Standard first line therapy for de novo HER2+ MBC should consist of a taxane (docetaxel or paclitaxel) in combination with pertuzumab and trastuzumab.  Patients who have received prior treatment with peruzumab and trastuzumab in either the (neo)adjuvant or metastatic setting may be considered for alternative 2^nd line therapies for disease progression within 6 months of finishing treatment.

Patients with HR+ disease should be initiated on endocrine therapy (when chemotherapy has completed) alongside maintenance anti-HER2 therapy.  Ovarian Function Suppression should be added for pre- and perimenopausal women.

Preferred regimen: Docetaxel in combination with Pertuzumab & Trastuzumab 

Alternative Regimens

• Docetaxel and Cyclophosphamide in combination with Trastuzumab
• Paclitaxel weekly in combination with Trastuzumab

SMC 928/13  Trastuzumab  is accepted for restricted use in treatment of HER2+ metastatic breast cancer

Sequential single-agent treatment is generally preferred but combination therapy should be considered if a rapid response is needed.  The optimal sequence of therapy in MBC has not been established. Available options should be discussed with the patient as part of shared decision making consultation.  The following treatments are not listed in order; restrictions to line of therapy are specified for each.

Trastuzumab deruxtecan 5.4mg/kg IV every 3 weeks until progression or toxicity

• Disease progression <6 months since (neo)adjuvant anti-HER2 treatment
• After progression on 1^st line anti-HER2 treatment for metastatic disease
• After trastuzumab emtansine

SMC 2545

Trastuzumab emtansine 3.6mg/kg IV every 3 weeks until progression or toxicity

• Disease progression <6 months since (neo)adjuvant treatment with anti-HER2 treatment
• After progression on 1^st line metastatic anti-HER2 treatment
• After trastuzumab deruxtecan

SMC 990/14

Anthracyline based treatment

Epirubicin 60mg/m²  and cyclophosphamide 600mg/m² IV  3-weekly for up to 6 cycles

Epirubicin 30mg/m² IV weekly until 12 weeks then move to 2 weekly maintenance until toxicity or disease progression.  (If proceeding with treatment beyond maximum cumulative dose of 900mg/m² the patient should be consulted and re-consented.)

Taxanes

Paclitaxel 80mg/m²  IV weekly for up to 12-18 weeks then reduce to 2 weekly until toxicity or disease progression

Docetaxel 75-80mg/m²  IV 3-weekly for up to 6 cycles

Capecitabine

Capecitabine 1000mg/m² PO bd d1-14 3-weekly. Continue until progression or toxicity

Eribulin

Eribulin 1.23mg/m²  IV on day 1 and 8 of a 21-day cycle continued until progression or toxicity

• SMC 1065/15 after at least two prior chemotherapeutic regimens for advanced disease which includes capecitabine if indicated

Tucatinib

• SMC 2398 after at least two prior anti-HER2 treatment regimens

Vinorelbine

Vinorelbine 60-80 mg/m² oral days 1+8, or 25mg/m² IV 3-weekly

Cyclophosphamide

Cyclophosphamide 50mg orally once daily continuously until progression or toxicity

Blohmer JU, Schmid P, Hilfrich J, Friese K, Kleine-Tebbe A, Koelbl H, Sommer H, Morack G, Wischnewsky MB, Lichtenegger W, Kuemmel S. Epirubicin and cyclophosphamide versus epirubicin and docetaxel as first-line therapy for women with metastatic breast cancer: final results of a randomised phase III trial. Ann Oncol. 2010 Jul;21(7):1430-1435. doi: 10.1093/annonc/mdp585. Epub 2010 Jan 20. PMID: 20089562.

Colleoni M, Rocca A, Sandri MT, et al. Low-dose oral methotrexate and cyclophosphamide in metastatic breast cancer: antitumor activity and correlation with vascular endothelial growth factor levels. Annals of Oncology Volume 13, Issue 1, January 2002, Pages 73-80.Ghersi D, Willson ML, Chan M, Simes J, Donoghue E, Wilcken N. Taxane-containing regimens for metastatic breast cancer. Cochrane Database of Systematic Reviews 2015, Issue 6. Art. No.: CD003366. DOI: 10.1002/14651858.CD003366.pub3.

Finn RS, Martin M, Rugo HS, Jones S, Im SA, Gelmon K, Harbeck N, Lipatov ON, Walshe JM, Moulder S, Gauthier E, Lu DR, Randolph S, Diéras V, Slamon DJ. Palbociclib and Letrozole in Advanced Breast Cancer. N Engl J Med. 2016 Nov 17;375(20):1925-1936. doi: 10.1056/NEJMoa1607303. PMID: 27959613.​

Goetz MP, Toi M, Campone M, Sohn J, Paluch-Shimon S, Huober J, Park IH, Trédan O, Chen SC, Manso L, Freedman OC, Garnica Jaliffe G, Forrester T, Frenzel M, Barriga S, Smith IC, Bourayou N, Di Leo A. MONARCH 3: Abemaciclib As Initial Therapy for Advanced Breast Cancer. J Clin Oncol. 2017 Nov 10;35(32):3638-3646. doi: 10.1200/JCO.2017.75.6155. Epub 2017 Oct 2. PMID: 28968163.

