Neoadjuvant therapy for newly diagnosed hormone-positive breast cancer
- Aditya Bardia, MD, MPH
Aditya Bardia, MD, MPH
- Attending Physician
- Massachusetts General Hospital Cancer Center
- Assistant Professor of Medicine
- Harvard Medical School
- J Michael Dixon, MD
J Michael Dixon, MD
- Professor of Surgery and Consultant Surgeon
- Edinburgh University
Hormone receptor (HR)-positive breast cancer is the most common subtype of breast cancer, comprising 70 to 80 percent of all breast cancers.
Neoadjuvant or presurgical therapy refers to administration of therapy before surgery and has been used for over two decades to downstage locally advanced and unresectable primary breast cancers to make them operable [1,2]. Several studies, including the landmark National Surgical Adjuvant Breast and Bowel Project (NSABP) 18 trial, have demonstrated that administration of the same chemotherapy in the neoadjuvant versus adjuvant setting is associated with similar outcomes [3-5]. While traditionally neoadjuvant chemotherapy has been used to downstage locally advanced and unresectable primary breast cancers, a number of studies have highlighted the role of neoadjuvant endocrine therapy as an alternative option to chemotherapy in HR-positive tumors, particularly for postmenopausal women.
In this topic, we will focus on the approaches and data specific to HR-positive breast cancers. The rationale and general approach to neoadjuvant treatment is discussed elsewhere. (See "General principles of neoadjuvant therapy for breast cancer".)
GOALS AND INDICATIONS
The goal of neoadjuvant therapy is to improve surgical outcomes by causing tumor shrinkage and to provide effective systemic therapy. It is appropriate for many patients with locally advanced breast cancer (regardless of subtype), generally defined as stage III cancers, as well as the subset of IIB cancers with T3 disease. For those with stage II disease, either primary surgery or neoadjuvant therapy may be used, the latter being appropriate, for example, for the patient who desires breast-conserving surgery (BCS) and is not a candidate due to a high tumor size: breast size ratio. It should be recognized, however, that HR-positive, human epidermal growth factor receptor 2 (HER2)-negative cancers are less likely to respond to neoadjuvant chemotherapy than other biologic subtypes [6-10]. For patients with stage I, estrogen receptor (ER)-positive, HER2-negative disease, we generally prefer primary surgery rather than neoadjuvant therapy given that such patients are likely to have good surgical outcomes.
Further discussion of appropriate candidates for neoadjuvant therapy is found elsewhere, including for those with HER2-positive disease. (See "General principles of neoadjuvant therapy for breast cancer", section on 'Patient selection' and "Neoadjuvant therapy for patients with HER2-positive breast cancer".)
- Perloff M, Lesnick GJ. Chemotherapy before and after mastectomy in stage III breast cancer. Arch Surg 1982; 117:879.
- Schick P, Goodstein J, Moor J, et al. Preoperative chemotherapy followed by mastectomy for locally advanced breast cancer. J Surg Oncol 1983; 22:278.
- 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; 15:2483.
- Mauri D, Pavlidis N, Ioannidis JP. Neoadjuvant versus adjuvant systemic treatment in breast cancer: a meta-analysis. J Natl Cancer Inst 2005; 97:188.
- Rastogi P, Anderson SJ, Bear HD, et al. Preoperative chemotherapy: updates of National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27. J Clin Oncol 2008; 26:778.
- Hayes DF. Targeting adjuvant chemotherapy: a good idea that needs to be proven! J Clin Oncol 2012; 30:1264.
- Coates AS, Colleoni M, Goldhirsch A. Is adjuvant chemotherapy useful for women with luminal a breast cancer? J Clin Oncol 2012; 30:1260.
- Schott AF, Hayes DF. Defining the benefits of neoadjuvant chemotherapy for breast cancer. J Clin Oncol 2012; 30:1747.
