsky AM, Shibata HR, Bandos H, Paik S, Costantino JP, Swain SM, Mamounas EP, Wolmark N. Lapatinib as a component of neoadjuvant therapy for HER2-positive operable breast cancer (NSABP protocol B-41): an open-label, randomised phase 3 trial. Lancet Oncol. 2013 Nov;14(12):1183-92. Epub 2013 Oct 4. link to original article contains protocol PubMed NCT00486668
3. CALGB 40601: Carey LA, Berry DA, Cirrincione CT, Barry WT, Pitcher BN, Harris LN, Ollila DW, Krop IE, Henry NL, Weckstein DJ, Anders CK, Singh B, Hoadley KA, Iglesia M, Cheang MC, Perou CM, Winer EP, Hudis CA. Molecular heterogeneity and response to neoadjuvant human epidermal growth factor receptor 2 targeting in CALGB 40601, a randomized phase III trial of paclitaxel plus trastuzumab with or without lapatinib. J Clin Oncol. 2016 Feb 20;34(6):542-9. Epub 2015 Nov 2. link to original article contains verified protocol link to PMC article PubMed NCT00770809
   1. Update: Fernandez-Martinez A, Krop IE, Hillman DW, Polley MY, Parker JS, Huebner L, Hoadley KA, Shepherd J, Tolaney S, Henry NL, Dang C, Harris L, Berry D, Hahn O, Hudis C, Winer E, Partridge A, Perou CM, Carey LA. Survival, Pathologic Response, and Genomics in CALGB 40601 (Alliance), a Neoadjuvant Phase III Trial of Paclitaxel-Trastuzumab With or Without Lapatinib in HER2-Positive Breast Cancer. J Clin Oncol. 2020 Dec 10;38(35):4184-4193. Epub 2020 Oct 23. link to original article link to PMC article PubMed

THP (Taxotere)

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THP: Taxotere (Docetaxel), Herceptin (Trastuzumab), Pertuzumab

Regimen variant #1, 3 cycles with loading doses

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Schneeweiss et al. 2013 (TRYPHAENA)	2009-2011	Randomized Phase II (E-RT-switch-ic)	See link	Not reported

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Preceding treatment

• FEC x 3

Chemotherapy

• Docetaxel (Taxotere) as follows:
  • Cycle 1 (4, overall): 75 mg/m² IV once on day 1
  • Cycles 2 & 3 (5 & 6, overall), if no toxic effects occurred: 100 mg/m² IV once on day 1

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV once on day 1
  • Cycles 2 to 4: 6 mg/kg IV once on day 1
• Pertuzumab (Perjeta) as follows:
  • Cycle 1: 840 mg IV once on day 1
  • Cycles 2 to 4: 420 mg IV once on day 1

21-day cycle for 3 cycles

Subsequent treatment

• Surgery, then further adjuvant treatment (radiotherapy, chemotherapy, hormonal treatment) according to local guidelines (a total of 1 year of trastuzumab was given)

Regimen variant #2, 3 cycles without loading doses

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Schneeweiss et al. 2013 (TRYPHAENA)	2009-2011	Randomized Phase II (E-RT-switch-ic)	See link	Not reported

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Preceding treatment

• FEC & HP x 3

Chemotherapy

• Docetaxel (Taxotere) as follows:
  • Cycle 1 (4, overall): 75 mg/m² IV once on day 1
  • Cycles 2 & 3 (5 & 6, overall), if no toxic effects occurred: 100 mg/m² IV once on day 1

Targeted therapy

• Trastuzumab (Herceptin) 6 mg/kg IV once on day 1
• Pertuzumab (Perjeta) 420 mg IV once on day 1

21-day cycle for 3 cycles

Subsequent treatment

• Surgery, then further adjuvant treatment (radiotherapy, chemotherapy, hormonal treatment) according to local guidelines (a total of 1 year of trastuzumab was given)

Regimen variant #3, 4 cycles with loading doses

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Gianni et al. 2011 (NeoSphere)	2007-2009	Randomized Phase II (E-RT-esc)	1. Docetaxel & Pertuzumab	Did not meet primary endpoint of pCR rate
			2. Pertuzumab & Trastuzumab	Did not meet primary endpoint of pCR rate
			3. TH	Seems to have superior pCR rate
Schneeweiss et al. 2013 (TRYPHAENA)	2009-2011	Randomized Phase II (E-RT-switch-ic)	See link	Not reported
Swain et al. 2018 (BERENICE)	2014-2015	Phase II (RT)

Preceding treatment

• BERENICE: FEC x 4

Chemotherapy

• Docetaxel (Taxotere) 75 mg/m² IV once on day 1
  • Based on tolerability, investigators could increase dose to 100 mg/m² IV once on day 1

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV once on day 1
  • Cycles 2 to 4: 6 mg/kg IV once on day 1
• Pertuzumab (Perjeta) as follows:
  • Cycle 1: 840 mg IV once on day 1
  • Cycles 2 to 4: 420 mg IV once on day 1

21-day cycle for 4 cycles

Subsequent treatment

• Surgery, then adjuvant FEC & H

References

1. NeoSphere: Gianni L, Pienkowski T, Im YH, Roman L, Tseng LM, Liu MC, Lluch A, Staroslawska E, de la Haba-Rodriguez J, Im SA, Pedrini JL, Poirier B, Morandi P, Semiglazov V, Srimuninnimit V, Bianchi G, Szado T, Ratnayake J, Ross G, Valagussa P. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol. 2012 Jan;13(1):25-32. Epub 2011 Dec 6. link to original article contains verified protocol PubMed NCT00545688
   1. Update: Gianni L, Pienkowski T, Im YH, Tseng LM, Liu MC, Lluch A, Starosławska E, de la Haba-Rodriguez J, Im SA, Pedrini JL, Poirier B, Morandi P, Semiglazov V, Srimuninnimit V, Bianchi GV, Magazzù D, McNally V, Douthwaite H, Ross G, Valagussa P. 5-year analysis of neoadjuvant pertuzumab and trastuzumab in patients with locally advanced, inflammatory, or early-stage HER2-positive breast cancer (NeoSphere): a multicentre, open-label, phase 2 randomised trial. Lancet Oncol. 2016 Jun;17(6):791-800. Epub 2016 May 11. link to original article PubMed
2. TRYPHAENA: Schneeweiss A, Chia S, Hickish T, Harvey V, Eniu A, Hegg R, Tausch C, Seo JH, Tsai YF, Ratnayake J, McNally V, Ross G, Cortés J. Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA). Ann Oncol. 2013 Sep;24(9):2278-84. Epub 2013 May 22. link to original article contains verified protocol PubMed NCT00976989
3. BERENICE: Swain SM, Ewer MS, Viale G, Delaloge S, Ferrero JM, Verrill M, Colomer R, Vieira C, Werner TL, Douthwaite H, Bradley D, Waldron-Lynch M, Kiermaier A, Eng-Wong J, Dang C; BERENICE Study Group. Pertuzumab, trastuzumab, and standard anthracycline- and taxane-based chemotherapy for the neoadjuvant treatment of patients with HER2-positive localized breast cancer (BERENICE): a phase II, open-label, multicenter, multinational cardiac safety study. Ann Oncol. 2018 Mar 1;29(3):646-653. link to original article link to PMC article contains verified protocol PubMed NCT02132949

TL (Taxol)

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TL: Taxol (Paclitaxel) & Lapatinib

Regimen variant #1, weekly paclitaxel x 12

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Baselga et al. 2012 (NeoALTTO)	2008-2010	Phase III (E-switch-ic)	See link	See link

Preceding treatment

• Lapatinib x 6 wk

Chemotherapy

• Paclitaxel (Taxol) 80 mg/m² IV once per day on days 1, 8, 15, 22

Targeted therapy

• Lapatinib (Tykerb) 1500 mg PO once per day

28-day cycle for 3 cycles

Subsequent treatment

• Surgery, then adjuvant FEC x 3

Regimen variant #2, weekly paclitaxel x 16

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Carey et al. 2015 (CALGB 40601)	2008-2012	Phase III (E-switch-ic)	1. TH	Not reported
			2. THL	Not reported

Note: this arm was closed early.

Chemotherapy

• Paclitaxel (Taxol) 80 mg/m² IV once per day on days 1, 8, 15, 22

Targeted therapy

• Lapatinib (Tykerb) 1500 mg PO once per day

28-day cycle for 4 cycles

Subsequent treatment

• Surgery; adjuvant AC x 4 or ddAC x 4, then trastuzumab for 36 weeks was recommended but not mandated

Regimen variant #3, paclitaxel 3 out of 4 weeks

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Robidoux et al. 2013 (NSABP B-41)	2007-2011	Phase III (E-switch-ic)	1. TH	Did not meet primary endpoint of pCR rate
			2. THL	Might have inferior pCR rate

Preceding treatment

• AC x 4

Chemotherapy

• Paclitaxel (Taxol) 80 mg/m² IV once per day on days 1, 8, 15

Targeted therapy

• Lapatinib (Tykerb) 1250 mg PO once per day

28-day cycle for 4 cycles

Subsequent treatment

• Surgery, then adjuvant trastuzumab for a total of 52 weeks of therapy

References

1. NeoALTTO: Baselga J, Bradbury I, Eidtmann H, Di Cosimo S, de Azambuja E, Aura C, Gómez H, Dinh P, Fauria K, Van Dooren V, Aktan G, Goldhirsch A, Chang TW, Horváth Z, Coccia-Portugal M, Domont J, Tseng LM, Kunz G, Sohn JH, Semiglazov V, Lerzo G, Palacova M, Probachai V, Pusztai L, Untch M, Gelber RD, Piccart-Gebhart M; NeoALTTO Study Team. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet. 2012 Feb 18;379(9816):633-40. Epub 2012 Jan 17. Erratum in: Lancet. 2012 Feb 18;379(9816):616. Dosage error in published abstract; MEDLINE/PubMed abstract corrected. link to original article link to PMC article contains verified protocol PubMed NCT00553358
   1. Update: de Azambuja E, Holmes AP, Piccart-Gebhart M, Holmes E, Di Cosimo S, Swaby RF, Untch M, Jackisch C, Lang I, Smith I, Boyle F, Xu B, Barrios CH, Perez EA, Azim HA Jr, Kim SB, Kuemmel S, Huang CS, Vuylsteke P, Hsieh RK, Gorbunova V, Eniu A, Dreosti L, Tavartkiladze N, Gelber RD, Eidtmann H, Baselga J. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): survival outcomes of a randomised, open-label, multicentre, phase 3 trial and their association with pathological complete response. Lancet Oncol. 2014 Sep;15(10):1137-46. Epub 2014 Aug 14. link to original article PubMed
   2. Update: Huober J, Holmes E, Baselga J, de Azambuja E, Untch M, Fumagalli D, Sarp S, Lang I, Smith I, Boyle F, Xu B, Lecocq C, Wildiers H, Jouannaud C, Hackman J, Dasappa L, Ciruelos E, Toral Pena JC, Adamchuk H, Hickish T, de la Pena L, Jackisch C, Gelber RD, Piccart-Gebhart M, Di Cosimo S. Survival outcomes of the NeoALTTO study (BIG 1-06): updated results of a randomised multicenter phase III neoadjuvant clinical trial in patients with HER2-positive primary breast cancer. Eur J Cancer. 2019 Sep;118:169-177. Epub 2019 Aug 1. link to original article PubMed
2. NSABP B-41: Robidoux A, Tang G, Rastogi P, Geyer CE Jr, Azar CA, Atkins JN, Fehrenbacher L, Bear HD, Baez-Diaz L, Sarwar S, Margolese RG, Farrar WB, Brufsky AM, Shibata HR, Bandos H, Paik S, Costantino JP, Swain SM, Mamounas EP, Wolmark N. Lapatinib as a component of neoadjuvant therapy for HER2-positive operable breast cancer (NSABP protocol B-41): an open-label, randomised phase 3 trial. Lancet Oncol. 2013 Nov;14(12):1183-92. Epub 2013 Oct 4. link to original article contains protocol PubMed NCT00486668
3. CALGB 40601: Carey LA, Berry DA, Cirrincione CT, Barry WT, Pitcher BN, Harris LN, Ollila DW, Krop IE, Henry NL, Weckstein DJ, Anders CK, Singh B, Hoadley KA, Iglesia M, Cheang MC, Perou CM, Winer EP, Hudis CA. Molecular heterogeneity and response to neoadjuvant human epidermal growth factor receptor 2 targeting in CALGB 40601, a randomized phase III trial of paclitaxel plus trastuzumab with or without lapatinib. J Clin Oncol. 2016 Feb 20;34(6):542-9. Epub 2015 Nov 2. link to original article contains verified protocol link to PMC article PubMed NCT00770809
   1. Update: Fernandez-Martinez A, Krop IE, Hillman DW, Polley MY, Parker JS, Huebner L, Hoadley KA, Shepherd J, Tolaney S, Henry NL, Dang C, Harris L, Berry D, Hahn O, Hudis C, Winer E, Partridge A, Perou CM, Carey LA. Survival, Pathologic Response, and Genomics in CALGB 40601 (Alliance), a Neoadjuvant Phase III Trial of Paclitaxel-Trastuzumab With or Without Lapatinib in HER2-Positive Breast Cancer. J Clin Oncol. 2020 Dec 10;38(35):4184-4193. Epub 2020 Oct 23. link to original article link to PMC article PubMed

Trastuzumab monotherapy

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Baselga et al. 2012 (NeoALTTO)	2008-2010	Phase III (C)	See link	See link

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Targeted therapy

• Trastuzumab (Herceptin) 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8, 15, 22, 29, 36

6-week course

Subsequent treatment

• TH (Taxol) x 12 wk, then surgery

References

1. NeoALTTO: Baselga J, Bradbury I, Eidtmann H, Di Cosimo S, de Azambuja E, Aura C, Gómez H, Dinh P, Fauria K, Van Dooren V, Aktan G, Goldhirsch A, Chang TW, Horváth Z, Coccia-Portugal M, Domont J, Tseng LM, Kunz G, Sohn JH, Semiglazov V, Lerzo G, Palacova M, Probachai V, Pusztai L, Untch M, Gelber RD, Piccart-Gebhart M; NeoALTTO Study Team. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet. 2012 Feb 18;379(9816):633-40. Epub 2012 Jan 17. Erratum in: Lancet. 2012 Feb 18;379(9816):616. Dosage error in published abstract; MEDLINE/PubMed abstract corrected. link to original article link to PMC article contains verified protocol PubMed NCT00553358
   1. Update: de Azambuja E, Holmes AP, Piccart-Gebhart M, Holmes E, Di Cosimo S, Swaby RF, Untch M, Jackisch C, Lang I, Smith I, Boyle F, Xu B, Barrios CH, Perez EA, Azim HA Jr, Kim SB, Kuemmel S, Huang CS, Vuylsteke P, Hsieh RK, Gorbunova V, Eniu A, Dreosti L, Tavartkiladze N, Gelber RD, Eidtmann H, Baselga J. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): survival outcomes of a randomised, open-label, multicentre, phase 3 trial and their association with pathological complete response. Lancet Oncol. 2014 Sep;15(10):1137-46. Epub 2014 Aug 14. link to original article PubMed
   2. Update: Huober J, Holmes E, Baselga J, de Azambuja E, Untch M, Fumagalli D, Sarp S, Lang I, Smith I, Boyle F, Xu B, Lecocq C, Wildiers H, Jouannaud C, Hackman J, Dasappa L, Ciruelos E, Toral Pena JC, Adamchuk H, Hickish T, de la Pena L, Jackisch C, Gelber RD, Piccart-Gebhart M, Di Cosimo S. Survival outcomes of the NeoALTTO study (BIG 1-06): updated results of a randomised multicenter phase III neoadjuvant clinical trial in patients with HER2-positive primary breast cancer. Eur J Cancer. 2019 Sep;118:169-177. Epub 2019 Aug 1. link to original article PubMed

Neoadjuvant response criteria

Clinical response rate (cRR)

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Although fairly dated, some trials such as ACOSOG Z1031 make use of the WHO criteria for response to neoadjuvant therapy. Included here primarily for historical purposes.

References

1. Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting results of cancer treatment. Cancer. 1981 Jan 1;47(1):207-14. link to original article PubMed

Miller-Payne scoring system

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• Grade 1: No change or some changes to individual malignant cells, but no reduction in overall cellularity
• Grade 2: Minor loss of tumor cells (up to 30%), but overall cellularity still high
• Grade 3: An estimated 30 to 90% reduction in the number of tumor cells
• Grade 4: Marked disappearance of tumor cells such that only small clusters or widely dispersed individual cells remain (loss of greater than 90% of tumor cells)
• Grade 5: No invasive cancer cells identifiable in sections from the site of the tumor (carcinoma in situ may be present)

References

1. Ogston KN, Miller ID, Payne S, Hutcheon AW, Sarkar TK, Smith I, Schofield A, Heys SD. A new histological grading system to assess response of breast cancers to primary chemotherapy: prognostic significance and survival. Breast. 2003 Oct;12(5):320-7. link to original article PubMed

Residual cancer burden (RCB)

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• The RCB is calculated as follows: RCB = 1.4 (f_inv*d_prim)^0.17 + [4(1 - 0.75^LN)d_met]^0.17
  • where d_prim is derived from the bidimensional diameters of the primary tumor bed in the resected specimen, f_inv is the proportion of the primary tumor bed that contains invasive carcinoma, LN is the number of axillary lymph nodes containing metastatic carcinoma, and d_met is the diameter of the largest metastasis in an axillary lymph node.
  • The cut-off points are 1.36 and 3.28.

References

1. Symmans WF, Peintinger F, Hatzis C, Rajan R, Kuerer H, Valero V, Assad L, Poniecka A, Hennessy B, Green M, Buzdar AU, Singletary SE, Hortobagyi GN, Pusztai L. Measurement of residual breast cancer burden to predict survival after neoadjuvant chemotherapy. J Clin Oncol. 2007 Oct 1;25(28):4414-22. Epub 2007 Sep 4. link to original article PubMed

Residual disease in breast and nodes (RDBN)

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• Level 1: pCR in breast and nodes with or without in situ carcinoma
• Levels 2 to 4: Residual disease, calculated as 0.2 (residual breast tumor size in cm) + index of involved nodes (0 for no positive nodes, 1 for 1 to 4 positive nodes, 2 for 5 to 7 positive nodes, and 3 for 8 positive nodes) + the Scarff–Bloom–Richardson grade (1, 2, or 3). The cut-off points are 3 and 4.3.

References

1. Chollet P, Abrial C, Durando X, Thivat E, Tacca O, Mouret-Reynier MA, Leheurteur M, Kwiatkowski F, Dauplat J, Penault-Llorca F. A new prognostic classification after primary chemotherapy for breast cancer: residual disease in breast and nodes (RDBN). Cancer J. 2008 Mar-Apr;14(2):128-32. link to original article PubMed

Sataloff's classification

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• Breast:
  • T-A: Total or nearly total therapeutic effect
  • T-B: Greater than 50% therapeutic effect
  • T-C: Less than 50% therapeutic effect
  • T-D: No therapeutic effect
• Lymph node:
  • N-A: Therapeutic effect but no metastasis
  • N-B: No metastasis, no therapeutic effect
  • N-C: Therapeutic effect but metastasis
  • N-D: Metastasis, no therapeutic effect

References

1. Sataloff DM, Mason BA, Prestipino AJ, Seinige UL, Lieber CP, Baloch Z. Pathologic response to induction chemotherapy in locally advanced carcinoma of the breast: a determinant of outcome. J Am Coll Surg. 1995 Mar;180(3):297-306. PubMed

Tumor response ratio

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Calculated as follows: Residual breast disease observed upon pathologic examination divided by the size of the tumor on the pre-neoadjuvant therapy image.

• TRR = 0: pathologic complete response (pCR)
• TRR greater than 0 up to 0.4: strong partial response
• TRR greater than 0.4 up to 1.0: weak partial response (WPR)
• TRR greater than 1.0: tumor growth

References

1. Miller M, Ottesen RA, Niland JC, Kruper L, Chen SL, Vito C. Tumor response ratio predicts overall survival in breast cancer patients treated with neoadjuvant chemotherapy. Ann Surg Oncol. 2014 Oct;21(10):3317-23. Epub 2014 Jul 25. link to original article PubMed

ypTNM staging

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This system is proprietary to the AJCC. Please visit their site or consult the AJCC Manual for further details.

Adjuvant chemotherapy

Cyclophosphamide & Doxorubicin (AC)

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AC: Adriamycin (Doxorubicin) and Cyclophosphamide
CA: Cyclophosphamide and Adriamycin (Doxorubicin)

Regimen variant #1, 60/600 x 4

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Van Pelt et al. 2003	2000-2002	Phase II
Romond et al. 2005 (NSABP B-31)	2000-2005	Non-randomized portion of RCT
Romond et al. 2005 (NCCTG N9831)	2000-2005	Non-randomized portion of RCT
Slamon et al. 2011 (BCIRG 006)	2001-2004	Phase III (C)	See link	See link

Preceding treatment

• Van Pelt et al. 2003: Neoadjuvant TH, then surgery
• NSABP B-31, NCCTG N9831, BCIRG 006: Surgery

Chemotherapy

• Doxorubicin (Adriamycin) 60 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 600 mg/m² IV once on day 1

21-day cycle for 4 cycles

Subsequent treatment

• Van Pelt et al. 2003: H x 12 mo
• NSABP B-31: weekly T (Taxol) x 12 versus TH (Taxol) x 12 mo
• NCCTG N9831: weekly T (Taxol) x 12 versus sequential weekly T (Taxol) x 12, then H x 12 mo versus concurrent TH (Taxol) x 12 mo
• BCIRG 006: q3wk T (Taxotere) x 4 versus TH (Taxotere) x 12 mo

Regimen variant #2, with range

Study	Evidence
von Minckwitz et al. 2017 (APHINITY)	Non-randomized portion of RCT

Patients in APHINITY had HER2-positive breast cancer. Note that ranges for AC are given in the protocol, replicated here. This is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Preceding treatment

• Surgery

Chemotherapy

• Doxorubicin (Adriamycin) 60 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 to 600 mg/m² IV once on day 1

21-day cycle for 4 cycles

Subsequent treatment

• TH (Taxol) versus THP (Taxol) or TH (Taxotere) versus THP (Taxotere)

References

1. Van Pelt AE, Mohsin S, Elledge RM, Hilsenbeck SG, Gutierrez MC, Lucci A Jr, Kalidas M, Granchi T, Scott BG, Allred DC, Chang JC. Neoadjuvant trastuzumab and docetaxel in breast cancer: preliminary results. Clin Breast Cancer. 2003 Dec;4(5):348-53. link to original article PubMed
2. NSABP B-31/NCCTG N9831: Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE Jr, Davidson NE, Tan-Chiu E, Martino S, Paik S, Kaufman PA, Swain SM, Pisansky TM, Fehrenbacher L, Kutteh LA, Vogel VG, Visscher DW, Yothers G, Jenkins RB, Brown AM, Dakhil SR, Mamounas EP, Lingle WL, Klein PM, Ingle JN, Wolmark N. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005 Oct 20;353(16):1673-84. link to original article PubMed NCT00004067; NCT00005970
   1. Update: Perez EA, Romond EH, Suman VJ, Jeong JH, Davidson NE, Geyer CE Jr, Martino S, Mamounas EP, Kaufman PA, Wolmark N. Four-year follow-up of trastuzumab plus adjuvant chemotherapy for operable human epidermal growth factor receptor 2-positive breast cancer: joint analysis of data from NCCTG N9831 and NSABP B-31. J Clin Oncol. 2011 Sep 1;29(25):3366-73. Epub 2011 Jul 18. link to original article link to PMC article PubMed
   2. Update: Perez EA, Suman VJ, Davidson NE, Gralow JR, Kaufman PA, Visscher DW, Chen B, Ingle JN, Dakhil SR, Zujewski J, Moreno-Aspitia A, Pisansky TM, Jenkins RB. Sequential versus concurrent trastuzumab in adjuvant chemotherapy for breast cancer. J Clin Oncol. 2011 Dec 1;29(34):4491-7. Epub 2011 Oct 31. link to original article link to PMC article PubMed
   3. Update: Perez EA, Romond EH, Suman VJ, Jeong JH, Sledge G, Geyer CE Jr, Martino S, Rastogi P, Gralow J, Swain SM, Winer EP, Colon-Otero G, Davidson NE, Mamounas E, Zujewski JA, Wolmark N. Trastuzumab plus adjuvant chemotherapy for human epidermal growth factor receptor 2-positive breast cancer: planned joint analysis of overall survival from NSABP B-31 and NCCTG N9831. J Clin Oncol. 2014 Nov 20;32(33):3744-52. link to original article link to PMC article PubMed
   4. Update and HRQoL analysis: Ganz PA, Romond EH, Cecchini RS, Rastogi P, Geyer CE Jr, Swain SM, Jeong JH, Fehrenbacher L, Gross HM, Brufsky AM, Flynn PJ, Wahl TA, Seay TE, Wade JL 3rd, Biggs DD, Atkins JN, Polikoff J, Zapas JL, Mamounas EP, Wolmark N. Long-term follow-up of cardiac function and quality of life for patients in NSABP protocol B-31/NRG Oncology: a randomized trial comparing the safety and efficacy of doxorubicin and cyclophosphamide (AC) followed by paclitaxel with AC followed by paclitaxel and trastuzumab in patients with node-positive breast cancer with tumors overexpressing human epidermal growth factor receptor 2. J Clin Oncol. 2017 Dec 10;35(35):3942-3948. Epub 2017 Oct 26. link to original article link to PMC article PubMed
3. BCIRG 006: Slamon D, Eiermann W, Robert N, Pienkowski T, Martín M, Press M, Mackey J, Glaspy J, Chan A, Pawlicki M, Pinter T, Valero V, Liu MC, Sauter G, von Minckwitz G, Visco F, Bee V, Buyse M, Bendahmane B, Tabah-Fisch I, Lindsay MA, Riva A, Crown J; Breast Cancer International Research Group. Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med. 2011 Oct 6;365(14):1273-83. link to original article link to PMC article PubMed NCT00021255
4. APHINITY: von Minckwitz G, Procter M, de Azambuja E, Zardavas D, Benyunes M, Viale G, Suter T, Arahmani A, Rouchet N, Clark E, Knott A, Lang I, Levy C, Yardley DA, Bines J, Gelber RD, Piccart M, Baselga J; APHINITY Steering Committee and Investigators. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med. 2017 Jul 13;377(2):122-131. Epub 2017 Jun 5. link to original article link to supplementary protocol contains verified protocol in supplementary protocol link to PMC article PubMed NCT01358877
   1. Update: Piccart M, Procter M, Fumagalli D, de Azambuja E, Clark E, Ewer MS, Restuccia E, Jerusalem G, Dent S, Reaby L, Bonnefoi H, Krop I, Liu TW, Pieńkowski T, Toi M, Wilcken N, Andersson M, Im YH, Tseng LM, Lueck HJ, Colleoni M, Monturus E, Sicoe M, Guillaume S, Bines J, Gelber RD, Viale G, Thomssen C; APHINITY Steering Committee and Investigators. Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer in the APHINITY Trial: 6 Years' Follow-Up. J Clin Oncol. 2021 May 1;39(13):1448-1457. Epub 2021 Feb 4. link to original article PubMed
5. RESPECT: Sawaki M, Taira N, Uemura Y, Saito T, Baba S, Kobayashi K, Kawashima H, Tsuneizumi M, Sagawa N, Bando H, Takahashi M, Yamaguchi M, Takashima T, Nakayama T, Kashiwaba M, Mizuno T, Yamamoto Y, Iwata H, Kawahara T, Ohashi Y, Mukai H; RESPECT study group. Randomized Controlled Trial of Trastuzumab With or Without Chemotherapy for HER2-Positive Early Breast Cancer in Older Patients. J Clin Oncol. 2020 Nov 10;38(32):3743-3752. Epub 2020 Sep 16. link to original article contains verified protocol PubMed NCT01104935

Dose-dense Cyclophosphamide & Doxorubicin (ddAC)

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ddAC: dose-dense Adriamycin (Doxorubicin) and Cyclophosphamide

Regimen variant #1, 60/600 x 4

Study	Years of enrollment	Evidence
Dang et al. 2008	2005	Phase II

Preceding treatment

• Surgery

Chemotherapy

• Doxorubicin (Adriamycin) 60 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 600 mg/m² IV once on day 1

Supportive medications

• Pegfilgrastim (Neulasta) 6 mg SC once on day 2, given 24 hours after chemotherapy

14-day cycle for 4 cycles

Subsequent treatment

• ddTH (Taxol)

Regimen variant #2, 4 cycles, with range

Study	Evidence
von Minckwitz et al. 2017 (APHINITY)	Non-randomized portion of RCT

Note that ranges for ddAC are given in the protocol, replicated here.

