Difference between revisions of "Breast cancer, HER2-positive"

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[[Category:Chemotherapy regimens]]
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[[Category:Breast cancer, HER-2 positive regimens]]
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Revision as of 14:40, 27 July 2017

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Is there a regimen missing from this list? Would you like to share a different dosage/schedule or an additional reference for a regimen? Have you noticed an error? Do you have an idea that will help the site grow to better meet your needs and the needs of many others? You are invited to contribute to the site.

Note: this page has regimens which are specific to breast cancer that is HER-2 receptor positive. Please see the breast cancer page for other chemotherapy regimens.

123 regimens on this page
203 variants on this page


Guidelines

ESMO

NCCN

Neoadjuvant chemotherapy

AC -> TH

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AC -> TH: Adriamycin (Doxorubicin) & Cyclophosphamide followed by Taxol (Paclitaxel) & Herceptin (Trastuzumab)
AC-TH: Adriamycin (Doxorubicin) & Cyclophosphamide followed by Taxol (Paclitaxel) & Herceptin (Trastuzumab)
AC-T-T: Adriamycin (Doxorubicin) & Cyclophosphamide followed by Taxol (Paclitaxel) & Trastuzumab

Regimen

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

Chemotherapy, AC portion

21-day cycle for 4 cycles, followed by:

Chemotherapy, TH portion

  • 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, followed by surgery

After surgery, patients proceeded to adjuvant trastuzumab for a total of 52 weeks of therapy.

References

  1. 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

AC -> THL

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AC -> THL: Adriamycin (Doxorubicin) & Cyclophosphamide followed by Taxol (Paclitaxel), Herceptin (Trastuzumab), Lapatinib

Regimen

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

Chemotherapy, AC portion

21-day cycle for 4 cycles, followed by:

Chemotherapy, THL portion

28-day cycle for 4 cycles, followed by surgery

After surgery, patients proceeded to adjuvant trastuzumab for a total of 52 weeks of therapy.

References

  1. 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

AC -> TL

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AC -> TL: Adriamycin (Doxorubicin) & Cyclophosphamide followed by Taxol (Paclitaxel) & Lapatinib

Regimen

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

Chemotherapy, AC portion

21-day cycle for 4 cycles, followed by:

Chemotherapy, TL portion

28-day cycle for 4 cycles, followed by surgery

After surgery, patients proceeded to adjuvant trastuzumab for a total of 52 weeks of therapy.

References

  1. 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

Docetaxel, Pertuzumab, Trastuzumab

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Regimen

Study Evidence Comparator Efficacy
Gianni et al. 2011 (NeoSphere) Randomized Phase II Docetaxel & Pertuzumab Seems not superior
Pertuzumab & Trastuzumab Seems not superior
TH Seems to have superior pCR rate

Chemotherapy

21-day cycle for 4 cycles, then surgery

After surgery, patients were treated with adjuvant FEC & H.

References

  1. 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

TCHP (Docetaxel)

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

Regimen

Study Evidence Comparator Efficacy
Schneeweiss et al. 2013 (TRYPHAENA) Randomized Phase II FEC & HP -> THP Not reported
FEC -> THP Not reported

Neoadjuvant chemotherapy

21-day cycle for 6 cycles, then surgery

Post-operative chemotherapy

  • Trastuzumab (Herceptin) 6 mg/kg IV once on day 1
  • "Further adjuvant treatment (radiotherapy, chemotherapy, hormonal treatment) according to local guidelines."

21-day cycles, to complete 1 year of total therapy with Trastuzumab (Herceptin)

References

  1. 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. link to original article contains verified protocol PubMed

TH (Taxol) -> AC

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TH -> AC: Taxol (Paclitaxel) & Herceptin (Trastuzumab) followed by Adriamycin (Doxorubicin) & Cyclophosphamide

Regimen

Study Evidence Comparator Efficacy
Park et al. 2016 (I-SPY 2) Adaptively Randomized Phase II Paclitaxel & Neratinib -> AC Seems to have inferior pCR rate

TH portion

12-week course, followed by:

AC portion

14- to 21-day cycle for 4 cycles, followed by surgery

References

  1. 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 PubMed

TH (Taxol) -> FEC & H

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TH -> FEC & H: Taxol (Paclitaxel) & Herceptin (Trastuzumab) followed by Fluorouracil, Epirubicin, Cyclophosphamide, Herceptin (Trastuzumab)

Regimen

Study Evidence Comparator Efficacy
Buzdar et al. 2005 Randomized T -> FEC Seems to have superior pCR rate