- Buzdar AU, Valero V, Theriault RL, et al. Pathological complete response to chemotherapy is related to hormone receptor status. Breast Cancer Res Treat 2003; 88: abstr 302.
- Parker JS, Mullins M, Cheang MC, et al. Supervised risk predictor of breast cancer based on intrinsic subtypes. J Clin Oncol 2009; 27:1160.
- 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.
- Ellis MJ, Coop A, Singh B, et al. Letrozole is more effective neoadjuvant endocrine therapy than tamoxifen for ErbB-1- and/or ErbB-2-positive, estrogen receptor-positive primary breast cancer: evidence from a phase III randomized trial. J Clin Oncol 2001; 19:3808.
- Guarneri V, Broglio K, Kau SW, et al. Prognostic value of pathologic complete response after primary chemotherapy in relation to hormone receptor status and other factors. J Clin Oncol 2006; 24:1037.
- Bardia A, Greenup R, Moy B, et al. Pathological complete remission after neoadjuvant chemotherapy predicts improved survival in the various breast cancer subtypes: Systematic review and meta-analyses. Presented at AACR Advances in Breast Cancer Research, San Francisco, CA, 2011.
- Kaufmann M, von Minckwitz G, Mamounas EP, et al. Recommendations from an international consensus conference on the current status and future of neoadjuvant systemic therapy in primary breast cancer. Ann Surg Oncol 2012; 19:1508.
- Colleoni M, Viale G, Zahrieh D, et al. Chemotherapy is more effective in patients with breast cancer not expressing steroid hormone receptors: a study of preoperative treatment. Clin Cancer Res 2004; 10:6622.
- Torrisi R, Bagnardi V, Pruneri G, et al. Antitumour and biological effects of letrozole and GnRH analogue as primary therapy in premenopausal women with ER and PgR positive locally advanced operable breast cancer. Br J Cancer 2007; 97:802.
- Alba E, Calvo L, Albanell J, et al. Chemotherapy (CT) and hormonotherapy (HT) as neoadjuvant treatment in luminal breast cancer patients: results from the GEICAM/2006-03, a multicenter, randomized, phase-II study. Ann Oncol 2012; 23:3069.
- Spring LM, Gupta A, Reynolds KL, et al. Neoadjuvant Endocrine Therapy for Estrogen Receptor-Positive Breast Cancer: A Systematic Review and Meta-analysis. JAMA Oncol 2016; 2:1477.
- Semiglazov VF, Semiglazov VV, Dashyan GA, et al. Phase 2 randomized trial of primary endocrine therapy versus chemotherapy in postmenopausal patients with estrogen receptor-positive breast cancer. Cancer 2007; 110:244.
- Palmieri C, Cleator S, Kilburn LS, et al. NEOCENT: a randomised feasibility and translational study comparing neoadjuvant endocrine therapy with chemotherapy in ER-rich postmenopausal primary breast cancer. Breast Cancer Res Treat 2014; 148:581.
- Alba E, Calvo L, Albanell J, et al. Chemotherapy (CT) versus hormone therapy (HT) as neoadjuvant treatment in luminal breast cancer: a multicenter, randomized phase II study GEICAM/2006-03). J Clin Oncol 2010; 28(7s):abs 500.
- Dixon JM, Renshaw L, Keys J, et al. Abstract P1-12-05: Factors Affecting Local Recurrence after Breast Conserving Surgery Following Neoadjuvant Endocrine Therapy with Letrozole. Cancer Res 2010; 70(24 Suppl):Abstract nr P1-12-05.
- Ellis MJ, Ma C. Letrozole in the neoadjuvant setting: the P024 trial. Breast Cancer Res Treat 2007; 105 Suppl 1:33.
- Eiermann W, Paepke S, Appfelstaedt J, et al. Preoperative treatment of postmenopausal breast cancer patients with letrozole: A randomized double-blind multicenter study. Ann Oncol 2001; 12:1527.