Preceding treatment

• Surgery

Chemotherapy

• Doxorubicin (Adriamycin) 60 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 to 600 mg/m² IV once on day 1

Supportive medications

• G-CSF support (drug/dose/schedule not specified)

14-day cycle for 4 cycles

Subsequent treatment

• TH (Taxol) versus THP (Taxol) or TH (Taxotere) versus THP (Taxotere)

References

1. Dang C, Fornier M, Sugarman S, Troso-Sandoval T, Lake D, D'Andrea G, Seidman A, Sklarin N, Dickler M, Currie V, Gilewski T, Moynahan ME, Drullinsky P, Robson M, Wasserheit-Leiblich C, Mills N, Steingart R, Panageas K, Norton L, Hudis C. The safety of dose-dense doxorubicin and cyclophosphamide followed by paclitaxel with trastuzumab in HER-2/neu overexpressed/amplified breast cancer. J Clin Oncol. 2008 Mar 10;26(8):1216-22. link to original article contains verified protocol PubMed
2. APHINITY: von Minckwitz G, Procter M, de Azambuja E, Zardavas D, Benyunes M, Viale G, Suter T, Arahmani A, Rouchet N, Clark E, Knott A, Lang I, Levy C, Yardley DA, Bines J, Gelber RD, Piccart M, Baselga J; APHINITY Steering Committee and Investigators. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med. 2017 Jul 13;377(2):122-131. Epub 2017 Jun 5. link to original article link to supplementary protocol contains verified protocol in supplementary protocol link to PMC article PubMed NCT01358877
   1. Update: Piccart M, Procter M, Fumagalli D, de Azambuja E, Clark E, Ewer MS, Restuccia E, Jerusalem G, Dent S, Reaby L, Bonnefoi H, Krop I, Liu TW, Pieńkowski T, Toi M, Wilcken N, Andersson M, Im YH, Tseng LM, Lueck HJ, Colleoni M, Monturus E, Sicoe M, Guillaume S, Bines J, Gelber RD, Viale G, Thomssen C; APHINITY Steering Committee and Investigators. Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer in the APHINITY Trial: 6 Years' Follow-Up. J Clin Oncol. 2021 May 1;39(13):1448-1457. Epub 2021 Feb 4. link to original article PubMed

Cyclophosphamide & Epirubicin (EC)

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EC: Epirubicin and Cyclophosphamide

Regimen

Study	Evidence
von Minckwitz et al. 2017 (APHINITY)	Non-randomized portion of RCT

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment. Patients had HER2-positive breast cancer.

Preceding treatment

• Surgery

Chemotherapy

• Epirubicin (Ellence) 90 to 120 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 to 600 mg/m² IV once on day 1

21-day cycle for 4 cycles

Subsequent treatment

• TH (Taxol) versus THP (Taxol) or TH (Taxotere) versus THP (Taxotere)

References

1. APHINITY: von Minckwitz G, Procter M, de Azambuja E, Zardavas D, Benyunes M, Viale G, Suter T, Arahmani A, Rouchet N, Clark E, Knott A, Lang I, Levy C, Yardley DA, Bines J, Gelber RD, Piccart M, Baselga J; APHINITY Steering Committee and Investigators. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med. 2017 Jul 13;377(2):122-131. Epub 2017 Jun 5. link to original article link to supplementary protocol contains verified protocol in supplementary protocol link to PMC article PubMed NCT01358877
   1. Update: Piccart M, Procter M, Fumagalli D, de Azambuja E, Clark E, Ewer MS, Restuccia E, Jerusalem G, Dent S, Reaby L, Bonnefoi H, Krop I, Liu TW, Pieńkowski T, Toi M, Wilcken N, Andersson M, Im YH, Tseng LM, Lueck HJ, Colleoni M, Monturus E, Sicoe M, Guillaume S, Bines J, Gelber RD, Viale G, Thomssen C; APHINITY Steering Committee and Investigators. Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer in the APHINITY Trial: 6 Years' Follow-Up. J Clin Oncol. 2021 May 1;39(13):1448-1457. Epub 2021 Feb 4. link to original article PubMed

ddEC

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ddEC: dose-dense Epirubicin and Cyclophosphamide

Regimen

Study	Evidence
von Minckwitz et al. 2017 (APHINITY)	Non-randomized portion of RCT

Note that ranges for ddEC are given in the protocol, replicated here.

Preceding treatment

• Surgery

Chemotherapy

• Epirubicin (Ellence) 90 to 120 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 to 600 mg/m² IV once on day 1

Supportive medications

• G-CSF support (drug/dose/schedule not specified)

14-day cycle for 4 cycles

Subsequent treatment

• TH (Taxol) versus THP (Taxol) or TH (Taxotere) versus THP (Taxotere)

References

1. APHINITY: von Minckwitz G, Procter M, de Azambuja E, Zardavas D, Benyunes M, Viale G, Suter T, Arahmani A, Rouchet N, Clark E, Knott A, Lang I, Levy C, Yardley DA, Bines J, Gelber RD, Piccart M, Baselga J; APHINITY Steering Committee and Investigators. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med. 2017 Jul 13;377(2):122-131. Epub 2017 Jun 5. link to original article link to supplementary protocol contains verified protocol in supplementary protocol link to PMC article PubMed NCT01358877
   1. Update: Piccart M, Procter M, Fumagalli D, de Azambuja E, Clark E, Ewer MS, Restuccia E, Jerusalem G, Dent S, Reaby L, Bonnefoi H, Krop I, Liu TW, Pieńkowski T, Toi M, Wilcken N, Andersson M, Im YH, Tseng LM, Lueck HJ, Colleoni M, Monturus E, Sicoe M, Guillaume S, Bines J, Gelber RD, Viale G, Thomssen C; APHINITY Steering Committee and Investigators. Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer in the APHINITY Trial: 6 Years' Follow-Up. J Clin Oncol. 2021 May 1;39(13):1448-1457. Epub 2021 Feb 4. link to original article PubMed

FAC

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FAC: Fluorouracil, Adriamycin (Doxorubicin), Cyclophosphamide
CAF: Cyclophosphamide, Adriamycin (Doxorubicin), Fluorouracil

Regimen

Study	Evidence
von Minckwitz et al. 2017 (APHINITY)	Non-randomized portion of RCT

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment. Note that ranges for FAC are given in the protocol, replicated here.

Preceding treatment

• Surgery

Chemotherapy

• Fluorouracil (5-FU) 500 to 600 mg/m² IV once on day 1
• Doxorubicin (Adriamycin) 50 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 to 600 mg/m² IV once on day 1

21-day cycle for 3 cycles

Subsequent treatment

• TH (Taxol) versus THP (Taxol) or TH (Taxotere) versus THP (Taxotere)

References

1. APHINITY: von Minckwitz G, Procter M, de Azambuja E, Zardavas D, Benyunes M, Viale G, Suter T, Arahmani A, Rouchet N, Clark E, Knott A, Lang I, Levy C, Yardley DA, Bines J, Gelber RD, Piccart M, Baselga J; APHINITY Steering Committee and Investigators. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med. 2017 Jul 13;377(2):122-131. Epub 2017 Jun 5. link to original article link to supplementary protocol contains verified protocol in supplementary protocol link to PMC article PubMed NCT01358877
   1. Update: Piccart M, Procter M, Fumagalli D, de Azambuja E, Clark E, Ewer MS, Restuccia E, Jerusalem G, Dent S, Reaby L, Bonnefoi H, Krop I, Liu TW, Pieńkowski T, Toi M, Wilcken N, Andersson M, Im YH, Tseng LM, Lueck HJ, Colleoni M, Monturus E, Sicoe M, Guillaume S, Bines J, Gelber RD, Viale G, Thomssen C; APHINITY Steering Committee and Investigators. Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer in the APHINITY Trial: 6 Years' Follow-Up. J Clin Oncol. 2021 May 1;39(13):1448-1457. Epub 2021 Feb 4. link to original article PubMed

FEC

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FEC: Fluorouracil, Epirubicin, Cyclophosphamide
CEF: Cyclophosphamide, Epirubicin, Fluorouracil

Regimen variant #1, 500/100/500 x 3 ("FEC 100")

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Baselga et al. 2012 (NeoALTTO)	2008-2010	Non-randomized portion of RCT

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Preceding treatment

• Surgery

Chemotherapy

• Fluorouracil (5-FU) 500 mg/m² IV once on day 1
• Epirubicin (Ellence) 100 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 mg/m² IV once on day 1

21-day cycle for 3 cycles

Subsequent treatment

• Lapatinib or Lapatinib & Trastuzumab or Trastuzumab, according to initial randomization

Regimen variant #2, 600/60/600 x 3

Study	Evidence
Joensuu et al. 2006 (FinHer)	Non-randomized portion of RCT

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Preceding treatment

• Docetaxel x 3 versus TH x 3 versus Vinorelbine x 3 versus VH x 3

Chemotherapy

• Fluorouracil (5-FU) 600 mg/m² IV once on day 1
• Epirubicin (Ellence) 60 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 600 mg/m² IV once on day 1

21-day cycle for 3 cycles

Regimen variant #3, 600/75/600 x 3

Study	Evidence
Joensuu et al. 2018 (SOLD)	Non-randomized portion of RCT

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Preceding treatment

• Surgery, then TH (Taxotere) x 3

Chemotherapy

• Fluorouracil (5-FU) 600 mg/m² IV once on day 1
• Epirubicin (Ellence) 75 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 600 mg/m² IV once on day 1

21-day cycle for 3 cycles

Subsequent treatment

• Trastuzumab maintenance for a total of 1 year versus no further treatment

Regimen variant #4, with range

Study	Evidence
von Minckwitz et al. 2017 (APHINITY)	Non-randomized portion of RCT

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment. Note that ranges for FEC are given in the protocol, replicated here.

Preceding treatment

• Surgery

Chemotherapy

• Fluorouracil (5-FU) 500 to 600 mg/m² IV once on day 1
• Epirubicin (Ellence) 90 to 120 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 to 600 mg/m² IV once on day 1

21-day cycle for 3 cycles

Subsequent treatment

• TH (Taxol) versus THP (Taxol) or TH (Taxotere) versus THP (Taxotere)

References

1. FinHer: Joensuu H, Kellokumpu-Lehtinen PL, Bono P, Alanko T, Kataja V, Asola R, Utriainen T, Kokko R, Hemminki A, Tarkkanen M, Turpeenniemi-Hujanen T, Jyrkkiö S, Flander M, Helle L, Ingalsuo S, Johansson K, Jääskeläinen AS, Pajunen M, Rauhala M, Kaleva-Kerola J, Salminen T, Leinonen M, Elomaa I, Isola J; FinHer Study Investigators. Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N Engl J Med. 2006 Feb 23;354(8):809-20. link to original article contains verified protocol PubMed ISRCTN76560285
   1. Update: Joensuu H, Bono P, Kataja V, Alanko T, Kokko R, Asola R, Utriainen T, Turpeenniemi-Hujanen T, Jyrkkiö S, Möykkynen K, Helle L, Ingalsuo S, Pajunen M, Huusko M, Salminen T, Auvinen P, Leinonen H, Leinonen M, Isola J, Kellokumpu-Lehtinen PL. Fluorouracil, epirubicin, and cyclophosphamide with either docetaxel or vinorelbine, with or without trastuzumab, as adjuvant treatments of breast cancer: final results of the FinHer trial. J Clin Oncol. 2009 Dec 1;27(34):5685-92. link to original article PubMed
2. NeoALTTO: Baselga J, Bradbury I, Eidtmann H, Di Cosimo S, de Azambuja E, Aura C, Gómez H, Dinh P, Fauria K, Van Dooren V, Aktan G, Goldhirsch A, Chang TW, Horváth Z, Coccia-Portugal M, Domont J, Tseng LM, Kunz G, Sohn JH, Semiglazov V, Lerzo G, Palacova M, Probachai V, Pusztai L, Untch M, Gelber RD, Piccart-Gebhart M; NeoALTTO Study Team. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet. 2012 Feb 18;379(9816):633-40. Epub 2012 Jan 17. Erratum in: Lancet. 2012 Feb 18;379(9816):616. Dosage error in published abstract; MEDLINE/PubMed abstract corrected. link to original article link to PMC article contains verified protocol PubMed NCT00553358
   1. Update: de Azambuja E, Holmes AP, Piccart-Gebhart M, Holmes E, Di Cosimo S, Swaby RF, Untch M, Jackisch C, Lang I, Smith I, Boyle F, Xu B, Barrios CH, Perez EA, Azim HA Jr, Kim SB, Kuemmel S, Huang CS, Vuylsteke P, Hsieh RK, Gorbunova V, Eniu A, Dreosti L, Tavartkiladze N, Gelber RD, Eidtmann H, Baselga J. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): survival outcomes of a randomised, open-label, multicentre, phase 3 trial and their association with pathological complete response. Lancet Oncol. 2014 Sep;15(10):1137-46. Epub 2014 Aug 14. link to original article PubMed
   2. Update: Huober J, Holmes E, Baselga J, de Azambuja E, Untch M, Fumagalli D, Sarp S, Lang I, Smith I, Boyle F, Xu B, Lecocq C, Wildiers H, Jouannaud C, Hackman J, Dasappa L, Ciruelos E, Toral Pena JC, Adamchuk H, Hickish T, de la Pena L, Jackisch C, Gelber RD, Piccart-Gebhart M, Di Cosimo S. Survival outcomes of the NeoALTTO study (BIG 1-06): updated results of a randomised multicenter phase III neoadjuvant clinical trial in patients with HER2-positive primary breast cancer. Eur J Cancer. 2019 Sep;118:169-177. Epub 2019 Aug 1. link to original article PubMed
3. APHINITY: von Minckwitz G, Procter M, de Azambuja E, Zardavas D, Benyunes M, Viale G, Suter T, Arahmani A, Rouchet N, Clark E, Knott A, Lang I, Levy C, Yardley DA, Bines J, Gelber RD, Piccart M, Baselga J; APHINITY Steering Committee and Investigators. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med. 2017 Jul 13;377(2):122-131. Epub 2017 Jun 5. link to original article link to supplementary protocol contains verified protocol in supplementary protocol link to PMC article PubMed NCT01358877
   1. Update: Piccart M, Procter M, Fumagalli D, de Azambuja E, Clark E, Ewer MS, Restuccia E, Jerusalem G, Dent S, Reaby L, Bonnefoi H, Krop I, Liu TW, Pieńkowski T, Toi M, Wilcken N, Andersson M, Im YH, Tseng LM, Lueck HJ, Colleoni M, Monturus E, Sicoe M, Guillaume S, Bines J, Gelber RD, Viale G, Thomssen C; APHINITY Steering Committee and Investigators. Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer in the APHINITY Trial: 6 Years' Follow-Up. J Clin Oncol. 2021 May 1;39(13):1448-1457. Epub 2021 Feb 4. link to original article PubMed
4. SOLD: Joensuu H, Fraser J, Wildiers H, Huovinen R, Auvinen P, Utriainen M, Nyandoto P, Villman KK, Halonen P, Granstam-Björneklett H, Lundgren L, Sailas L, Turpeenniemi-Hujanen T, Tanner M, Yachnin J, Ritchie D, Johansson O, Huttunen T, Neven P, Canney P, Harvey VJ, Kellokumpu-Lehtinen PL, Lindman H. Effect of adjuvant trastuzumab for a duration of 9 weeks vs 1 year with concomitant chemotherapy for early human epidermal growth factor receptor 2-positive breast cancer: the SOLD randomized clinical trial. JAMA Oncol. 2018 Sep 1;4(9):1199-1206. link to original article contains verified protocol PubMed NCT00593697
5. RESPECT: Sawaki M, Taira N, Uemura Y, Saito T, Baba S, Kobayashi K, Kawashima H, Tsuneizumi M, Sagawa N, Bando H, Takahashi M, Yamaguchi M, Takashima T, Nakayama T, Kashiwaba M, Mizuno T, Yamamoto Y, Iwata H, Kawahara T, Ohashi Y, Mukai H; RESPECT study group. Randomized Controlled Trial of Trastuzumab With or Without Chemotherapy for HER2-Positive Early Breast Cancer in Older Patients. J Clin Oncol. 2020 Nov 10;38(32):3743-3752. Epub 2020 Sep 16. link to original article contains verified protocol PubMed NCT01104935

ddFEC

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ddFEC: dose-dense Fluorouracil, Epirubicin, Cyclophosphamide

Regimen

Study	Years of enrollment	Evidence
Mavroudis et al. 2015 (HORG CT/04.23)	2004-2012	Non-randomized portion of RCT

Note: This is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Preceding treatment

• Surgery

Chemotherapy

• Fluorouracil (5-FU) 700 mg/m² IV over 5 to 15 minutes once on day 1
• Epirubicin (Ellence) 75 mg/m² IV over 5 to 15 minutes once on day 1
• Cyclophosphamide (Cytoxan) 700 mg/m² IV over 30 to 60 minutes once on day 1

Supportive medications

• Filgrastim (Neupogen) 300 or 480 mcg SC once per day on days 3 to 10

14-day cycle for 4 cycles

Subsequent treatment

• ddTH (Taxotere) x 4

References

1. HORG CT/04.23: Mavroudis D, Saloustros E, Malamos N, Kakolyris S, Boukovinas I, Papakotoulas P, Kentepozidis N, Ziras N, Georgoulias V; Hellenic Oncology Research Group. Six versus 12 months of adjuvant trastuzumab in combination with dose-dense chemotherapy for women with HER2-positive breast cancer: a multicenter randomized study by the Hellenic Oncology Research Group (HORG). Ann Oncol. 2015 Jul;26(7):1333-40. Epub 2015 May 1. link to original article contains verified protocol PubMed

FEC & H

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Regimen

Study	Evidence
Gianni et al. 2011 (NeoSphere)	Non-randomized portion of RCT

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Preceding treatment

• Neoadjuvant Docetaxel & Pertuzumab versus THP (Taxotere) versus pertuzumab & trastuzumab versus TH (Taxotere), then surgery

Chemotherapy

• Fluorouracil (5-FU) as follows:
  • Cycles 1 to 3: 600 mg/m² IV once on day 1
• Epirubicin (Ellence) as follows:
  • Cycles 1 to 3: 90 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) as follows:
  • Cycles 1 to 3: 600 mg/m² IV once on day 1

Targeted therapy

• Trastuzumab (Herceptin) 6 mg/kg IV once on day 1

21-day cycle for 18 cycles

Subsequent treatment

• Radiotherapy and/or hormone therapy for ER positive patients is given "per local guidelines"

References

1. NeoSphere: Gianni L, Pienkowski T, Im YH, Roman L, Tseng LM, Liu MC, Lluch A, Staroslawska E, de la Haba-Rodriguez J, Im SA, Pedrini JL, Poirier B, Morandi P, Semiglazov V, Srimuninnimit V, Bianchi G, Szado T, Ratnayake J, Ross G, Valagussa P. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol. 2012 Jan;13(1):25-32. Epub 2011 Dec 6. link to original article contains verified protocol PubMed NCT00545688
   1. Update: Gianni L, Pienkowski T, Im YH, Tseng LM, Liu MC, Lluch A, Starosławska E, de la Haba-Rodriguez J, Im SA, Pedrini JL, Poirier B, Morandi P, Semiglazov V, Srimuninnimit V, Bianchi GV, Magazzù D, McNally V, Douthwaite H, Ross G, Valagussa P. 5-year analysis of neoadjuvant pertuzumab and trastuzumab in patients with locally advanced, inflammatory, or early-stage HER2-positive breast cancer (NeoSphere): a multicentre, open-label, phase 2 randomised trial. Lancet Oncol. 2016 Jun;17(6):791-800. Epub 2016 May 11. link to original article PubMed

Lapatinib & Trastuzumab

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Piccart-Gebhart et al. 2015 (ALTTO)	2007-2011	Phase III (E-esc)	1. Lapatinib 2. Trastuzumab	Did not meet primary endpoint of DFS
Baselga et al. 2012 (NeoALTTO)	2008-2010	Phase III (E-esc)	See link	See link

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Preceding treatment

• NeoALTTO: Surgery, then adjuvant FEC x 3

Targeted therapy

• Lapatinib (Tykerb) 1000 mg PO once per day
• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV over 90 minutes once on day 1
  • Cycles 2 to 12: 6 mg/kg IV over 30 minutes once on day 1

21-day cycle for 12 cycles (34-week course)

References

1. NeoALTTO: Baselga J, Bradbury I, Eidtmann H, Di Cosimo S, de Azambuja E, Aura C, Gómez H, Dinh P, Fauria K, Van Dooren V, Aktan G, Goldhirsch A, Chang TW, Horváth Z, Coccia-Portugal M, Domont J, Tseng LM, Kunz G, Sohn JH, Semiglazov V, Lerzo G, Palacova M, Probachai V, Pusztai L, Untch M, Gelber RD, Piccart-Gebhart M; NeoALTTO Study Team. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet. 2012 Feb 18;379(9816):633-40. Epub 2012 Jan 17. Erratum in: Lancet. 2012 Feb 18;379(9816):616. Dosage error in published abstract; MEDLINE/PubMed abstract corrected. link to original article link to PMC article contains verified protocol PubMed NCT00553358
   1. Update: de Azambuja E, Holmes AP, Piccart-Gebhart M, Holmes E, Di Cosimo S, Swaby RF, Untch M, Jackisch C, Lang I, Smith I, Boyle F, Xu B, Barrios CH, Perez EA, Azim HA Jr, Kim SB, Kuemmel S, Huang CS, Vuylsteke P, Hsieh RK, Gorbunova V, Eniu A, Dreosti L, Tavartkiladze N, Gelber RD, Eidtmann H, Baselga J. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): survival outcomes of a randomised, open-label, multicentre, phase 3 trial and their association with pathological complete response. Lancet Oncol. 2014 Sep;15(10):1137-46. Epub 2014 Aug 14. link to original article PubMed
   2. Update: Huober J, Holmes E, Baselga J, de Azambuja E, Untch M, Fumagalli D, Sarp S, Lang I, Smith I, Boyle F, Xu B, Lecocq C, Wildiers H, Jouannaud C, Hackman J, Dasappa L, Ciruelos E, Toral Pena JC, Adamchuk H, Hickish T, de la Pena L, Jackisch C, Gelber RD, Piccart-Gebhart M, Di Cosimo S. Survival outcomes of the NeoALTTO study (BIG 1-06): updated results of a randomised multicenter phase III neoadjuvant clinical trial in patients with HER2-positive primary breast cancer. Eur J Cancer. 2019 Sep;118:169-177. Epub 2019 Aug 1. link to original article PubMed
2. ALTTO: Piccart-Gebhart M, Holmes E, Baselga J, de Azambuja E, Dueck AC, Viale G, Zujewski JA, Goldhirsch A, Armour A, Pritchard KI, McCullough AE, Dolci S, McFadden E, Holmes AP, Tonghua L, Eidtmann H, Dinh P, Di Cosimo S, Harbeck N, Tjulandin S, Im YH, Huang CS, Diéras V, Hillman DW, Wolff AC, Jackisch C, Lang I, Untch M, Smith I, Boyle F, Xu B, Gomez H, Suter T, Gelber RD, Perez EA. Adjuvant lapatinib and trastuzumab for early human epidermal growth factor receptor 2-positive breast cancer: results from the randomized phase III Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization trial. J Clin Oncol. 2016 Apr 1;34(10):1034-42. Epub 2015 Nov 23. link to original article link to protocol contains verified protocol in supplement link to PMC article PubMed NCT00490139

Neratinib monotherapy

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Regimen

FDA-recommended dose

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Chan et al. 2016 (ExteNET)	2009-2011	Phase III (E-RT-esc)	Placebo	Superior invasive DFS

Preceding treatment

• Surgery and trastuzumab-containing chemotherapy (neoadjuvant or adjuvant)

Targeted therapy

• Neratinib (Nerlynx) 240 mg PO once per day, with food

Supportive medications

• (per FDA package insert)
• Loperamide (Imodium) as follows:
  • Weeks 1 & 2: 4 mg PO three times per day
  • Weeks 3 to 8: 4 mg PO twice per day
  • Weeks 9 to 52: 4 mg PO as needed for diarrhea, not to exceed 16 mg/d

12-month course

References

1. ExteNET: Chan A, Delaloge S, Holmes FA, Moy B, Iwata H, Harvey VJ, Robert NJ, Silovski T, Gokmen E, von Minckwitz G, Ejlertsen B, Chia SK, Mansi J, Barrios CH, Gnant M, Buyse M, Gore I, Smith J 2nd, Harker G, Masuda N, Petrakova K, Zotano AG, Iannotti N, Rodriguez G, Tassone P, Wong A, Bryce R, Ye Y, Yao B, Martin M; ExteNET Study Group. Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (ExteNET): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2016 Mar;17(3):367-77. Epub 2016 Feb 10. link to original article contains verified protocol PubMed NCT00878709
   1. Update: Martin M, Holmes FA, Ejlertsen B, Delaloge S, Moy B, Iwata H, von Minckwitz G, Chia SKL, Mansi J, Barrios CH, Gnant M, Tomašević Z, Denduluri N, Šeparović R, Gokmen E, Bashford A, Ruiz Borrego M, Kim SB, Jakobsen EH, Ciceniene A, Inoue K, Overkamp F, Heijns JB, Armstrong AC, Link JS, Joy AA, Bryce R, Wong A, Moran S, Yao B, Xu F, Auerbach A, Buyse M, Chan A; ExteNET Study Group. Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2017 Dec;18(12):1688-1700. Epub 2017 Nov 13. link to original article PubMed
   2. HRQoL analysis: Delaloge S, Cella D, Ye Y, Buyse M, Chan A, Barrios CH, Holmes FA, Mansi J, Iwata H, Ejlertsen B, Moy B, Chia SKL, Gnant M, Smichkoska S, Ciceniene A, Martinez N, Filipović S, Ben-Baruch NE, Joy AA, Langkjer ST, Senecal F, de Boer RH, Moran S, Yao B, Bryce R, Auerbach A, Fallowfield L, Martin M. Effects of neratinib on health-related quality of life in women with HER2-positive early-stage breast cancer: longitudinal analyses from the randomized phase III ExteNET trial. Ann Oncol. 2019 Apr 1;30(4):567-574. link to original article PubMed
   3. Subgroup analysis: Iwata H, Masuda N, Kim SB, Inoue K, Rai Y, Fujita T, Chiu J, Ohtani S, Takahashi M, Miyaki T, Lu YS, Xu B, Yap YS, Bustam A, Yao B, Zhang B, Bryce R, Chan A. Neratinib after trastuzumab-based adjuvant therapy in patients from Asia with early stage HER2-positive breast cancer. Future Oncol. 2019 Jul;15(21):2489-2501. Epub 2019 May 29. link to original article PubMed

TCH (Taxotere, Carboplatin)

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TCH: Taxotere (Docetaxel), Carboplatin, Herceptin (Trastuzumab)

Regimen variant #1, capped carboplatin

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
von Minckwitz et al. 2017 (APHINITY)	2011-2013	Phase III (C)	TCHP (Taxotere)	Inferior IDFS1

¹Reported efficacy is based on the 2021 update.