TH portion

  • 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, followed by:

FEC & H portion

21-day cycle for 4 cycles, followed by 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

TH (Taxotere) -> FEC & H

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TH -> FEC & H: Taxotere (Docetaxel) & Herceptin (Trastuzumab) followed by Fluorouracil, Epirubicin, Cyclophosphamide, Herceptin (Trastuzumab)

Regimen #1, IV trastuzumab

Study Evidence Comparator Efficacy
Ismael et al. 2012 (HannaH) Randomized TH -> FEC & H (SC) Non-inferior pCR rate

TH portion

21-day cycle for 4 cycles, followed by:

FEC & H portion

21-day cycle for 4 cycles, followed by surgery

Regimen #1, SC trastuzumab

Study Evidence Comparator Efficacy
Ismael et al. 2012 (HannaH) Randomized TH -> FEC & H (IV) Non-inferior pCR rate

TH portion

21-day cycle for 4 cycles, followed by:

FEC & H portion

21-day cycle for 4 cycles, followed by surgery

References

  1. 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 SD article contains verified protocol PubMed

Adjuvant chemotherapy, HER-2 positive

AC -> T -> H

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AC -> T -> H: Adriamycin (Doxorubicin) & Cyclophosphamide followed by Taxol (Paclitaxel) followed by Herceptin (Trastuzumab)

Regimen

Study Evidence Comparator Efficacy
Romond et al. 2005 (NCCTG N9831) Phase III AC -> T Superior OS
AC -> TH Not reported

This dosing schema was evaluated in NCCTG N9831 but is not commonly used and is here for reference purposes only.

AC portion

21-day cycle for 4 cycles, followed by:

T portion

12-week course, followed by:

H portion

52-week course

Monitoring

  • Cardiac function: echocardiogram at baseline, then every 3 months while on Trastuzumab (Herceptin)

References

  1. 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, 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

AC -> TH (Taxol)

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AC -> TH: Adriamycin (Doxorubicin) & Cyclophosphamide followed by Taxol (Paclitaxel) & Herceptin (Trastuzumab)
AC-TH: Adriamycin (Doxorubicin) & Cyclophosphamide followed by Taxol (Paclitaxel) & Herceptin (Trastuzumab)
AC-T-T: Adriamycin (Doxorubicin) & Cyclophosphamide followed by Taxol (Paclitaxel) & Trastuzumab

Regimen

Study Evidence Comparator Efficacy
Romond et al. 2005 (NSABP B-31/NCCTG N9831) Phase III AC -> T Superior OS

Chemotherapy, AC portion

21-day cycle for 4 cycles, followed by:

Chemotherapy, TH portion

  • Paclitaxel (Taxol) 175 mg/m2 IV over 3 hours 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, followed by:

Chemotherapy, trastuzumab monotherapy

40 additional weeks to complete a total of 52 weeks of therapy

References

  1. 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, 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

AC -> TH (Taxotere)

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AC -> TH: Adriamycin (Doxorubicin) & Cyclophosphamide followed by Taxotere (Docetaxel) & Herceptin (Trastuzumab)

Regimen

Study Evidence Comparator Efficacy
Slamon et al. 2011 (BCIRG 006) Phase III AC -> T Superior OS
TCH Seems not superior

AC portion

21-day cycle for 4 cycles, followed by:

TH portion

  • 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, followed by:

3-week cycle for 14 additional cycles to complete a total of 52 weeks of therapy

Monitoring

  • Cardiac function: echocardiogram at baseline, then every 3 months while on Trastuzumab (Herceptin)

References

  1. 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 PubMed

ddAC -> H

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ddAC -> H: dose-dense Adriamycin (Doxorubicin) & Cyclophosphamide followed by Herceptin (Trastuzumab)

Regimen

Study Evidence Comparator Efficacy
Shulman et al. 2012 (CALGB 40101) Phase III TH Seems not superior
T -> H Seems not superior

ddAC portion

Supportive medications

  • Recommended growth factor support with one of the following:
    • Filgrastim (Neupogen) 5 mcg/kg (rounded to 300 mcg or 480 mcg, whichever is closer) SC on days 3 to 10; may be discontinued before day 10 if ANC has recovered to an "acceptable range, as determined by the treating physician"
    • Sargramostim (Leukine) 250 to 500 mcg/m2 SC on days 3 to 10; may be discontinued before day 10 if ANC has recovered to an "acceptable range, as determined by the treating physician"
    • Pegfilgrastim (Neulasta) 6 mg SC, administered once 24 to 36 hours after chemotherapy

