Breast cancer, HER2-positive

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Hermina Fernandes, MD
Bismarck, ND

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

51 regimens on this page
100 variants on this page

Contents


Guidelines

ASCO

Older

ESMO

NCCN

Neoadjuvant chemotherapy

ECH

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ECH: Epirubicin, Cyclophosphamide, Herceptin (Trastuzumab)

Regimen

Study Evidence Comparator Efficacy
Untch et al. 2012 (GeparQuinto) 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

21-day cycle for 4 cycles

Subsequent treatment

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 (GBG); Arbeitsgemeinschaft Gynäkologische Onkologie-Breast (AGO-B) 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 SD article contains verified protocol PubMed

FEC & H

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

Variant #1, IV trastuzumab

Study Evidence Comparator Efficacy
Ismael et al. 2012 (HannaH) Randomized (C) See link See link
Pivot et al. 2018 (SB3-G31-BC) 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

Chemotherapy

21-day cycle for 4 cycles

Subsequent treatment

Variant #2, SC trastuzumab

Study Evidence Comparator Efficacy
Ismael et al. 2012 (HannaH) Randomized (E) 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

Chemotherapy

21-day cycle for 4 cycles

Subsequent treatment

  • Surgery

Variant #3

Study Evidence Comparator Efficacy
Buzdar et al. 2005 Randomized (E) 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

Chemotherapy

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
  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

Lapatinib & Trastuzumab

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Regimen

Study Evidence Comparator Efficacy
Baselga et al. 2012 (NeoALTTO) Phase III (E) 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

6-week course

Subsequent treatment

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
    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

Neratinib & Paclitaxel

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Regimen

Study Evidence Comparator Efficacy
Park et al. 2016 (I-SPY 2) Adaptively Randomized Phase II (E) TH Seems to have superior pCR rate

Chemotherapy

Supportive medications

12-week course

Subsequent treatment

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

TCHP (Taxotere)

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

Regimen

Study Evidence Comparator Efficacy
Schneeweiss et al. 2013 (TRYPHAENA) Randomized Phase II (E) See link Not reported
Hurvitz et al. 2017 (KRISTINE) Phase III (C) Pertuzumab & T-DM1 Seems to have superior pCR rate

Chemotherapy

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
  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

TH (Taxol)

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

Variant #1, weekly paclitaxel x 12, weekly trastuzumab

Study Evidence Comparator Efficacy
Baselga et al. 2012 (NeoALTTO) Phase III (C) See link See link
Buzdar et al. 2013 (ACOSOG Z1041) Phase III (*) See link See link
Park et al. 2016 (I-SPY 2) 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

Chemotherapy

12-week course

Subsequent treatment

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

Variant #2, weekly paclitaxel x 12, q3wk trastuzumab

Study Evidence Comparator Efficacy
von Minckwitz et al. 2018 (LILAC) Phase III (C) Paclitaxel & ABP 980 Inconclusive whether equivalent

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

12-week course

Subsequent treatment

  • Surgery

Variant #3, weekly paclitaxel x 16

Study Evidence Comparator Efficacy
Carey et al. 2015 (CALGB 40601) Phase III (C) 1. THL Seems not superior
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

16-week course

Subsequent treatment

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

Variant #4, paclitaxel 3 out of 4 weeks

Study Evidence Comparator Efficacy
Robidoux et al. 2013 (NSABP B-41) Phase III (C) 1. THL Might have inferior pCR rate
2. TL Seems not superior

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

Chemotherapy

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

Variant #5, q3wk, paclitaxel 175 mg/m2

Study Evidence Comparator Efficacy
von Minckwitz et al. 2018 (LILAC) Phase III (C) Paclitaxel & ABP 980 Inconclusive whether equivalent

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

21-day cycle for 4 cycles

Subsequent treatment

  • Surgery

Variant #6, q3wk, paclitaxel 225 mg/m2

Study Evidence Comparator Efficacy
Buzdar et al. 2005 Randomized (E) 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
  • 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

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
    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
  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
  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 investigators. 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
  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
  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
  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

TH (Taxotere)

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TH: Taxotere (Docetaxel) & Herceptin (Trastuzumab)

Variant #1, 75 mg/m2 q3wk docetaxel, q3wk trastuzumab (IV)

Study Evidence Comparator Efficacy
Ismael et al. 2012 (HannaH) Randomized (C) See link See link
Pivot et al. 2018 (SB3-G31-BC) 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

21-day cycle for 4 cycles

Subsequent treatment

Variant #2, 75 mg/m2 q3wk docetaxel, q3wk trastuzumab (SC)

Study Evidence Comparator Efficacy
Ismael et al. 2012 (HannaH) Randomized (E) 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

21-day cycle for 4 cycles

Subsequent treatment

Variant #3, 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

21-day cycle for 5 cycles

Subsequent treatment

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

Variant #1, 100 mg/m2 q3wk docetaxel, q3wk trastuzumab

Study Evidence Comparator Efficacy
Untch et al. 2012 (GeparQuinto) 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. No loading dose was used for trastuzumab because the load occurred during the ECH part of the regimen.