Preceding treatment

• Surgery

Chemotherapy

• Docetaxel (Taxotere) as follows:
  • Cycles 1 to 6: 75 mg/m² IV once on day 1
• Carboplatin (Paraplatin) as follows:
  • Cycles 1 to 6: AUC 6 (maximum dose of 900 mg) IV once on day 1

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV once on day 1
  • Cycle 2 onwards: 6 mg/kg IV once on day 1

21-day cycle for up to 18 cycles (1 year)

Regimen variant #2, no cap

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Slamon et al. 2011 (BCIRG 006)	2001-2004	Phase III (E-RT-esc)	1. AC, then T (Taxotere)	Seems to have superior OS
			2. AC, then TH (Taxotere)	Did not meet primary endpoint of DFS
Piccart-Gebhart et al. 2015 (ALTTO)	2007-2011	Phase III (C)	1. TCL 2. TCH, then Lapatinib 3. TCHL	Did not meet primary endpoint of DFS

Preceding treatment

• Surgery

Chemotherapy

• Docetaxel (Taxotere) as follows:
  • Cycles 1 to 6: 75 mg/m² IV once on day 1
• Carboplatin (Paraplatin) as follows:
  • Cycles 1 to 6: AUC 6 IV once on day 1

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8 & 15
  • Cycles 2 to 6: 2 mg/kg IV once per day on days 1, 8, 15
  • Cycles 7 to 18: 6 mg/kg IV once on day 1

Supportive medications

• ALTTO: G-CSF use is mandatory (details not provided)

21-day cycle for 18 cycles (1 year)

References

1. BCIRG 006: Slamon D, Eiermann W, Robert N, Pienkowski T, Martin M, Press M, Mackey J, Glaspy J, Chan A, Pawlicki M, Pinter T, Valero V, Liu MC, Sauter G, von Minckwitz G, Visco F, Bee V, Buyse M, Bendahmane B, Tabah-Fisch I, Lindsay MA, Riva A, Crown J; Breast Cancer International Research Group. Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med. 2011 Oct 6;365(14):1273-83. link to original article link to PMC article PubMed NCT00021255
2. APHINITY: von Minckwitz G, Procter M, de Azambuja E, Zardavas D, Benyunes M, Viale G, Suter T, Arahmani A, Rouchet N, Clark E, Knott A, Lang I, Levy C, Yardley DA, Bines J, Gelber RD, Piccart M, Baselga J; APHINITY Steering Committee and Investigators. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med. 2017 Jul 13;377(2):122-131. Epub 2017 Jun 5. link to original article link to supplementary protocol contains verified protocol in supplementary protocol link to PMC article PubMed NCT01358877
   1. Update: Piccart M, Procter M, Fumagalli D, de Azambuja E, Clark E, Ewer MS, Restuccia E, Jerusalem G, Dent S, Reaby L, Bonnefoi H, Krop I, Liu TW, Pieńkowski T, Toi M, Wilcken N, Andersson M, Im YH, Tseng LM, Lueck HJ, Colleoni M, Monturus E, Sicoe M, Guillaume S, Bines J, Gelber RD, Viale G, Thomssen C; APHINITY Steering Committee and Investigators. Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer in the APHINITY Trial: 6 Years' Follow-Up. J Clin Oncol. 2021 May 1;39(13):1448-1457. Epub 2021 Feb 4. link to original article PubMed
3. ALTTO: Piccart-Gebhart M, Holmes E, Baselga J, de Azambuja E, Dueck AC, Viale G, Zujewski JA, Goldhirsch A, Armour A, Pritchard KI, McCullough AE, Dolci S, McFadden E, Holmes AP, Tonghua L, Eidtmann H, Dinh P, Di Cosimo S, Harbeck N, Tjulandin S, Im YH, Huang CS, Diéras V, Hillman DW, Wolff AC, Jackisch C, Lang I, Untch M, Smith I, Boyle F, Xu B, Gomez H, Suter T, Gelber RD, Perez EA. Adjuvant lapatinib and trastuzumab for early human epidermal growth factor receptor 2-positive breast cancer: results from the randomized phase III Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization trial. J Clin Oncol. 2016 Apr 1;34(10):1034-42. Epub 2015 Nov 23. link to original article link to protocol contains verified protocol in supplement link to PMC article PubMed NCT00490139
4. RESPECT: Sawaki M, Taira N, Uemura Y, Saito T, Baba S, Kobayashi K, Kawashima H, Tsuneizumi M, Sagawa N, Bando H, Takahashi M, Yamaguchi M, Takashima T, Nakayama T, Kashiwaba M, Mizuno T, Yamamoto Y, Iwata H, Kawahara T, Ohashi Y, Mukai H; RESPECT study group. Randomized Controlled Trial of Trastuzumab With or Without Chemotherapy for HER2-Positive Early Breast Cancer in Older Patients. J Clin Oncol. 2020 Nov 10;38(32):3743-3752. Epub 2020 Sep 16. link to original article contains verified protocol PubMed NCT01104935

TCH (Taxotere, Cyclophosphamide)

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TCH: Taxotere, Cyclophosphamide, Herceptin

Regimen

Study	Years of enrollment	Evidence
Jones et al. 2013 (US Oncology 06-038)	2007-2009	Phase II

Preceding treatment

• Surgery, within 84 days

Chemotherapy

• Docetaxel (Taxotere) as follows:
  • Cycles 1 to 4: 75 mg/m² IV over 60 minutes once on day 1
• Cyclophosphamide (Cytoxan) as follows:
  • Cycles 1 to 4: 600 mg/m² IV over 15 to 30 minutes once on day 1

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 4 mg/kg IV over 90 minutes once on day 1, then 2 mg/kg IV over 30 to 60 minutes once per day on days 8 & 15
  • Cycles 2 to 4: 2 mg/kg IV over 30 to 60 minutes once per day on days 1, 8, 15
  • Cycles 6 to 18: 6 mg/kg IV once on day 1

Supportive medications

• Use of Filgrastim (Neupogen) or Pegfilgrastim (Neulasta) was allowed.
• Prophylactic antibiotics were not recommended.

21-day cycle for 18 cycles

References

1. US Oncology 06-038: Jones SE, Collea R, Paul D, Sedlacek S, Favret AM, Gore I Jr, Lindquist DL, Holmes FA, Allison MA, Brooks BD, Portillo RM, Vukelja SJ, Steinberg MS, Stokoe C, Crockett MW, Wang Y, Asmar L, Robert NJ, O'Shaughnessy J. Adjuvant docetaxel and cyclophosphamide plus trastuzumab in patients with HER2-amplified early stage breast cancer: a single-group, open-label, phase 2 study. Lancet Oncol. 2013 Oct;14(11):1121-8. Epub 2013 Sep 2. link to original article contains verified protocol PubMed NCT00493649
2. RESPECT: Sawaki M, Taira N, Uemura Y, Saito T, Baba S, Kobayashi K, Kawashima H, Tsuneizumi M, Sagawa N, Bando H, Takahashi M, Yamaguchi M, Takashima T, Nakayama T, Kashiwaba M, Mizuno T, Yamamoto Y, Iwata H, Kawahara T, Ohashi Y, Mukai H; RESPECT study group. Randomized Controlled Trial of Trastuzumab With or Without Chemotherapy for HER2-Positive Early Breast Cancer in Older Patients. J Clin Oncol. 2020 Nov 10;38(32):3743-3752. Epub 2020 Sep 16. link to original article contains verified protocol PubMed NCT01104935

TCHP (Taxotere)

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TCHP: Taxotere (Docetaxel), Carboplatin, Herceptin (Trastuzumab), Pertuzumab

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
von Minckwitz et al. 2017 (APHINITY)	2011-2013	Phase III (E-RT-esc)	TCH	Superior IDFS1 IDFS72: 91% vs 88% (HR 0.76, 95% CI 0.64-0.91)

¹Reported efficacy is based on the 2021 update.

Preceding treatment

• Surgery

Chemotherapy

• Docetaxel (Taxotere) as follows:
  • Cycles 1 to 6: 75 mg/m² IV once on day 1
• Carboplatin (Paraplatin) as follows:
  • Cycles 1 to 6: AUC 6 (maximum dose: 900 mg) IV once on day 1

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV once on day 1
  • Cycle 2 onwards: 6 mg/kg IV once on day 1
• Pertuzumab (Perjeta) as follows:
  • Cycle 1: 840 mg IV once on day 1
  • Cycle 2 onwards: 420 mg IV once on day 1

21-day cycle for up to 18 cycles (1 year)

References

1. APHINITY: von Minckwitz G, Procter M, de Azambuja E, Zardavas D, Benyunes M, Viale G, Suter T, Arahmani A, Rouchet N, Clark E, Knott A, Lang I, Levy C, Yardley DA, Bines J, Gelber RD, Piccart M, Baselga J; APHINITY Steering Committee and Investigators. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med. 2017 Jul 13;377(2):122-131. Epub 2017 Jun 5. link to original article link to supplementary protocol contains verified protocol in supplementary protocol link to PMC article PubMed NCT01358877
   1. Update: Piccart M, Procter M, Fumagalli D, de Azambuja E, Clark E, Ewer MS, Restuccia E, Jerusalem G, Dent S, Reaby L, Bonnefoi H, Krop I, Liu TW, Pieńkowski T, Toi M, Wilcken N, Andersson M, Im YH, Tseng LM, Lueck HJ, Colleoni M, Monturus E, Sicoe M, Guillaume S, Bines J, Gelber RD, Viale G, Thomssen C; APHINITY Steering Committee and Investigators. Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer in the APHINITY Trial: 6 Years' Follow-Up. J Clin Oncol. 2021 May 1;39(13):1448-1457. Epub 2021 Feb 4. link to original article PubMed

TH (Taxol)

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TH: Taxol (Paclitaxel) & Herceptin (Trastuzumab)
PH: Paclitaxel & Herceptin (Trastuzumab)

Regimen variant #1, weekly paclitaxel, weekly trastuzumab

Study	Evidence
Tolaney et al. 2015 (APT)	Phase II

Preceding treatment

• Surgery

Chemotherapy

• Paclitaxel (Taxol) as follows:
  • Cycles 1 to 4: 80 mg/m² IV once per day on days 1, 8, 15

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8 & 15
  • Cycles 2 to 18: 2 mg/kg IV once per day on days 1, 8, 15

21-day cycle for 18 cycles (1 year)

Regimen variant #2, weekly paclitaxel, weekly then q3wk trastuzumab

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Tolaney et al. 2015 (APT)	2007-2010	Phase II
Piccart-Gebhart et al. 2015 (ALTTO)	2007-2011	Phase III (C)	1. TH (Taxol), then Lapatinib 2. THL (Taxol) 3. TL (Taxol)	Did not meet primary endpoint of DFS

Preceding treatment

• APT: Surgery
• ALTTO: Surgery, then anthracycline-based chemotherapy

Chemotherapy

• Paclitaxel (Taxol) as follows:
  • Cycles 1 to 4: 80 mg/m² IV once per day on days 1, 8, 15

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8 & 15
  • Cycles 2 to 4: 2 mg/kg IV once per day on days 1, 8, 15
  • Cycles 5 to 18: 6 mg/kg IV once on day 1

21-day cycle for 18 cycles (1 year)

Regimen variant #3, weekly paclitaxel, q3wk trastuzumab

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Sawaki et al. 2020 (RESPECT)	2009-2014	Randomized (C)	Trastuzumab x 12 mo	Inconclusive whether non-inferior DFS
von Minckwitz et al. 2017 (APHINITY)	2011-2013	Phase III (C)	THP (Taxol)	Inferior IDFS1

¹Reported efficacy for APHINITY is based on the 2021 update.

Preceding treatment

• RESPECT: Surgery
• APHINITY: Surgery, then AC x 4 or ddAC x 4 or ddEC x 4 or EC x 4 or FAC x 4 or FEC x 4

Chemotherapy

• Paclitaxel (Taxol) as follows:
  • Cycles 1 to 4: 80 mg/m² IV once per day on days 1, 8, 15

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV once on day 1
  • Cycles 2 to 18: 6 mg/kg IV once on day 1

21-day cycle for 18 cycles (1 year)

Regimen variant #4, q3wk paclitaxel, weekly trastuzumab

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Romond et al. 2005 (NSABP B-31)	2000-2005	Phase III (E-RT-esc)	1. weekly T (Taxol) 2. q3wk T (Taxol)	Superior OS	Might have superior DASI score
Romond et al. 2005 (NCCTG N9831)	2000-2005	Phase III (E-RT-esc)	See link	See link

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Preceding treatment

• AC x 4

Chemotherapy

• Paclitaxel (Taxol) as follows:
  • Cycles 1 to 4: 175 mg/m² IV over 3 hours once on day 1

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8 & 15
  • Cycles 2 to 18: 2 mg/kg IV once per day on days 1, 8, 15

21-day cycle for 18 cycles (1 year)

References

1. NSABP B-31/NCCTG N9831: Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE Jr, Davidson NE, Tan-Chiu E, Martino S, Paik S, Kaufman PA, Swain SM, Pisansky TM, Fehrenbacher L, Kutteh LA, Vogel VG, Visscher DW, Yothers G, Jenkins RB, Brown AM, Dakhil SR, Mamounas EP, Lingle WL, Klein PM, Ingle JN, Wolmark N. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005 Oct 20;353(16):1673-84. link to original article PubMed NCT00004067; NCT00005970
   1. Update: Perez EA, Romond EH, Suman VJ, Jeong JH, Davidson NE, Geyer CE Jr, Martino S, Mamounas EP, Kaufman PA, Wolmark N. Four-year follow-up of trastuzumab plus adjuvant chemotherapy for operable human epidermal growth factor receptor 2-positive breast cancer: joint analysis of data from NCCTG N9831 and NSABP B-31. J Clin Oncol. 2011 Sep 1;29(25):3366-73. Epub 2011 Jul 18. link to original article link to PMC article PubMed
   2. Update: Perez EA, Suman VJ, Davidson NE, Gralow JR, Kaufman PA, Visscher DW, Chen B, Ingle JN, Dakhil SR, Zujewski J, Moreno-Aspitia A, Pisansky TM, Jenkins RB. Sequential versus concurrent trastuzumab in adjuvant chemotherapy for breast cancer. J Clin Oncol. 2011 Dec 1;29(34):4491-7. Epub 2011 Oct 31. link to original article link to PMC article PubMed
   3. Update: Perez EA, Romond EH, Suman VJ, Jeong JH, Sledge G, Geyer CE Jr, Martino S, Rastogi P, Gralow J, Swain SM, Winer EP, Colon-Otero G, Davidson NE, Mamounas E, Zujewski JA, Wolmark N. Trastuzumab plus adjuvant chemotherapy for human epidermal growth factor receptor 2-positive breast cancer: planned joint analysis of overall survival from NSABP B-31 and NCCTG N9831. J Clin Oncol. 2014 Nov 20;32(33):3744-52. link to original article link to PMC article PubMed
   4. Update and HRQoL analysis: Ganz PA, Romond EH, Cecchini RS, Rastogi P, Geyer CE Jr, Swain SM, Jeong JH, Fehrenbacher L, Gross HM, Brufsky AM, Flynn PJ, Wahl TA, Seay TE, Wade JL 3rd, Biggs DD, Atkins JN, Polikoff J, Zapas JL, Mamounas EP, Wolmark N. Long-term follow-up of cardiac function and quality of life for patients in NSABP protocol B-31/NRG Oncology: a randomized trial comparing the safety and efficacy of doxorubicin and cyclophosphamide (AC) followed by paclitaxel with AC followed by paclitaxel and trastuzumab in patients with node-positive breast cancer with tumors overexpressing human epidermal growth factor receptor 2. J Clin Oncol. 2017 Dec 10;35(35):3942-3948. Epub 2017 Oct 26. link to original article link to PMC article PubMed
2. CALGB 40101: Shulman LN, Cirrincione CT, Berry DA, Becker HP, Perez EA, O'Regan R, Martino S, Atkins JN, Mayer E, Schneider CJ, Kimmick G, Norton L, Muss H, Winer EP, Hudis C. Six Cycles of Doxorubicin and Cyclophosphamide or Paclitaxel Are Not Superior to Four Cycles As Adjuvant Chemotherapy for Breast Cancer in Women With Zero to Three Positive Axillary Nodes: Cancer and Leukemia Group B 40101. J Clin Oncol. 2012 Nov 20;30(33):4071-6. Epub 2012 Jul 23. link to original article does not contain protocol link to study protocol PDF link to PMC article PubMed NCT00041119
   1. Update: Shulman LN, Berry DA, Cirrincione CT, Becker HP, Perez EA, O'Regan R, Martino S, Shapiro CL, Schneider CJ, Kimmick G, Burstein HJ, Norton L, Muss H, Hudis CA, Winer EP. Comparison of doxorubicin and cyclophosphamide versus single-agent paclitaxel as adjuvant therapy for breast cancer in women with 0 to 3 positive axillary nodes: CALGB 40101 (Alliance). J Clin Oncol. 2014 Aug 1;32(22):2311-7. link to PMC article PubMed
3. APT: Tolaney SM, Barry WT, Dang CT, Yardley DA, Moy B, Marcom PK, Albain KS, Rugo HS, Ellis M, Shapira I, Wolff AC, Carey LA, Overmoyer BA, Partridge AH, Guo H, Hudis CA, Krop IE, Burstein HJ, Winer EP. Adjuvant paclitaxel and trastuzumab for node-negative, HER2-positive breast cancer. N Engl J Med. 2015 Jan 8;372(2):134-41. Erratum in: N Engl J Med. 2015 Nov 12;373(20):1989. link to original article link to PMC article PubMed NCT00542451
   1. Update:Tolaney SM, Guo H, Pernas S, et al. Seven-Year Follow-Up Analysis of Adjuvant Paclitaxel and Trastuzumab Trial for Node-Negative, Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer. J Clin Oncol. 2019;37(22):1868-1875 link to original article link to PMC article PubMed NCT00542451
4. ALTTO: Piccart-Gebhart M, Holmes E, Baselga J, de Azambuja E, Dueck AC, Viale G, Zujewski JA, Goldhirsch A, Armour A, Pritchard KI, McCullough AE, Dolci S, McFadden E, Holmes AP, Tonghua L, Eidtmann H, Dinh P, Di Cosimo S, Harbeck N, Tjulandin S, Im YH, Huang CS, Diéras V, Hillman DW, Wolff AC, Jackisch C, Lang I, Untch M, Smith I, Boyle F, Xu B, Gomez H, Suter T, Gelber RD, Perez EA. Adjuvant lapatinib and trastuzumab for early human epidermal growth factor receptor 2-positive breast cancer: results from the randomized phase III Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization trial. J Clin Oncol. 2016 Apr 1;34(10):1034-42. Epub 2015 Nov 23. link to original article link to protocol contains verified protocol in supplement link to PMC article PubMed NCT00490139
5. APHINITY: von Minckwitz G, Procter M, de Azambuja E, Zardavas D, Benyunes M, Viale G, Suter T, Arahmani A, Rouchet N, Clark E, Knott A, Lang I, Levy C, Yardley DA, Bines J, Gelber RD, Piccart M, Baselga J; APHINITY Steering Committee and Investigators. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med. 2017 Jul 13;377(2):122-131. Epub 2017 Jun 5. link to original article link to supplementary protocol contains verified protocol in supplementary protocol link to PMC article PubMed NCT01358877
   1. Update: Piccart M, Procter M, Fumagalli D, de Azambuja E, Clark E, Ewer MS, Restuccia E, Jerusalem G, Dent S, Reaby L, Bonnefoi H, Krop I, Liu TW, Pieńkowski T, Toi M, Wilcken N, Andersson M, Im YH, Tseng LM, Lueck HJ, Colleoni M, Monturus E, Sicoe M, Guillaume S, Bines J, Gelber RD, Viale G, Thomssen C; APHINITY Steering Committee and Investigators. Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer in the APHINITY Trial: 6 Years' Follow-Up. J Clin Oncol. 2021 May 1;39(13):1448-1457. Epub 2021 Feb 4. link to original article PubMed
6. RESPECT: Sawaki M, Taira N, Uemura Y, Saito T, Baba S, Kobayashi K, Kawashima H, Tsuneizumi M, Sagawa N, Bando H, Takahashi M, Yamaguchi M, Takashima T, Nakayama T, Kashiwaba M, Mizuno T, Yamamoto Y, Iwata H, Kawahara T, Ohashi Y, Mukai H; RESPECT study group. Randomized Controlled Trial of Trastuzumab With or Without Chemotherapy for HER2-Positive Early Breast Cancer in Older Patients. J Clin Oncol. 2020 Nov 10;38(32):3743-3752. Epub 2020 Sep 16. link to original article contains verified protocol PubMed NCT01104935

ddTH (Taxol)

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ddTH: dose-dense Taxol (Paclitaxel) & Herceptin (Trastuzumab)

Regimen

Study	Evidence
Dang et al. 2008	Phase II

Preceding treatment

• ddAC x 4

Chemotherapy

• Paclitaxel (Taxol) 175 mg/m² IV over 3 hours once on day 1

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once on day 8
  • Cycles 2 to 4: 2 mg/kg IV once per day on days 1 & 8

Supportive medications

• Pegfilgrastim (Neulasta) 6 mg SC once on day 2

14-day cycle for 4 cycles

Subsequent treatment

• Trastuzumab for a total of 52 weeks

References

1. Dang C, Fornier M, Sugarman S, Troso-Sandoval T, Lake D, D'Andrea G, Seidman A, Sklarin N, Dickler M, Currie V, Gilewski T, Moynahan ME, Drullinsky P, Robson M, Wasserheit-Leiblich C, Mills N, Steingart R, Panageas K, Norton L, Hudis C. The safety of dose-dense doxorubicin and cyclophosphamide followed by paclitaxel with trastuzumab in HER-2/neu overexpressed/amplified breast cancer. J Clin Oncol. 2008 Mar 10;26(8):1216-22. link to original article contains verified protocol PubMed

TH (Taxotere)

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TH: Taxotere (Docetaxel) & Herceptin (Trastuzumab)

Regimen variant #1, 75 x 4, q3wk trastuzumab

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Sawaki et al. 2020 (RESPECT)	2009-2014	Randomized (C)	Trastuzumab x 12 mo	Inconclusive whether non-inferior DFS
von Minckwitz et al. 2017 (APHINITY)	2011-2013	Phase III (C)	THP (Taxotere)	Inferior IDFS1

¹Reported efficacy for APHINITY is based on the 2021 update.

Preceding treatment

• RESPECT: Surgery
• APHINITY: Surgery, then AC x 4 or ddAC x 4 or ddEC x 4 or EC x 4 or FAC x 4 or FEC x 4

Chemotherapy

• Docetaxel (Taxotere) 75 mg/m² IV once on day 1

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV once on day 1
  • Cycles 2 to 4: 6 mg/kg IV once on day 1

21-day cycle for 4 cycles

Subsequent treatment

• Trastuzumab maintenance (q3wk) for a total of 1 year

Regimen variant #2, 75 x 4, weekly trastuzumab

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Piccart-Gebhart et al. 2015 (ALTTO)	2007-2011	Phase III (C)	1. TH (Taxotere), then Lapatinib 2. THL (Taxotere) 3. TL (Taxotere)	Did not meet primary endpoint of DFS

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Preceding treatment

• Surgery, then anthracycline-based chemotherapy

Chemotherapy

• Docetaxel (Taxotere) 75 mg/m² IV once on day 1

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8 & 15
  • Cycles 2 to 4: 2 mg/kg IV once per day on days 1, 8, 15

21-day cycle for 4 cycles

Subsequent treatment

• Trastuzumab maintenance (q3wk) for a total of 1 year

Regimen variant #3, 75-100 x 3, q3wk trastuzumab

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
von Minckwitz et al. 2017 (APHINITY)	2011-2013	Phase III (C)	THP (Taxotere)	Inferior IDFS1

¹Reported efficacy is based on the 2021 update.
Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Preceding treatment

• Surgery, then AC x 4 or ddAC x 4 or ddEC x 4 or EC x 4 or FAC x 4 or FEC x 4

Chemotherapy

• Docetaxel (Taxotere) as follows:
  • Cycle 1: 75 mg/m² IV once on day 1
  • Cycles 2 & 3: 100 mg/m² IV once on day 1

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV once on day 1
  • Cycle 2 onwards: 6 mg/kg IV once on day 1

21-day cycle for 3 cycles

Subsequent treatment

• Trastuzumab maintenance (q3wk) for a total of 1 year

Regimen variant #4, 80 x 3, q3wk trastuzumab

Study	Evidence
Joensuu et al. 2018 (SOLD)	Non-randomized portion of RCT

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Preceding treatment

• Surgery

Chemotherapy

• Docetaxel (Taxotere) 80 mg/m² IV once on day 1

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV once on day 1
  • Cycles 2 & 3: 6 mg/kg IV once on day 1

21-day cycle for 3 cycles

Subsequent treatment

• FEC x 3, then trastuzumab maintenance for a total of 1 year versus no further treatment

Regimen variant #5, 80 x 3, weekly trastuzumab

Study	Evidence
Joensuu et al. 2018 (SOLD)	Non-randomized portion of RCT

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Preceding treatment

• Surgery

Chemotherapy

• Docetaxel (Taxotere) 80 mg/m² IV once on day 1

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8 & 15
  • Cycles 2 & 3: 2 mg/kg IV once per day on days 1, 8, 15

21-day cycle for 3 cycles

Subsequent treatment

• FEC x 3, then trastuzumab maintenance for a total of 1 year versus no further treatment

Regimen variant #6, 100 x 3, q3wk trastuzumab

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Joensuu et al. 2018 (SOLD)	2008-2014	Non-randomized portion of RCT
von Minckwitz et al. 2017 (APHINITY)	2011-2013	Phase III (C)	THP (Taxotere)	Inferior IDFS1

¹Reported efficacy for APHINITY is based on the 2021 update.
Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Preceding treatment

• Surgery, then AC x 4 or ddAC x 4 or ddEC x 4 or EC x 4 or FAC x 4 or FEC x 4

Chemotherapy

• Docetaxel (Taxotere) 100 mg/m² IV once on day 1

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV once on day 1
  • Cycles 2 & 3: 6 mg/kg IV once on day 1

21-day cycle for 3 cycles

Subsequent treatment

• APHINITY: Trastuzumab maintenance for a total of 1 year
• SOLD: FEC x 3, then trastuzumab maintenance for a total of 1 year versus no further treatment

Regimen variant #7, 100 x 3, weekly trastuzumab

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Joensuu et al. 2006 (FinHer)	2000-2003	Phase III (E-esc)	1. T 2. V	Did not meet primary endpoint of RFS
			3. VH	Not reported
Joensuu et al. 2018 (SOLD)	2008-2014	Non-randomized portion of RCT

Preceding treatment

• Surgery

Chemotherapy

• Docetaxel (Taxotere) 100 mg/m² IV over 60 minutes once on day 1

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8 & 15
  • Cycles 2 & 3: 2 mg/kg IV once per day on days 1, 8, 15

21-day cycle for 3 cycles

Subsequent treatment

• FinHer: FEC
• SOLD: FEC x 3, then trastuzumab maintenance for a total of 1 year versus no further treatment

Regimen variant #8, 100 x 4, weekly trastuzumab

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Slamon et al. 2011 (BCIRG 006)	2001-2004	Phase III (E-RT-esc)	See link	See link

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Preceding treatment

• Surgery, then AC x 4

Chemotherapy

• Docetaxel (Taxotere) 100 mg/m² IV once on day 1

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8 & 15
  • Cycles 2 to 4: 2 mg/kg IV once per day on days 1, 8, 15

