While historically breast cancer has been treated with primary surgery followed by adjuvant therapy, the delivery of systemic therapy in the neoadjuvant setting has become increasingly common, especially for triple-negative and HER2-positive breast cancer. The initial motivations for pursuing neoadjuvant chemotherapy (NAC) were decreasing the tumor burden in the breast and axilla to enable de-escalation of surgery, and use the strategy to advance drug development. While these remain of interest, recent trials have additionally demonstrated survival advantages from escalation of systemic treatment in patients with residual disease, and new studies are testing de-escalation of systemic therapy based on pathologic response. Thus, response information to NAC has become pivotal to guide adjuvant treatment recommendations, and has resulted in NAC being the preferred approach for most HER2-positive and triple-negative breast cancers. Herein, we review select landmark trials that have paved the way for the use of chemotherapy in the neoadjuvant setting for breast cancer.
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Piltin MA, Hoskin TL, Day CN, Davis J, Boughey JC. Oncologic outcomes of sentinel lymph node surgery after neoadjuvant chemotherapy for node-positive breast cancer. Ann Surg Oncol. 2020;27(12):4795–801.
Boughey JC, Alvarado MD, Lancaster RB, et al. Surgical standards for management of the axilla in breast cancer clinical trials with pathological complete response endpoint. NPJ Breast Cancer. 2018;4:26.
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(9938):164–72.
Symmans WF, Peintinger F, Hatzis C, et al. Measurement of residual breast cancer burden to predict survival after neoadjuvant chemotherapy. J Clin Oncol. 2007;25(28):4414–22.
Boughey JC, Ballman KV, McCall LM, et al. Tumor biology and response to chemotherapy impact breast cancer-specific survival in node-positive breast cancer patients treated with neoadjuvant chemotherapy: long-term follow-up from ACOSOG Z1071 (Alliance). Ann Surg. 2017;266(4):667–76.
Symmans WF, Wei C, Gould R, et al. Long-term prognostic risk after neoadjuvant chemotherapy associated with residual cancer burden and breast cancer subtype. J Clin Oncol. 2017;35(10):1049–60.
Fisher B, Brown A, Mamounas E, et al. Effect of preoperative chemotherapy on local-regional disease in women with operable breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-18. J Clin Oncol. 1997;15(7):2483–93.
Asselain B, Barlow W, Bartlett J, et al. Long-term outcomes for neoadjuvant versus adjuvant chemotherapy in early breast cancer: meta-analysis of individual patient data from ten randomised trials. Lancet Oncol. 2018;19(1):27–39.
Mieog JSD, van der Hage JA, van de Velde CJH. Neoadjuvant chemotherapy for operable breast cancer. Br J Surg. 2007;94(10):1189–200.
Mauri D, Pavlidis N, Ioannidis JPA. Neoadjuvant versus adjuvant systemic treatment in breast cancer: a meta-analysis. J Natl Cancer Inst. 2005;97(3):188–94.
Boughey JC, McCall LM, Ballman KV, et al. Tumor biology correlates with rates of breast-conserving surgery and pathologic complete response after neoadjuvant chemotherapy for breast cancer: findings from the ACOSOG Z1071 (Alliance) Prospective Multicenter Clinical Trial. Ann Surg. 2014;260(4):608–14.
Murphy BL, Day CN, Hoskin TL, Habermann EB, Boughey JC. Neoadjuvant chemotherapy use in breast Cancer is greatest in excellent responders: triple-negative and HER2 + subtypes. Ann Surg Oncol. 2018;25(8):2241–48.
Yee D, DeMichele AM, Yau C, et al. Association of event-free and distant recurrence–free survival with individual-level pathologic complete response in neoadjuvant treatment of stages 2 and 3 breast cancer: three-year follow-up analysis for the I-SPY2 adaptively randomized clinical trial. JAMA Oncol. 2020;6(9):1355–62.
