Neoadjuvant therapy for patients with HER2-positive breast cancer
- William M Sikov, MD, FACP
William M Sikov, MD, FACP
- Associate Professor of Medicine
- Obstetrics and Gynecology
- Warren Alpert Medical School of Brown University
Persistent activation of signaling pathways as a result of amplification of the human epidermal growth factor receptor 2 (HER2) in patients with HER2-positive breast cancer leads to a biologically aggressive malignancy with heightened sensitivity to cytotoxic chemotherapy. Compared with most other subtypes of breast cancer, a higher percentage of HER2-positive patients achieve a pathologic complete response (pCR) to neoadjuvant chemotherapy (NACT), even in the absence of HER2-targeted therapy [1,2]. Using targeted therapy to block activation of those pathways further enhances the chemosensitivity of HER2-positive breast cancer, increasing the pCR rate. Clinical trial results from the last few years suggest that newer HER2-targeted agents may allow more effective inhibition of HER2 and expand options for the NACT regimen administered with HER2-targeted therapy based on the patient’s risk factors and overall medical condition.
This topic will review issues pertaining specifically to administration of neoadjuvant therapy in patients with HER2-positive breast cancer. General principles of neoadjuvant chemotherapy, including patient selection for neoadjuvant therapy, assessment of response to therapy, and surgical management after neoadjuvant chemotherapy, are discussed in detail elsewhere. (See "General principles of neoadjuvant therapy for breast cancer".)
Adjuvant treatment for patients with HER2-positive disease who have received neoadjuvant treatment is also discussed elsewhere. (See "Adjuvant systemic therapy for HER2-positive breast cancer", section on 'Patients who were treated with neoadjuvant therapy'.)
Neoadjuvant chemotherapy (NACT) is appropriate for many patients with locally advanced breast cancer regardless of subtype, because a response may allow both less aggressive surgery and improved surgical outcomes. We generally define locally advanced as stage III cancers as well as the subset of IIB cancers with T3 disease. In addition, patients with earlier-stage, HER2-positive disease (stage I or II) may also be candidates for neoadjuvant therapy if they meet any of the following criteria:
●The patient desires breast-conserving surgery (BCS) but is not a candidate for BCS or is likely to have a suboptimal cosmetic outcome with BCS due to tumor location or size relative to the size of the patient’s breast, and may be a better candidate if neoadjuvant therapy decreases the extent of her tumor.
- Cortazar P, Zhang L, Untch M, et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet 2014; 384:164.
- Esserman LJ, Berry DA, DeMichele A, et al. Pathologic complete response predicts recurrence-free survival more effectively by cancer subset: results from the I-SPY 1 TRIAL--CALGB 150007/150012, ACRIN 6657. J Clin Oncol 2012; 30:3242.
- Carey LA, Dees EC, Sawyer L, et al. The triple negative paradox: primary tumor chemosensitivity of breast cancer subtypes. Clin Cancer Res 2007; 13:2329.
- Rouzier R, Perou CM, Symmans WF, et al. Breast cancer molecular subtypes respond differently to preoperative chemotherapy. Clin Cancer Res 2005; 11:5678.
- von Minckwitz G, Untch M, Blohmer JU, et al. Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes. J Clin Oncol 2012; 30:1796.
- Untch M, Fasching PA, Konecny GE, et al. Pathologic complete response after neoadjuvant chemotherapy plus trastuzumab predicts favorable survival in human epidermal growth factor receptor 2-overexpressing breast cancer: results from the TECHNO trial of the AGO and GBG study groups. J Clin Oncol 2011; 29:3351.
- Broglio KR, Quintana M, Foster M, et al. Association of Pathologic Complete Response to Neoadjuvant Therapy in HER2-Positive Breast Cancer With Long-Term Outcomes: A Meta-Analysis. JAMA Oncol 2016; 2:751.
- Gralow JR, Burstein HJ, Wood W, et al. Preoperative therapy in invasive breast cancer: pathologic assessment and systemic therapy issues in operable disease. J Clin Oncol 2008; 26:814.