21-day cycle for 4 cycles

Subsequent treatment

• Trastuzumab maintenance (q3wk) for a total of 1 year

References

1. FinHer: Joensuu H, Kellokumpu-Lehtinen PL, Bono P, Alanko T, Kataja V, Asola R, Utriainen T, Kokko R, Hemminki A, Tarkkanen M, Turpeenniemi-Hujanen T, Jyrkkiö S, Flander M, Helle L, Ingalsuo S, Johansson K, Jääskeläinen AS, Pajunen M, Rauhala M, Kaleva-Kerola J, Salminen T, Leinonen M, Elomaa I, Isola J; FinHer Study Investigators. Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N Engl J Med. 2006 Feb 23;354(8):809-20. link to original article PubMed ISRCTN76560285
   1. Update: Joensuu H, Bono P, Kataja V, Alanko T, Kokko R, Asola R, Utriainen T, Turpeenniemi-Hujanen T, Jyrkkiö S, Möykkynen K, Helle L, Ingalsuo S, Pajunen M, Huusko M, Salminen T, Auvinen P, Leinonen H, Leinonen M, Isola J, Kellokumpu-Lehtinen PL. Fluorouracil, epirubicin, and cyclophosphamide with either docetaxel or vinorelbine, with or without trastuzumab, as adjuvant treatments of breast cancer: final results of the FinHer trial. J Clin Oncol. 2009 Dec 1;27(34):5685-92. link to original article PubMed
2. BCIRG 006: Slamon D, Eiermann W, Robert N, Pienkowski T, Martin M, Press M, Mackey J, Glaspy J, Chan A, Pawlicki M, Pinter T, Valero V, Liu MC, Sauter G, von Minckwitz G, Visco F, Bee V, Buyse M, Bendahmane B, Tabah-Fisch I, Lindsay MA, Riva A, Crown J; Breast Cancer International Research Group. Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med. 2011 Oct 6;365(14):1273-83. link to original article link to PMC article contains verified protocol PubMed NCT00021255
3. ALTTO: Piccart-Gebhart M, Holmes E, Baselga J, de Azambuja E, Dueck AC, Viale G, Zujewski JA, Goldhirsch A, Armour A, Pritchard KI, McCullough AE, Dolci S, McFadden E, Holmes AP, Tonghua L, Eidtmann H, Dinh P, Di Cosimo S, Harbeck N, Tjulandin S, Im YH, Huang CS, Diéras V, Hillman DW, Wolff AC, Jackisch C, Lang I, Untch M, Smith I, Boyle F, Xu B, Gomez H, Suter T, Gelber RD, Perez EA. Adjuvant lapatinib and trastuzumab for early human epidermal growth factor receptor 2-positive breast cancer: results from the randomized phase III Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization trial. J Clin Oncol. 2016 Apr 1;34(10):1034-42. Epub 2015 Nov 23. link to original article link to protocol contains verified protocol in supplement link to PMC article PubMed NCT00490139
4. APHINITY: von Minckwitz G, Procter M, de Azambuja E, Zardavas D, Benyunes M, Viale G, Suter T, Arahmani A, Rouchet N, Clark E, Knott A, Lang I, Levy C, Yardley DA, Bines J, Gelber RD, Piccart M, Baselga J; APHINITY Steering Committee and Investigators. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med. 2017 Jul 13;377(2):122-131. Epub 2017 Jun 5. link to original article link to supplementary protocol contains verified protocol in supplementary protocol link to PMC article PubMed NCT01358877
   1. Update: Piccart M, Procter M, Fumagalli D, de Azambuja E, Clark E, Ewer MS, Restuccia E, Jerusalem G, Dent S, Reaby L, Bonnefoi H, Krop I, Liu TW, Pieńkowski T, Toi M, Wilcken N, Andersson M, Im YH, Tseng LM, Lueck HJ, Colleoni M, Monturus E, Sicoe M, Guillaume S, Bines J, Gelber RD, Viale G, Thomssen C; APHINITY Steering Committee and Investigators. Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer in the APHINITY Trial: 6 Years' Follow-Up. J Clin Oncol. 2021 May 1;39(13):1448-1457. Epub 2021 Feb 4. link to original article PubMed
5. SOLD: Joensuu H, Fraser J, Wildiers H, Huovinen R, Auvinen P, Utriainen M, Nyandoto P, Villman KK, Halonen P, Granstam-Björneklett H, Lundgren L, Sailas L, Turpeenniemi-Hujanen T, Tanner M, Yachnin J, Ritchie D, Johansson O, Huttunen T, Neven P, Canney P, Harvey VJ, Kellokumpu-Lehtinen PL, Lindman H. Effect of adjuvant trastuzumab for a duration of 9 weeks vs 1 year with concomitant chemotherapy for early human epidermal growth factor receptor 2-positive breast cancer: the SOLD randomized clinical trial. JAMA Oncol. 2018 Sep 1;4(9):1199-1206. link to original article contains verified protocol PubMed NCT00593697
6. RESPECT: Sawaki M, Taira N, Uemura Y, Saito T, Baba S, Kobayashi K, Kawashima H, Tsuneizumi M, Sagawa N, Bando H, Takahashi M, Yamaguchi M, Takashima T, Nakayama T, Kashiwaba M, Mizuno T, Yamamoto Y, Iwata H, Kawahara T, Ohashi Y, Mukai H; RESPECT study group. Randomized Controlled Trial of Trastuzumab With or Without Chemotherapy for HER2-Positive Early Breast Cancer in Older Patients. J Clin Oncol. 2020 Nov 10;38(32):3743-3752. Epub 2020 Sep 16. link to original article contains verified protocol PubMed NCT01104935

ddTH (Taxotere)

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ddTH: dose-dense Taxotere (Docetaxel) & Herceptin (Trastuzumab)

Regimen

Study	Years of enrollment	Evidence
Mavroudis et al. 2015 (HORG CT/04.23)	2004-2012	Non-randomized portion of RCT

Preceding treatment

• ddFEC x 4

Chemotherapy

• Docetaxel (Taxotere) 75 mg/m² IV over 60 minutes once on day 1

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 6 mg/kg IV once on day 1
  • Cycles 2 to 4: 4 mg/kg IV once on day 1

Supportive medications

• Filgrastim (Neupogen) 300 or 480 mcg SC once per day on days 3 to 10

14-day cycle for 4 cycles

Subsequent treatment

• Trastuzumab x a total of 26 weeks versus Trastuzumab x a total of 52 weeks

References

1. HORG CT/04.23: Mavroudis D, Saloustros E, Malamos N, Kakolyris S, Boukovinas I, Papakotoulas P, Kentepozidis N, Ziras N, Georgoulias V; Hellenic Oncology Research Group. Six versus 12 months of adjuvant trastuzumab in combination with dose-dense chemotherapy for women with HER2-positive breast cancer: a multicenter randomized study by the Hellenic Oncology Research Group (HORG). Ann Oncol. 2015 Jul;26(7):1333-40. Epub 2015 May 1. link to original article contains verified protocol PubMed

TH (Taxotere/SC)

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TH: Taxotere (Docetaxel) & Herceptin Hylecta (Trastuzumab and hyaluronidase)

Regimen variant #1, 80 x 3, q3wk trastuzumab

Study	Evidence
Joensuu et al. 2018 (SOLD)	Non-randomized portion of RCT

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Preceding treatment

• Surgery

Chemotherapy

• Docetaxel (Taxotere) 80 mg/m² IV once on day 1

Targeted therapy

• Trastuzumab and hyaluronidase (Herceptin Hylecta) 600 mg/10,000 units SC once on day 1

21-day cycle for 3 cycles

Subsequent treatment

• FEC x 3, then trastuzumab maintenance for a total of 1 year versus no further treatment

Regimen variant #2, 100 x 3, q3wk trastuzumab

Study	Evidence
Joensuu et al. 2018 (SOLD)	Non-randomized portion of RCT

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Preceding treatment

• Surgery

Chemotherapy

• Docetaxel (Taxotere) 100 mg/m² IV once on day 1

Targeted therapy

• Trastuzumab and hyaluronidase (Herceptin Hylecta) 600 mg/10,000 units SC once on day 1

21-day cycle for 3 cycles

Subsequent treatment

• FEC x 3, then trastuzumab maintenance for a total of 1 year versus no further treatment

References

1. SOLD: Joensuu H, Fraser J, Wildiers H, Huovinen R, Auvinen P, Utriainen M, Nyandoto P, Villman KK, Halonen P, Granstam-Björneklett H, Lundgren L, Sailas L, Turpeenniemi-Hujanen T, Tanner M, Yachnin J, Ritchie D, Johansson O, Huttunen T, Neven P, Canney P, Harvey VJ, Kellokumpu-Lehtinen PL, Lindman H. Effect of adjuvant trastuzumab for a duration of 9 weeks vs 1 year with concomitant chemotherapy for early human epidermal growth factor receptor 2-positive breast cancer: the SOLD randomized clinical trial. JAMA Oncol. 2018 Sep 1;4(9):1199-1206. link to original article contains verified protocol PubMed NCT00593697

THP (Taxol)

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THP: Taxol (Paclitaxel), Herceptin (Trastuzumab), Pertuzumab

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
von Minckwitz et al. 2017 (APHINITY)	2011-2013	Phase III (E-RT-esc)	TH (Taxol)	Superior IDFS1 IDFS72: 91% vs 88% (HR 0.76, 95% CI 0.64-0.91)

¹Reported efficacy is based on the 2021 update.
Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Preceding treatment

• Surgery, then AC x 4 or ddAC x 4 or ddEC x 4 or EC x 4 or FAC x 4 or FEC x 4

Chemotherapy

• Paclitaxel (Taxol) as follows:
  • Cycles 1 to 4: 80 mg/m² IV once per day on days 1, 8, 15

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV once on day 1
  • Cycles 2 to 18: 6 mg/kg IV once on day 1
• Pertuzumab (Perjeta) as follows:
  • Cycle 1: 840 mg IV once on day 1
  • Cycles 2 to 18: 420 mg IV once on day 1

21-day cycle for up to 18 cycles (1 year)

References

1. APHINITY: von Minckwitz G, Procter M, de Azambuja E, Zardavas D, Benyunes M, Viale G, Suter T, Arahmani A, Rouchet N, Clark E, Knott A, Lang I, Levy C, Yardley DA, Bines J, Gelber RD, Piccart M, Baselga J; APHINITY Steering Committee and Investigators. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med. 2017 Jul 13;377(2):122-131. Epub 2017 Jun 5. link to original article link to supplementary protocol contains verified protocol in supplementary protocol link to PMC article PubMed NCT01358877
   1. Update: Piccart M, Procter M, Fumagalli D, de Azambuja E, Clark E, Ewer MS, Restuccia E, Jerusalem G, Dent S, Reaby L, Bonnefoi H, Krop I, Liu TW, Pieńkowski T, Toi M, Wilcken N, Andersson M, Im YH, Tseng LM, Lueck HJ, Colleoni M, Monturus E, Sicoe M, Guillaume S, Bines J, Gelber RD, Viale G, Thomssen C; APHINITY Steering Committee and Investigators. Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer in the APHINITY Trial: 6 Years' Follow-Up. J Clin Oncol. 2021 May 1;39(13):1448-1457. Epub 2021 Feb 4. link to original article PubMed
2. KAITLIN: NCT01966471

THP (Taxotere)

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THP: Taxotere (Docetaxel), Herceptin (Trastuzumab), Pertuzumab

Regimen variant #1

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
von Minckwitz et al. 2017 (APHINITY)	2011-2013	Phase III (E-RT-esc)	TH (Taxotere)	Superior IDFS1 IDFS72: 91% vs 88% (HR 0.76, 95% CI 0.64-0.91)

¹Reported efficacy is based on the 2021 update.
Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Preceding treatment

• Surgery, then AC x 4 or ddAC x 4 or ddEC x 4 or EC x 4 or FAC x 4 or FEC x 4

Chemotherapy

• Docetaxel (Taxotere) as follows:
  • Cycles 1 to 3: 100 mg/m² IV once on day 1

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV once on day 1
  • Cycle 2 onwards: 6 mg/kg IV once on day 1
• Pertuzumab (Perjeta) as follows:
  • Cycle 1: 840 mg IV once on day 1
  • Cycle 2 onwards: 420 mg IV once on day 1

21-day cycle for up to 18 cycles (1 year)

Regimen variant #2

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
von Minckwitz et al. 2017 (APHINITY)	2011-2013	Phase III (E-RT-esc)	TH (Taxotere)	Superior IDFS1 IDFS72: 91% vs 88% (HR 0.76, 95% CI 0.64-0.91)

¹Reported efficacy is based on the 2021 update.
Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Preceding treatment

• Surgery, then AC x 4 or ddAC x 4 or ddEC x 4 or EC x 4 or FAC x 4 or FEC x 4

Chemotherapy

• Docetaxel (Taxotere) as follows:
  • Cycle 1: 75 mg/m² IV once on day 1
  • Cycles 2 & 3: 100 mg/m² IV once on day 1

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV once on day 1
  • Cycle 2 onwards: 6 mg/kg IV once on day 1
• Pertuzumab (Perjeta) as follows:
  • Cycle 1: 840 mg IV once on day 1
  • Cycle 2 onwards: 420 mg IV once on day 1

21-day cycle for up to 18 cycles (1 year)

Regimen variant #3

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
von Minckwitz et al. 2017 (APHINITY)	2011-2013	Phase III (E-RT-esc)	TH (Taxotere)	Superior IDFS1 IDFS72: 91% vs 88% (HR 0.76, 95% CI 0.64-0.91)

¹Reported efficacy is based on the 2021 update.
Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Preceding treatment

• Surgery, then AC x 4 or ddAC x 4 or ddEC x 4 or EC x 4 or FAC x 4 or FEC x 4

Chemotherapy

• Docetaxel (Taxotere) as follows:
  • Cycles 1 to 4: 75 mg/m² IV once on day 1

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV once on day 1
  • Cycle 2 onwards: 6 mg/kg IV once on day 1
• Pertuzumab (Perjeta) as follows:
  • Cycle 1: 840 mg IV once on day 1
  • Cycle 2 onwards: 420 mg IV once on day 1

21-day cycle for up to 18 cycles (1 year)

References

1. APHINITY: von Minckwitz G, Procter M, de Azambuja E, Zardavas D, Benyunes M, Viale G, Suter T, Arahmani A, Rouchet N, Clark E, Knott A, Lang I, Levy C, Yardley DA, Bines J, Gelber RD, Piccart M, Baselga J; APHINITY Steering Committee and Investigators. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med. 2017 Jul 13;377(2):122-131. Epub 2017 Jun 5. link to original article link to supplementary protocol contains verified protocol in supplementary protocol link to PMC article PubMed NCT01358877
   1. Update: Piccart M, Procter M, Fumagalli D, de Azambuja E, Clark E, Ewer MS, Restuccia E, Jerusalem G, Dent S, Reaby L, Bonnefoi H, Krop I, Liu TW, Pieńkowski T, Toi M, Wilcken N, Andersson M, Im YH, Tseng LM, Lueck HJ, Colleoni M, Monturus E, Sicoe M, Guillaume S, Bines J, Gelber RD, Viale G, Thomssen C; APHINITY Steering Committee and Investigators. Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer in the APHINITY Trial: 6 Years' Follow-Up. J Clin Oncol. 2021 May 1;39(13):1448-1457. Epub 2021 Feb 4. link to original article PubMed
2. KAITLIN: NCT01966471

Trastuzumab monotherapy

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Regimen variant #1, 6 mo course

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Earl et al. 2019 (PERSEPHONE)	2007-2015	Phase III (E-de-esc)	Trastuzumab x 12 mo	Non-inferior DFS

Preceding treatment

• Not explicitly specified (pragmatic trial)

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV over 90 minutes once on day 1
  • Cycle 2 onwards: 6 mg/kg IV over 90 minutes once on day 1

21-day cycle for 9 cycles (6 months)

Regimen variant #2, 30-week course, q3wk

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Pivot et al. 2018 (SB3-G31-BC)	2014-2015	Phase III (C)	See link	See link

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Preceding treatment

• Neoadjuvant TH (Taxotere) x 4, then FEC & H x 4, then surgery

Targeted therapy

• Trastuzumab (Herceptin) 6 mg/kg IV over 30 minutes once on day 1

21-day cycle for 10 cycles (30-week course)

Regimen variant #3, 34-week course, q3wk

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Baselga et al. 2012 (NeoALTTO)	2008-2010	Phase III (C)	See link	See link

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Preceding treatment

• Surgery, then adjuvant FEC x 3

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV over 90 minutes once on day 1
  • Cycles 2 to 12: 6 mg/kg IV over 30 minutes once on day 1

21-day cycle for 12 cycles (34-week course)

Regimen variant #4, 42-week course, q3wk

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
von Minckwitz et al. 2018 (KATHERINE)	2013-2015	Phase III (C)	T-DM1	Inferior IDFS

Note: the loading dose in cycle 1 was only used if it had been more than 6 weeks since any preceding dose of trastuzumab.

Preceding treatment

• Surgery, with residual invasive disease

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV once on day 1
  • Cycles 2 to 14: 6 mg/kg IV once on day 1

21-day cycle for 14 cycles

Regimen variant #5, 1-year course, weekly

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Van Pelt et al. 2003	2000-2002	Phase II
Romond et al. 2005 (NCCTG N9831)	2000-2005	Phase III (E-RT-esc)	See link	See link

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment. Van Pelt et al. 2003 does not describe a loading dose (in the abstract).

Preceding treatment

• Van Pelt et al. 2003: AC x 4
• NCCTG N9831: weekly T x 12

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8, 15, 22
  • Cycles 2 to 13: 2 mg/kg IV once per day on days 1, 8, 15, 22

28-day cycle for 13 cycles (1 year)

Regimen variant #6, 1-year total course, q3wk

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Piccart-Gebhart et al. 2005 (HERA)	2001-2005	Phase III (E-RT-esc)	1. No trastuzumab after (neo-)adjuvant chemotherapy	Superior OS
			2. Trastuzumab x 2 y	Did not meet primary endpoint of DFS
Gianni et al. 2010 (NOAH)	2002-2005	Phase III (E-esc)	See link	See link
Pivot et al. 2013 (PHARE)	2006-2010	Phase III (C)	Trastuzumab x 6 mo	Inconclusive whether non-inferior DFS
Piccart-Gebhart et al. 2015 (ALTTO)	2007-2011	Phase III (C)	1. Lapatinib 2. Trastuzumab, then Lapatinib 3. Lapatinib & Trastuzumab	Did not meet primary endpoint of DFS
Earl et al. 2019 (PERSEPHONE)	2007-2015	Phase III (C)	Trastuzumab x 6 mo	Non-inferior DFS
Joensuu et al. 2018 (SOLD)	2008-2014	Phase III (C)	No further treatment	Inconclusive whether non-inferior DFS
Conte et al. 2018 (Short-HER)	NR	Phase III (C)	Trastuzumab x 9 wks	Inconclusive whether non-inferior DFS
Sawaki et al. 2020 (RESPECT)	2009-2014	Randomized (E-de-esc)	1. AC, then H 2. CMF & H 3. CMF, then H EC, then H 4. FEC, then H 5. T (Taxol), then H 6. T (Taxotere), then H 7. TC, then H 8. TCH 9. TH (Taxol) 10. TH (Taxotere)	Inconclusive whether non-inferior DFS

Note: for patients already receiving trastuzumab prior to transitioning to monotherapy, re-loading is not necessary.

Preceding treatment

• HERA: Participants had already received at least four courses of an approved (neo-)adjuvant chemotherapy regimen and surgery (see individual trials)
• PERSEPHONE: Not explicitly specified (pragmatic trial)
• SOLD: Surgery, then TH (Taxotere) x 3, then FEC x 3
• Short-HER: Surgery, then AC or EC x 4, then TH (Taxol) or TH (Taxotere)
• RESPECT: Surgery

Targeted therapy

• Trastuzumab (Herceptin) as follows (see note):
  • Cycle 1: 8 mg/kg IV over 90 minutes once on day 1
  • Cycle 2 onwards: 6 mg/kg IV over 90 minutes once on day 1

21-day cycle for 18 cycles (1 year)

Regimen variant #7, 2-year course

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Piccart-Gebhart et al. 2005 (HERA)	2001-2005	Phase III (E-RT-esc)	1. No trastuzumab after (neo-)adjuvant chemotherapy	Not reported
			2. Trastuzumab x 1 y	Did not meet primary endpoint of DFS

Preceding treatment

• HERA: Participants had already received at least four courses of an approved (neo-)adjuvant chemotherapy regimen and surgery

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV over 90 minutes once on day 1
  • Cycle 2 onwards: 6 mg/kg IV over 90 minutes once on day 1

21-day cycle for 35 cycles (2 years)