Preceding treatment

Chemotherapy

21-day cycle for 4 cycles

Subsequent treatment

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. 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 (GBG); Arbeitsgemeinschaft Gynäkologische Onkologie-Breast (AGO-B) 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 SD article contains verified protocol 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
  4. 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

THL (Taxol)

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

Variant #1, weekly paclitaxel x 12

Study Evidence Comparator Efficacy
Baselga et al. 2012 (NeoALTTO) Phase III (E) See link See link

Preceding treatment

Chemotherapy

12-week course

Subsequent treatment

Variant #2, weekly paclitaxel x 16

Study Evidence Comparator Efficacy
Carey et al. 2015 (CALGB 40601) Phase III (E) 1. TH Seems not superior
2. TL Not reported

Chemotherapy

16-week course

Subsequent treatment

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

Variant #3, paclitaxel 3 out of 4 weeks

Study Evidence Comparator Efficacy
Robidoux et al. 2013 (NSABP B-41) Phase III (E) 1. TH Might have superior pCR rate
2. TL Might have superior pCR rate

Preceding treatment

Chemotherapy

28-day cycle for 4 cycles

Subsequent treatment

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
    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. 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
  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

THP (Taxotere)

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

Variant #1, 3 cycles with loading doses

Study Evidence Comparator Efficacy
Schneeweiss et al. 2013 (TRYPHAENA) Randomized Phase II (E) 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

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
  • 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)

Variant #2, 3 cycles without loading doses

Study Evidence Comparator Efficacy
Schneeweiss et al. 2013 (TRYPHAENA) Randomized Phase II (E) 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

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)

Variant #3, 4 cycles with loading doses

Study Evidence Comparator Efficacy
Gianni et al. 2011 (NeoSphere) Randomized Phase II (E) 1. Docetaxel & Pertuzumab Seems not superior
2. Pertuzumab & Trastuzumab Seems not superior
3. TH Seems to have superior pCR rate
Schneeweiss et al. 2013 (TRYPHAENA) Randomized Phase II (E) See link Not reported

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
  • 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

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
    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

TL (Taxol)

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TL: Taxol (Paclitaxel) & Lapatinib

Variant #1, weekly paclitaxel x 12

Study Evidence Comparator Efficacy
Baselga et al. 2012 (NeoALTTO) Phase III (E) See link See link

Preceding treatment

  • Lapatinib x 6 wk

Chemotherapy

12-week course

Subsequent treatment

Variant #2, weekly paclitaxel x 16

Study Evidence Comparator Efficacy
Carey et al. 2015 (CALGB 40601) Phase III (E) 1. TH Not reported
2. THL Not reported

Note: this arm was closed early.

Chemotherapy

16-week course

Subsequent treatment

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

Variant #3, paclitaxel 3 out of 4 weeks

Study Evidence Comparator Efficacy
Robidoux et al. 2013 (NSABP B-41) Phase III (E) 1. TH Seems not superior
2. THL Might have inferior pCR rate

Preceding treatment

Chemotherapy

28-day cycle for 4 cycles

Subsequent treatment

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
    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. 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
  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

T-DM1 monotherapy

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T-DM1: Trastuzumab-DM1 (ado-Trastuzumab emtansine)

Regimen

Study Evidence Comparator Efficacy
Harbeck et al. 2017 (WGSG ADAPT) Randomized Phase II (E) 1. T-DM1 & ET Not reported
2. Trastuzumab & ET Superior pCR rate

Chemotherapy

21-day cycle for 4 cycles

Subsequent treatment

  • Surgery was performed within 3 weeks of the end of therapy. Adjuvant therapy consisted of EC, then TH (Taxol), unless the patient had pCR in which case adjuvant therapy was optional