Yau C, van der Noordaa M, Wei J, et al. Residual cancer burden after neoadjuvant therapy and long-term survival outcomes in breast cancer: a multi-center pooled analysis. Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10–14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):abstract no. GS5-01.
Tutt A, Tovey H, Cheang MCU, et al. Carboplatin in BRCA1/2-mutated and triple-negative breast cancer BRCAness subgroups: the TNT Trial. Nat Med. 2018;24(5):628–37.
Von Minckwitz G, Schneeweiss A, Loibl S, et al. Neoadjuvant carboplatin in patients with triple-negative and HER2-positive early breast cancer (GeparSixto; GBG 66): a randomised phase 2 trial. Lancet Oncol. 2014;15(7):747–56.
Sikov WM, Berry DA, Perou CM, et al. Impact of the addition of carboplatin and/or bevacizumab to neoadjuvant once-per-week paclitaxel followed by dose-dense doxorubicin and cyclophosphamide on pathologic complete response rates in stage II to III triple-negative breast cancer: CALGB 40603 (Alliance). J Clin Oncol. 2015;33(1):13–21.
Loibl S, O’Shaughnessy J, Untch M, et al. Addition of the PARP inhibitor veliparib plus carboplatin or carboplatin alone to standard neoadjuvant chemotherapy in triple-negative breast cancer (BrighTNess): a randomised, phase 3 trial. Lancet Oncol. 2018;19(4):497–509.
Schmid P, Adams S, Rugo HS, et al. Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N Engl J Med. 2018;379(22):2108–121.
Nanda R, Liu MC, Yau C, et al. Effect of pembrolizumab plus neoadjuvant chemotherapy on pathologic complete response in women with early-stage breast cancer: an analysis of the ongoing phase 2 adaptively randomized I-SPY2 trial. JAMA Oncol. 2020;6(5):676–84.
Schmid P, Cortes J, Pusztai L, et al. Pembrolizumab for early triple-negative breast cancer. N Engl J Med. 2020;382(9):810–21.
Mittendorf EA, Zhang H, Barrios CH, et al. Neoadjuvant atezolizumab in combination with sequential nab-paclitaxel and anthracycline-based chemotherapy versus placebo and chemotherapy in patients with early-stage triple-negative breast cancer (IMpassion031): a randomised, double-blind, phase 3 trial. Lancet. 2020;396(10257):1090–100.
Loibl S, Untch M, Burchardi N, et al. A randomised phase II study investigating durvalumab in addition to an anthracycline taxane-based neoadjuvant therapy in early triple-negative breast cancer: clinical results and biomarker analysis of GeparNuevo study. Ann Oncol. 2019;30(8):1279–88.
Gianni L, Huang C-S, Egle D, et al. Pathologic complete response (pCR) to neoadjuvant treatment with or without atezolizumab in triple negative, early high-risk and locally advanced breast cancer. NeoTRIPaPDL1 Michelangelo randomized study. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10–14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):abstract no. GS3-04
Robson M, Im S-A, Senkus E, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N Engl J Med. 2017;377(6):523–33.
Litton JK, Rugo HS, Ettl J, et al. Talazoparib in patients with advanced breast cancer and a germline BRCA mutation. N Engl J Med. 2018;379(8):753–63.
Masuda N, Lee S-J, Ohtani S, et al. Adjuvant capecitabine for breast cancer after preoperative chemotherapy. N Engl J Med. 2017;376(22):2147–59.
Van Mackelenbergh M, Seither F, Möbus V, et al. Effects of capecitabine as part of neo-/adjuvant chemotherapy. A meta-analysis of individual patient data from 12 randomized trials including 15,457 patients. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10–14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):abstract no. GS1-07.
Buzdar AU, Ibrahim NK, Francis D, et al. 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;23(16):3676–85.
Buzdar AU, Valero V, Ibrahim NK, et al. 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;13(1):228–33.
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(6):640–7.
Gianni L, Pienkowski T, Im Y-H, 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(1):25–32.