References

1. Van Pelt AE, Mohsin S, Elledge RM, Hilsenbeck SG, Gutierrez MC, Lucci A Jr, Kalidas M, Granchi T, Scott BG, Allred DC, Chang JC. Neoadjuvant trastuzumab and docetaxel in breast cancer: preliminary results. Clin Breast Cancer. 2003 Dec;4(5):348-53. link to original article PubMed
2. HERA: Piccart-Gebhart MJ, Procter M, Leyland-Jones B, Goldhirsch A, Untch M, Smith I, Gianni L, Baselga J, Bell R, Jackisch C, Cameron D, Dowsett M, Barrios CH, Steger G, Huang CS, Andersson M, Inbar M, Lichinitser M, Láng I, Nitz U, Iwata H, Thomssen C, Lohrisch C, Suter TM, Rüschoff J, Suto T, Greatorex V, Ward C, Straehle C, McFadden E, Dolci MS, Gelber RD; Herceptin Adjuvant (HERA) Trial Study Team. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med. 2005 Oct 20;353(16):1659-72. link to original article contains verified protocol link to data supplement] PubMed NCT00045032
   1. Update: Smith I, Procter M, Gelber RD, Guillaume S, Feyereislova A, Dowsett M, Goldhirsch A, Untch M, Mariani G, Baselga J, Kaufmann M, Cameron D, Bell R, Bergh J, Coleman R, Wardley A, Harbeck N, Lopez RI, Mallmann P, Gelmon K, Wilcken N, Wist E, Sánchez Rovira P, Piccart-Gebhart MJ; HERA study team. 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial. Lancet. 2007 Jan 6;369(9555):29-36. link to original article contains verified protocol PubMed
   2. Update: Gianni L, Dafni U, Gelber RD, Azambuja E, Muehlbauer S, Goldhirsch A, Untch M, Smith I, Baselga J, Jackisch C, Cameron D, Mano M, Pedrini JL, Veronesi A, Mendiola C, Pluzanska A, Semiglazov V, Vrdoljak E, Eckart MJ, Shen Z, Skiadopoulos G, Procter M, Pritchard KI, Piccart-Gebhart MJ, Bell R; Herceptin Adjuvant (HERA) Trial Study Team. Treatment with trastuzumab for 1 year after adjuvant chemotherapy in patients with HER2-positive early breast cancer: a 4-year follow-up of a randomised controlled trial. Lancet Oncol. 2011 Mar;12(3):236-44. Epub 2011 Feb 25. link to original article contains verified protocol PubMed
   3. Update: Goldhirsch A, Gelber RD, Piccart-Gebhart MJ, de Azambuja E, Procter M, Suter TM, Jackisch C, Cameron D, Weber HA, Heinzmann D, Dal Lago L, McFadden E, Dowsett M, Untch M, Gianni L, Bell R, Köhne CH, Vindevoghel A, Andersson M, Brunt AM, Otero-Reyes D, Song S, Smith I, Leyland-Jones B, Baselga J; Herceptin Adjuvant (HERA) Trial Study Team. 2 years versus 1 year of adjuvant trastuzumab for HER2-positive breast cancer (HERA): an open-label, randomised controlled trial. Lancet. 2013 Sep 21;382(9897):1021-8. link to original article PubMed
   4. Update: Cameron D, Piccart-Gebhart MJ, Gelber RD, Procter M, Goldhirsch A, de Azambuja E, Castro G Jr, Untch M, Smith I, Gianni L, Baselga J, Al-Sakaff N, Lauer S, McFadden E, Leyland-Jones B, Bell R, Dowsett M, Jackisch C; Herceptin Adjuvant (HERA) Trial Study Team. 11 years' follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive early breast cancer: final analysis of the HERceptin Adjuvant (HERA) trial. Lancet. 2017 Mar 25;389(10075):1195-1205. Epub 2017 Feb 17. link to original article link to PMC article PubMed
3. NCCTG N9831: Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE Jr, Davidson NE, Tan-Chiu E, Martino S, Paik S, Kaufman PA, Swain SM, Pisansky TM, Fehrenbacher L, Kutteh LA, Vogel VG, Visscher DW, Yothers G, Jenkins RB, Brown AM, Dakhil SR, Mamounas EP, Lingle WL, Klein PM, Ingle JN, Wolmark N. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005 Oct 20;353(16):1673-84. link to original article PubMed NCT00005970
   1. Update: Perez EA, Romond EH, Suman VJ, Jeong JH, Davidson NE, Geyer CE Jr, Martino S, Mamounas EP, Kaufman PA, Wolmark N. Four-year follow-up of trastuzumab plus adjuvant chemotherapy for operable human epidermal growth factor receptor 2-positive breast cancer: joint analysis of data from NCCTG N9831 and NSABP B-31. J Clin Oncol. 2011 Sep 1;29(25):3366-73. Epub 2011 Jul 18. link to original article link to PMC article PubMed
   2. Update: Perez EA, Suman VJ, Davidson NE, Gralow JR, Kaufman PA, Visscher DW, Chen B, Ingle JN, Dakhil SR, Zujewski J, Moreno-Aspitia A, Pisansky TM, Jenkins RB. Sequential versus concurrent trastuzumab in adjuvant chemotherapy for breast cancer. J Clin Oncol. 2011 Dec 1;29(34):4491-7. Epub 2011 Oct 31. link to original article link to PMC article PubMed
   3. Update: Perez EA, Romond EH, Suman VJ, Jeong JH, Sledge G, Geyer CE Jr, Martino S, Rastogi P, Gralow J, Swain SM, Winer EP, Colon-Otero G, Davidson NE, Mamounas E, Zujewski JA, Wolmark N. Trastuzumab plus adjuvant chemotherapy for human epidermal growth factor receptor 2-positive breast cancer: planned joint analysis of overall survival from NSABP B-31 and NCCTG N9831. J Clin Oncol. 2014 Nov 20;32(33):3744-52. link to original article link to PMC article PubMed
4. NOAH: Gianni L, Eiermann W, Semiglazov V, Manikhas A, Lluch A, Tjulandin S, Zambetti M, Vazquez F, Byakhow M, Lichinitser M, Climent MA, Ciruelos E, Ojeda B, Mansutti M, Bozhok A, Baronio R, Feyereislova A, Barton C, Valagussa P, Baselga J. Neoadjuvant chemotherapy with trastuzumab followed by adjuvant trastuzumab versus neoadjuvant chemotherapy alone, in patients with HER2-positive locally advanced breast cancer (the NOAH trial): a randomised controlled superiority trial with a parallel HER2-negative cohort. Lancet. 2010 Jan 30;375(9712):377-84. link to original article contains verified protocol PubMed ISRCTN86043495
   1. Update: Gianni L, Eiermann W, Semiglazov V, Lluch A, Tjulandin S, Zambetti M, Moliterni A, Vazquez F, Byakhov MJ, Lichinitser M, Climent MA, Ciruelos E, Ojeda B, Mansutti M, Bozhok A, Magazzù D, Heinzmann D, Steinseifer J, Valagussa P, Baselga J. Neoadjuvant and adjuvant trastuzumab in patients with HER2-positive locally advanced breast cancer (NOAH): follow-up of a randomised controlled superiority trial with a parallel HER2-negative cohort. Lancet Oncol. 2014 May;15(6):640-7. Epub 2014 Mar 20. Erratum in: Lancet Oncol. 2018 Dec;19(12):e667. link to original article PubMed
5. NeoALTTO: Baselga J, Bradbury I, Eidtmann H, Di Cosimo S, de Azambuja E, Aura C, Gómez H, Dinh P, Fauria K, Van Dooren V, Aktan G, Goldhirsch A, Chang TW, Horváth Z, Coccia-Portugal M, Domont J, Tseng LM, Kunz G, Sohn JH, Semiglazov V, Lerzo G, Palacova M, Probachai V, Pusztai L, Untch M, Gelber RD, Piccart-Gebhart M; NeoALTTO Study Team. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet. 2012 Feb 18;379(9816):633-40. Epub 2012 Jan 17. Erratum in: Lancet. 2012 Feb 18;379(9816):616. Dosage error in published abstract; MEDLINE/PubMed abstract corrected. link to original article link to PMC article contains verified protocol PubMed NCT00553358
   1. Update: de Azambuja E, Holmes AP, Piccart-Gebhart M, Holmes E, Di Cosimo S, Swaby RF, Untch M, Jackisch C, Lang I, Smith I, Boyle F, Xu B, Barrios CH, Perez EA, Azim HA Jr, Kim SB, Kuemmel S, Huang CS, Vuylsteke P, Hsieh RK, Gorbunova V, Eniu A, Dreosti L, Tavartkiladze N, Gelber RD, Eidtmann H, Baselga J. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): survival outcomes of a randomised, open-label, multicentre, phase 3 trial and their association with pathological complete response. Lancet Oncol. 2014 Sep;15(10):1137-46. Epub 2014 Aug 14. link to original article PubMed
   2. Update: Huober J, Holmes E, Baselga J, de Azambuja E, Untch M, Fumagalli D, Sarp S, Lang I, Smith I, Boyle F, Xu B, Lecocq C, Wildiers H, Jouannaud C, Hackman J, Dasappa L, Ciruelos E, Toral Pena JC, Adamchuk H, Hickish T, de la Pena L, Jackisch C, Gelber RD, Piccart-Gebhart M, Di Cosimo S. Survival outcomes of the NeoALTTO study (BIG 1-06): updated results of a randomised multicenter phase III neoadjuvant clinical trial in patients with HER2-positive primary breast cancer. Eur J Cancer. 2019 Sep;118:169-177. Epub 2019 Aug 1. link to original article PubMed
6. CALGB 40101: Shulman LN, Cirrincione CT, Berry DA, Becker HP, Perez EA, O'Regan R, Martino S, Atkins JN, Mayer E, Schneider CJ, Kimmick G, Norton L, Muss H, Winer EP, Hudis C. Six Cycles of Doxorubicin and Cyclophosphamide or Paclitaxel Are Not Superior to Four Cycles As Adjuvant Chemotherapy for Breast Cancer in Women With Zero to Three Positive Axillary Nodes: Cancer and Leukemia Group B 40101. J Clin Oncol. 2012 Nov 20;30(33):4071-6. Epub 2012 Jul 23. link to original article contains verified protocol link to study protocol PDF link to PMC article PubMed NCT00041119
   1. Update: Shulman LN, Berry DA, Cirrincione CT, Becker HP, Perez EA, O'Regan R, Martino S, Shapiro CL, Schneider CJ, Kimmick G, Burstein HJ, Norton L, Muss H, Hudis CA, Winer EP. Comparison of doxorubicin and cyclophosphamide versus single-agent paclitaxel as adjuvant therapy for breast cancer in women with 0 to 3 positive axillary nodes: CALGB 40101 (Alliance). J Clin Oncol. 2014 Aug 1;32(22):2311-7. link to PMC article PubMed
7. PHARE: Pivot X, Romieu G, Debled M, Pierga JY, Kerbrat P, Bachelot T, Lortholary A, Espié M, Fumoleau P, Serin D, Jacquin JP, Jouannaud C, Rios M, Abadie-Lacourtoisie S, Tubiana-Mathieu N, Cany L, Catala S, Khayat D, Pauporté I, Kramar A; PHARE trial investigators. 6 months versus 12 months of adjuvant trastuzumab for patients with HER2-positive early breast cancer (PHARE): a randomised phase 3 trial. Lancet Oncol. 2013 Jul;14(8):741-8. Epub 2013 Jun 11. link to original article PubMed NCT00381901
   1. Update: Pivot X, Romieu G, Debled M, Pierga JY, Kerbrat P, Bachelot T, Lortholary A, Espié M, Fumoleau P, Serin D, Jacquin JP, Jouannaud C, Rios M, Abadie-Lacourtoisie S, Venat-Bouvet L, Cany L, Catala S, Khayat D, Gambotti L, Pauporté I, Faure-Mercier C, Paget-Bailly S, Henriques J, Grouin JM; PHARE trial investigators. 6 months versus 12 months of adjuvant trastuzumab in early breast cancer (PHARE): final analysis of a multicentre, open-label, phase 3 randomised trial. Lancet. 2019 Jun 29;393(10191):2591-2598. Epub 2019 Jun 6. link to original article PubMed
8. NSABP B-41: Robidoux A, Tang G, Rastogi P, Geyer CE Jr, Azar CA, Atkins JN, Fehrenbacher L, Bear HD, Baez-Diaz L, Sarwar S, Margolese RG, Farrar WB, Brufsky AM, Shibata HR, Bandos H, Paik S, Costantino JP, Swain SM, Mamounas EP, Wolmark N. Lapatinib as a component of neoadjuvant therapy for HER2-positive operable breast cancer (NSABP protocol B-41): an open-label, randomised phase 3 trial. Lancet Oncol. 2013 Nov;14(12):1183-92. Epub 2013 Oct 4. link to original article PubMed NCT00486668
9. HORG CT/04.23: Mavroudis D, Saloustros E, Malamos N, Kakolyris S, Boukovinas I, Papakotoulas P, Kentepozidis N, Ziras N, Georgoulias V; Hellenic Oncology Research Group. Six versus 12 months of adjuvant trastuzumab in combination with dose-dense chemotherapy for women with HER2-positive breast cancer: a multicenter randomized study by the Hellenic Oncology Research Group (HORG). Ann Oncol. 2015 Jul;26(7):1333-40. Epub 2015 May 1. link to original article contains verified protocol PubMed
10. ALTTO: Piccart-Gebhart M, Holmes E, Baselga J, de Azambuja E, Dueck AC, Viale G, Zujewski JA, Goldhirsch A, Armour A, Pritchard KI, McCullough AE, Dolci S, McFadden E, Holmes AP, Tonghua L, Eidtmann H, Dinh P, Di Cosimo S, Harbeck N, Tjulandin S, Im YH, Huang CS, Diéras V, Hillman DW, Wolff AC, Jackisch C, Lang I, Untch M, Smith I, Boyle F, Xu B, Gomez H, Suter T, Gelber RD, Perez EA. Adjuvant lapatinib and trastuzumab for early human epidermal growth factor receptor 2-positive breast cancer: results from the randomized phase III Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization trial. J Clin Oncol. 2016 Apr 1;34(10):1034-42. Epub 2015 Nov 23. link to original article link to protocol contains verified protocol in supplement link to PMC article PubMed NCT00490139
11. SB3-G31-BC: Pivot X, Bondarenko I, Nowecki Z, Dvorkin M, Trishkina E, Ahn JH, Vinnyk Y, Im SA, Sarosiek T, Chatterjee S, Wojtukiewicz MZ, Moiseyenko V, Shparyk Y, Bello M 3rd, Semiglazov V, Song S, Lim J. Phase III, randomized, double-blind study comparing the efficacy, safety, and immunogenicity of SB3 (trastuzumab biosimilar) and reference trastuzumab in patients treated with neoadjuvant therapy for human epidermal growth factor receptor 2-positive early breast cancer. J Clin Oncol. 2018 Apr 1;36(10):968-974. Epub 2018 Jan 26. link to original article contains verified protocol PubMed
12. SOLD: Joensuu H, Fraser J, Wildiers H, Huovinen R, Auvinen P, Utriainen M, Nyandoto P, Villman KK, Halonen P, Granstam-Björneklett H, Lundgren L, Sailas L, Turpeenniemi-Hujanen T, Tanner M, Yachnin J, Ritchie D, Johansson O, Huttunen T, Neven P, Canney P, Harvey VJ, Kellokumpu-Lehtinen PL, Lindman H. Effect of adjuvant trastuzumab for a duration of 9 weeks vs 1 year with concomitant chemotherapy for early human epidermal growth factor receptor 2-positive breast cancer: the SOLD randomized clinical trial. JAMA Oncol. 2018 Sep 1;4(9):1199-1206. link to original article contains verified protocol PubMed NCT00593697
13. Short-HER: Conte P, Frassoldati A, Bisagni G, Brandes AA, Donadio M, Garrone O, Piacentini F, Cavanna L, Giotta F, Aieta M, Gebbia V, Molino A, Musolino A, Ferro A, Maltoni R, Danese S, Zamagni C, Rimanti A, Cagossi K, Russo A, Pronzato P, Giovanardi F, Moretti G, Lombardo L, Schirone A, Beano A, Amaducci L, Bajardi EA, Vicini R, Balduzzi S, D'Amico R, Guarneri V; Reader study level-I and level-II Groups. Nine weeks versus 1 year adjuvant trastuzumab in combination with chemotherapy: final results of the phase III randomized Short-HER study. Ann Oncol. 2018 Dec 1;29(12):2328-2333. link to original article contains verified protocol PubMed NCT00629278
14. KATHERINE: von Minckwitz G, Huang CS, Mano MS, Loibl S, Mamounas EP, Untch M, Wolmark N, Rastogi P, Schneeweiss A, Redondo A, Fischer HH, Jacot W, Conlin AK, Arce-Salinas C, Wapnir IL, Jackisch C, DiGiovanna MP, Fasching PA, Crown JP, Wülfing P, Shao Z, Rota Caremoli E, Wu H, Lam LH, Tesarowski D, Smitt M, Douthwaite H, Singel SM, Geyer CE Jr; KATHERINE Investigators. Trastuzumab Emtansine for Residual Invasive HER2-Positive Breast Cancer. N Engl J Med. 2019 Feb 14;380(7):617-628. Epub 2018 Dec 5. link to original article contains verified protocol PubMed NCT01772472
15. PERSEPHONE: Earl HM, Hiller L, Vallier AL, Loi S, McAdam K, Hughes-Davies L, Harnett AN, Ah-See ML, Simcock R, Rea D, Raj S, Woodings P, Harries M, Howe D, Raynes K, Higgins HB, Wilcox M, Plummer C, Mansi J, Gounaris I, Mahler-Araujo B, Provenzano E, Chhabra A, Abraham JE, Caldas C, Hall PS, McCabe C, Hulme C, Miles D, Wardley AM, Cameron DA, Dunn JA; PERSEPHONE Steering Committee and Trial Investigators. 6 versus 12 months of adjuvant trastuzumab for HER2-positive early breast cancer (PERSEPHONE): 4-year disease-free survival results of a randomised phase 3 non-inferiority trial. Lancet. 2019 Jun 29;393(10191):2599-2612. Epub 2019 Jun 6. link to original article contains protocol link to PMC article PubMed NCT00712140
16. RESPECT: Sawaki M, Taira N, Uemura Y, Saito T, Baba S, Kobayashi K, Kawashima H, Tsuneizumi M, Sagawa N, Bando H, Takahashi M, Yamaguchi M, Takashima T, Nakayama T, Kashiwaba M, Mizuno T, Yamamoto Y, Iwata H, Kawahara T, Ohashi Y, Mukai H; RESPECT study group. Randomized Controlled Trial of Trastuzumab With or Without Chemotherapy for HER2-Positive Early Breast Cancer in Older Patients. J Clin Oncol. 2020 Nov 10;38(32):3743-3752. Epub 2020 Sep 16. link to original article contains verified protocol PubMed NCT01104935

Trastuzumab and hyaluronidase monotherapy

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Regimen variant #1, 6 mos

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Earl et al. 2019 (PERSEPHONE)	2007-2015	Phase III (E-de-esc)	Trastuzumab x 12 mo	Non-inferior DFS

Preceding treatment

• Not explicitly specified (pragmatic trial)

Targeted therapy

• Trastuzumab and hyaluronidase (Herceptin Hylecta) 600 mg/10,000 units SC once on day 1

21-day cycle for 9 cycles (6 months)

Regimen variant #2, 12 mos

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Earl et al. 2019 (PERSEPHONE)	2007-2015	Phase III (C)	Trastuzumab x 6 mo	Non-inferior DFS
Joensuu et al. 2018 (SOLD)	2008-2014	Phase III (C)	No further treatment	Inconclusive whether non-inferior DFS

Preceding treatment

• SOLD: Surgery, then TH (Taxotere) x 3, then FEC x 3
• PERSEPHONE: Not explicitly specified (pragmatic trial)

Targeted therapy

• Trastuzumab and hyaluronidase (Herceptin Hylecta) 600 mg/10,000 units SC once on day 1

21-day cycle for 18 cycles (1 year)

References

1. SOLD: Joensuu H, Fraser J, Wildiers H, Huovinen R, Auvinen P, Utriainen M, Nyandoto P, Villman KK, Halonen P, Granstam-Björneklett H, Lundgren L, Sailas L, Turpeenniemi-Hujanen T, Tanner M, Yachnin J, Ritchie D, Johansson O, Huttunen T, Neven P, Canney P, Harvey VJ, Kellokumpu-Lehtinen PL, Lindman H. Effect of adjuvant trastuzumab for a duration of 9 weeks vs 1 year with concomitant chemotherapy for early human epidermal growth factor receptor 2-positive breast cancer: the SOLD randomized clinical trial. JAMA Oncol. 2018 Sep 1;4(9):1199-1206. link to original article contains verified protocol PubMed NCT00593697
2. PERSEPHONE: Earl HM, Hiller L, Vallier AL, Loi S, McAdam K, Hughes-Davies L, Harnett AN, Ah-See ML, Simcock R, Rea D, Raj S, Woodings P, Harries M, Howe D, Raynes K, Higgins HB, Wilcox M, Plummer C, Mansi J, Gounaris I, Mahler-Araujo B, Provenzano E, Chhabra A, Abraham JE, Caldas C, Hall PS, McCabe C, Hulme C, Miles D, Wardley AM, Cameron DA, Dunn JA; PERSEPHONE Steering Committee and Trial Investigators. 6 versus 12 months of adjuvant trastuzumab for HER2-positive early breast cancer (PERSEPHONE): 4-year disease-free survival results of a randomised phase 3 non-inferiority trial. Lancet. 2019 Jun 29;393(10191):2599-2612. Epub 2019 Jun 6. link to original article contains protocol link to PMC article PubMed NCT00712140

Ado-trastuzumab emtansine monotherapy

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T-DM1: Trastuzumab-DM1 (Ado-trastuzumab emtansine)

Example orders

• Example orders for Ado-trastuzumab emtansine (Kadcyla) in breast cancer

Regimen

FDA-recommended dose

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
von Minckwitz et al. 2018 (KATHERINE)	2013-2015	Phase III (E-RT-switch-ic)	Trastuzumab	Superior IDFS IDFS36: 88% vs 77% (HR 0.50, 95% CI 0.39-0.64)

Preceding treatment

• Surgery, with residual invasive disease

Antibody-drug conjugate therapy

• Ado-trastuzumab emtansine (Kadcyla) 3.6 mg/kg IV once on day 1

21-day cycle for 14 cycles

References

1. KATHERINE: von Minckwitz G, Huang CS, Mano MS, Loibl S, Mamounas EP, Untch M, Wolmark N, Rastogi P, Schneeweiss A, Redondo A, Fischer HH, Jacot W, Conlin AK, Arce-Salinas C, Wapnir IL, Jackisch C, DiGiovanna MP, Fasching PA, Crown JP, Wülfing P, Shao Z, Rota Caremoli E, Wu H, Lam LH, Tesarowski D, Smitt M, Douthwaite H, Singel SM, Geyer CE Jr; KATHERINE Investigators. Trastuzumab Emtansine for Residual Invasive HER2-Positive Breast Cancer. N Engl J Med. 2019 Feb 14;380(7):617-628. Epub 2018 Dec 5. link to original article contains verified protocol PubMed NCT01772472

Vinorelbine & Trastuzumab (VH)

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VH: Vinorelbine & Herceptin (Trastuzumab)

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Joensuu et al. 2006 (FinHer)	2000-2003	Phase III (E-esc)	1. T 2. V	Did not meet primary endpoint of RFS
			3. TH (Taxotere)	Not reported

Preceding treatment

• Surgery

Chemotherapy

• Vinorelbine (Navelbine) 24 mg/m² IV over 5 to 10 minutes once per day on days 1, 8, 15

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8 & 15
  • Cycles 2 & 3: 2 mg/kg IV once per day on days 1, 8, 15

21-day cycle for 3 cycles

Subsequent treatment

• FEC

References

1. FinHer: Joensuu H, Kellokumpu-Lehtinen PL, Bono P, Alanko T, Kataja V, Asola R, Utriainen T, Kokko R, Hemminki A, Tarkkanen M, Turpeenniemi-Hujanen T, Jyrkkiö S, Flander M, Helle L, Ingalsuo S, Johansson K, Jääskeläinen AS, Pajunen M, Rauhala M, Kaleva-Kerola J, Salminen T, Leinonen M, Elomaa I, Isola J; FinHer Study Investigators. Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N Engl J Med. 2006 Feb 23;354(8):809-20. link to original article PubMed ISRCTN76560285
   1. Update: Joensuu H, Bono P, Kataja V, Alanko T, Kokko R, Asola R, Utriainen T, Turpeenniemi-Hujanen T, Jyrkkiö S, Möykkynen K, Helle L, Ingalsuo S, Pajunen M, Huusko M, Salminen T, Auvinen P, Leinonen H, Leinonen M, Isola J, Kellokumpu-Lehtinen PL. Fluorouracil, epirubicin, and cyclophosphamide with either docetaxel or vinorelbine, with or without trastuzumab, as adjuvant treatments of breast cancer: final results of the FinHer trial. J Clin Oncol. 2009 Dec 1;27(34):5685-92. link to original article PubMed

Metastatic or unresectable disease, first-line

Note: some patients in these trials were pre-treated with non-HER2-targeted therapies.

ACH

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ACH: Adriamycin (Doxorubicin), Cyclophosphamide, Herceptin (Trastuzumab)

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Slamon et al. 2001	1995-1997	Phase III (E-RT-esc)	AC	Seems to have superior OS

Note: patients had not previously received adjuvant (postoperative) therapy with an anthracycline. Not commonly used; here for reference purposes only.

Chemotherapy

• Doxorubicin (Adriamycin)
• Cyclophosphamide (Cytoxan)

Targeted therapy

• Trastuzumab (Herceptin)

References

1. Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, Baselga J, Norton L. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001 Mar 15;344(11):783-92. link to original article PubMed

Capecitabine, Bevacizumab, Trastuzumab

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Regimen

Study	Evidence	Efficacy
Martín et al. 2012 (MO21926)	Phase II	ORR: 73% (95% CI 62-82)

Chemotherapy

• Capecitabine (Xeloda) 1000 mg/m² PO twice per day on days 1 to 14

Targeted therapy

• Bevacizumab (Avastin) 15 mg/kg IV once on day 1
• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV once on day 1
  • Cycle 2 onwards: 6 mg/kg IV once on day 1

21-day cycles

References

1. MO21926: Martín M, Makhson A, Gligorov J, Lichinitser M, Lluch A, Semiglazov V, Scotto N, Mitchell L, Tjulandin S. Phase II study of bevacizumab in combination with trastuzumab and capecitabine as first-line treatment for HER-2-positive locally recurrent or metastatic breast cancer. Oncologist. 2012;17(4):469-75. Epub 2012 Mar 30. link to original article contains verified protocol link to PMC article PubMed

Capecitabine & Lapatinib

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Pivot et al. 2015 (CEREBEL)	2009-2012	Phase III (E-switch-ic)	Capecitabine & Trastuzumab	Did not meet primary endpoint of CNS site of first relapse

Chemotherapy

• Capecitabine (Xeloda) 1000 mg/m² PO twice per day on days 1 to 14

Targeted therapy

• Lapatinib (Tykerb) 1250 mg PO once per day

21-day cycles

References

1. CEREBEL: Pivot X, Manikhas A, Żurawski B, Chmielowska E, Karaszewska B, Allerton R, Chan S, Fabi A, Bidoli P, Gori S, Ciruelos E, Dank M, Hornyak L, Margolin S, Nusch A, Parikh R, Nagi F, DeSilvio M, Santillana S, Swaby RF, Semiglazov V. CEREBEL (EGF111438): A phase III, randomized, open-label study of lapatinib plus capecitabine versus trastuzumab plus capecitabine in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer. J Clin Oncol. 2015 May 10;33(14):1564-73. Epub 2015 Jan 20. link to original article PubMed NCT00820222

Capecitabine & Trastuzumab (XH)

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XH: Xeloda (Capecitabine) & Herceptin

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Pivot et al. 2015 (CEREBEL)	2009-2012	Phase III (C)	Capecitabine & Lapatanib	Did not meet primary endpoint of CNS site of first relapse

Chemotherapy

• Capecitabine (Xeloda) 1250 mg/m² PO twice per day on days 1 to 14

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV once on day 1
  • Cycle 2 onwards: 6 mg/kg IV once on day 1

21-day cycles

References

1. CEREBEL: Pivot X, Manikhas A, Żurawski B, Chmielowska E, Karaszewska B, Allerton R, Chan S, Fabi A, Bidoli P, Gori S, Ciruelos E, Dank M, Hornyak L, Margolin S, Nusch A, Parikh R, Nagi F, DeSilvio M, Santillana S, Swaby RF, Semiglazov V. CEREBEL (EGF111438): A phase III, randomized, open-label study of lapatinib plus capecitabine versus trastuzumab plus capecitabine in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer. J Clin Oncol. 2015 May 10;33(14):1564-73. Epub 2015 Jan 20. link to original article contains protocol PubMed NCT00820222

ECH

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ECH: Epirubicin, Cyclophosphamide, Herceptin (Trastuzumab)

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Slamon et al. 2001	1995-1997	Phase III (E-RT-esc)	EC	Seems to have superior OS

Not commonly used; here for reference purposes only.

Chemotherapy

• Epirubicin (Ellence)
• Cyclophosphamide (Cytoxan)

Targeted therapy

• Trastuzumab (Herceptin)

References

1. Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, Baselga J, Norton L. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001 Mar 15;344(11):783-92. link to original article PubMed

nab-Paclitaxel & Trastuzumab

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Regimen

Study	Evidence
Mirtsching et al. 2011	Phase II

Chemotherapy

• Paclitaxel, nanoparticle albumin-bound (Abraxane) 125 mg/m² IV over 30 minutes once per day on days 1, 8, 15

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 4 mg/kg IV over 90 minutes once on day 1, then 2 mg/kg IV over 30 minutes once per day on days 8, 15, 22
  • Cycle 2 onwards: 2 mg/kg IV over 30 minutes once per day on days 1, 8, 15, 22

28-day cycles

References

1. Mirtsching B, Cosgriff T, Harker G, Keaton M, Chidiac T, Min M. A phase II study of weekly nanoparticle albumin-bound paclitaxel with or without trastuzumab in metastatic breast cancer. Clin Breast Cancer. 2011 Apr;11(2):121-8. Epub 2011 Apr 11. link to original article contains verified protocol PubMed

Pertuzumab & T-DM1

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Pertuzumab & T-DM1: Pertuzumab & Trastuzumab-DM1 (Ado-trastuzumab emtansine)

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Perez et al. 2016 (MARIANNE)	2010-2012	Phase III (E-esc)	1. T-DM1	Non-inferior PFS
			2. TH (Taxotere) 3. TH (Taxol)	Non-inferior PFS

Targeted therapy

• Pertuzumab (Perjeta) as follows:
  • Cycle 1: 840 mg IV once on day 1
  • Cycle 2 onwards: 420 mg IV once on day 1

Antibody-drug conjugate therapy

• Ado-trastuzumab emtansine (Kadcyla) 3.6 mg/kg IV once on day 1

21-day cycles

References

1. MARIANNE: Perez EA, Barrios C, Eiermann W, Toi M, Im YH, Conte P, Martin M, Pienkowski T, Pivot X, Burris H 3rd, Petersen JA, Stanzel S, Strasak A, Patre M, Ellis P. Trastuzumab emtansine with or without pertuzumab versus trastuzumab plus taxane for human epidermal growth factor receptor 2-positive, advanced breast cancer: primary results from the phase III MARIANNE study. J Clin Oncol. 2017 Jan 10;35(2):141-148. Epub 2016 Nov 7. link to original article link to PMC article contains verified protocol PubMed NCT01120184
   1. Update: Perez EA, Barrios C, Eiermann W, Toi M, Im YH, Conte P, Martin M, Pienkowski T, Pivot XB, Burris HA 3rd, Petersen JA, De Haas S, Hoersch S, Patre M, Ellis PA. Trastuzumab emtansine with or without pertuzumab versus trastuzumab with taxane for human epidermal growth factor receptor 2-positive advanced breast cancer: final results from MARIANNE. Cancer. 2019 Nov 15;125(22):3974-3984. Epub 2019 Jul 18. link to original article PubMed

TCH (Taxotere, Carboplatin)

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TCH: Taxotere (Docetaxel), Carboplatin, Herceptin (Trastuzumab)

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Valero et al. 2011 (BCIRG 007)	2001-2004	Phase III (E-esc)	TH	Did not meet primary endpoint of TTP

Chemotherapy

• Docetaxel (Taxotere) 75 mg/m² IV once on day 1
• Carboplatin (Paraplatin) AUC 6 IV once on day 1

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8 & 15
  • Cycles 2 to 8: 2 mg/kg IV once per day on days 1, 8, 15

21-day cycle for 8 cycles

Subsequent treatment

• Trastuzumab maintenance

References

1. BCIRG 007: Valero V, Forbes J, Pegram MD, Pienkowski T, Eiermann W, von Minckwitz G, Roche H, Martin M, Crown J, Mackey JR, Fumoleau P, Rolski J, Mrsic-Krmpotic Z, Jagiello-Gruszfeld A, Riva A, Buyse M, Taupin H, Sauter G, Press MF, Slamon DJ. Multicenter phase III randomized trial comparing docetaxel and trastuzumab with docetaxel, carboplatin, and trastuzumab as first-line chemotherapy for patients with HER2-gene-amplified metastatic breast cancer (BCIRG 007 study): two highly active therapeutic regimens. J Clin Oncol. 2011 Jan 10;29(2):149-56. Epub 2010 Nov 29. link to original article contains verified protocol PubMed NCT00047255

TH (Taxotere)

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TH: Taxotere (Docetaxel) & Herceptin (Trastuzumab)
HT: Herceptin (Trastuzumab) & Taxotere (Docetaxel)
H+D: Herceptin (Trastuzumab) & Docetaxel

Regimen variant #1, 35 mg/m² docetaxel, 3 out of 4 weeks

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Esteva et al. 2002	NR	Phase II
Burstein et al. 2007 (TRAVIOTA)	2001-2003	Phase III (E-switch-ic)	VH	Might have inferior TTP

Esteva et al. 2002 described the day before the start of a cycle as "day 0," which is not the typical convention, so day -1 is being used instead.

Chemotherapy

• Docetaxel (Taxotere) 35 mg/m² IV over 30 minutes once per day on days 1, 8, 15, given first

Targeted therapy

• Trastuzumab (Herceptin) given second as follows:
  • Cycle 1: 4 mg/kg IV over 90 minutes once on day -1, then 2 mg/kg IV over 30 minutes once per day on days 8 & 15
  • Cycle 2 onwards: 2 mg/kg IV over 30 minutes once per day on days 1, 8, 15

Supportive medications

• Dexamethasone (Decadron) 4 mg PO every 12 hours x 3 doses on cycles 1 & 2, starting the night before Docetaxel (Taxotere). Patients who did not have "hypersensitivity reactions and no significant fluid retention during the first 8 weeks" received 4 mg PO twice per day on day 1 for at least the next two cycles. Patients who "remained free of fluid retention after 8 additional weeks" then received 4 mg PO once on day 1 prior to Docetaxel (Taxotere) in subsequent cycles.

28-day cycles

Regimen variant #2, 60 mg/m² q3wk docetaxel, weekly trastuzumab

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Inoue et al. 2009 (JO17360)	2004-2008	Phase III (C)	H --> H + D	Seems to have superior OS

Chemotherapy

• Docetaxel (Taxotere) 60 mg/m² IV once on day 1

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8 & 15
  • Cycle 2 onwards: 2 mg/kg IV once per day on days 1, 8, 15

21-day cycles

Regimen variant #3, 75 mg/m² q3wk docetaxel, q3wk trastuzumab

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Hurvitz et al. 2013 (TDM4450g)	2008-2009	Randomized Phase II (C)	T-DM1	Seems to have inferior PFS
Baselga et al. 2011 (CLEOPATRA)	2008-2010	Phase III (C)	THP	Inferior OS1
Gelmon et al. 2015 (NCIC-CTG MA.31)	2008-2011	Phase III (C)	Docetaxel & Lapatinib	Superior PFS
Perez et al. 2016 (MARIANNE)	2010-2012	Phase III (C)	1. T-DM1	Non-inferior PFS
			2. Pertuzumab & T-DM1	Non-inferior PFS
			3. TH (Taxol)	Not reported

¹Reported efficacy for CLEOPATRA is based on the 2020 update.
Note: Dose of docetaxel in TDM4450g and MARIANNE was per investigator's discretion. CLEOPATRA has an unusual schedule with both medications being given on day 2 of cycle 1, due to this regimen being the control arm, in which patients in one arm received a placebo instead of pertuzumab on day 1. It is reasonable to assume that in practice, drugs in this regimen will be given on day 1 from the beginning.