References

  1. Harbeck N, Gluz O, Christgen M, Kates RE, Braun M, Küemmel S, Schumacher C, Potenberg J, Kraemer S, Kleine-Tebbe A, Augustin D, Aktas B, Forstbauer H, Tio J, von Schumann R, Liedtke C, Grischke EM, Schumacher J, Wuerstlein R, Kreipe HH, Nitz UA. De-escalation strategies in human epidermal growth factor receptor 2 (HER2)-positive early breast cancer (BC): Final analysis of the West German Study Group Adjuvant Dynamic marker-Adjusted Personalized Therapy trial optimizing risk assessment and therapy response prediction in early BC HER2- and hormone receptor-positive phase II randomized trial-efficacy, safety, and predictive markers for 12 weeks of neoadjuvant trastuzumab emtansine with or without endocrine therapy (ET) versus trastuzumab plus ET. J Clin Oncol. 2017 Sep 10;35(26):3046-3054. Epub 2017 Jul 6. link to original article contains verified protocol PubMed

T-DM1 & ET

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T-DM1 & ET: Trastuzumab-DM1 (ado-Trastuzumab emtansine) & Endocrine Therapy

Regimen

Study Evidence Comparator Efficacy
Harbeck et al. 2017 (WGSG ADAPT) Randomized Phase II (E) 1. T-DM1 Not reported
2. Trastuzumab & ET Superior pCR rate

Chemotherapy

21-day cycle for 4 cycles

Surgery was performed within 3 weeks of the end of therapy. Adjuvant therapy consisted of EC, then TH (Taxol), unless the patient had pCR in which case adjuvant therapy was optional.

References

  1. Harbeck N, Gluz O, Christgen M, Kates RE, Braun M, Küemmel S, Schumacher C, Potenberg J, Kraemer S, Kleine-Tebbe A, Augustin D, Aktas B, Forstbauer H, Tio J, von Schumann R, Liedtke C, Grischke EM, Schumacher J, Wuerstlein R, Kreipe HH, Nitz UA. De-escalation strategies in human epidermal growth factor receptor 2 (HER2)-positive early breast cancer (BC): Final analysis of the West German Study Group Adjuvant Dynamic marker-Adjusted Personalized Therapy trial optimizing risk assessment and therapy response prediction in early BC HER2- and hormone receptor-positive phase II randomized trial-efficacy, safety, and predictive markers for 12 weeks of neoadjuvant trastuzumab emtansine with or without endocrine therapy (ET) versus trastuzumab plus ET. J Clin Oncol. 2017 Sep 10;35(26):3046-3054. Epub 2017 Jul 6. link to original article contains verified protocol PubMed

Trastuzumab monotherapy

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Regimen

Study Evidence Comparator Efficacy
Baselga et al. 2012 (NeoALTTO) 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

6-week course

Subsequent treatment

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
    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

Trastuzumab & ET

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ET: Endocrine Therapy

Regimen

Study Evidence Comparator Efficacy
Harbeck et al. 2017 (WGSG ADAPT) Randomized Phase II (C) T-DM1
T-DM1 & ET
Inferior pCR rate

Chemotherapy

21-day cycle for 4 cycles

Surgery was performed within 3 weeks of the end of therapy. Adjuvant therapy consisted of EC, then TH (Taxol), unless the patient had pCR in which case adjuvant therapy was optional.

References

  1. Harbeck N, Gluz O, Christgen M, Kates RE, Braun M, Küemmel S, Schumacher C, Potenberg J, Kraemer S, Kleine-Tebbe A, Augustin D, Aktas B, Forstbauer H, Tio J, von Schumann R, Liedtke C, Grischke EM, Schumacher J, Wuerstlein R, Kreipe HH, Nitz UA. De-escalation strategies in human epidermal growth factor receptor 2 (HER2)-positive early breast cancer (BC): Final analysis of the West German Study Group Adjuvant Dynamic marker-Adjusted Personalized Therapy trial optimizing risk assessment and therapy response prediction in early BC HER2- and hormone receptor-positive phase II randomized trial-efficacy, safety, and predictive markers for 12 weeks of neoadjuvant trastuzumab emtansine with or without endocrine therapy (ET) versus trastuzumab plus ET. J Clin Oncol. 2017 Sep 10;35(26):3046-3054. Epub 2017 Jul 6. link to original article contains verified protocol 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 (finv*dprim)0.17 + [4(1 - 0.75LN)dmet]0.17
    • where dprim is derived from the bidimensional diameters of the primary tumor bed in the resected specimen, finv is the proportion of the primary tumor bed that contains invasive carcinoma, LN is the number of axillary lymph nodes containing metastatic carcinoma, and dmet 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

ddTH (Taxol)

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

Regimen

Study Evidence
Dang et al. 2008 Phase II

Preceding treatment

Chemotherapy

Supportive medications

14-day cycle for 4 cycles

Subsequent treatment

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

ddTH (Taxotere)