- Kaufmann M, Hortobagyi GN, Goldhirsch A, et al. Recommendations from an international expert panel on the use of neoadjuvant (primary) systemic treatment of operable breast cancer: an update. J Clin Oncol 2006; 24:1940.
- Schwartz GF, Hortobagyi GN. Proceedings of the consensus conference on neoadjuvant chemotherapy in carcinoma of the breast, April 26-28, 2003, Philadelphia, Pennsylvania. Cancer 2004; 100:2512.
- Shannon C, Smith I. Is there still a role for neoadjuvant therapy in breast cancer? Crit Rev Oncol Hematol 2003; 45:77.
- Walter P, Bernhard U, Menger M, et al. New immunosuppressive agents in experimental allogeneic heart transplantation. Transplant Proc 1990; 22:2324.
- Bayraktar S, Bayraktar UD, Reis IM, et al. Neoadjuvant Dose-Dense Docetaxel, Carboplatinum and Trastuzumab Chemotherapy for HER2 Overexpressing Breast Cancer. J Clin Oncol 2009; 27:15S, abstr e11557.
- Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 2005; 353:1673.
- Buzdar AU, Suman VJ, Meric-Bernstam F, et al. 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; 14:1317.
- Robidoux A, Tang G, Rastogi P, et al. 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; 14:1183.
- Untch M, Loibl S, Bischoff J, et al. Lapatinib versus trastuzumab in combination with neoadjuvant anthracycline-taxane-based chemotherapy (GeparQuinto, GBG 44): a randomised phase 3 trial. Lancet Oncol 2012; 13:135.
- Slamon D, Eiermann W, Robert N, et al. Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med 2011; 365:1273.
- Coudert BP, Largillier R, Arnould L, et al. Multicenter phase II trial of neoadjuvant therapy with trastuzumab, docetaxel, and carboplatin for human epidermal growth factor receptor-2-overexpressing stage II or III breast cancer: results of the GETN(A)-1 trial. J Clin Oncol 2007; 25:2678.
- Chen XS, Nie XQ, Chen CM, et al. Weekly paclitaxel plus carboplatin is an effective nonanthracycline-containing regimen as neoadjuvant chemotherapy for breast cancer. Ann Oncol 2010; 21:961.
- Sikov WM, Dizon DS, Strenger R, et al. Frequent pathologic complete responses in aggressive stages II to III breast cancers with every-4-week carboplatin and weekly paclitaxel with or without trastuzumab: a Brown University Oncology Group Study. J Clin Oncol 2009; 27:4693.
- Yu KD, Liu GY, Chen CM, et al. Weekly paclitaxel/carboplatin/trastuzumab therapy improves pathologic complete remission in aggressive HER2-positive breast cancers, especially in luminal-B subtype, compared with a once-every-3-weeks schedule. Oncologist 2013; 18:511.
- Schneeweiss A, Chia S, Hickish T, et al. 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; 24:2278.
- Bayraktar S, Gonzalez-Angulo AM, Lei X, et al. Efficacy of neoadjuvant therapy with trastuzumab concurrent with anthracycline- and nonanthracycline-based regimens for HER2-positive breast cancer. Cancer 2012; 118:2385.
- Loibl S, Jackisch C, Schneeweiss A, et al. Dual HER2-blockade with pertuzumab and trastuzumab in HER2-positive early breast cancer: a subanalysis of data from the randomized phase III GeparSepto trial. Ann Oncol 2017; 28:497.
- Jones SE, Collea R, Paul D, et al. 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; 14:1121.
- Tolaney SM, Barry WT, Dang CT, et al. Adjuvant paclitaxel and trastuzumab for node-negative, HER2-positive breast cancer. N Engl J Med 2015; 372:134.
- Gianni L, Eiermann W, Semiglazov V, et al. 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; 375:377.
- Gianni L, Eiermann W, Semiglazov V, et al. Neoadjuvant and adjuvant trastuzumab in patients with HER2-positive locally advanced breast cancer (NOAH): follow-up of a randomised controlled superiority trial with a parallel HER2-negative cohort. Lancet Oncol 2014; 15:640.