- Smith IE, Dowsett M, Ebbs SR, et al. Neoadjuvant treatment of postmenopausal breast cancer with anastrozole, tamoxifen, or both in combination: the Immediate Preoperative Anastrozole, Tamoxifen, or Combined with Tamoxifen (IMPACT) multicenter double-blind randomized trial. J Clin Oncol 2005; 23:5108.
- Cataliotti L, Buzdar AU, Noguchi S, et al. Comparison of anastrozole versus tamoxifen as preoperative therapy in postmenopausal women with hormone receptor-positive breast cancer: the Pre-Operative "Arimidex" Compared to Tamoxifen (PROACT) trial. Cancer 2006; 106:2095.
- Leal F, Liutti VT, Antunes dos Santos VC, et al. Neoadjuvant endocrine therapy for resectable breast cancer: A systematic review and meta-analysis. Breast 2015; 24:406.
- Ellis MJ, Suman VJ, Hoog J, et al. Randomized phase II neoadjuvant comparison between letrozole, anastrozole, and exemestane for postmenopausal women with estrogen receptor-rich stage 2 to 3 breast cancer: clinical and biomarker outcomes and predictive value of the baseline PAM50-based intrinsic subtype--ACOSOG Z1031. J Clin Oncol 2011; 29:2342.
- Seo JH, Kim YH, Kim JS. Meta-analysis of pre-operative aromatase inhibitor versus tamoxifen in postmenopausal woman with hormone receptor-positive breast cancer. Cancer Chemother Pharmacol 2009; 63:261.
- Dixon JM, Renshaw L, Young O, et al. Letrozole suppresses plasma estradiol and estrone sulphate more completely than anastrozole in postmenopausal women with breast cancer. J Clin Oncol 2008; 26:1671.
- Toi M, Saji S, Masuda N, et al. Ki67 index changes, pathological response and clinical benefits in primary breast cancer patients treated with 24 weeks of aromatase inhibition. Cancer Sci 2011; 102:858.
- Dixon JM. Neoadjuvant therapy: Surgical perspectives. In: Endocrine therapy in breast cancer, Miller WR, Ingle JN. (Eds), Marcel Dekker, New York 2002. p.197.
- Dixon JM, Renshaw L, Macaskill EJ, et al. Increase in response rate by prolonged treatment with neoadjuvant letrozole. Breast Cancer Res Treat 2009; 113:145.
- Akashi-Tanaka S, Shimizu C, Ando M, et al. 21-Gene expression profile assay on core needle biopsies predicts responses to neoadjuvant endocrine therapy in breast cancer patients. Breast 2009; 18:171.
- Dixon JM, Turnbull AK, Fan C, et al. Abstract S1-05: In-depth genomic analysis of ER+ breast cancers during development of endocrine resistance. Cancer Res 2015; 75: S1.
- Miller WR, Larionov A, Renshaw L, et al. Gene expression profiles differentiating between breast cancers clinically responsive or resistant to letrozole. J Clin Oncol 2009; 27:1382.
- Dixon JM, Renshaw L, Dixon J, Thomas J. Invasive lobular carcinoma: response to neoadjuvant letrozole therapy. Breast Cancer Res Treat 2011; 130:871.
- Thomas JS, Julian HS, Green RV, et al. Histopathology of breast carcinoma following neoadjuvant systemic therapy: a common association between letrozole therapy and central scarring. Histopathology 2007; 51:219.
- Kimmick GG, Cirrincione C, Duggan DB, et al. Fifteen-year median follow-up results after neoadjuvant doxorubicin, followed by mastectomy, followed by adjuvant cyclophosphamide, methotrexate, and fluorouracil (CMF) followed by radiation for stage III breast cancer: a phase II trial (CALGB 8944). Breast Cancer Res Treat 2009; 113:479.