14-day cycle for 4 cycles; the study protocol originally specified 21-day cycles but was amended to 14-day cycles after results of CALGB 9741 - Citron et al. 2003 were available

Trastuzumab (Herceptin) to begin 3 to 8 weeks after the completion of AC:

H portion

  • One of the following doses & schedules of trastuzumab:

52-week course

References

  1. 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 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

ddAC -> PT

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ddAC -> PT: dose-dense Adriamycin (Doxorubicin) & Cyclophosphamide followed by Paclitaxel & Trastuzumab

Regimen

Study Evidence
Dang et al. 2008 Phase II

ddAC portion

14-day cycle for 4 cycles, followed by:

PT portion

  • Paclitaxel (Taxol) 175 mg/m2 IV over 3 hours once on day 1
  • Trastuzumab (Herceptin) as follows:
    • Cycle 1: 4 mg/kg IV once with first dose of paclitaxel, then 2 mg/kg IV once on day 8
    • Cycles 2 to 4: 2 mg/kg IV once per day on days 1 & 8

14-day cycle for 4 cycles, followed by:

  • EITHER Trastuzumab (Herceptin) 2 mg/kg IV, 1-week cycle for 44 additional cycles/weeks to complete a total of 52 weeks of therapy
  • OR Trastuzumab (Herceptin) 6 mg/kg IV, 3-week cycle for 15 additional cycles/weeks to complete a total of 52 weeks of therapy

Supportive medications

All chemotherapy cycles given with Filgrastim (Neupogen) support

Monitoring

  • Cardiac function: echocardiogram at baseline, then every 3 months while on Trastuzumab (Herceptin)

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 PubMed

FEC & H

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Regimen

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

Treatment preceded by neoadjuvant docetaxel & pertuzumab versus neoadjuvant docetaxel, pertuzumab, trastuzumab versus neoadjuvant pertuzumab & trastuzumab versus neoadjvuant TH.

Chemotherapy

21-day cycle for 3 cycles, followed by:

  • Trastuzumab (Herceptin) 6 mg/kg IV once on day 1
  • Radiation therapy and/or hormone therapy for ER positive patients is given "per local guidelines"

21-day cycles, to complete 1 year of total therapy with trastuzumab

References

  1. 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

Neratinib (Nerlynx)

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Regimen

Study Evidence Comparator Efficacy
Chan et al. 2016 (ExteNET) Phase III Placebo Superior invasive DFS

Treatment preceded by surgery and trastuzumab-containing chemotherapy (neoadjuvant or adjuvant).

Chemotherapy

12-month course

References

  1. 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 SD article contains verified protocol PubMed

Placebo

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Regimen

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

No further treatment after surgery and trastuzumab-containing chemotherapy (neoadjuvant or adjuvant).

References

  1. 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 SD article contains verified protocol PubMed

TCH (Carboplatin)

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

Regimen

Study Evidence Comparator Efficacy
Slamon et al. 2011 (BCIRG 006) Phase III AC -> T Seems to have superior OS
AC -> TH Seems not superior

Chemotherapy

21-day cycle for 6 cycles, followed by:

3-week cycle for 12 additional cycles to complete a total of 52 weeks of therapy

Monitoring

References

  1. 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 PubMed

TCH (Cyclophosphamide)

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TCH: Taxotere, Cyclophosphamide, Herceptin

Regimen

Study Evidence
Jones et al. 2013 Phase II

Induction therapy

Chemotherapy started within 84 days of surgery.

Supportive medications

21-day cycle for 4 cycles, then proceed to trastuzumab monotherapy

Trastuzumab monotherapy

21-day cycles, given until patient receives 1 year total of trastuzumab therapy

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

TH

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TH: Taxol (Paclitaxel), Herceptin (Trastuzumab)

Regimen

Study Evidence Comparator Efficacy
Shulman et al. 2012 (CALGB 40101) Phase III ddAC -> H Seems not superior
T -> H Seems not superior

TH portion

  • Paclitaxel (Taxol) 175 mg/m2 IV over 3 hours once on day 1
  • Trastuzumab (Herceptin) as follows:
    • Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once on day 8
    • Cycles 2 to 4: 2 mg/kg IV once per day on days 1 & 8