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

Regimen

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

Preceding treatment

Chemotherapy

Supportive medications

14-day cycle for 4 cycles

Subsequent treatment

References

  1. HORG CT/04.23: Mavroudis D, Saloustros E, Malamos N, Kakolyris S, Boukovinas I, Papakotoulas P, Kentepozidis N, Ziras N, Georgoulias V; Breast Cancer Investigators of Hellenic Oncology Research Group (HORG), Athens, Greece. 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

Preceding treatment

Chemotherapy

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
    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 Evidence Comparator Efficacy
Baselga et al. 2012 (NeoALTTO) Phase III (E) See link See link
Piccart-Gebhart et al. 2015 (ALTTO) Phase III (E) Lapatinib
Trastuzumab
Seems not superior

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

Chemotherapy

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
    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. 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

Neratinib monotherapy

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Regimen

FDA-recommended dose
Study Evidence Comparator Efficacy
Chan et al. 2016 (ExteNET) Phase III (E) Placebo Superior invasive DFS

Preceding treatment

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

Chemotherapy

Supportive medications

  • (per FDA package insert)
  • Loperamide (Imodium) as follows:
    • Weeks 1 & 2: 4 mg PO TID
    • Weeks 3 to 8: 4 mg PO BID
    • 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
    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

Placebo

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Regimen

Study Evidence Comparator Efficacy
Chan et al. 2016 (ExteNET) Phase III (C) Neratinib Inferior invasive DFS

No further treatment.

Preceding treatment

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

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
    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

TCH (Taxotere, Carboplatin)

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

Variant #1, capped carboplatin

Study Evidence Comparator Efficacy
von Minckwitz et al. 2017 (APHINITY) Phase III (C) TCHP (Taxotere) Seems to have inferior invasive DFS

Preceding treatment

  • Surgery

Chemotherapy

21-day cycle for up to 1 year of therapy (18 doses of trastuzumab)

Variant #2, no cap

Study Evidence Comparator Efficacy
Slamon et al. 2011 (BCIRG 006) Phase III (E) 1. AC, then T (Taxotere) Seems to have superior OS
2. AC, then TH (Taxotere) Seems not superior
Piccart-Gebhart et al. 2015 (ALTTO) Phase III (C) 1. TCL (Taxotere)
2. TCH (Taxotere), then Lapatinib
3. TCHL (Taxotere)
Seems not superior

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
  • 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

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
  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
  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

TCH (Taxotere, Cyclophosphamide)

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TCH: Taxotere, Cyclophosphamide, Herceptin

Regimen

Study Evidence
Jones et al. 2013 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
  • 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

21-day cycle for 18 cycles

References

  1. 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

TCHP (Taxotere)

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

Regimen

Study Evidence Comparator Efficacy
von Minckwitz et al. 2017 (APHINITY) Phase III (E) TCH Seems to have superior invasive DFS

Preceding treatment

  • Surgery

Chemotherapy

21-day cycle for up to 1 year of therapy (18 doses of trastuzumab & pertuzumab)

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

TH (Taxol)

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

Variant #1, weekly paclitaxel, weekly trastuzumab

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

Preceding treatment

  • Surgery

Chemotherapy

12 weeks of paclitaxel, 52 weeks of trastuzumab

Variant #2, weekly paclitaxel, weekly then q3wk trastuzumab

Study Evidence Comparator Efficacy
Tolaney et al. 2015 (APT) Phase II
Piccart-Gebhart et al. 2015 (ALTTO) Phase III (C) TH (Taxol), then Lapatinib
THL (Taxol)
TL (Taxol)
Seems not superior

Preceding treatment

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

Chemotherapy

  • Paclitaxel (Taxol) 80 mg/m2 IV once per week on weeks 1 to 12
  • Trastuzumab (Herceptin) as follows:
    • Week 1: 4 mg/kg IV once on day 1 with the first dose of paclitaxel
    • Weeks 2 to 12: 2 mg/kg IV once per week
    • Weeks 13 to 52: 6 mg/kg IV once every 3 weeks

12 weeks of paclitaxel, 52 weeks of trastuzumab

Variant #3, weekly paclitaxel, q3wk trastuzumab

Study Evidence Comparator Efficacy
von Minckwitz et al. 2017 (APHINITY) Phase III (C) THP (Taxol) Seems to have inferior invasive 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

Chemotherapy

Up to 1 year of therapy (18 doses of trastuzumab)

Variant #4, q3wk paclitaxel, weekly trastuzumab

Study Evidence Comparator Efficacy Toxicity
Romond et al. 2005 (NSABP B-31) Phase III (E) weekly T (Taxol)
q3wk T (Taxol)
Superior OS Might have superior DASI score
Romond et al. 2005 (NCCTG N9831) Phase III (E) 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