- Ellis MJ, Tao Y, Luo J, et al. Outcome prediction for estrogen receptor-positive breast cancer based on postneoadjuvant endocrine therapy tumor characteristics. J Natl Cancer Inst 2008; 100:1380.
- Ellis MJ, Suman VJ, Hoog J, et al. Ki67 Proliferation Index as a Tool for Chemotherapy Decisions During and After Neoadjuvant Aromatase Inhibitor Treatment of Breast Cancer: Results From the American College of Surgeons Oncology Group Z1031 Trial (Alliance). J Clin Oncol 2017; 35:1061.
- Ellis MJ, Coop A, Singh B, et al. Letrozole inhibits tumor proliferation more effectively than tamoxifen independent of HER1/2 expression status. Cancer Res 2003; 63:6523.
- Dowsett M, Smith IE, Ebbs SR, et al. Prognostic value of Ki67 expression after short-term presurgical endocrine therapy for primary breast cancer. J Natl Cancer Inst 2007; 99:167.
- Mohammadianpanah M, Ashouri Y, Hoseini S, et al. The efficacy and safety of neoadjuvant chemotherapy +/- letrozole in postmenopausal women with locally advanced breast cancer: a randomized phase III clinical trial. Breast Cancer Res Treat 2012; 132:853.
- Baselga J, Semiglazov V, van Dam P, et al. Phase II randomized study of neoadjuvant everolimus plus letrozole compared with placebo plus letrozole in patients with estrogen receptor-positive breast cancer. J Clin Oncol 2009; 27:2630.
- Chow LW, Yip AY, Loo WT, et al. Celecoxib anti-aromatase neoadjuvant (CAAN) trial for locally advanced breast cancer. J Steroid Biochem Mol Biol 2008; 111:13.
- Fasching PA, Jud SM, Hauschild M, et al. FemZone trial: a randomized phase II trial comparing neoadjuvant letrozole and zoledronic acid with letrozole in primary breast cancer patients. BMC Cancer 2014; 14:66.
- Polychronis A, Sinnett HD, Hadjiminas D, et al. Preoperative gefitinib versus gefitinib and anastrozole in postmenopausal patients with oestrogen-receptor positive and epidermal-growth-factor-receptor-positive primary breast cancer: a double-blind placebo-controlled phase II randomised trial. Lancet Oncol 2005; 6:383.
- Guarneri V, Generali DG, Frassoldati A, et al. Double-blind, placebo-controlled, multicenter, randomized, phase IIb neoadjuvant study of letrozole-lapatinib in postmenopausal hormone receptor-positive, human epidermal growth factor receptor 2-negative, operable breast cancer. J Clin Oncol 2014; 32:1050.
- Ma CX, Gao F, Northfelt D, et al. A phase II trial of neoadjuvant palbociclib, a cyclin-dependent kinase (CDK) 4/6 inhibitor, in combination with anastrozole for clinical stage 2 or 3 estrogen receptor positive HER2 negative (ER+HER2-) breast cancer (BC). Abstract S6-05, SABCS 2015.
- Kuter I, Gee JM, Hegg R, et al. Dose-dependent change in biomarkers during neoadjuvant endocrine therapy with fulvestrant: results from NEWEST, a randomized Phase II study. Breast Cancer Res Treat 2012; 133:237.
- GOALS AND INDICATIONS
- THERAPEUTIC OPTIONS
- Selection of treatment
- - Premenopausal women
- - Postmenopausal women
- Medically fit
- Medically frail
- - HER2-positive cancers
- Neoadjuvant chemotherapy
- - Efficacy
- - Prognostic features
- Neoadjuvant endocrine therapy
- - Efficacy
- Premenopausal women
- Postmenopausal women
- - Choice of endocrine therapy
- - Duration of endocrine treatment
- - Investigational options
- TREATMENT AFTER NEOADJUVANT THERAPY
- Assessment of response
- Adjuvant treatment
- SUMMARY AND RECOMMENDATIONS