Supportive medications

  • Diphenhydramine (Benadryl) 12.5-50 mg IV once 30 to 60 minutes prior to paclitaxel
  • One of the following H2 blockers:
  • One of the following dexamethasone choices:
  • Recommended growth factor support with one of the following:
    • Filgrastim (Neupogen) 5 mcg/kg (rounded to 300 mcg or 480 mcg, whichever is closer) SC once per day on days 3 to 10; may be discontinued before day 10 if ANC has recovered to an "acceptable range, as determined by the treating physician"
    • Sargramostim (Leukine) 250 to 500 mcg/m2 SC once per day on days 3 to 10; may be discontinued before day 10 if ANC has recovered to an "acceptable range, as determined by the treating physician"
    • Pegfilgrastim (Neulasta) 6 mg SC once, given 24 to 36 hours after chemotherapy

14-day cycle for 4 cycles, followed by:

Trastuzumab monotherapy

44-week course, which, counting doses given as part of TH, will result in a total of 52 weeks of trastuzumab therapy

Regimen #2

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

TH portion

12-week course, then proceed to trastuzumab only phase

Trastuzumab monotherapy

3-week cycle for 13 additional cycles (for 39 weeks of trastuzumab only therapy)

References

  1. 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 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
  2. 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 PubMed

T -> H

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T -> H: Sequential Taxol (Paclitaxel), Herceptin (Trastuzumab)

Regimen

Study Evidence Comparator Efficacy
Shulman et al. 2012 (CALGB 40101) Phase III ddAC -> H Seems not superior
TH Seems not superior

T portion

Supportive medications

  • Diphenhydramine (Benadryl) 12.5 to 50 mg IV once 30 to 60 minutes prior to paclitaxel
  • One of the following H2 blockers:
  • One of the following dexamethasone choices:
  • Recommended growth factor support with one of the following:
    • Filgrastim (Neupogen) 5 mcg/kg (rounded to 300 mcg or 480 mcg, whichever is closer) SC once per day on days 3 to 10; may be discontinued before day 10 if ANC has recovered to an "acceptable range, as determined by the treating physician"
    • Sargramostim (Leukine) 250 to 500 mcg/m2 SC once per day on days 3 to 10; may be discontinued before day 10 if ANC has recovered to an "acceptable range, as determined by the treating physician"
    • Pegfilgrastim (Neulasta) 6 mg SC once, given 24 to 36 hours after chemotherapy

14-day cycle for 4 cycles, followed by:

Trastuzumab monotherapy

One of the following doses & schedules of trastuzumab:

52-week course of therapy

References

  1. 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 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

TH (Taxotere) -> FEC

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TH -> FEC: Taxotere (Docetaxel) & Herceptin (Trastuzumab) followed by Fluorouracil, Epirubicin, Cyclophosphamide

Regimen

Study Evidence Comparator Efficacy
Joensuu et al. 2006 (FinHer) Phase III T -> FEC
V -> FEC 		Seems not superior
VH -> FEC Not reported

TH portion

  • Docetaxel (Taxotere) 100 mg/m2 IV over 1 hour 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, followed by:

FEC portion

21-day cycle for 3 cycles

Monitoring

  • Cardiac function: echocardiogram at baseline, after last cycle of FEC, 12 months after completion of chemotherapy, and 36 months after completion of chemotherapy

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

VH -> FEC

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VH -> FEC: Vinorelbine & Herceptin (Trastuzumab) followed by Fluorouracil, Epirubicin, Cyclophosphamide

Regimen

Study Evidence Comparator Efficacy
Joensuu et al. 2006 (FinHer) Phase III T -> FEC
V -> FEC 		Seems not superior
TH -> FEC Not reported

VH portion

  • 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, followed by:

FEC portion

21-day cycle for 3 cycles

Monitoring

  • Cardiac function: echocardiogram at baseline, after last cycle of FEC, 12 months after completion of chemotherapy, and 36 months after completion of chemotherapy

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 (Herceptin)

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Regimen #1, 1-year course

Study Evidence Comparator Efficacy
Piccart-Gebhart et al. 2005 (HERA/BIG 01-01) Phase III No trastuzumab after (neo-)adjuvant chemotherapy Superior OS
Trastuzumab x 2 years Seems not superior

Participants in HERA had already received at least four courses of an approved (neo-)adjuvant chemotherapy regimen. See supplement for a list of these regimens.

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

3-week cycle for 1 year

Regimen #2, 2-year course

Study Evidence Comparator Efficacy
Piccart-Gebhart et al. 2005 (HERA/BIG 01-01) Phase III No trastuzumab after (neo-)adjuvant chemotherapy Not reported
Trastuzumab x 1 year Seems not superior

Participants in HERA had already received at least four courses of an approved (neo-)adjuvant chemotherapy regimen. See supplement for a list of these regimens.