Chemotherapy

• Docetaxel (Taxotere) 75 mg/m² IV once on day 1

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV once on day 2
  • Cycle 2 onwards: 6 mg/kg IV once on day 1

21-day cycle for at least 6 cycles

Subsequent treatment

• CLEOPATRA: If it is decided to no longer administer docetaxel with this regimen, then patients could continue to receive trastuzumab maintenance
• NCIC-CTG MA.31: Trastuzumab maintenance, after 8 cycles

Regimen variant #4, 100 mg/m² q3wk docetaxel, weekly trastuzumab

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Marty et al. 2005 (M77001)	2000-2002	Randomized Phase II (E-esc)	Docetaxel	Seems to have superior OS
Valero et al. 2010 (BCIRG 007)	2001-2004	Phase III (C)	TCH	Did not meet primary endpoint of TTP

Chemotherapy

• Docetaxel (Taxotere) 100 mg/m² IV once on day 1

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 4 mg/kg IV over 90 minutes once on day 1, then 2 mg/kg IV over 30 minutes once per day on days 8 & 15
  • Cycles 2 to 8: 2 mg/kg IV over 30 minutes once per day on days 1, 8, 15

Supportive medications

• Dexamethasone (Decadron) 8 mg (or equivalent) PO twice per day x 6 doses, starting the night before Docetaxel (Taxotere)
• "Antiemetic premedication was mandatory" (no additional details given).

21-day cycle for 6 cycles (M77001; see note) or 8 cycles (BCIRG 007)

Subsequent treatment

• M77001: Patients could receive docetaxel beyond six cycles at the discretion of the investigator. Otherwise, patients proceeded to trastuzumab maintenance.
• BCIRG 007: Trastuzumab maintenance

Regimen variant #5, 100 mg/m² q3wk docetaxel, q3wk trastuzumab

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Andersson et al. 2010 (HERNATA)	2004-2008	Phase III (C)	VH	Did not meet primary endpoint of TTP
Gianni et al. 2013 (AVAREL)	2006-2010	Randomized Phase II (C)	BTH	Might have inferior PFS
Hurvitz et al. 2013 (TDM4450g)	2008-2009	Randomized Phase II (C)	T-DM1	Seems to have inferior PFS
Perez et al. 2016 (MARIANNE)	2010-2012	Phase III (E-esc)	1. T-DM1	Non-inferior PFS
			2. Pertuzumab & T-DM1	Non-inferior PFS
			3. TH (Taxol)	Not reported

Note: In HERNATA, the day of docetaxel and trastuzumab were reversed in cycle 1. Dose of docetaxel in TDM4450g and MARIANNE was per investigator's discretion.

Chemotherapy

• Docetaxel (Taxotere) 100 mg/m² IV over 60 minutes once on day 1 (see note)

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV over 90 minutes once on day 2 (see note)
  • Cycle 2 onwards: 6 mg/kg IV over 30 minutes once on day 1

21-day cycles

References

1. Esteva FJ, Valero V, Booser D, Guerra LT, Murray JL, Pusztai L, Cristofanilli M, Arun B, Esmaeli B, Fritsche HA, Sneige N, Smith TL, Hortobagyi GN. Phase II study of weekly docetaxel and trastuzumab for patients with HER-2-overexpressing metastatic breast cancer. J Clin Oncol. 2002 Apr 1;20(7):1800-8. link to original article contains verified protocol PubMed
2. M77001: Marty M, Cognetti F, Maraninchi D, Snyder R, Mauriac L, Tubiana-Hulin M, Chan S, Grimes D, Antón A, Lluch A, Kennedy J, O'Byrne K, Conte P, Green M, Ward C, Mayne K, Extra JM. Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer administered as first-line treatment: the M77001 study group. J Clin Oncol. 2005 Jul 1;23(19):4265-74. Epub 2005 May 23. link to original article contains verified protocol PubMed
3. TRAVIOTA: Burstein HJ, Keshaviah A, Baron AD, Hart RD, Lambert-Falls R, Marcom PK, Gelman R, Winer EP. Trastuzumab plus vinorelbine or taxane chemotherapy for HER2-overexpressing metastatic breast cancer: the trastuzumab and vinorelbine or taxane study. Cancer. 2007 Sep 1;110(5):965-72. link to original article PubMed
4. JO17360: Inoue K, Nakagami K, Mizutani M, Hozumi Y, Fujiwara Y, Masuda N, Tsukamoto F, Saito M, Miura S, Eguchi K, Shinkai T, Ando M, Watanabe T, Masuda N, Ohashi Y, Sano M, Noguchi S. Randomized phase III trial of trastuzumab monotherapy followed by trastuzumab plus docetaxel versus trastuzumab plus docetaxel as first-line therapy in patients with HER2-positive metastatic breast cancer: the JO17360 Trial Group. Breast Cancer Res Treat. 2010 Jan;119(1):127-36. Epub 2009 Aug 19. link to original article contains protocol PubMed
5. BCIRG 007: Valero V, Forbes J, Pegram MD, Pienkowski T, Eiermann W, von Minckwitz G, Roche H, Martin M, Crown J, Mackey JR, Fumoleau P, Rolski J, Mrsic-Krmpotic Z, Jagiello-Gruszfeld A, Riva A, Buyse M, Taupin H, Sauter G, Press MF, Slamon DJ. Multicenter phase III randomized trial comparing docetaxel and trastuzumab with docetaxel, carboplatin, and trastuzumab as first-line chemotherapy for patients with HER2-gene-amplified metastatic breast cancer (BCIRG 007 study): two highly active therapeutic regimens. J Clin Oncol. 2011 Jan 10;29(2):149-56. Epub 2010 Nov 29. link to original article contains verified protocol PubMed NCT00047255
6. HERNATA: Andersson M, Lidbrink E, Bjerre K, Wist E, Enevoldsen K, Jensen AB, Karlsson P, Tange UB, Sørensen PG, Møller S, Bergh J, Langkjer ST. Phase III randomized study comparing docetaxel plus trastuzumab with vinorelbine plus trastuzumab as first-line therapy of metastatic or locally advanced human epidermal growth factor receptor 2-positive breast cancer: the HERNATA study. J Clin Oncol. 2011 Jan 20;29(3):264-71. Epub 2010 Dec 13. link to original article contains verified protocol PubMed
7. CLEOPATRA: Baselga J, Cortés J, Kim SB, Im SA, Hegg R, Im YH, Roman L, Pedrini JL, Pienkowski T, Knott A, Clark E, Benyunes MC, Ross G, Swain SM; CLEOPATRA Study Group. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012 Jan 12;366(2):109-19. Epub 2011 Dec 7. link to original article contains verified protocol link to PMC article PubMed NCT00567190
   1. Update: Swain SM, Kim SB, Cortés J, Ro J, Semiglazov V, Campone M, Ciruelos E, Ferrero JM, Schneeweiss A, Knott A, Clark E, Ross G, Benyunes MC, Baselga J. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): overall survival results from a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2013 May;14(6):461-71. Epub 2013 Apr 18. link to original article contains verified protocol link to PMC article PubMed
   2. Update: Swain SM, Baselga J, Kim SB, Ro J, Semiglazov V, Campone M, Ciruelos E, Ferrero JM, Schneeweiss A, Heeson S, Clark E, Ross G, Benyunes MC, Cortés J; CLEOPATRA Study Group. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med. 2015 Feb 19;372(8):724-34. link to original article PubMed
   3. Update: Swain SM, Miles D, Kim SB, Im YH, Im SA, Semiglazov V, Ciruelos E, Schneeweiss A, Loi S, Monturus E, Clark E, Knott A, Restuccia E, Benyunes MC, Cortés J; CLEOPATRA study group. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA): end-of-study results from a double-blind, randomised, placebo-controlled, phase 3 study. Lancet Oncol. 2020 Apr;21(4):519-530. Epub 2020 Mar 12. link to original article PubMed
8. TDM4450g: Hurvitz SA, Dirix L, Kocsis J, Bianchi GV, Lu J, Vinholes J, Guardino E, Song C, Tong B, Ng V, Chu YW, Perez EA. Phase II randomized study of trastuzumab emtansine versus trastuzumab plus docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer. J Clin Oncol. 2013 Mar 20;31(9):1157-63. Epub 2013 Feb 4. Erratum in: J Clin Oncol. 2013 Aug 10;31(23):2977. link to original article contains verified protocol PubMed NCT00679341
9. AVAREL: Gianni L, Romieu GH, Lichinitser M, Serrano SV, Mansutti M, Pivot X, Mariani P, Andre F, Chan A, Lipatov O, Chan S, Wardley A, Greil R, Moore N, Prot S, Pallaud C, Semiglazov V. AVEREL: a randomized phase III trial evaluating bevacizumab in combination with docetaxel and trastuzumab as first-line therapy for HER2-positive locally recurrent/metastatic breast cancer. J Clin Oncol. 2013 May 10;31(14):1719-25. Epub 2013 Apr 8. link to original article contains verified protocol PubMed NCT00391092
10. NCIC-CTG MA.31: Gelmon KA, Boyle FM, Kaufman B, Huntsman DG, Manikhas A, Di Leo A, Martin M, Schwartzberg LS, Lemieux J, Aparicio S, Shepherd LE, Dent S, Ellard SL, Tonkin K, Pritchard KI, Whelan TJ, Nomikos D, Nusch A, Coleman RE, Mukai H, Tjulandin S, Khasanov R, Rizel S, Connor AP, Santillana SL, Chapman JA, Parulekar WR. Lapatinib or trastuzumab plus taxane therapy for human epidermal growth factor receptor 2-positive advanced breast cancer: final results of NCIC-CTG MA.31. J Clin Oncol. 2015 May 10;33(14):1574-83. Epub 2015 Mar 16. link to original article contains verified protocol PubMed NCT00667251
11. MARIANNE: Perez EA, Barrios C, Eiermann W, Toi M, Im YH, Conte P, Martin M, Pienkowski T, Pivot X, Burris H 3rd, Petersen JA, Stanzel S, Strasak A, Patre M, Ellis P. Trastuzumab emtansine with or without pertuzumab versus trastuzumab plus taxane for human epidermal growth factor receptor 2-positive, advanced breast cancer: primary results from the phase III MARIANNE study. J Clin Oncol. 2017 Jan 10;35(2):141-148. Epub 2016 Nov 7. link to original article link to PMC article contains verified protocol PubMed NCT01120184
    1. Update: Perez EA, Barrios C, Eiermann W, Toi M, Im YH, Conte P, Martin M, Pienkowski T, Pivot XB, Burris HA 3rd, Petersen JA, De Haas S, Hoersch S, Patre M, Ellis PA. Trastuzumab emtansine with or without pertuzumab versus trastuzumab with taxane for human epidermal growth factor receptor 2-positive advanced breast cancer: final results from MARIANNE. Cancer. 2019 Nov 15;125(22):3974-3984. Epub 2019 Jul 18. link to original article PubMed

TH (Taxol)

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TH: Taxol (Paclitaxel), Herceptin (Trastuzumab)
TP: Trastuzumab, Paclitaxel

Regimen variant #1, weekly paclitaxel (80 mg/m²)

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Seidman et al. 2008 (CALGB 9840)	1998-NR	Phase III (E-switch-ic)	TH; q3wk paclitaxel	Superior OS
Burstein et al. 2007 (TRAVIOTA)	2001-2003	Phase III (E-switch-ic)	VH	Might have inferior TTP
Baselga et al. 2014 (STM01-102)	2006-2009	Phase III (C)	MTP	Did not meet primary endpoint of PFS
Perez et al. 2016 (MARIANNE)	2010-2012	Phase III (C)	1. T-DM1	Non-inferior PFS
			2. Pertuzumab & T-DM1	Non-inferior PFS
			3. TH (Taxotere)	Not reported

Chemotherapy

• Paclitaxel (Taxol) 80 mg/m² IV once per day on days 1, 8, 15, 22

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8, 15, 22
  • Cycle 2 onwards: 2 mg/kg IV once per day on days 1, 8, 15, 22

28-day cycles

Regimen variant #2, weekly paclitaxel (90 mg/m²)

Study	Evidence
Seidman et al. 2001	Phase II

Chemotherapy

• Paclitaxel (Taxol) 90 mg/m² IV once per day on days 1, 8, 15, 22

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 4 mg/kg IV once on day 0, then 2 mg/kg IV once per day on days 8, 15, 22
  • Cycle 2 onwards: 2 mg/kg IV once per day on days 1, 8, 15, 22

28-day cycles

Regimen variant #3, paclitaxel 3 weeks out of 4, 6 cycles

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Gelmon et al. 2015 (NCIC-CTG MA.31)	2008-2011	Phase III (C)	Lapatinib & Paclitaxel	Superior PFS

Chemotherapy

• Paclitaxel (Taxol) 80 mg/m² IV once per day on days 1, 8, 15

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8, 15, 22
  • Cycle 2 onwards: 2 mg/kg IV once per day on days 1, 8, 15, 22

28-day cycle for 6 cycles

Subsequent treatment

• Trastuzumab maintenance

Regimen variant #4, paclitaxel 3 weeks out of 4, indefinite

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Hurvitz et al. 2015 (BOLERO-1)	2009-2012	Phase III (C)	TH & Everolimus	Did not meet primary endpoint of PFS
Awada et al. 2016 (NEfERT-T)	2009-2014	Phase III (C)	Neratinib & Paclitaxel	Did not meet primary endpoint of PFS

Chemotherapy

• Paclitaxel (Taxol) 80 mg/m² IV once per day on days 1, 8, 15

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8, 15, 22
  • Cycle 2 onwards: 2 mg/kg IV once per day on days 1, 8, 15, 22

28-day cycles

Regimen variant #5, q3wk paclitaxel

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Slamon et al. 2001	1995-1997	Phase III (E-RT-esc)	Paclitaxel	Seems to have superior OS
Robert et al. 2006	1998-2002	Phase III (C)	TPC	Seems to have inferior PFS
Seidman et al. 2008 (CALGB 9840)	1998-NR	Phase III (C)	TH, weekly paclitaxel (80 mg/m2)	Inferior OS

Chemotherapy

• Paclitaxel (Taxol) as follows:
  • Cycles 1 to 6: 175 mg/m² IV once on day 2
  • Cycle 7 onwards: continued at investigator's discretion

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8 & 15
  • Cycle 2 onwards: 2 mg/kg IV once per day on days 1, 8, 15

21-day cycle for at least 6 cycles

References

1. Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, Baselga J, Norton L. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001 Mar 15;344(11):783-92. link to original article PubMed
2. Seidman AD, Fornier MN, Esteva FJ, Tan L, Kaptain S, Bach A, Panageas KS, Arroyo C, Valero V, Currie V, Gilewski T, Theodoulou M, Moynahan ME, Moasser M, Sklarin N, Dickler M, D'Andrea G, Cristofanilli M, Rivera E, Hortobagyi GN, Norton L, Hudis CA. Weekly trastuzumab and paclitaxel therapy for metastatic breast cancer with analysis of efficacy by HER2 immunophenotype and gene amplification. J Clin Oncol. 2001 May 15;19(10):2587-95. link to original article PubMed
3. Robert N, Leyland-Jones B, Asmar L, Belt R, Ilegbodu D, Loesch D, Raju R, Valentine E, Sayre R, Cobleigh M, Albain K, McCullough C, Fuchs L, Slamon D. Randomized phase III study of trastuzumab, paclitaxel, and carboplatin compared with trastuzumab and paclitaxel in women with HER-2-overexpressing metastatic breast cancer. J Clin Oncol. 2006 Jun 20;24(18):2786-92. link to original article PubMed
4. TRAVIOTA: Burstein HJ, Keshaviah A, Baron AD, Hart RD, Lambert-Falls R, Marcom PK, Gelman R, Winer EP. Trastuzumab plus vinorelbine or taxane chemotherapy for HER2-overexpressing metastatic breast cancer: the trastuzumab and vinorelbine or taxane study. Cancer. 2007 Sep 1;110(5):965-72. link to original article PubMed
5. CALGB 9840: Seidman AD, Berry D, Cirrincione C, Harris L, Muss H, Marcom PK, Gipson G, Burstein H, Lake D, Shapiro CL, Ungaro P, Norton L, Winer E, Hudis C. Randomized phase III trial of weekly compared with every-3-weeks paclitaxel for metastatic breast cancer, with trastuzumab for all HER-2 overexpressors and random assignment to trastuzumab or not in HER-2 nonoverexpressors: final results of Cancer and Leukemia Group B protocol 9840. J Clin Oncol. 2008 Apr 1;26(10):1642-9. link to original article PubMed
6. STM01-102: Baselga J, Manikhas A, Cortés J, Llombart A, Roman L, Semiglazov VF, Byakhov M, Lokanatha D, Forenza S, Goldfarb RH, Matera J, Azarnia N, Hudis CA, Rozencweig M. Phase III trial of nonpegylated liposomal doxorubicin in combination with trastuzumab and paclitaxel in HER2-positive metastatic breast cancer. Ann Oncol. 2014 Mar;25(3):592-8. Epub 2014 Jan 8. link to original article link to PMC article contains protocol PubMed NCT00294996
7. NCIC-CTG MA.31: Gelmon KA, Boyle FM, Kaufman B, Huntsman DG, Manikhas A, Di Leo A, Martin M, Schwartzberg LS, Lemieux J, Aparicio S, Shepherd LE, Dent S, Ellard SL, Tonkin K, Pritchard KI, Whelan TJ, Nomikos D, Nusch A, Coleman RE, Mukai H, Tjulandin S, Khasanov R, Rizel S, Connor AP, Santillana SL, Chapman JA, Parulekar WR. Lapatinib or trastuzumab plus taxane therapy for human epidermal growth factor receptor 2-positive advanced breast cancer: final results of NCIC-CTG MA.31. J Clin Oncol. 2015 May 10;33(14):1574-83. Epub 2015 Mar 16. link to original article contains verified protocol PubMed NCT00667251
8. BOLERO-1: Hurvitz SA, Andre F, Jiang Z, Shao Z, Mano MS, Neciosup SP, Tseng LM, Zhang Q, Shen K, Liu D, Dreosti LM, Burris HA, Toi M, Buyse ME, Cabaribere D, Lindsay MA, Rao S, Pacaud LB, Taran T, Slamon D. Combination of everolimus with trastuzumab plus paclitaxel as first-line treatment for patients with HER2-positive advanced breast cancer (BOLERO-1): a phase 3, randomised, double-blind, multicentre trial. Lancet Oncol. 2015 Jul;16(7):816-29. Epub 2015 Jun 16. link to original article PubMed NCT00876395
9. MARIANNE: Perez EA, Barrios C, Eiermann W, Toi M, Im YH, Conte P, Martin M, Pienkowski T, Pivot X, Burris H 3rd, Petersen JA, Stanzel S, Strasak A, Patre M, Ellis P. Trastuzumab emtansine with or without pertuzumab versus trastuzumab plus taxane for human epidermal growth factor receptor 2-positive, advanced breast cancer: primary results from the phase III MARIANNE study. J Clin Oncol. 2017 Jan 10;35(2):141-148. Epub 2016 Nov 7. link to original article link to PMC article contains verified protocol PubMed NCT01120184
   1. Update: Perez EA, Barrios C, Eiermann W, Toi M, Im YH, Conte P, Martin M, Pienkowski T, Pivot XB, Burris HA 3rd, Petersen JA, De Haas S, Hoersch S, Patre M, Ellis PA. Trastuzumab emtansine with or without pertuzumab versus trastuzumab with taxane for human epidermal growth factor receptor 2-positive advanced breast cancer: final results from MARIANNE. Cancer. 2019 Nov 15;125(22):3974-3984. Epub 2019 Jul 18. link to original article PubMed
10. NEfERT-T: Awada A, Colomer R, Inoue K, Bondarenko I, Badwe RA, Demetriou G, Lee SC, Mehta AO, Kim SB, Bachelot T, Goswami C, Deo S, Bose R, Wong A, Xu F, Yao B, Bryce R, Carey LA. neratinib plus paclitaxel vs trastuzumab plus paclitaxel in previously untreated metastatic ERBB2-positive breast cancer: The NEfERT-T randomized clinical trial. JAMA Oncol. 2016 Dec 1;2(12):1557-1564. link to original article contains verified protocol PubMed NCT00915018

THP (Taxotere)

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THP: Taxotere (Docetaxel), Herceptin (Trastuzumab), Pertuzumab

Regimen

FDA-recommended dose

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Baselga et al. 2011 (CLEOPATRA)	2008-2010	Phase III (E-RT-esc)	Docetaxel & Trastuzumab	Superior OS1 Median OS: 57.1 vs 40.8 mo (HR 0.69, 95% CI 0.58-0.82)
Xu et al. 2020 (PUFFIN)	2016-2017	Phase III (E-esc)	Docetaxel & Trastuzumab	Seems to have superior PFS Median PFS: 14.5 vs 12.4 mo (HR 0.69, 95% CI 0.49-0.99)

¹Reported efficacy for CLEOPATRA is based on the 2020 update.

Chemotherapy

• Docetaxel (Taxotere) given third as follows:
  • Cycle 1: 75 mg/m² IV once on day 2
  • Cycle 2 onwards: 75 mg/m² IV once on day 1

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV over 90 minutes once on day 2
  • Cycle 2 onwards: 6 mg/kg IV over 30 to 90 minutes once on day 1
• Pertuzumab (Perjeta) as follows:
  • Cycle 1: 840 mg IV over 60 minutes once on day 1
  • Cycle 2 onwards: 420 mg IV over 30 to 60 minutes once on day 1

21-day cycle for at least 6 cycles

Subsequent treatment

• If it is decided to no longer administer docetaxel, then patients could continue to receive pertuzumab & trastuzumab maintenance.

References

1. CLEOPATRA: Baselga J, Cortés J, Kim SB, Im SA, Hegg R, Im YH, Roman L, Pedrini JL, Pienkowski T, Knott A, Clark E, Benyunes MC, Ross G, Swain SM; CLEOPATRA Study Group. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012 Jan 12;366(2):109-19. Epub 2011 Dec 7. link to original article contains verified protocol link to PMC article PubMed NCT00567190
   1. Update: Swain SM, Kim SB, Cortés J, Ro J, Semiglazov V, Campone M, Ciruelos E, Ferrero JM, Schneeweiss A, Knott A, Clark E, Ross G, Benyunes MC, Baselga J. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): overall survival results from a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2013 May;14(6):461-71. Epub 2013 Apr 18. link to original article contains verified protocol link to PMC article PubMed
   2. Update: Swain SM, Baselga J, Kim SB, Ro J, Semiglazov V, Campone M, Ciruelos E, Ferrero JM, Schneeweiss A, Heeson S, Clark E, Ross G, Benyunes MC, Cortés J; CLEOPATRA Study Group. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med. 2015 Feb 19;372(8):724-34. link to original article PubMed
   3. Update: Swain SM, Miles D, Kim SB, Im YH, Im SA, Semiglazov V, Ciruelos E, Schneeweiss A, Loi S, Monturus E, Clark E, Knott A, Restuccia E, Benyunes MC, Cortés J; CLEOPATRA study group. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA): end-of-study results from a double-blind, randomised, placebo-controlled, phase 3 study. Lancet Oncol. 2020 Apr;21(4):519-530. Epub 2020 Mar 12. link to original article PubMed
2. PUFFIN: Xu B, Li W, Zhang Q, Shao Z, Li Q, Wang X, Li H, Sun T, Yin Y, Zheng H, Feng J, Zhang H, Lei G, Restuccia E. Pertuzumab, trastuzumab, and docetaxel for Chinese patients with previously untreated HER2-positive locally recurrent or metastatic breast cancer (PUFFIN): a phase III, randomized, double-blind, placebo-controlled study. Breast Cancer Res Treat. 2020 Aug;182(3):689-697. Epub 2020 Jun 20. link to original article link to PMC article contains verified protocol PubMed NCT02896855

TL (Taxol)

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TL: Taxol (Paclitaxel) & Lapatinib

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Guan et al. 2013 (EGF104535)	2006-2009	Phase III (E-esc)	Paclitaxel	Seems to have superior OS

Chemotherapy

• Paclitaxel (Taxol) 80 mg/m² IV once per day on days 1, 8, 15

Targeted therapy

• Lapatinib (Tykerb) 1500 mg PO once per day

28-day cycles

References

1. EGF104535: Guan Z, Xu B, DeSilvio ML, Shen Z, Arpornwirat W, Tong Z, Lorvidhaya V, Jiang Z, Yang J, Makhson A, Leung WL, Russo MW, Newstat B, Wang L, Chen G, Oliva C, Gomez H. Randomized trial of lapatinib versus placebo added to paclitaxel in the treatment of human epidermal growth factor receptor 2-overexpressing metastatic breast cancer. J Clin Oncol. 2013 Jun 1;31(16):1947-53. Epub 2013 Mar 18. link to original article contains verified protocol PubMed NCT00281658
2. NCIC-CTG MA.31: Gelmon KA, Boyle FM, Kaufman B, Huntsman DG, Manikhas A, Di Leo A, Martin M, Schwartzberg LS, Lemieux J, Aparicio S, Shepherd LE, Dent S, Ellard SL, Tonkin K, Pritchard KI, Whelan TJ, Nomikos D, Nusch A, Coleman RE, Mukai H, Tjulandin S, Khasanov R, Rizel S, Connor AP, Santillana SL, Chapman JA, Parulekar WR. Lapatinib or trastuzumab plus taxane therapy for human epidermal growth factor receptor 2-positive advanced breast cancer: final results of NCIC-CTG MA.31. J Clin Oncol. 2015 May 10;33(14):1574-83. Epub 2015 Mar 16. link to original article PubMed NCT00667251

TPC

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TPC: Trastuzumab, Paclitaxel, Carboplatin
TCH: Taxol (Paclitaxel), Carboplatin, Herceptin (Trastuzumab)

Regimen variant #1, weekly

Study	Evidence
Perez et al. 2005 (NCCTG 983252)	Phase II

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8, 15, 22
  • Cycles 2 to 6: 2 mg/kg IV once per day on days 1, 8, 15, 22

Chemotherapy

• Paclitaxel (Taxol) 80 mg/m² IV once per day on days 1, 8, 15
• Carboplatin (Paraplatin) AUC 2 IV once per day on days 1, 8, 15

28-day cycle for 6 cycles

Subsequent treatment

• Trastuzumab maintenance (weekly)

Regimen variant #2, weekly T, q3wk PC

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Robert et al. 2006	1998-2002	Phase III (E-esc)	TP	Seems to have superior PFS

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8 & 15
  • Cycle 2 onwards: 2 mg/kg IV once per day on days 1, 8, 15

Chemotherapy

• Paclitaxel (Taxol) 175 mg/m² IV once on day 2
• Carboplatin (Paraplatin) AUC 6 IV once on day 2

21-day cycle for at least 6 cycles

Subsequent treatment

• Trastuzumab maintenance (weekly)

Regimen variant #3, q3wk

Study	Evidence
Perez et al. 2005 (NCCTG 983252)	Phase II

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV once on day 1
  • Cycles 2 to 8: 6 mg/kg IV once on day 1

Chemotherapy

• Paclitaxel (Taxol) 200 mg/m² IV once on day 1
• Carboplatin (Paraplatin) AUC 6 IV once on day 1

21-day cycle for 8 cycles

Subsequent treatment

• Trastuzumab maintenance (q3wk)

References

1. NCCTG 983252: Perez EA, Suman VJ, Rowland KM, Ingle JN, Salim M, Loprinzi CL, Flynn PJ, Mailliard JA, Kardinal CG, Krook JE, Thrower AR, Visscher DW, Jenkins RB. Two concurrent phase II trials of paclitaxel/carboplatin/trastuzumab (weekly or every-3-week schedule) as first-line therapy in women with HER2-overexpressing metastatic breast cancer: NCCTG study 983252. Clin Breast Cancer. 2005 Dec;6(5):425-32. link to original article PubMed
2. Robert N, Leyland-Jones B, Asmar L, Belt R, Ilegbodu D, Loesch D, Raju R, Valentine E, Sayre R, Cobleigh M, Albain K, McCullough C, Fuchs L, Slamon D. Randomized phase III study of trastuzumab, paclitaxel, and carboplatin compared with trastuzumab and paclitaxel in women with HER-2-overexpressing metastatic breast cancer. J Clin Oncol. 2006 Jun 20;24(18):2786-92. link to original article contains verified protocol PubMed

Ado-trastuzumab emtansine monotherapy

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T-DM1: Trastuzumab-DM1 (Ado-trastuzumab emtansine)

Example orders

• Example orders for Ado-trastuzumab emtansine (Kadcyla) in breast cancer

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Hurvitz et al. 2013 (TDM4450g)	2008-2009	Randomized Phase II (E-de-esc)	TH	Seems to have superior PFS
Perez et al. 2016 (MARIANNE)	2010-2012	Phase III (E-de-esc)	1. T-DM1 & Pertuzumab	Non-inferior PFS
			2. TH (Taxotere) 3. TH (Taxol)	Non-inferior PFS

Antibody-drug conjugate therapy

• Ado-trastuzumab emtansine (Kadcyla) 3.6 mg/kg IV once on day 1

21-day cycles

References

1. TDM4450g: Hurvitz SA, Dirix L, Kocsis J, Bianchi GV, Lu J, Vinholes J, Guardino E, Song C, Tong B, Ng V, Chu YW, Perez EA. Phase II randomized study of trastuzumab emtansine versus trastuzumab plus docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer. J Clin Oncol. 2013 Mar 20;31(9):1157-63. Epub 2013 Feb 4. Erratum in: J Clin Oncol. 2013 Aug 10;31(23):2977. link to original article contains verified protocol PubMed NCT00679341
2. MARIANNE: Perez EA, Barrios C, Eiermann W, Toi M, Im YH, Conte P, Martin M, Pienkowski T, Pivot X, Burris H 3rd, Petersen JA, Stanzel S, Strasak A, Patre M, Ellis P. Trastuzumab emtansine with or without pertuzumab versus trastuzumab plus taxane for human epidermal growth factor receptor 2-positive, advanced breast cancer: primary results from the phase III MARIANNE study. J Clin Oncol. 2017 Jan 10;35(2):141-148. Epub 2016 Nov 7. link to original article link to PMC article contains verified protocol PubMed NCT01120184
   1. Update: Perez EA, Barrios C, Eiermann W, Toi M, Im YH, Conte P, Martin M, Pienkowski T, Pivot XB, Burris HA 3rd, Petersen JA, De Haas S, Hoersch S, Patre M, Ellis PA. Trastuzumab emtansine with or without pertuzumab versus trastuzumab with taxane for human epidermal growth factor receptor 2-positive advanced breast cancer: final results from MARIANNE. Cancer. 2019 Nov 15;125(22):3974-3984. Epub 2019 Jul 18. link to original article PubMed

Trastuzumab monotherapy

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Regimen variant #1

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Pagani et al. 2017 (SAKK 22/99)	1999-2013	Phase III (C)	Chemotherapy & Trastuzumab	Did not meet primary endpoint of TTP

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 4 mg/kg IV once on day 1
  • Cycle 2 onwards: 2 mg/kg IV once on day 1

7-day cycles

Regimen variant #2, flat dose

Study	Evidence
Baselga et al. 1996	Phase II

Note: this is of historical interest, only.