Chemotherapy

4 cycles of paclitaxel, 52 weeks of trastuzumab

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
    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
    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
  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
  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

TH (Taxotere)

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TH: Taxotere (Docetaxel) & Herceptin (Trastuzumab)

Variant #1, 75 x 4, q3wk trastuzumab

Study Evidence Comparator Efficacy
von Minckwitz et al. 2017 (APHINITY) Phase III (C) THP (Taxotere) Seems to have inferior invasive 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

Chemotherapy

21-day cycle for 4 cycles

Subsequent treatment

Variant #2, 75 x 4, weekly trastuzumab

Study Evidence Comparator Efficacy
Piccart-Gebhart et al. 2015 (ALTTO) Phase III (C) TH (Taxotere), then Lapatinib
THL (Taxotere)
TL (Taxotere)
Seems not superior

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
  • 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

Variant #3, 75-100 x 3, q3wk trastuzumab

Study Evidence Comparator Efficacy
von Minckwitz et al. 2017 (APHINITY) Phase III (C) THP (Taxotere) Seems to have inferior invasive 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

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
  • 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

Variant #4, 80 x 3, q3wk trastuzumab (IV)

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

21-day cycle for 3 cycles

Subsequent treatment

Variant #5, 80 x 3, q3wk trastuzumab (SC)

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

21-day cycle for 3 cycles

Subsequent treatment

Variant #6, 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
  • 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

Variant #7, 100 x 3, q3wk trastuzumab (IV)

Study Evidence Comparator Efficacy
von Minckwitz et al. 2017 (APHINITY) Phase III (C) THP (Taxotere) Seems to have inferior invasive DFS
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

Chemotherapy

21-day cycle for 3 cycles

Subsequent treatment

Variant #8, 100 x 3, q3wk trastuzumab (SC)

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

21-day cycle for 3 cycles

Subsequent treatment

Variant #9, 100 x 3, weekly trastuzumab

Study Evidence Comparator Efficacy
Joensuu et al. 2006 (FinHer) Phase III (E) 1. T
2. V
Seems not superior
3. VH Not reported
Joensuu et al. 2018 (SOLD) Non-randomized portion of RCT

Preceding treatment

  • Surgery

Chemotherapy

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

Variant #10, 100 x 4, weekly trastuzumab

Study Evidence Comparator Efficacy
Slamon et al. 2011 (BCIRG 006) Phase III (E) 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
  • 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

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
    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
  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
  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
  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

THP (Taxol)

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

Regimen

Study Evidence Comparator Efficacy
von Minckwitz et al. 2017 (APHINITY) Phase III (E) TH (Taxol) Seems to have superior invasive 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

Chemotherapy

21-day cycle for up to 1 year of therapy (18 doses of trastuzumab)

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

THP (Taxotere)

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

Variant #1

Study Evidence Comparator Efficacy
von Minckwitz et al. 2017 (APHINITY) Phase III (E) TH (Taxotere) Seems to have superior invasive 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

Chemotherapy

21-day cycle for up to 1 year of therapy (18 doses of trastuzumab)

Variant #2

Study Evidence Comparator Efficacy
von Minckwitz et al. 2017 (APHINITY) Phase III (E) TH (Taxotere) Seems to have superior invasive 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

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
  • 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 1 year of therapy (18 doses of trastuzumab)

Variant #3

Study Evidence Comparator Efficacy
von Minckwitz et al. 2017 (APHINITY) Phase III (E) TH (Taxotere) Seems to have superior invasive 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

Chemotherapy

21-day cycle for up to 1 year of therapy (18 doses of trastuzumab)

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

VH

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VH: Vinorelbine & Herceptin (Trastuzumab)

Regimen

Study Evidence Comparator Efficacy
Joensuu et al. 2006 (FinHer) Phase III (E) 1. T
2. V
Seems not superior
3. TH (Taxotere) Not reported

Chemotherapy

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

References

  1. 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
    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

Trastuzumab monotherapy

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Variant #1, 30-week course, q3wk

Study Evidence Comparator Efficacy
Pivot et al. 2018 (SB3-G31-BC) 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

Chemotherapy

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

Variant #2, 34-week course, q3wk

Study Evidence Comparator Efficacy
Baselga et al. 2012 (NeoALTTO) 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

Chemotherapy

  • 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)

Variant #3, 1-year course, weekly

Study Evidence Comparator Efficacy
Van Pelt et al. 2003 Phase II
Romond et al. 2005 (NCCTG N9831) Phase III (E) 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