- Gianni L, Pienkowski T, Im YH, et al. 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; 13:25.
- Gianni L, Pienkowski T, Im YH, et al. 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; 17:791.
- Untch M, Jackisch C, Schneeweib A, et al. A randomized phase III trial comparing neoadjuvant chemotherapy with weekly nanoparticle-based paclitaxel with solvent-based paclitaxel followed by anthracyline/cyclophosphamide for patients with early breast cancer (GeparSepto); GBG 69. San Antonio Breast Cancer Symposium 2014; S2-07.
- Guarneri V, Frassoldati A, Bottini A, et al. Preoperative chemotherapy plus trastuzumab, lapatinib, or both in human epidermal growth factor receptor 2-positive operable breast cancer: results of the randomized phase II CHER-LOB study. J Clin Oncol 2012; 30:1989.
- Baselga J, Bradbury I, Eidtmann H, et al. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet 2012; 379:633.
- Robidoux A, Tang G, Rastogi P, et al.. Evaluation of lapatinib as a component of neoadjuvant therapy for HER2+ operable breast cancer: NSABP protocol B-41. J Clin Oncol 2012; 30s: LBA506.
- Carey LA, Berry DA, Ollila D, et al. Clinical and translational results of CALGB 40601: A neoadjuvant phase III trial of weekly paclitaxel and trastuzumab with or without lapatinib for HER2-positive breast cancer. J Clin Oncol 2013; 31s: 500.
- von Minckwitz G, Loibl S, Untch M, et al. Survival after neoadjuvant chemotherapy with or without bevacizumab or everolimus for HER2-negative primary breast cancer (GBG 44-GeparQuinto)†. Ann Oncol 2014; 25:2363.
- Hicks M, Macrae ER, Abdel-Rasoul M, et al. Neoadjuvant dual HER2-targeted therapy with lapatinib and trastuzumab improves pathologic complete response in patients with early stage HER2-positive breast cancer: a meta-analysis of randomized prospective clinical trials. Oncologist 2015; 20:337.
- de Azambuja E, Holmes AP, Piccart-Gebhart M, et al. 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; 15:1137.
- Piccart-Gebhart MJ, Holmes AP, Baselga J, De Azambuja E. First results from the phase III ALTTO trial (BIG 2-06; NCCTG [Alliance] N063D) comparing one year of anti-HER2 therapy with lapatinib alone (L), trastuzumab alone (T), their sequence (T->L), or their combination (T+L) in the adjuvant treatment of HER2-positive early breast cancer (EBC). J Clin Oncol 2014; 15S, LBA4.
- Rimawi MF, Mayer IA, Forero A, et al. Multicenter phase II study of neoadjuvant lapatinib and trastuzumab with hormonal therapy and without chemotherapy in patients with human epidermal growth factor receptor 2-overexpressing breast cancer: TBCRC 006. J Clin Oncol 2013; 31:1726.
- Rimawi MF, Niravath PA, Wang T, et al. TBCRC023: A randomized multicenter phase II neoadjuvant trial of lapatinib plus trastuzumab, with endcorine therapy and without chemotherapy, for 12 vs. 24 weeks in patients with HER2 overexpressing breast cancer. Cancer Res 2015; 75 (9S):S602 (SABCS).
- DeMichele AM, Moulder S, Buxton M, et al. Efficacy of T-DM1+pertuzumab over standard therapy for HER2+ breast cancer: Results from the neoadjuvant I-SPY 2 TRIAL. AACR 2016.
- Hurvitz SA, Symmans WF, Jung KH, Huang CS. Pathologic complete response (pCR) rates after neoadjuvant trastuzumab emtansine (T-DM1 [K]) + pertuzumab (P) vs docetaxel + carboplatin + trastuzumab + P (TCHP) treatment in patients with HER2-positive (HER2+) early breast cancer (EBC) (KRISTINE). J Clin Oncol 2016; 34S: ASCO #500.