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 250 mg IV once on day 1
  • Cycles 2 to 11: 100 mg IV once on day 1

7-day cycle for 11 cycles

References

1. Baselga J, Tripathy D, Mendelsohn J, Baughman S, Benz CC, Dantis L, Sklarin NT, Seidman AD, Hudis CA, Moore J, Rosen PP, Twaddell T, Henderson IC, Norton L. Phase II study of weekly intravenous recombinant humanized anti-p185HER2 monoclonal antibody in patients with HER2/neu-overexpressing metastatic breast cancer. J Clin Oncol. 1996 Mar;14(3):737-44. link to original article PubMed
2. SAKK 22/99: Pagani O, Klingbiel D, Ruhstaller T, Nolè F, Eppenberger S, Oehlschlegel C, Bernhard J, Brauchli P, Hess D, Mamot C, Munzone E, Pestalozzi B, Rabaglio M, Aebi S, Ribi K, Rochlitz C, Rothgiesser K, Thürlimann B, von Moos R, Zaman K, Goldhirsch A; Swiss Group for Clinical Cancer Research. Do all patients with advanced HER2 positive breast cancer need upfront-chemo when receiving trastuzumab? Randomized phase III trial SAKK 22/99. Ann Oncol. 2017 Feb 1;28(2):305-312. link to original article contains verified protocol PubMed NCT00004935

Vinorelbine & Trastuzumab (VH)

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VH: Vinorelbine & Herceptin (Trastuzumab)

Regimen variant #1, vinorelbine 25 mg/m²

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Burstein et al. 2007 (TRAVIOTA)	2001-2003	Phase III (E-switch-ic)	1. TH (Taxotere) 2. TH (Taxol)	Might have superior TTP

Chemotherapy

• Vinorelbine (Navelbine) 25 mg/m² IV once per day on days 1, 8, 15, 22

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8, 15, 22
  • Cycle 2 onwards: 2 mg/kg IV once per day on days 1, 8, 15, 22

28-day cycles

Regimen variant #2, vinorelbine 30 mg/m², 2 out of 3 weeks

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Andersson et al. 2010 (HERNATA)	2004-2008	Phase III (E-switch-ic)	TH (Taxotere)	Did not meet primary endpoint of TTP

Chemotherapy

• Vinorelbine (Navelbine) 30 mg/m² IV once per day on days 1 & 8

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV over 90 minutes once on day 1
  • Cycle 2 onwards: 6 mg/kg IV over 30 minutes once on day 1

21-day cycles

Regimen variant #3, vinorelbine 35 mg/m², 2 out of 3 weeks

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Andersson et al. 2010 (HERNATA)	2004-2008	Phase III (E-switch-ic)	TH (Taxotere)	Did not meet primary endpoint of TTP

Chemotherapy

• Vinorelbine (Navelbine) 35 mg/m² IV once per day on days 1 & 8

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV over 90 minutes once on day 1
  • Cycle 2 onwards: 6 mg/kg IV over 30 minutes once on day 1

21-day cycles

References

1. TRAVIOTA: Burstein HJ, Keshaviah A, Baron AD, Hart RD, Lambert-Falls R, Marcom PK, Gelman R, Winer EP. Trastuzumab plus vinorelbine or taxane chemotherapy for HER2-overexpressing metastatic breast cancer: the trastuzumab and vinorelbine or taxane study. Cancer. 2007 Sep 1;110(5):965-72. link to original article PubMed
2. HERNATA: Andersson M, Lidbrink E, Bjerre K, Wist E, Enevoldsen K, Jensen AB, Karlsson P, Tange UB, Sørensen PG, Møller S, Bergh J, Langkjer ST. Phase III randomized study comparing docetaxel plus trastuzumab with vinorelbine plus trastuzumab as first-line therapy of metastatic or locally advanced human epidermal growth factor receptor 2-positive breast cancer: the HERNATA study. J Clin Oncol. 2011 Jan 20;29(3):264-71. Epub 2010 Dec 13. link to original article contains verified protocol PubMed

Metastatic or unresectable disease, subsequent lines

Capecitabine & Lapatinib

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Geyer et al. 2006 (EGF100151)	2004-2005	Phase III (E-RT-esc)	Capecitabine	Superior TTP
Verma et al. 2012 (EMILIA)	2009-2011	Phase III (C)	T-DM1	Inferior OS
Pivot et al. 2015 (CEREBEL)	2009-2012	Phase III (C)	Capecitabine & Trastuzumab	Did not meet primary endpoint of CNS site of first relapse
Saura et al. 2020 (NALA)	2013-2017	Phase III (C)	Capecitabine & Neratinib	Inferior PFS
Xu et al. 2021 (PHOEBE)	2017-2018	Phase III (C)	Capecitabine & Pyrotinib	Inferior PFS

Note: the primary endpoint of CEREBEL was incidence of CNS as site of first relapse; this was very low in both arms, with no statistically significant difference.

Chemotherapy

• Capecitabine (Xeloda) 1000 mg/m² PO twice per day on days 1 to 14

Targeted therapy

• Lapatinib (Tykerb) 1250 mg PO once per day

21-day cycles

References

1. EGF100151: Geyer CE, Forster J, Lindquist D, Chan S, Romieu CG, Pienkowski T, Jagiello-Gruszfeld A, Crown J, Chan A, Kaufman B, Skarlos D, Campone M, Davidson N, Berger M, Oliva C, Rubin SD, Stein S, Cameron D. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med. 2006 Dec 28;355(26):2733-43. link to original article contains protocol PubMed NCT00078572
   1. Update: Cameron D, Casey M, Press M, Lindquist D, Pienkowski T, Romieu CG, Chan S, Jagiello-Gruszfeld A, Kaufman B, Crown J, Chan A, Campone M, Viens P, Davidson N, Gorbounova V, Raats JI, Skarlos D, Newstat B, Roychowdhury D, Paoletti P, Oliva C, Rubin S, Stein S, Geyer CE. A phase III randomized comparison of lapatinib plus capecitabine versus capecitabine alone in women with advanced breast cancer that has progressed on trastuzumab: updated efficacy and biomarker analyses. Breast Cancer Res Treat. 2008 Dec;112(3):533-43. link to original article PubMed
   2. Update: Cameron D, Casey M, Oliva C, Newstat B, Imwalle B, Geyer CE. Lapatinib plus capecitabine in women with HER-2-positive advanced breast cancer: final survival analysis of a phase III randomized trial. Oncologist. 2010;15(9):924-34. link to original article link to PMC article PubMed
2. EMILIA: Verma S, Miles D, Gianni L, Krop IE, Welslau M, Baselga J, Pegram M, Oh DY, Diéras V, Guardino E, Fang L, Lu MW, Olsen S, Blackwell K; EMILIA Study Group. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med. 2012 Nov 8;367(19):1783-91. Epub 2012 Oct 1. Erratum in: N Engl J Med. 2013 Jun 20;368(25):2442. link to original article contains verified protocol link to PMC article PubMed NCT00829166
   1. Update: Diéras V, Miles D, Verma S, Pegram M, Welslau M, Baselga J, Krop IE, Blackwell K, Hoersch S, Xu J, Green M, Gianni L. Trastuzumab emtansine versus capecitabine plus lapatinib in patients with previously treated HER2-positive advanced breast cancer (EMILIA): a descriptive analysis of final overall survival results from a randomised, open-label, phase 3 trial. Lancet Oncol. 2017 Jun;18(6):732-742. Epub 2017 May 16. link to original article link to PMC article PubMed
3. CEREBEL: Pivot X, Manikhas A, Żurawski B, Chmielowska E, Karaszewska B, Allerton R, Chan S, Fabi A, Bidoli P, Gori S, Ciruelos E, Dank M, Hornyak L, Margolin S, Nusch A, Parikh R, Nagi F, DeSilvio M, Santillana S, Swaby RF, Semiglazov V. CEREBEL (EGF111438): A phase III, randomized, open-label study of lapatinib plus capecitabine versus trastuzumab plus capecitabine in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer. J Clin Oncol. 2015 May 10;33(14):1564-73. Epub 2015 Jan 20. link to original article PubMed NCT00820222
4. NALA: Saura C, Oliveira M, Feng YH, Dai MS, Chen SW, Hurvitz SA, Kim SB, Moy B, Delaloge S, Gradishar W, Masuda N, Palacova M, Trudeau ME, Mattson J, Yap YS, Hou MF, De Laurentiis M, Yeh YM, Chang HT, Yau T, Wildiers H, Haley B, Fagnani D, Lu YS, Crown J, Lin J, Takahashi M, Takano T, Yamaguchi M, Fujii T, Yao B, Bebchuk J, Keyvanjah K, Bryce R, Brufsky A; NALA Investigators. Neratinib Plus Capecitabine Versus Lapatinib Plus Capecitabine in HER2-Positive Metastatic Breast Cancer Previously Treated With ≥ 2 HER2-Directed Regimens: Phase III NALA Trial. J Clin Oncol. 2020 Sep 20;38(27):3138-3149. Epub 2020 Jul 17. link to original article contains protocol link to PMC article PubMed NCT01808573
5. PHOEBE: Xu B, Yan M, Ma F, Hu X, Feng J, Ouyang Q, Tong Z, Li H, Zhang Q, Sun T, Wang X, Yin Y, Cheng Y, Li W, Gu Y, Chen Q, Liu J, Cheng J, Geng C, Qin S, Wang S, Lu J, Shen K, Liu Q, Wang X, Wang H, Luo T, Yang J, Wu Y, Yu Z, Zhu X, Chen C, Zou J; PHOEBE Investigators. Pyrotinib plus capecitabine versus lapatinib plus capecitabine for the treatment of HER2-positive metastatic breast cancer (PHOEBE): a multicentre, open-label, randomised, controlled, phase 3 trial. Lancet Oncol. 2021 Feb 11:S1470-2045(20)30702-6. Epub ahead of print. link to original article contains protocol PubMed NCT03080805

Capecitabine & Margetuximab

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Rugo et al. 2021 (SOPHIA)	2015-2018	Phase III (E-RT-switch-ic)	XH	Seems to have superior PFS Median PFS: 6 mo vs 5 mo (HR 0.76, 95% CI 0.59-0.98)

Chemotherapy

• Capecitabine (Xeloda) 1000 mg/m² PO twice per day on days 1 to 14

Targeted therapy

• Margetuximab (Margenza) 15 mg/kg IV over 120 minutes once on day 1

21-day cycles

References

1. SOPHIA: Rugo HS, Im SA, Cardoso F, Cortés J, Curigliano G, Musolino A, Pegram MD, Wright GS, Saura C, Escrivá-de-Romaní S, De Laurentiis M, Levy C, Brown-Glaberman U, Ferrero JM, de Boer M, Kim SB, Petráková K, Yardley DA, Freedman O, Jakobsen EH, Kaufman B, Yerushalmi R, Fasching PA, Nordstrom JL, Bonvini E, Koenig S, Edlich S, Hong S, Rock EP, Gradishar WJ; SOPHIA Study Group. Efficacy of Margetuximab vs Trastuzumab in Patients With Pretreated ERBB2-Positive Advanced Breast Cancer: A Phase 3 Randomized Clinical Trial. JAMA Oncol. 2021 Apr 1;7(4):573-584. link to original article link to PMC article contains verified protocol PubMed NCT02492711

Capecitabine & Neratinib

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Saura et al. 2014 (3144A1-2206)	2008-NR	Phase I/II		ORR: 64%
Saura et al. 2020 (NALA)	2013-2017	Phase III (E-RT-switch-ic)	Capecitabine & Lapatinib	Superior PFS

Chemotherapy

• Capecitabine (Xeloda) 750 mg/m² PO twice per day on days 1 to 14

Targeted therapy

• Neratinib (Nerlynx) 240 mg PO once per day

21-day cycles

References

1. 3144A1-2206: Saura C, Garcia-Saenz JA, Xu B, Harb W, Moroose R, Pluard T, Cortés J, Kiger C, Germa C, Wang K, Martin M, Baselga J, Kim SB. Safety and efficacy of neratinib in combination with capecitabine in patients with metastatic human epidermal growth factor receptor 2-positive breast cancer. J Clin Oncol. 2014 Nov 10;32(32):3626-33. Epub 2014 Oct 6. link to original article contains verified protocol PubMed NCT00741260
2. NALA: Saura C, Oliveira M, Feng YH, Dai MS, Chen SW, Hurvitz SA, Kim SB, Moy B, Delaloge S, Gradishar W, Masuda N, Palacova M, Trudeau ME, Mattson J, Yap YS, Hou MF, De Laurentiis M, Yeh YM, Chang HT, Yau T, Wildiers H, Haley B, Fagnani D, Lu YS, Crown J, Lin J, Takahashi M, Takano T, Yamaguchi M, Fujii T, Yao B, Bebchuk J, Keyvanjah K, Bryce R, Brufsky A; NALA Investigators. Neratinib Plus Capecitabine Versus Lapatinib Plus Capecitabine in HER2-Positive Metastatic Breast Cancer Previously Treated With ≥ 2 HER2-Directed Regimens: Phase III NALA Trial. J Clin Oncol. 2020 Sep 20;38(27):3138-3149. Epub 2020 Jul 17. link to original article contains protocol link to PMC article PubMed NCT01808573

Capecitabine, Pertuzumab, Trastuzumab

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Urruticoechea et al. 2017 (PHEREXA)	2010-2013	Phase III (E-esc)	Capecitabine & Trastuzumab	Might have superior PFS

Chemotherapy

• Capecitabine (Xeloda) 1000 mg/m² PO twice per day on days 1 to 14

Targeted therapy

• Pertuzumab (Perjeta) as follows:
  • Cycle 1: 840 mg IV once on day 1
  • Cycle 2 onwards: 420 mg IV once on day 1
• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV once on day 1
  • Cycle 2 onwards: 6 mg/kg IV once on day 1

21-day cycles

References

1. PHEREXA: Urruticoechea A, Rizwanullah M, Im SA, Ruiz ACS, Láng I, Tomasello G, Douthwaite H, Badovinac Crnjevic T, Heeson S, Eng-Wong J, Muñoz M. Randomized phase III trial of trastuzumab plus capecitabine with or without pertuzumab in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer who experienced disease progression during or after trastuzumab-based therapy. J Clin Oncol. 2017 Sep 10;35(26):3030-3038. Epub 2017 Apr 24. link to original article contains verified protocol PubMed NCT01026142

Capecitabine & Trastuzumab (XH)

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XH: Xeloda (Capecitabine) & Herceptin

Regimen variant #1, 2000/6, with loading dose

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Rugo et al. 2021 (SOPHIA)	2015-2018	Phase III (C)	Capecitabine & Margetuximab	Seems to have inferior PFS
Murthy et al. 2019 (HER2CLIMB)	2016-2019	Phase III (C)	Capecitabine, Tucatinib, Trastuzumab	Inferior OS

Chemotherapy

• Capecitabine (Xeloda) 1000 mg/m² PO twice per day on days 1 to 14

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV once on day 1
  • Cycle 2 onwards: 6 mg/kg IV once on day 1

21-day cycles

Regimen variant #2, 2500/6, with loading dose

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Bartsch et al. 2007	2004-2006	Phase II
Pivot et al. 2015 (CEREBEL)	2009-2012	Phase III (C)	Capecitabine & Lapatanib	Did not meet primary endpoint of CNS site of first relapse
Urruticoechea et al. 2017 (PHEREXA)	2010-2013	Phase III (C)	Capecitabine, Pertuzumab, Trastuzumab	Might have inferior PFS

Note: the only difference between this and variant #2 is the use of a loading dose of trastuzumab. The primary endpoint of CEREBEL was incidence of CNS as site of first relapse; this was very low in both arms, with no statistically significant difference.

Chemotherapy

• Capecitabine (Xeloda) 1250 mg/m² PO twice per day on days 1 to 14

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV once on day 1
  • Cycle 2 onwards: 6 mg/kg IV once on day 1

21-day cycles

Regimen variant #3, 2500/6, no loading dose

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
von Minckwitz et al. 2009 (GBG 26/BIG 3-05)	2003-NR	Phase III (E-esc)	Capecitabine	Seems to have superior TTP

This is a continuation of trastuzumab so there is no loading dose.

Chemotherapy

• Capecitabine (Xeloda) 1250 mg/m² PO twice per day on days 1 to 14

Targeted therapy

• Trastuzumab (Herceptin) 6 mg/kg IV once on day 1

21-day cycles

References

1. Bartsch R, Wenzel C, Altorjai G, Pluschnig U, Rudas M, Mader RM, Gnant M, Zielinski CC, Steger GG. Capecitabine and trastuzumab in heavily pretreated metastatic breast cancer. J Clin Oncol. 2007 Sep 1;25(25):3853-8. Epub 2007 Aug 6. link to original article contains verified protocol PubMed
2. GBG 26/BIG 3-05: von Minckwitz G, du Bois A, Schmidt M, Maass N, Cufer T, de Jongh FE, Maartense E, Zielinski C, Kaufmann M, Bauer W, Baumann KH, Clemens MR, Duerr R, Uleer C, Andersson M, Stein RC, Nekljudova V, Loibl S. Trastuzumab beyond progression in human epidermal growth factor receptor 2-positive advanced breast cancer: a German Breast Group 26/Breast International Group 03-05 study. J Clin Oncol. 2009 Apr 20;27(12):1999-2006. Epub 2009 Mar 16. link to original article contains verified protocol PubMed
   1. Update: von Minckwitz G, Schwedler K, Schmidt M, Barinoff J, Mundhenke C, Cufer T, Maartense E, de Jongh FE, Baumann KH, Bischoff J, Harbeck N, Lück HJ, Maass N, Zielinski C, Andersson M, Stein RC, Nekljudova V, Loibl S; GBG 26/BIG 03-05 study group and participating investigators. Trastuzumab beyond progression: overall survival analysis of the GBG 26/BIG 3-05 phase III study in HER2-positive breast cancer. Eur J Cancer. 2011 Oct;47(15):2273-81. Epub 2011 Jul 7. link to original article PubMed
3. CEREBEL: Pivot X, Manikhas A, Żurawski B, Chmielowska E, Karaszewska B, Allerton R, Chan S, Fabi A, Bidoli P, Gori S, Ciruelos E, Dank M, Hornyak L, Margolin S, Nusch A, Parikh R, Nagi F, DeSilvio M, Santillana S, Swaby RF, Semiglazov V. CEREBEL (EGF111438): A phase III, randomized, open-label study of lapatinib plus capecitabine versus trastuzumab plus capecitabine in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer. J Clin Oncol. 2015 May 10;33(14):1564-73. Epub 2015 Jan 20. link to original article contains protocol PubMed NCT00820222
4. PHEREXA: Urruticoechea A, Rizwanullah M, Im SA, Ruiz ACS, Láng I, Tomasello G, Douthwaite H, Badovinac Crnjevic T, Heeson S, Eng-Wong J, Muñoz M. Randomized phase III trial of trastuzumab plus capecitabine with or without pertuzumab in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer who experienced disease progression during or after trastuzumab-based therapy. J Clin Oncol. 2017 Sep 10;35(26):3030-3038. Epub 2017 Apr 24. link to original article contains verified protocol PubMed NCT01026142
5. HER2CLIMB: Murthy RK, Loi S, Okines A, Paplomata E, Hamilton E, Hurvitz SA, Lin NU, Borges V, Abramson V, Anders C, Bedard PL, Oliveira M, Jakobsen E, Bachelot T, Shachar SS, Müller V, Braga S, Duhoux FP, Greil R, Cameron D, Carey LA, Curigliano G, Gelmon K, Hortobagyi G, Krop I, Loibl S, Pegram M, Slamon D, Palanca-Wessels MC, Walker L, Feng W, Winer EP. Tucatinib, Trastuzumab, and Capecitabine for HER2-Positive Metastatic Breast Cancer. N Engl J Med. 2020 Feb 13;382(7):597-609. Epub 2019 Dec 11. Erratum in: N Engl J Med. 2020 Feb 6;382(6):586. link to original article contains verified protocol PubMed NCT02614794
   1. Subgroup analysis: Lin NU, Borges V, Anders C, Murthy RK, Paplomata E, Hamilton E, Hurvitz S, Loi S, Okines A, Abramson V, Bedard PL, Oliveira M, Mueller V, Zelnak A, DiGiovanna MP, Bachelot T, Chien AJ, O'Regan R, Wardley A, Conlin A, Cameron D, Carey L, Curigliano G, Gelmon K, Loibl S, Mayor J, McGoldrick S, An X, Winer EP. Intracranial Efficacy and Survival With Tucatinib Plus Trastuzumab and Capecitabine for Previously Treated HER2-Positive Breast Cancer With Brain Metastases in the HER2CLIMB Trial. J Clin Oncol. 2020 Aug 10;38(23):2610-2619. Epub 2020 May 29. link to original article link to PMC article PubMed
6. SOPHIA: Rugo HS, Im SA, Cardoso F, Cortés J, Curigliano G, Musolino A, Pegram MD, Wright GS, Saura C, Escrivá-de-Romaní S, De Laurentiis M, Levy C, Brown-Glaberman U, Ferrero JM, de Boer M, Kim SB, Petráková K, Yardley DA, Freedman O, Jakobsen EH, Kaufman B, Yerushalmi R, Fasching PA, Nordstrom JL, Bonvini E, Koenig S, Edlich S, Hong S, Rock EP, Gradishar WJ; SOPHIA Study Group. Efficacy of Margetuximab vs Trastuzumab in Patients With Pretreated ERBB2-Positive Advanced Breast Cancer: A Phase 3 Randomized Clinical Trial. JAMA Oncol. 2021 Apr 1;7(4):573-584. link to original article link to PMC article contains verified protocol PubMed NCT02492711

Capecitabine, Tucatinib, Trastuzumab

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Murthy et al. 2019 (HER2CLIMB)	2016-2019	Phase III (E-RT)	XH	Superior OS

Chemotherapy

• Capecitabine (Xeloda) 1000 mg/m² PO twice per day on days 1 to 14

Targeted therapy

• Tucatinib (Tukysa) 300 mg PO twice per day
• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV once on day 1
  • Cycle 2 onwards: 6 mg/kg IV once on day 1

21-day cycles

References

1. HER2CLIMB: Murthy RK, Loi S, Okines A, Paplomata E, Hamilton E, Hurvitz SA, Lin NU, Borges V, Abramson V, Anders C, Bedard PL, Oliveira M, Jakobsen E, Bachelot T, Shachar SS, Müller V, Braga S, Duhoux FP, Greil R, Cameron D, Carey LA, Curigliano G, Gelmon K, Hortobagyi G, Krop I, Loibl S, Pegram M, Slamon D, Palanca-Wessels MC, Walker L, Feng W, Winer EP. Tucatinib, Trastuzumab, and Capecitabine for HER2-Positive Metastatic Breast Cancer. N Engl J Med. 2020 Feb 13;382(7):597-609. Epub 2019 Dec 11. Erratum in: N Engl J Med. 2020 Feb 6;382(6):586. link to original article contains verified protocol PubMed NCT02614794
   1. Subgroup analysis: Lin NU, Borges V, Anders C, Murthy RK, Paplomata E, Hamilton E, Hurvitz S, Loi S, Okines A, Abramson V, Bedard PL, Oliveira M, Mueller V, Zelnak A, DiGiovanna MP, Bachelot T, Chien AJ, O'Regan R, Wardley A, Conlin A, Cameron D, Carey L, Curigliano G, Gelmon K, Loibl S, Mayor J, McGoldrick S, An X, Winer EP. Intracranial Efficacy and Survival With Tucatinib Plus Trastuzumab and Capecitabine for Previously Treated HER2-Positive Breast Cancer With Brain Metastases in the HER2CLIMB Trial. J Clin Oncol. 2020 Aug 10;38(23):2610-2619. Epub 2020 May 29. link to original article link to PMC article PubMed

Eribulin & Margetuximab

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Rugo et al. 2021 (SOPHIA)	2015-2018	Phase III (E-RT-switch-ic)	Eribulin & Trastuzumab	Seems to have superior PFS Median PFS: 6 mo vs 5 mo (HR 0.76, 95% CI 0.59-0.98)

Chemotherapy

• Eribulin (Halaven) 1.4 mg/m² IV once per day on days 1 & 8

Targeted therapy

• Margetuximab (Margenza) 15 mg/kg IV over 120 minutes once on day 1

21-day cycles

References

1. SOPHIA: Rugo HS, Im SA, Cardoso F, Cortés J, Curigliano G, Musolino A, Pegram MD, Wright GS, Saura C, Escrivá-de-Romaní S, De Laurentiis M, Levy C, Brown-Glaberman U, Ferrero JM, de Boer M, Kim SB, Petráková K, Yardley DA, Freedman O, Jakobsen EH, Kaufman B, Yerushalmi R, Fasching PA, Nordstrom JL, Bonvini E, Koenig S, Edlich S, Hong S, Rock EP, Gradishar WJ; SOPHIA Study Group. Efficacy of Margetuximab vs Trastuzumab in Patients With Pretreated ERBB2-Positive Advanced Breast Cancer: A Phase 3 Randomized Clinical Trial. JAMA Oncol. 2021 Apr 1;7(4):573-584. link to original article link to PMC article contains verified protocol PubMed NCT02492711

Eribulin & Trastuzumab

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Rugo et al. 2021 (SOPHIA)	2015-2018	Phase III (C)	Eribulin & Margetuximab	Seems to have inferior PFS

Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.