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

3-week cycle for 2 years

References

  1. 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 SD 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 PubMed

Metastatic disease, HER-2 positive

ACH

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

Regimen

Study Evidence Comparator Efficacy
Slamon et al. 2001 Phase III 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

Ado-trastuzumab emtansine (Kadcyla)

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Example orders

Regimen

Study Evidence Comparator Efficacy
Verma et al. 2012 (EMILIA) Phase III Capecitabine & Lapatinib Superior OS
Hurvitz et al. 2013 Randomized Phase II TH Seems to have superior PFS
Krop et al. 2014 (TH3RESA) Phase III Physician's choice Superior OS (*)

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

Chemotherapy

21-day cycles, given until progression of disease or unacceptable toxicity

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 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 articlePubMed
  2. 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
  3. 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 articlePubMed

Bevacizumab, Capecitabine, Trastuzumab

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Regimen

Study Evidence
Martín et al. 2012 Phase II

Chemotherapy

21-day cycles, given until progression of disease or unacceptable toxicity

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 [1]
  2. A Study of Avastin (Bevacizumab) in Combination With Herceptin (Trastuzumab) and Xeloda (Capecitabine) in Patients With HER2-Positive Breast Cancer at ClinicalTrials.gov, NCT00811135

Capecitabine & Lapatinib

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Regimen

Study Evidence Comparator Efficacy
Geyer et al. 2006 Phase III Capecitabine Superior TTP
Verma et al. 2012 (EMILIA) Phase III T-DM1 Inferior OS

Chemotherapy

21-day cycles

References

  1. 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 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 PubMed
  2. 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 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 articlePubMed

ECH

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ECH: Epirubicin, Cyclophosphamide, Herceptin (Trastuzumab)

Regimen

Study Evidence Comparator Efficacy
Slamon et al. 2001 Phase III 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

Lapatinib (Tykerb)

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Regimen

Study Evidence Comparator Efficacy
Blackwell et al. 2010 (EGF104900) Phase III Lapatinib & Trastuzumab Seems to have inferior 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

Lapatinib & Trastuzumab

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Regimen

Study Evidence Comparator Efficacy
Blackwell et al. 2010 (EGF104900) Phase III 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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Regimen #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.

Regimen #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 PubMed

TCH (Docetaxel)

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

Regimen

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

Chemotherapy

21-day cycle for 8 cycles, followed by:

References

  1. 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

TCH (Paclitaxel)

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

Regimen

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

Chemotherapy

21-day cycle for at least 6 cycles, followed by:

21-day cycles until progression or intolerance

Monitoring

  • Cardiac function: echocardiogram at baseline, then every 3 months while on Trastuzumab (Herceptin)

References

  1. 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 PubMed

TH (Paclitaxel)

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

Regimen #1, weekly paclitaxel (3 weeks on, 1 week off)

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

4-week cycles, continued until progression or intolerance

Regimen #2, q3wk paclitaxel

Study Evidence Comparator Efficacy
Slamon et al. 2001 Phase III Paclitaxel Seems to have superior OS
Robert et al. 2006 Phase III TPC Seems to have inferior PFS
Seidman et al. 2008 (CALGB 9840) Phase III TH, weekly paclitaxel (80 mg/m2) Inferior OS

Chemotherapy, initial

  • Paclitaxel (Taxol) 175 mg/m2 IV once on day 2
  • 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, followed by:

Chemotherapy, maintenance

21-day cycles until progression or intolerance

Monitoring

  • Cardiac function: echocardiogram at baseline, then every 3 months while on Trastuzumab (Herceptin)

Regimen #3, weekly paclitaxel (80 mg/m2)

Study Evidence Comparator Efficacy
Burstein et al. 2007 (TRAVIOTA) Phase III Trastuzumab & Vinorelbine Might have inferior TTP
Seidman et al. 2008 (CALGB 9840) Phase III TH, q3wk paclitaxel Superior OS

Chemotherapy

8-week cycles

Regimen #4, weekly paclitaxel (90 mg/m2)

Study Evidence
Seidman et al. 2001 Phase II

Chemotherapy

Given until progression

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. 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. 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. 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
  7. 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

TH (Docetaxel)

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TH: Taxotere (Docetaxel), Herceptin (Trastuzumab)