- Park JW, Liu MC, Yee D, et al. Adaptive Randomization of Neratinib in Early Breast Cancer. N Engl J Med 2016; 375:11.
- Jacobs SA A, Robidoux A, Garcia JMP M P, Abraham J. NSABP FB-7: A phase II randomized trial evaluating neoadjuvant therapy with weekly paclitaxel (P) plus neratinib (N) or. SABCS 2015; #PD5-04.
- Ismael G, Hegg R, Muehlbauer S, et al. 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; 13:869.
- Jackisch C, Hegg R, Stryoyakovskiy D, Ahn JS. Total pathologic complete response (tpCR) and event-free survival (EFS) with subcutaneous (SC) or intravenous (IV) trastuzumab in HER2-positive early breast cancer (EBC). J Clin Oncol 2015; 15S: 585.
- Pivot X, Gligorov J, Müller V, et al. Preference for subcutaneous or intravenous administration of trastuzumab in patients with HER2-positive early breast cancer (PrefHer): an open-label randomised study. Lancet Oncol 2013; 14:962.
- Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001; 344:783.
- Prat A, Carey LA, Adamo B, et al. Molecular features and survival outcomes of the intrinsic subtypes within HER2-positive breast cancer. J Natl Cancer Inst 2014; 106.
- Carey LA, Berry DA, Cirrincione CT, et al. 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; 34:542.
- Loibl S, von Minckwitz G, Schneeweiss A, et al. PIK3CA mutations are associated with lower rates of pathologic complete response to anti-human epidermal growth factor receptor 2 (her2) therapy in primary HER2-overexpressing breast cancer. J Clin Oncol 2014; 32:3212.
- Majewski IJ, Nuciforo P, Mittempergher L, et al. PIK3CA mutations are associated with decreased benefit to neoadjuvant human epidermal growth factor receptor 2-targeted therapies in breast cancer. J Clin Oncol 2015; 33:1334.
- Pogue-Geile KL, Song N, Jeong JH, et al. Intrinsic subtypes, PIK3CA mutation, and the degree of benefit from adjuvant trastuzumab in the NSABP B-31 trial. J Clin Oncol 2015; 33:1340.
- Loibl S, Majewski I, Guarneri V, et al. PIK3CA mutations are associated with reduced pathological complete response rates in primary HER2-positive breast cancer: pooled analysis of 967 patients from five prospective trials investigating lapatinib and trastuzumab. Ann Oncol 2016; 27:1519.
- Denkert C, Loibl S, Noske A, et al. Tumor-associated lymphocytes as an independent predictor of response to neoadjuvant chemotherapy in breast cancer. J Clin Oncol 2010; 28:105.
- Denkert C, von Minckwitz G, Brase JC, et al. Tumor-infiltrating lymphocytes and response to neoadjuvant chemotherapy with or without carboplatin in human epidermal growth factor receptor 2-positive and triple-negative primary breast cancers. J Clin Oncol 2015; 33:983.
- Salgado R, Denkert C, Campbell C, et al. Tumor-Infiltrating Lymphocytes and Associations With Pathological Complete Response and Event-Free Survival in HER2-Positive Early-Stage Breast Cancer Treated With Lapatinib and Trastuzumab: A Secondary Analysis of the NeoALTTO Trial. JAMA Oncol 2015; 1:448.
- OUTCOME MEASURES
- COMPONENTS OF THERAPY
- - Standard regimens
- Anthracycline-based treatment
- Nonanthracycline-based treatment
- Choice of taxane
- - Alternatives for those with low-risk disease or comorbidities
- Biologic therapy
- - Trastuzumab
- - Pertuzumab
- - Investigational approaches
- Lapatinib with chemotherapy
- HER2-targeted therapy without chemotherapy
- Other agents
- TIMING OF HER2-DIRECTED AGENTS
- TUMOR PROGNOSTIC FEATURES
- EVALUATION OF RESPONSE AND SURGICAL MANAGEMENT
- ADJUVANT THERAPY AFTER NEOADJUVANT THERAPY
- SUMMARY AND RECOMMENDATIONS