Slamon D, Eiermann W, Robert NJ, et al. Ten year follow-up of BCIRG-006 comparing doxorubicin plus cyclophosphamide followed by docetaxel (AC → T) with doxorubicin plus cyclophosphamide followed by docetaxel and trastuzumab (AC → TH) with docetaxel, carboplatin and trastuzumab (TCH) in HER2 + early breast cancer. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8–12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):abstract no. S5-04.
Van Ramshorst MS, van der Voort A, van Werkhoven ED, et al. Neoadjuvant chemotherapy with or without anthracyclines in the presence of dual HER2 blockade for HER2-positive breast cancer (TRAIN-2): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2018;19(12):1630–40.
Van der Voort A, van Ramshorst MS, van Werkhoven ED, et al. Three-year follow-up of neoadjuvant chemotherapy with or without anthracyclines in the presence of dual HER2-blockade for HER2-positive breast cancer (TRAIN-2): a randomized phase III trial. J Clin Oncol. 2020;38(15 Suppl):501.
Von Minckwitz G, Huang C-S, Mano MS, et al. Trastuzumab emtansine for residual invasive HER2-positive breast cancer. N Engl J Med. 2019;380(7):617–28.
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(9):2385–93.
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(2):134–41.
Tolaney SM, Guo H, Pernas S, et al. Seven-year follow-up analysis of adjuvant paclitaxel and trastuzumab trial for node-negative, human epidermal growth factor receptor 2–positive breast cancer. J Clin Oncol. 2019;37(22):1868–75.
Anderson TL, Glazebrook KN, Murphy BL, Viers LD, Hieken TJ. Cross-sectional imaging to evaluate the extent of regional nodal disease in breast cancer patients undergoing neoadjuvant systemic therapy. Eur J Radiol. 2017;89:163–8.
Hieken TJ, Boughey JC, Jones KN, Shah SS, Glazebrook KN. Imaging response and residual metastatic axillary lymph node disease after neoadjuvant chemotherapy for primary breast cancer. Ann Surg Oncol. 2013;20(10):3199–204.
Al‐Hilli Z, Hieken TJ, Hoskin TL, Heins CN, Boughey JC. Impact of neoadjuvant chemotherapy on pathologic axillary nodal status in HER-2 positive patients presenting with clinically node‐negative disease. J Surg Oncol. 2015;112(5):453–7.
Nguyen TT, Hieken TJ, Glazebrook KN, Boughey JC. Localizing the clipped node in patients with node-positive breast cancer treated with neoadjuvant chemotherapy: early learning experience and challenges. Ann Surg Oncol. 2017;24(10):3011–16.
Fisher CS, Margenthaler JA, Hunt KK, Schwartz T. The landmark series: axillary management in breast cancer. Ann Surg Oncol. 2020;27(3):724–9.
Heil J, Schaefgen B, Sinn P, et al. Can a pathological complete response of breast cancer after neoadjuvant chemotherapy be diagnosed by minimal invasive biopsy? Eur J Cancer. 2016;69:142–50.
Heil J, Kümmel S, Schaefgen B, et al. Diagnosis of pathological complete response to neoadjuvant chemotherapy in breast cancer by minimal invasive biopsy techniques. Br J Cancer. 2015;113(11):1565–70.
Kuerer HM, Rauch GM, Krishnamurthy S, et al. A clinical feasibility trial for identification of exceptional responders in whom breast cancer surgery can be eliminated following neoadjuvant systemic therapy. Ann Surg. 2018;267(5):946–51.
Tasoulis MK, Roche N, Rusby JE, et al. Post neoadjuvant chemotherapy vacuum assisted biopsy in breast cancer: can it determine pathologic complete response before surgery? J Clin Oncol. 2018;36(15 Suppl):567.
Lee H-B, Han W, Kim S-Y, et al. Prediction of pathologic complete response using image-guided biopsy after neoadjuvant chemotherapy in breast cancer patients selected based on MRI findings: a prospective feasibility trial. Breast Cancer Res Treatment. 2020;182(1):97–105.