Chemotherapy

52-week course

Variant #4, 1-year total course, q3wk (IV)

Study Evidence Comparator Efficacy
Piccart-Gebhart et al. 2005 (HERA) Phase III (E) 1. No trastuzumab after (neo-)adjuvant chemotherapy Superior OS
2. Trastuzumab x 2 y Seems not superior
Gianni et al. 2010 (NOAH) Phase III (E) See link See link
Pivot et al. 2013 (PHARE) Phase III (C) Trastuzumab x 6 mo Inconclusive whether non-inferior
Piccart-Gebhart et al. 2015 (ALTTO) Phase III (C) Lapatinib
Trastuzumab, then Lapatinib
Lapatinib & Trastuzumab
Seems not superior
Joensuu et al. 2018 (SOLD) Phase III (C) No further treatment Inconclusive whether non-inferior

Preceding treatment

  • Participants had already received at least four courses of an approved (neo-)adjuvant chemotherapy regimen (see individual trials)
  • SOLD: Surgery, then TH (Taxotere) x 3, then FEC x 3

Chemotherapy

  • 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 cycles for 1 year

Variant #5, 1-year total course, q3wk (SC)

Study Evidence Comparator Efficacy
Joensuu et al. 2018 (SOLD) Phase III (C) No further treatment Inconclusive whether non-inferior

Preceding treatment

Chemotherapy

21-day cycles for 1 year

Variant #6, 2-year course

Study Evidence Comparator Efficacy
Piccart-Gebhart et al. 2005 (HERA) Phase III (E) 1. No trastuzumab after (neo-)adjuvant chemotherapy Not reported
2. Trastuzumab x 1 y Seems not superior

Preceding treatment

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

Chemotherapy

  • 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 cycles for 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. 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
    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
    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
  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
    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
  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
    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
  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
  9. HORG CT/04.23: Mavroudis D, Saloustros E, Malamos N, Kakolyris S, Boukovinas I, Papakotoulas P, Kentepozidis N, Ziras N, Georgoulias V; Breast Cancer Investigators of Hellenic Oncology Research Group (HORG), Athens, Greece. 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
  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

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 Evidence Comparator Efficacy
Slamon et al. 2001 Phase III (E) 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

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

Anastrozole & Trastuzumab

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Regimen

Study Evidence Comparator Efficacy
Kaufman et al. 2009 (TAnDEM) Phase III (E) Anastrozole Superior PFS

Note: this regimen was intended for patients who were HER2+ and ER/PR-positive.

Chemotherapy

Continued indefinitely

References

  1. TAnDEM: Kaufman B, Mackey JR, Clemens MR, Bapsy PP, Vaid A, Wardley A, Tjulandin S, Jahn M, Lehle M, Feyereislova A, Révil C, Jones A. Trastuzumab plus anastrozole versus anastrozole alone for the treatment of postmenopausal women with human epidermal growth factor receptor 2-positive, hormone receptor-positive metastatic breast cancer: results from the randomized phase III TAnDEM study. J Clin Oncol. 2009 Nov 20;27(33):5529-37. Epub 2009 Sep 28. link to original article contains protocol PubMed

T-DM1 monotherapy

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T-DM1: Trastuzumab-DM1 (ado-Trastuzumab emtansine)

Example orders

Regimen

Study Evidence Comparator Efficacy
Hurvitz et al. 2013 Randomized Phase II (E) TH Seems to have superior PFS
Perez et al. 2016 (MARIANNE) Phase III (E) 1. T-DM1 & Pertuzumab Non-inferior PFS
2. TH (Taxotere)
3. TH (Taxol)
Non-inferior PFS

Chemotherapy

21-day cycles

References

  1. 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
  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

Capecitabine, Bevacizumab, Trastuzumab

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Regimen

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

Chemotherapy

21-day cycles

References

  1. 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 Evidence Comparator Efficacy
Pivot et al. 2015 (CEREBEL) Phase III (E) Capecitabine & Trastuzumab Seems not superior

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

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

Capecitabine & Trastuzumab

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XH: Xeloda (Capecitabine) & Herceptin

Regimen

Study Evidence Comparator Efficacy
Pivot et al. 2015 (CEREBEL) Phase III (C) Capecitabine & Lapatanib Seems not superior

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

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

ECH

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ECH: Epirubicin, Cyclophosphamide, Herceptin (Trastuzumab)

Regimen

Study Evidence Comparator Efficacy
Slamon et al. 2001 Phase III (E) EC Seems to have superior OS

Not commonly used; here for reference purposes only.