Hamberg P, Bos MM, Braun HJ, Stouthard JM, van Deijk GA, Erdkamp FL, van der Stelt-Frissen IN, Bontenbal M, Creemers GJ, Portielje JE, Pruijt JF, Loosveld OJ, Smit WM, Muller EW, Schmitz PI, Seynaeve C, Klijn JG; Dutch Breast Cancer Trialists' Group (BOOG). Randomized phase II study comparing efficacy and safety of combination-therapy trastuzumab and docetaxel vs. sequential therapy of trastuzumab followed by docetaxel alone at progression as first-line chemotherapy in patients with HER2+ metastatic breast cancer: HERTAX trial. Clin Breast Cancer. 2011 Apr;11(2):103-13. doi: 10.1016/j.clbc.2011.03.003. Epub 2011 Apr 11. PMID: 21569996.

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. doi: 10.1007/s10549-009-0498-7. Epub 2009 Aug 19. PMID: 19690954​

John M, Hinke A, Stauch M, Wolf H, Mohr B, Hindenburg HJ, Papke J, Schlosser J; FAKT Study Group. Weekly paclitaxel plus trastuzumab in metastatic breast cancer pretreated with anthracyclines--a phase II multipractice study. BMC Cancer. 2012 May 4;12:165. doi: 10.1186/1471-2407-12-165. PMID: 22559145; PMCID: PMC3443018.

Jones SE, Collea R, Paul D, Sedlacek S, Favret AM, Gore I Jr, Lindquist DL, Holmes FA, Allison MAK, 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):1121-1128. doi: 10.1016/S1470-2045(13)70384-X. Epub 2013 Sep 3. PMID: 24007746.

Kaufman B, Mackey JR, Clemens MR et al. 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. doi: 10.1200/JCO.2008.20.6847. Epub 2009 Sep 28. PMID: 19786670.​

von Minckwitz G, Schneeweiss A, Loibl S, Salat C, Denkert C, Rezai M, Blohmer JU, Jackisch C, Paepke S, Gerber B, Zahm DM, Kümmel S, Eidtmann H, Klare P, Huober J, Costa S, Tesch H, Hanusch C, Hilfrich J, Khandan F, Fasching PA, Sinn BV, Engels K, Mehta K, Nekljudova V, Untch M. Neoadjuvant carboplatin in patients with triple-negative and HER2-positive early breast cancer (GeparSixto; GBG 66): a randomised phase 2 trial. Lancet Oncol. 2014 Jun;15(7):747-56. doi: 10.1016/S1470-2045(14)70160-3. Epub 2014 Apr 30. PMID: 24794243.

Martín M, Ruiz A, Muñoz M, Balil A, et al; Spanish Breast Cancer Research Group (GEICAM) trial. Gemcitabine plus vinorelbine versus vinorelbine monotherapy in patients with metastatic breast cancer previously treated with anthracyclines and taxanes: final results of the phase III Spanish Breast Cancer Research Group (GEICAM) trial. Lancet Oncol. 2007 Mar;8(3):219-25. doi: 10.1016/S1470-2045(07)70041-4. PMID: 17329192.

Mauri D, Kamposioras K, Tsali L, Bristianou M, Valachis A, Karathanasi I, Georgiou C, Polyzos NP. Overall survival benefit for weekly vs. three-weekly taxanes regimens in advanced breast cancer: A meta-analysis. Cancer Treat Rev. 2010 Feb;36(1):69-74. doi: 10.1016/j.ctrv.2009.10.006. Epub 2009 Nov 27. PMID: 19945225.

Nakatsukasa K, Koyama H, Oouchi Y, Imanishi S, Mizuta N, Sakaguchi K, Fujita Y, Imai A, Okamoto A, Hamaoka A, Soushi M, Fujiwara I, Kotani T, Matsuda T, Fukuda K, Morita M, Kawakami S, Kadotani Y, Konishi E, Yanagisawa A, Goto M, Yamada K, Taguchi T. Docetaxel, cyclophosphamide, and trastuzumab as neoadjuvant chemotherapy for HER2-positive primary breast cancer. Breast Cancer. 2017 Jan;24(1):92-97. doi: 10.1007/s12282-016-0677-4. Epub 2016 Feb 13. PMID: 26874836.

Oshaughnessy JA, Blum J, Moiseyenko V et al. Randomized, open-label, phase II trial of oral capecitabine (Xeloda) vs. a reference arm of intravenous CMF (cyclophosphamide, methotrexate and 5-fluorouracil) as first-line therapy for advanced/metastatic breast cancer. Ann Oncol. 2001 Sep;12(9):1247-54. doi: 10.1023/a:1012281104865. PMID: 11697835.