Basik M, Cecchini RS, De Los Santos JF, et al. Primary analysis of NRG-BR005, a phase II trial assessing accuracy of tumor bed biopsies in predicting pathologic complete response (pCR) in patients with clinical/radiological complete response after neoadjuvant chemotherapy (NCT) to explore the feasibility of breast-conserving treatment without surgery. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5–9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):abstract no. GS5-05.
Tasoulis MK, Lee H-B, Yang W, et al. Accuracy of post–neoadjuvant chemotherapy image-guided breast biopsy to predict residual cancer. JAMA Surg. 2020;155(12):e204103.
Mamounas EP, Bandos H, White JR, et al. NRG Oncology/NSABP B-51/RTOG 1304: Phase III trial to determine if chest wall and regional nodal radiotherapy (CWRNRT) post mastectomy (Mx) or the addition of RNRT to breast RT post breast-conserving surgery (BCS) reduces invasive breast cancer recurrence-free interval (IBCR-FI) in patients (pts) with positive axillary (PPAx) nodes who are ypN0 after neoadjuvant chemotherapy (NC). J Clin Oncol. 2019;37(15 Suppl):TPS589.
Kupstas A, Hoskin T, Day C, Boughey J, Habermann E, Hieken T. Biological subtype, treatment response and outcomes in inflammatory breast cancer using data from the National Cancer Database. Br J Surg. 2020; 107(8):1033–41.
Hieken TJ, Murphy BL, Boughey JC, Degnim AC, Glazebrook KN, Hoskin TL. Influence of biologic subtype of inflammatory breast cancer on response to neoadjuvant therapy and cancer outcomes. Clin Breast Cancer. 2018;18(4):e501–e506.
Denkert C, von Minckwitz G, Darb-Esfahani S, et al. Tumour-infiltrating lymphocytes and prognosis in different subtypes of breast cancer: a pooled analysis of 3771 patients treated with neoadjuvant therapy. Lancet Oncol. 2018;19(1):40–50.
Hahnen E, Lederer B, Hauke J, et al. Germline mutation status, pathological complete response, and disease-free survival in triple-negative breast cancer: secondary analysis of the GeparSixto randomized clinical trial. JAMA Oncol. 2017;3(10):1378–85.
Leon-Ferre RA, McGrath K, Carter JM, et al. Deep phenotyping using CyTOF identifies peripheral blood immune signatures associated with clinical outcomes and molecular subtypes in patients with early-stage triple negative breast cancer (TNBC). In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):abstract no. P5-04-09.
Leon-Ferre RA, McGrath K, Suman VJ, et al. Liquid biopsy of the immune environment: Evaluation of peripheral blood mononuclear cells (PBMCs) with CyTOF and response to trastuzumab (T)-based neoadjuvant chemotherapy (NAC) in HER2 + breast cancer (BC). J Clin Oncol. 2020;38(15 Suppl):592.
Radovich M, Jiang G, Hancock BA, et al. Association of circulating tumor DNA and circulating tumor cells after neoadjuvant chemotherapy with disease recurrence in patients with triple-negative breast cancer: Preplanned secondary analysis of the BRE12-158 randomized clinical trial. JAMA Oncol. 2020;6(9):1410–15.
This publication was supported in part by CTSA grant number KL2 TR002379 from the National Center for Advancing Translational Science (NCATS), and the Mayo Clinic Breast Cancer SPORE Grant P50 CA116201, Career Enhancement Program, from the National Institutes of Health (NIH). The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.
Roberto Leon Ferre has received travel support from Immunomedics, and Tina Hieken has received unrelated research funding from Genentech. Judy C. Boughey has received unrelated research funding from Eli Lilly.
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Leon-Ferre, R.A., Hieken, T.J. & Boughey, J.C. The Landmark Series: Neoadjuvant Chemotherapy for Triple-Negative and HER2-Positive Breast Cancer. Ann Surg Oncol 28, 2111–2119 (2021). https://doi.org/10.1245/s10434-020-09480-9