Chemotherapy

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

Pertuzumab & T-DM1

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Pertuzumab & T-DM1: Pertuzumab & Trastuzumab-DM1 (ado-Trastuzumab emtansine)

Regimen

Study Evidence Comparator Efficacy
Perez et al. 2016 (MARIANNE) Phase III (E) 1. T-DM1 Non-inferior PFS
2. TH (Taxotere)
3. TH (Taxol)
Non-inferior PFS

Chemotherapy

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

TCH (Taxotere, Carboplatin)

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

Regimen

Study Evidence Comparator Efficacy
Valero et al. 2011 (BCIRG 007) Phase III (E) TH Seems not superior

Chemotherapy

21-day cycle for 8 cycles

Subsequent treatment

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

TH (Taxotere)

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

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

Study Evidence Comparator Efficacy
Esteva et al. 2002 Phase II
Burstein et al. 2007 (TRAVIOTA) Phase III (E) 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
  • 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 BID 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

Variant #2, 60 mg/m2 q3wk docetaxel, weekly trastuzumab

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

Chemotherapy

21-day cycles

Variant #3, 75 mg/m2 q3wk docetaxel, q3wk trastuzumab

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

Note: Dose of docetaxel in Hurvitz et al. 2013 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. Efficacy for CLEOPATRA is based on the 2013 update.

Chemotherapy

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

Variant #4, 100 mg/m2 q3wk docetaxel, weekly trastuzumab

Study Evidence Comparator Efficacy
Marty et al. 2005 (M77001) Randomized Phase II (E) Docetaxel Seems to have superior OS
Valero et al. 2010 (BCIRG 007) Phase III (C) TCH Seems not superior

Chemotherapy

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

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

Subsequent treatment

Variant #5, 100 mg/m2 q3wk docetaxel, q3wk trastuzumab

Study Evidence Comparator Efficacy
Andersson et al. 2010 (HERNATA) Phase III (C) VH Seems not superior
Hurvitz et al. 2013 (TDM4450g) Randomized Phase II (C) T-DM1 Seems to have inferior PFS
Gianni et al. 2013 (AVAREL) Randomized Phase II (C) BTH Might have inferior PFS
Perez et al. 2016 (MARIANNE) Phase III (E) 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 Hurvitz et al. 2013 and MARIANNE was per investigator's discretion.

Chemotherapy

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

TH (Taxol)

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

Variant #1, weekly paclitaxel (80 mg/m2)

Study Evidence Comparator Efficacy
Burstein et al. 2007 (TRAVIOTA) Phase III (E) VH Might have inferior TTP
Seidman et al. 2008 (CALGB 9840) Phase III (E) TH, q3wk paclitaxel Superior OS
Baselga et al. 2014 (STM01-102) Phase III (C) MTP Seems not superior
Perez et al. 2016 (MARIANNE) Phase III (C) 1. T-DM1 Non-inferior PFS
2. Pertuzumab & T-DM1 Non-inferior PFS
3. TH (Taxotere) Not reported

Chemotherapy

Continued indefinitely

Variant #2, weekly paclitaxel (90 mg/m2)

Study Evidence
Seidman et al. 2001 Phase II

Chemotherapy

Continued indefinitely

Variant #3, paclitaxel 3 weeks out of 4, 6 cycles

Study Evidence Comparator Efficacy
Gelmon et al. 2015 (NCIC CTG MA.31) Phase III (C) Lapatinib & Paclitaxel Superior PFS

Chemotherapy

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

Variant #4, paclitaxel 3 weeks out of 4, indefinite

Study Evidence Comparator Efficacy
Hurvitz et al. 2015 (BOLERO-1) Phase III (C) Everolimus, Paclitaxel, Trastuzumab Seems not superior
Awada et al. 2016 (NEfERT-T) Phase III (C) Neratinib & Paclitaxel Seems not superior

Chemotherapy

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

Variant #5, q3wk paclitaxel

Study Evidence Comparator Efficacy
Slamon et al. 2001 Phase III (E) Paclitaxel Seems to have superior OS
Robert et al. 2006 Phase III (C) TPC Seems to have inferior PFS
Seidman et al. 2008 (CALGB 9840) 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
  • 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
  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
  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
  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
  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

THP (Taxotere)

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

Regimen

FDA-recommended dose
Study Evidence Comparator Efficacy
Baselga et al. 2011 (CLEOPATRA) Phase III (E) Docetaxel & Trastuzumab Superior OS (*)

Efficacy is based on the 2013 update.