Regimen #1

Study Evidence Comparator Efficacy
Hurvitz et al. 2013 Randomized Phase II T-DM1 Seems to have inferior PFS
Gianni et al. 2013 (AVAREL) Randomized Phase II BTH Might have inferior PFS

Chemotherapy

  • Docetaxel (Taxotere) 75 or 100 mg/m2 IV once on day 1
    • Dose in Hurvitz et al. 2013 was per investigator's discretion; all patients in AVAREL received 100 mg/m2
  • Trastuzumab (Herceptin) as follows:
    • Cycle 1: 8 mg/kg IV once on day 2
    • Cycle 2 onwards: 6 mg/kg IV once on day 1

21-day cycles, given until progression of disease or unacceptable toxicity

Regimen #2

Study Evidence Comparator Efficacy
Baselga et al. 2011 (CLEOPATRA) Phase III THP Inferior OS

This unusual schedule with both medications being given on day 2 of cycle 1 is due to this regimen being the control arm of CLEOPATRA, in which patients in one arm received a placebo instead of pertuzumab on day 1. It is reasonable to assume that in practice, drugs in this regimen will be given on day 1 from the beginning.

Chemotherapy

  • Docetaxel (Taxotere) as follows:
    • 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 once on day 2
    • Cycle 2 onwards: 6 mg/kg IV once on day 1

21-day cycle for at least 6 cycles, given until progression of disease or unacceptable toxicity

If it is decided to no longer administer Docetaxel (Taxotere) with this regimen, then patients could continue to receive:

21-day cycles, given until progression of disease or unacceptable toxicity

Regimen #3

Study Evidence Comparator Efficacy
Valero et al. 2010 (BCIRG 007) Phase III TCH Seems not superior

Induction therapy

  • 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

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

21-day cycle for 8 cycles

Patients then proceeded to maintenance trastuzumab therapy:

Maintenance trastuzumab

Given until progression of disease or unacceptable toxicity

Regimen #4

Study Evidence Comparator Efficacy
Esteva et al. 2002 Phase II
Burstein et al. 2007 (TRAVIOTA) Phase III Trastuzumab & Vinorelbine 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, given until progression of disease or unacceptable toxicity

Regimen #5

Study Evidence Comparator Efficacy
Marty et al. 2005 (M77001) Randomized Phase II Docetaxel Seems to have superior OS

Marty et al. 2005 did not exactly specify days of therapy; this is the best guess for what was used based on the description.

Induction therapy

  • 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 6: 2 mg/kg IV once per day on days 1, 8, 15

Supportive medications

21-day cycle for 6 cycles, given until progression of disease or unacceptable toxicity

Patients could receive docetaxel beyond six cycles at the discretion of the investigator. Otherwise, patients proceeded to maintenance trastuzumab therapy:

Maintenance trastuzumab

Given until progression of disease or unacceptable toxicity

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. 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. 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. 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. 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 link to PMC article contains verified protocol 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. 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
  7. 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

THP (Docetaxel)

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

Regimen

Study Evidence Comparator Efficacy
Baselga et al. 2011 (CLEOPATRA) Phase III Docetaxel & Trastuzumab Superior OS

Chemotherapy

  • Docetaxel (Taxotere) as follows:
    • 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 once on day 2
    • 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 at least 6 cycles, given until progression of disease or unacceptable toxicity

If it is decided to no longer administer Docetaxel (Taxotere) with this regimen, then patients could continue to receive:

21-day cycles, given until progression of disease or unacceptable toxicity

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 link to PMC article contains verified protocol 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

XH

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XH: Xeloda, Herceptin

Regimen #1

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

Chemotherapy

21-day cycles

Regimen #2

Study Evidence
Bartsch et al. 2007 Phase II

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 PubMed
  2. 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 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

Trastuzumab (Herceptin) & other single agent chemotherapy

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Regimen

21-day cycles

References

See single agent chemotherapy regimens

Trastuzumab & Vinorelbine

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Regimen

Study Evidence Comparator Efficacy
Burstein et al. 2007 (TRAVIOTA) Phase III TH (Docetaxel)
TH (Paclitaxel) 		Might have superior TTP
André et al. 2014 (BOLERO-3) Phase III Everolimus, Trastuzumab, Vinorelbine Inferior PFS
Harbeck et al. 2016 (LUX-Breast 1) Phase III Afatinib & Vinorelbine Seems not superior

Chemotherapy

Given until progression, intolerance, or request to discontinue therapy

References

  1. 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. 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
  3. 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 SD article contains verified protocol PubMed

Additional resources

Patient information

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