Chemotherapy

• Eribulin (Halaven) 1.4 mg/m² IV once per day on days 1 & 8

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV once on day 1
  • Cycle 2 onwards: 6 mg/kg IV once on day 1

21-day cycles

References

1. SOPHIA: Rugo HS, Im SA, Cardoso F, Cortés J, Curigliano G, Musolino A, Pegram MD, Wright GS, Saura C, Escrivá-de-Romaní S, De Laurentiis M, Levy C, Brown-Glaberman U, Ferrero JM, de Boer M, Kim SB, Petráková K, Yardley DA, Freedman O, Jakobsen EH, Kaufman B, Yerushalmi R, Fasching PA, Nordstrom JL, Bonvini E, Koenig S, Edlich S, Hong S, Rock EP, Gradishar WJ; SOPHIA Study Group. Efficacy of Margetuximab vs Trastuzumab in Patients With Pretreated ERBB2-Positive Advanced Breast Cancer: A Phase 3 Randomized Clinical Trial. JAMA Oncol. 2021 Apr 1;7(4):573-584. link to original article link to PMC article contains verified protocol PubMed NCT02492711

Gemcitabine & Margetuximab

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Rugo et al. 2021 (SOPHIA)	2015-2018	Phase III (E-RT-switch-ic)	Gemcitabine & Trastuzumab	Seems to have superior PFS Median PFS: 6 mo vs 5 mo (HR 0.76, 95% CI 0.59-0.98)

Chemotherapy

• Gemcitabine (Gemzar) 1000 mg/m² IV once per day on days 1 & 8

Targeted therapy

• Margetuximab (Margenza) 15 mg/kg IV over 120 minutes once on day 1

21-day cycles

References

1. SOPHIA: Rugo HS, Im SA, Cardoso F, Cortés J, Curigliano G, Musolino A, Pegram MD, Wright GS, Saura C, Escrivá-de-Romaní S, De Laurentiis M, Levy C, Brown-Glaberman U, Ferrero JM, de Boer M, Kim SB, Petráková K, Yardley DA, Freedman O, Jakobsen EH, Kaufman B, Yerushalmi R, Fasching PA, Nordstrom JL, Bonvini E, Koenig S, Edlich S, Hong S, Rock EP, Gradishar WJ; SOPHIA Study Group. Efficacy of Margetuximab vs Trastuzumab in Patients With Pretreated ERBB2-Positive Advanced Breast Cancer: A Phase 3 Randomized Clinical Trial. JAMA Oncol. 2021 Apr 1;7(4):573-584. link to original article link to PMC article contains verified protocol PubMed NCT02492711

Gemcitabine & Trastuzumab

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Regimen variant #1, q3wk

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Rugo et al. 2021 (SOPHIA)	2015-2018	Phase III (C)	Gemcitabine & Margetuximab	Seems to have inferior PFS

Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.

Chemotherapy

• Gemcitabine (Gemzar) 1000 mg/m² IV once per day on days 1 & 8

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV once on day 1
  • Cycle 2 onwards: 6 mg/kg IV once on day 1

21-day cycles

Regimen variant #2, weekly

Study	Evidence
O'Shaughnessy et al. 2004	Phase II

Chemotherapy

• Gemcitabine (Gemzar) 1200 mg/m² IV once per day on days 1 & 8

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8 & 15
  • Cycle 2 onwards: 2 mg/kg IV once per day on days 1, 8, 15

21-day cycles

References

1. O'Shaughnessy JA, Vukelja S, Marsland T, Kimmel G, Ratnam S, Pippen JE. Phase II study of trastuzumab plus gemcitabine in chemotherapy-pretreated patients with metastatic breast cancer. Clin Breast Cancer. 2004 Jun;5(2):142-7. link to original article contains protocol PubMed
2. SOPHIA: Rugo HS, Im SA, Cardoso F, Cortés J, Curigliano G, Musolino A, Pegram MD, Wright GS, Saura C, Escrivá-de-Romaní S, De Laurentiis M, Levy C, Brown-Glaberman U, Ferrero JM, de Boer M, Kim SB, Petráková K, Yardley DA, Freedman O, Jakobsen EH, Kaufman B, Yerushalmi R, Fasching PA, Nordstrom JL, Bonvini E, Koenig S, Edlich S, Hong S, Rock EP, Gradishar WJ; SOPHIA Study Group. Efficacy of Margetuximab vs Trastuzumab in Patients With Pretreated ERBB2-Positive Advanced Breast Cancer: A Phase 3 Randomized Clinical Trial. JAMA Oncol. 2021 Apr 1;7(4):573-584. link to original article link to PMC article contains verified protocol PubMed NCT02492711

Lapatinib & Trastuzumab

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Blackwell et al. 2010 (EGF104900)	2005-2006	Phase III (E-esc)	Lapatinib	Seems to have superior OS

Targeted therapy

• Lapatinib (Tykerb) 1000 mg PO once per day
• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8, 15, 22
  • Cycle 2 onwards: 2 mg/kg IV once per day on days 1, 8, 15, 22

28-day cycles

References

1. EGF104900: Blackwell KL, Burstein HJ, Storniolo AM, Rugo H, Sledge G, Koehler M, Ellis C, Casey M, Vukelja S, Bischoff J, Baselga J, O'Shaughnessy J. Randomized study of Lapatinib alone or in combination with trastuzumab in women with ErbB2-positive, trastuzumab-refractory metastatic breast cancer. J Clin Oncol. 2010 Mar 1;28(7):1124-30. Epub 2010 Feb 1. link to original article PubMed NCT00320385
   1. Update: Blackwell KL, Burstein HJ, Storniolo AM, Rugo HS, Sledge G, Aktan G, Ellis C, Florance A, Vukelja S, Bischoff J, Baselga J, O'Shaughnessy J. Overall survival benefit with lapatinib in combination with trastuzumab for patients with human epidermal growth factor receptor 2-positive metastatic breast cancer: final results from the EGF104900 Study. J Clin Oncol. 2012 Jul 20;30(21):2585-92. Epub 2012 Jun 11. link to original article PubMed

Paclitaxel, Pertuzumab, Ado-trastuzumab emtansine

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Regimen variant #1, q3wk T-DM1

Study	Evidence
Krop et al. 2016 (TDM4652g)	Phase 1b/2a

Note: this is the MTD.

Chemotherapy

• Paclitaxel (Taxol) 80 mg/m² IV once per day on days 1, 8, 15

Targeted therapy

• Pertuzumab (Perjeta) as follows:
  • Cycle 1: 840 mg IV once on day 1
  • Cycle 2 onwards: 420 mg IV once on day 1

Antibody-drug conjugate therapy

• Ado-trastuzumab emtansine (Kadcyla) 3.6 mg/kg IV once on day 1

21-day cycles

Regimen variant #2, weekly T-DM1

Study	Evidence
Krop et al. 2016 (TDM4652g)	Phase 1b/2a

Note: this is the MTD.

Chemotherapy

• Paclitaxel (Taxol) 80 mg/m² IV once per day on days 1, 8, 15

Targeted therapy

• Pertuzumab (Perjeta) as follows:
  • Cycle 1: 840 mg IV once on day 1
  • Cycle 2 onwards: 420 mg IV once on day 1

Antibody-drug conjugate therapy

• Ado-trastuzumab emtansine (Kadcyla) 2.4 mg/kg IV once per day on days 1, 8, 15

21-day cycles

References

1. TDM4652g: Krop IE, Modi S, LoRusso PM, Pegram M, Guardino E, Althaus B, Lu D, Strasak A, Elias A. Phase 1b/2a study of trastuzumab emtansine (T-DM1), paclitaxel, and pertuzumab in HER2-positive metastatic breast cancer. Breast Cancer Res. 2016 Mar 15;18(1):34. link to original article link to PMC article contains protocol PubMed

Pertuzumab & Trastuzumab

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Regimen variant #1, q3wk trastuzumab

Study	Evidence
Baselga et al. 2010	Phase II

Targeted therapy

• Pertuzumab (Perjeta) as follows, given second:
  • Cycle 1: 840 mg IV once on day 2
  • Cycle 2 onwards: 420 mg IV once on day 1
• Trastuzumab (Herceptin) as follows:
  • Loading dose: 8 mg/kg IV once on day -28 (that is, 28 days before the start of cycle 1)
  • Cycle 1 onwards: 6 mg/kg IV once on day 1, given first

21-day cycle for 8 cycles

Treatment can be continued if there is no progressive disease.

Regimen variant #2, weekly trastuzumab

Study	Evidence
Baselga et al. 2010 (NCI-P6660)	Phase II

Targeted therapy

• Pertuzumab (Perjeta) given second as follows:
  • Cycle 1: 840 mg IV once on day 2
  • Cycles 2 to 8: 420 mg IV once on day 1
• Trastuzumab (Herceptin) given first as follows:
  • Cycle 0: 4 mg/kg IV once on day -28 (that is, 28 days before the start of cycle 1)
  • Cycles 1 to 8: 2 mg/kg IV once per day on days 1, 8, 15

21-day cycle for 8 cycles; treatment can be continued if there is no progressive disease

References

1. NCI-P6660: Baselga J, Gelmon KA, Verma S, Wardley A, Conte P, Miles D, Bianchi G, Cortes J, McNally VA, Ross GA, Fumoleau P, Gianni L. Phase II trial of pertuzumab and trastuzumab in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer that progressed during prior trastuzumab therapy. J Clin Oncol. 2010 Mar 1;28(7):1138-44. Epub 2010 Feb 1. link to original article contains verified protocol link to PMC article PubMed NCT00301899

Ado-trastuzumab emtansine monotherapy

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T-DM1: Trastuzumab-DM1 (Ado-trastuzumab emtansine)

Example orders

• Example orders for Ado-trastuzumab emtansine (Kadcyla) in breast cancer

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Verma et al. 2012 (EMILIA)	2009-2011	Phase III (E-RT-switch-ooc)	Capecitabine & Lapatinib	Superior OS1 (HR 0.75, 95% CI 0.64-0.88)
Krop et al. 2014 (TH3RESA)	2011-2012	Phase III (E-switch-ooc)	Physician's choice	Superior OS2 (HR 0.68, 95% CI 0.54-0.85)

¹Reported efficacy for EMILIA is based on the 2017 update.
²Reported efficacy for TH3RESA is based on the 2017 update.

Antibody-drug conjugate therapy

• Ado-trastuzumab emtansine (Kadcyla) 3.6 mg/kg IV once on day 1

21-day cycles

References

1. EMILIA: Verma S, Miles D, Gianni L, Krop IE, Welslau M, Baselga J, Pegram M, Oh DY, Diéras V, Guardino E, Fang L, Lu MW, Olsen S, Blackwell K; EMILIA Study Group. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med. 2012 Nov 8;367(19):1783-91. Epub 2012 Oct 1. Erratum in: N Engl J Med. 2013 Jun 20;368(25):2442. link to original article contains verified protocol link to PMC article PubMed NCT00829166
   1. Update: Diéras V, Miles D, Verma S, Pegram M, Welslau M, Baselga J, Krop IE, Blackwell K, Hoersch S, Xu J, Green M, Gianni L. Trastuzumab emtansine versus capecitabine plus lapatinib in patients with previously treated HER2-positive advanced breast cancer (EMILIA): a descriptive analysis of final overall survival results from a randomised, open-label, phase 3 trial. Lancet Oncol. 2017 Jun;18(6):732-742. Epub 2017 May 16. link to original article link to PMC article PubMed
2. TH3RESA: Krop IE, Kim SB, González-Martín A, LoRusso PM, Ferrero JM, Smitt M, Yu R, Leung AC, Wildiers H; TH3RESA study collaborators. Trastuzumab emtansine versus treatment of physician's choice for pretreated HER2-positive advanced breast cancer (TH3RESA): a randomised, open-label, phase 3 trial. Lancet Oncol. 2014 Jun;15(7):689-99. Epub 2014 May 2. link to original article contains protocol PubMed NCT01419197
   1. Update: Krop IE, Kim SB, Martin AG, LoRusso PM, Ferrero JM, Badovinac-Crnjevic T, Hoersch S, Smitt M, Wildiers H. Trastuzumab emtansine versus treatment of physician's choice in patients with previously treated HER2-positive metastatic breast cancer (TH3RESA): final overall survival results from a randomised open-label phase 3 trial. Lancet Oncol. 2017 Jun;18(6):743-754. Epub 2017 May 16. link to original article PubMed

Fam-trastuzumab deruxtecan monotherapy

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Regimen

FDA-recommended dose

Study	Years of enrollment	Evidence
Modi et al. 2019 (DESTINY-Breast01)	2017-2018	Phase II (RT)

Antibody-drug conjugate therapy

• Fam-trastuzumab deruxtecan (Enhertu) 5.4 mg/kg IV once on day 1

21-day cycles

References

1. DESTINY-Breast01: Modi S, Saura C, Yamashita T, Park YH, Kim SB, Tamura K, Andre F, Iwata H, Ito Y, Tsurutani J, Sohn J, Denduluri N, Perrin C, Aogi K, Tokunaga E, Im SA, Lee KS, Hurvitz SA, Cortes J, Lee C, Chen S, Zhang L, Shahidi J, Yver A, Krop I; DESTINY-Breast01 Investigators. Trastuzumab Deruxtecan in Previously Treated HER2-Positive Breast Cancer. N Engl J Med. 2020 Feb 13;382(7):610-621. Epub 2019 Dec 11. link to original article contains protocol PubMed NCT03248492

Trastuzumab monotherapy

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Regimen

Study	Years of enrollment	Evidence
Cobleigh et al. 1999	1995-1996	Phase II (RT)

Targeted therapy

• Trastuzumab (Herceptin)

References

1. Cobleigh MA, Vogel CL, Tripathy D, Robert NJ, Scholl S, Fehrenbacher L, Wolter JM, Paton V, Shak S, Lieberman G, Slamon DJ. Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J Clin Oncol. 1999 Sep;17(9):2639-48. link to original article PubMed

Vinorelbine & Margetuximab

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Regimen variant #1, 25 mg/m²

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Rugo et al. 2021 (SOPHIA)	2015-2018	Phase III (E-RT-switch-ic)	VH	Seems to have superior PFS Median PFS: 6 mo vs 5 mo (HR 0.76, 95% CI 0.59-0.98)

Note: this is the lower bound of dosing described in SOPHIA.

Chemotherapy

• Vinorelbine (Navelbine) 25 mg/m² IV once per day on days 1 & 8

Targeted therapy

• Margetuximab (Margenza) 15 mg/kg IV over 120 minutes once on day 1

21-day cycles

Regimen variant #2, 30 mg/m²

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Rugo et al. 2021 (SOPHIA)	2015-2018	Phase III (E-RT-switch-ic)	VH	Seems to have superior PFS Median PFS: 6 mo vs 5 mo (HR 0.76, 95% CI 0.59-0.98)

Note: this is the upper bound of dosing described in SOPHIA.

Chemotherapy

• Vinorelbine (Navelbine) 30 mg/m² IV once per day on days 1 & 8

Targeted therapy

• Margetuximab (Margenza) 15 mg/kg IV over 120 minutes once on day 1

21-day cycles

References

1. SOPHIA: Rugo HS, Im SA, Cardoso F, Cortés J, Curigliano G, Musolino A, Pegram MD, Wright GS, Saura C, Escrivá-de-Romaní S, De Laurentiis M, Levy C, Brown-Glaberman U, Ferrero JM, de Boer M, Kim SB, Petráková K, Yardley DA, Freedman O, Jakobsen EH, Kaufman B, Yerushalmi R, Fasching PA, Nordstrom JL, Bonvini E, Koenig S, Edlich S, Hong S, Rock EP, Gradishar WJ; SOPHIA Study Group. Efficacy of Margetuximab vs Trastuzumab in Patients With Pretreated ERBB2-Positive Advanced Breast Cancer: A Phase 3 Randomized Clinical Trial. JAMA Oncol. 2021 Apr 1;7(4):573-584. link to original article link to PMC article contains verified protocol PubMed NCT02492711

Vinorelbine & Trastuzumab (VH)

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VH: Vinorelbine & Herceptin (Trastuzumab)

Regimen variant #1, 25 mg/m²

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Rugo et al. 2021 (SOPHIA)	2015-2018	Phase III (C)	Vinorelbine & Margetuximab	Seems to have inferior PFS

Note: this is the lower bound of dosing described in SOPHIA.

Chemotherapy

• Vinorelbine (Navelbine) 25 mg/m² IV once per day on days 1 & 8

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV once on day 1
  • Cycle 2 onwards: 6 mg/kg IV once on day 1

21-day cycles

Regimen variant #2, 30 mg/m²

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Rugo et al. 2021 (SOPHIA)	2015-2018	Phase III (C)	Vinorelbine & Margetuximab	Seems to have inferior PFS

Note: this is the upper bound of dosing described in SOPHIA.

Chemotherapy

• Vinorelbine (Navelbine) 30 mg/m² IV once per day on days 1 & 8

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 8 mg/kg IV once on day 1
  • Cycle 2 onwards: 6 mg/kg IV once on day 1

21-day cycles

Regimen variant #3, weekly

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
André et al. 2014 (BOLERO-3)	2009-2012	Phase III (C)	VH & Everolimus	Inferior PFS
Harbeck et al. 2016 (LUX-Breast 1)	2010-2013	Phase III (C)	Afatinib & Vinorelbine	Did not meet primary endpoint of PFS

Chemotherapy

• Vinorelbine (Navelbine) 25 mg/m² IV once per day on days 1, 8, 15, 22

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8, 15, 22
  • Cycle 2 onwards: 2 mg/kg IV once per day on days 1, 8, 15, 22

28-day cycles

References

1. BOLERO-3: André F, O'Regan R, Ozguroglu M, Toi M, Xu B, Jerusalem G, Masuda N, Wilks S, Arena F, Isaacs C, Yap YS, Papai Z, Lang I, Armstrong A, Lerzo G, White M, Shen K, Litton J, Chen D, Zhang Y, Ali S, Taran T, Gianni L. Everolimus for women with trastuzumab-resistant, HER2-positive, advanced breast cancer (BOLERO-3): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet Oncol. 2014 May;15(6):580-91. Epub 2014 Apr 14. link to original article PubMed NCT01007942
2. LUX-Breast 1: Harbeck N, Huang CS, Hurvitz S, Yeh DC, Shao Z, Im SA, Jung KH, Shen K, Ro J, Jassem J, Zhang Q, Im YH, Wojtukiewicz M, Sun Q, Chen SC, Goeldner RG, Uttenreuther-Fischer M, Xu B, Piccart-Gebhart M; LUX-Breast 1 study group. Afatinib plus vinorelbine versus trastuzumab plus vinorelbine in patients with HER2-overexpressing metastatic breast cancer who had progressed on one previous trastuzumab treatment (LUX-Breast 1): an open-label, randomised, phase 3 trial. Lancet Oncol. 2016 Mar;17(3):357-66. link to original article contains verified protocol PubMed NCT01125566
3. SOPHIA: Rugo HS, Im SA, Cardoso F, Cortés J, Curigliano G, Musolino A, Pegram MD, Wright GS, Saura C, Escrivá-de-Romaní S, De Laurentiis M, Levy C, Brown-Glaberman U, Ferrero JM, de Boer M, Kim SB, Petráková K, Yardley DA, Freedman O, Jakobsen EH, Kaufman B, Yerushalmi R, Fasching PA, Nordstrom JL, Bonvini E, Koenig S, Edlich S, Hong S, Rock EP, Gradishar WJ; SOPHIA Study Group. Efficacy of Margetuximab vs Trastuzumab in Patients With Pretreated ERBB2-Positive Advanced Breast Cancer: A Phase 3 Randomized Clinical Trial. JAMA Oncol. 2021 Apr 1;7(4):573-584. link to original article link to PMC article contains verified protocol PubMed NCT02492711

Vinorelbine & Trastuzumab (VH) & Everolimus

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VH & Everolimus: Vinorelbine, Herceptin (Trastuzumab), Everolimus

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
André et al. 2014 (BOLERO-3)	2009-2012	Phase III (E-esc)	VH	Superior PFS

Chemotherapy

• Vinorelbine (Navelbine) 25 mg/m² IV once per day on days 1, 8, 15, 22

Targeted therapy

• Trastuzumab (Herceptin) as follows:
  • Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8, 15, 22
  • Cycle 2 onwards: 2 mg/kg IV once per day on days 1, 8, 15, 22
• Everolimus (Afinitor) 5 mg PO once per day

28-day cycles

References

1. BOLERO-3: André F, O'Regan R, Ozguroglu M, Toi M, Xu B, Jerusalem G, Masuda N, Wilks S, Arena F, Isaacs C, Yap YS, Papai Z, Lang I, Armstrong A, Lerzo G, White M, Shen K, Litton J, Chen D, Zhang Y, Ali S, Taran T, Gianni L. Everolimus for women with trastuzumab-resistant, HER2-positive, advanced breast cancer (BOLERO-3): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet Oncol. 2014 May;15(6):580-91. Epub 2014 Apr 14. link to original article PubMed NCT01007942

Maintenance for metastatic or unresectable disease

Pertuzumab & Trastuzumab

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Regimen

Study	Evidence
Baselga et al. 2011 (CLEOPATRA)	Non-randomized portion of RCT

Preceding treatment

• THP (Taxotere) for at least 6 cycles

Targeted therapy

• Pertuzumab (Perjeta) 420 mg IV once on day 1
• Trastuzumab (Herceptin) 6 mg/kg IV once on day 1

21-day cycles

References

1. CLEOPATRA: Baselga J, Cortés J, Kim SB, Im SA, Hegg R, Im YH, Roman L, Pedrini JL, Pienkowski T, Knott A, Clark E, Benyunes MC, Ross G, Swain SM; CLEOPATRA Study Group. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012 Jan 12;366(2):109-19. Epub 2011 Dec 7. link to original article contains verified protocol link to PMC article PubMed NCT00567190
   1. Update: Swain SM, Kim SB, Cortés J, Ro J, Semiglazov V, Campone M, Ciruelos E, Ferrero JM, Schneeweiss A, Knott A, Clark E, Ross G, Benyunes MC, Baselga J. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): overall survival results from a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2013 May;14(6):461-71. Epub 2013 Apr 18. link to original article contains verified protocol link to PMC article PubMed
   2. Update: Swain SM, Baselga J, Kim SB, Ro J, Semiglazov V, Campone M, Ciruelos E, Ferrero JM, Schneeweiss A, Heeson S, Clark E, Ross G, Benyunes MC, Cortés J; CLEOPATRA Study Group. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med. 2015 Feb 19;372(8):724-34. link to original article PubMed

Trastuzumab monotherapy

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Regimen variant #1, q3wk dosing

Study	Evidence
Perez et al. 2005 (NCCTG 983252)	Phase II
Valero et al. 2010 (BCIRG 007)	Non-randomized portion of RCT
Baselga et al. 2011 (CLEOPATRA)	Non-randomized portion of RCT
Gelmon et al. 2015 (NCIC-CTG MA.31)	Non-randomized portion of RCT

Preceding treatment

• NCCTG 983252: TPC (q3wk) x 8
• BCIRG 0007: TH (Taxotere) x 8 versus TCH (Taxotere) x 8
• CLEOPATRA: TH (Taxotere)
• NCIC-CTG MA.31: TH (Taxol) x 6 or TH (Taxotere) x 8

Targeted therapy

• Trastuzumab (Herceptin) 6 mg/kg IV once on day 1

21-day cycles

Regimen variant #2, weekly dosing

Study	Evidence
Marty et al. 2005 (M77001)	Non-randomized portion of RCT
Perez et al. 2005 (NCCTG 983252)	Phase II
Robert et al. 2006	Non-randomized portion of RCT

Preceding treatment

• M77001: TH (Taxotere) for at least 6 cycles
• NCCTG 983252: TPC (weekly) x 6
• Robert et al. 2006: TP x 6 versus TPC x 6

Targeted therapy

• Trastuzumab (Herceptin) 2 mg/kg IV once per day on days 1, 8, 15, 22

28-day cycles

References

1. M77001: Marty M, Cognetti F, Maraninchi D, Snyder R, Mauriac L, Tubiana-Hulin M, Chan S, Grimes D, Antón A, Lluch A, Kennedy J, O'Byrne K, Conte P, Green M, Ward C, Mayne K, Extra JM. Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer administered as first-line treatment: the M77001 study group. J Clin Oncol. 2005 Jul 1;23(19):4265-74. Epub 2005 May 23. link to original article contains verified protocol PubMed
2. NCCTG 983252: Perez EA, Suman VJ, Rowland KM, Ingle JN, Salim M, Loprinzi CL, Flynn PJ, Mailliard JA, Kardinal CG, Krook JE, Thrower AR, Visscher DW, Jenkins RB. Two concurrent phase II trials of paclitaxel/carboplatin/trastuzumab (weekly or every-3-week schedule) as first-line therapy in women with HER2-overexpressing metastatic breast cancer: NCCTG study 983252. Clin Breast Cancer. 2005 Dec;6(5):425-32. link to original article PubMed
3. Robert N, Leyland-Jones B, Asmar L, Belt R, Ilegbodu D, Loesch D, Raju R, Valentine E, Sayre R, Cobleigh M, Albain K, McCullough C, Fuchs L, Slamon D. Randomized phase III study of trastuzumab, paclitaxel, and carboplatin compared with trastuzumab and paclitaxel in women with HER-2-overexpressing metastatic breast cancer. J Clin Oncol. 2006 Jun 20;24(18):2786-92. link to original article PubMed
4. BCIRG 007: Valero V, Forbes J, Pegram MD, Pienkowski T, Eiermann W, von Minckwitz G, Roche H, Martin M, Crown J, Mackey JR, Fumoleau P, Rolski J, Mrsic-Krmpotic Z, Jagiello-Gruszfeld A, Riva A, Buyse M, Taupin H, Sauter G, Press MF, Slamon DJ. Multicenter phase III randomized trial comparing docetaxel and trastuzumab with docetaxel, carboplatin, and trastuzumab as first-line chemotherapy for patients with HER2-gene-amplified metastatic breast cancer (BCIRG 007 study): two highly active therapeutic regimens. J Clin Oncol. 2011 Jan 10;29(2):149-56. Epub 2010 Nov 29. link to original article contains verified protocol PubMed NCT00047255
5. CLEOPATRA: Baselga J, Cortés J, Kim SB, Im SA, Hegg R, Im YH, Roman L, Pedrini JL, Pienkowski T, Knott A, Clark E, Benyunes MC, Ross G, Swain SM; CLEOPATRA Study Group. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012 Jan 12;366(2):109-19. Epub 2011 Dec 7. link to original article contains verified protocol link to PMC article PubMed NCT00567190
   1. Update: Swain SM, Kim SB, Cortés J, Ro J, Semiglazov V, Campone M, Ciruelos E, Ferrero JM, Schneeweiss A, Knott A, Clark E, Ross G, Benyunes MC, Baselga J. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): overall survival results from a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2013 May;14(6):461-71. Epub 2013 Apr 18. link to original article contains verified protocol link to PMC article PubMed
   2. Update: Swain SM, Baselga J, Kim SB, Ro J, Semiglazov V, Campone M, Ciruelos E, Ferrero JM, Schneeweiss A, Heeson S, Clark E, Ross G, Benyunes MC, Cortés J; CLEOPATRA Study Group. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med. 2015 Feb 19;372(8):724-34. link to original article PubMed
6. NCIC-CTG MA.31: Gelmon KA, Boyle FM, Kaufman B, Huntsman DG, Manikhas A, Di Leo A, Martin M, Schwartzberg LS, Lemieux J, Aparicio S, Shepherd LE, Dent S, Ellard SL, Tonkin K, Pritchard KI, Whelan TJ, Nomikos D, Nusch A, Coleman RE, Mukai H, Tjulandin S, Khasanov R, Rizel S, Connor AP, Santillana SL, Chapman JA, Parulekar WR. Lapatinib or trastuzumab plus taxane therapy for human epidermal growth factor receptor 2-positive advanced breast cancer: final results of NCIC-CTG MA.31. J Clin Oncol. 2015 May 10;33(14):1574-83. Epub 2015 Mar 16. link to original article contains verified protocol PubMed NCT00667251

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