Chemotherapy

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

TL (Taxol)

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TL: Taxol (Paclitaxel) & Lapatinib

Regimen

Study Evidence Comparator Efficacy
Guan et al. 2013 (EGF104535) Phase III (E) Paclitaxel Seems to have superior OS

Chemotherapy

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
  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

TPC

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

Variant #1, weekly

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

Chemotherapy

28-day cycle for 6 cycles

Subsequent treatment

Variant #2, weekly T, q3wk PC

Study Evidence Comparator Efficacy
Robert et al. 2006 Phase III (E) TP Seems to have superior PFS

Chemotherapy

21-day cycle for at least 6 cycles

Subsequent treatment

Variant #3, q3wk

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

Chemotherapy

21-day cycle for 8 cycles

Subsequent treatment

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

VH

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VH: Vinorelbine & Herceptin (Trastuzumab)

Variant #1, vinorelbine 25 mg/m2

Study Evidence Comparator Efficacy
Burstein et al. 2007 (TRAVIOTA) Phase III (E) TH (Taxotere)
TH (Taxol)
Might have superior TTP

Chemotherapy

Given indefinitely

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

Study Evidence Comparator Efficacy
Andersson et al. 2010 (HERNATA) Phase III (E) TH (Taxotere) Seems not superior

Chemotherapy

21-day cycles

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

Study Evidence Comparator Efficacy
Andersson et al. 2010 (HERNATA) Phase III (E) TH (Taxotere) Seems not superior

Chemotherapy

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

T-DM1 monotherapy

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T-DM1: Trastuzumab-DM1 (ado-Trastuzumab emtansine)

Example orders

Regimen

Study Evidence Comparator Efficacy
Verma et al. 2012 (EMILIA) Phase III (E) Capecitabine & Lapatinib Superior OS
Krop et al. 2014 (TH3RESA) Phase III (E) Physician's choice Superior OS (*)

Note: reported efficacy for TH3RESA is based on the 2017 update.

Chemotherapy

21-day cycles

References

  1. 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
    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. 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
    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

Capecitabine & Lapatinib

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Regimen

Study Evidence Comparator Efficacy
Geyer et al. 2006 (EGF100151) Phase III (E) Capecitabine Superior TTP
Verma et al. 2012 (EMILIA) Phase III (C) T-DM1 Inferior OS
Pivot et al. 2015 (CEREBEL) Phase III (C) Capecitabine & Trastuzumab Seems not superior

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

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
    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
    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

Capecitabine & Neratinib

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Regimen

Study Evidence Efficacy
Saura et al. 2014 Phase I/II ORR: 64%

Note: this is the MTD dose from the phase II portion.

Chemotherapy

21-day cycles

References

  1. 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

Capecitabine, Pertuzumab, Trastuzumab

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Regimen

Study Evidence Comparator Efficacy
Urruticoechea et al. 2017 (PHEREXA) Phase III (E) Capecitabine & Trastuzumab Might have superior PFS

Chemotherapy

21-day cycles

References

  1. 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

Capecitabine & Trastuzumab

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XH: Xeloda (Capecitabine) & Herceptin

Variant #1

Study Evidence Comparator Efficacy
Bartsch et al. 2007 Phase II ORR: 20%
Pivot et al. 2015 (CEREBEL) Phase III (C) Capecitabine & Lapatanib Seems not superior
Urruticoechea et al. 2017 (PHEREXA) 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

21-day cycles

Variant #2

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

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

Chemotherapy

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
  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

Lapatinib & Trastuzumab

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Regimen

Study Evidence Comparator Efficacy
Blackwell et al. 2010 (EGF104900) Phase III (E) Lapatinib Seems to have superior OS

Chemotherapy

(presumably) given until progression of disease or unacceptable toxicity

References

  1. 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
    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

Pertuzumab & Trastuzumab

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Variant #1, q3wk trastuzumab

Study Evidence
Baselga et al. 2010 Phase II

Chemotherapy

  • 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.

Variant #2, weekly trastuzumab

Study Evidence
Baselga et al. 2010 Phase II

Chemotherapy

Loading dose:

Cycles 1 to 8:

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

References

  1. 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

VH

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VH: Vinorelbine & Herceptin (Trastuzumab)

Regimen

Study Evidence Comparator Efficacy
André et al. 2014 (BOLERO-3) Phase III (C) Everolimus, Trastuzumab, Vinorelbine Inferior PFS
Harbeck et al. 2016 (LUX-Breast 1) Phase III (C) Afatinib & Vinorelbine Seems not superior

Chemotherapy

Given indefinitely

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
  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

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

Chemotherapy

21-day cycles

References

  1. 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 PubMed
    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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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

Chemotherapy

21-day cycles

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

Chemotherapy

Given indefinitely

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
  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 PubMed
    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

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