O'Shaughnessy J, Thaddeus Beck J, Royce M. Everolimus-based combination therapies for HR+, HER2- metastatic breast cancer. Cancer Treat Rev. 2018 Sep;69:204-214. doi: 10.1016/j.ctrv.2018.07.013. Epub 2018 Jul 23. PMID: 30092555.

Pagani O, Klingbiel D, Ruhstaller T, Nolè F et al. A; Swiss Group for Clinical Cancer Research (SAKK). Do all patients with advanced HER2 positive breast cancer need upfront-chemo when receiving trastuzumab? Randomized phase III trial SAKK 22/99. Ann Oncol. 2017 Feb 1;28(2):305-312. doi: 10.1093/annonc/mdw622. PMID: 27998961.​

Piccart M, Hortobagyi GN, Campone M, Pritchard KI, Lebrun F, Ito Y, Noguchi S, Perez A, Rugo HS, Deleu I, Burris HA 3rd, Provencher L, Neven P, Gnant M, Shtivelband M, Wu C, Fan J, Feng W, Taran T, Baselga J. Everolimus plus exemestane for hormone-receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer: overall survival results from BOLERO-2†. Ann Oncol. 2014 Dec;25(12):2357-2362. doi: 10.1093/annonc/mdu456. Epub 2014 Sep 17. PMID: 25231953; PMCID: PMC6267855.

Piccart-Gebhart MJ, Burzykowski T, Buyse M, Sledge G, Carmichael J, Lück HJ, Mackey JR, Nabholtz JM, Paridaens R, Biganzoli L, Jassem J, Bontenbal M, Bonneterre J, Chan S, Basaran GA, Therasse P. Taxanes alone or in combination with anthracyclines as first-line therapy of patients with metastatic breast cancer. J Clin Oncol. 2008 Apr 20;26(12):1980-6. doi: 10.1200/JCO.2007.10.8399. PMID: 18421049.

Slamon DJ, Neven P, Chia S, Fasching PA, De Laurentiis M, Im SA, Petrakova K, Bianchi GV, Esteva FJ, Martín M, Nusch A, Sonke GS, De la Cruz-Merino L, Beck JT, Pivot X, Vidam G, Wang Y, Rodriguez Lorenc K, Miller M, Taran T, Jerusalem G. Phase III Randomized Study of Ribociclib and Fulvestrant in Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: MONALEESA-3. J Clin Oncol. 2018 Aug 20;36(24):2465-2472. doi: 10.1200/JCO.2018.78.9909. Epub 2018 Jun 3. PMID: 29860922.

Sledge GW Jr, Toi M, Neven P, Sohn J, Inoue K, Pivot X, Burdaeva O, Okera M, Masuda N, Kaufman PA, Koh H, Grischke EM, Frenzel M, Lin Y, Barriga S, Smith IC, Bourayou N, Llombart-Cussac A. MONARCH 2: Abemaciclib in Combination With Fulvestrant in Women With HR+/HER2- Advanced Breast Cancer Who Had Progressed While Receiving Endocrine Therapy. J Clin Oncol. 2017 Sep 1;35(25):2875-2884. doi: 10.1200/JCO.2017.73.7585. Epub 2017 Jun 3. PMID: 28580882.​

Swain SM, Miles D, Kim SB, Im YH, Im SA, Semiglazov V, Ciruelos E, Schneeweiss A, Loi S, Monturus E, Clark E, Knott A, Restuccia E, Benyunes MC, Cortés J; CLEOPATRA study group. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA): end-of-study results from a double-blind, randomised, placebo-controlled, phase 3 study. Lancet Oncol. 2020 Apr;21(4):519-530. doi: 10.1016/S1470-2045(19)30863-0. Epub 2020 Mar 12. PMID: 32171426.

Turner NC, Slamon DJ, Ro J, Bondarenko I, Im SA, Masuda N, Colleoni M, DeMichele A, Loi S, Verma S, Iwata H, Harbeck N, Loibl S, André F, Puyana Theall K, Huang X, Giorgetti C, Huang Bartlett C, Cristofanilli M. Overall Survival with Palbociclib and Fulvestrant in Advanced Breast Cancer. N Engl J Med. 2018 Nov 15;379(20):1926-1936. doi: 10.1056/NEJMoa1810527. Epub 2018 Oct 20. PMID: 30345905.

Ueno T, Masuda N, Sato N, Ohtani S, Yamamura J, Matsunami N, Kashiwaba M, Takano T, Takahashi M, Kaneko K, Ohno S, Morita S, Toi M. Multicenter study of primary systemic therapy with docetaxel, cyclophosphamide and trastuzumab for HER2-positive operable breast cancer: the JBCRG-10 study. Jpn J Clin Oncol. 2020 Jan 24;50(1):3-11. doi: 10.1093/jjco/hyz119. PMID: 31821506; PMCID: PMC6978625.

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. doi: 10.1056/NEJMoa1209124. Epub 2012 Oct 1. Erratum in: N Engl J Med. 2013 Jun 20;368(25):2442. PMID: 23020162; PMCID: PMC5125250.​