Neoadjuvant Endocrine Therapy for Estrogen Receptor-Positive Breast Cancer: A Systematic Review and Meta-analysis

Laura M Spring, Arjun Gupta, Kerry L Reynolds, Michele A Gadd, Leif W Ellisen, Steven J Isakoff, Beverly Moy, Aditya Bardia, Laura M Spring, Arjun Gupta, Kerry L Reynolds, Michele A Gadd, Leif W Ellisen, Steven J Isakoff, Beverly Moy, Aditya Bardia

Abstract

Importance: Estrogen receptor-positive (ER+) tumors of the breast are generally highly responsive to endocrine treatment. Although endocrine therapy is the mainstay of adjuvant treatment for ER+ breast cancer, the role of endocrine therapy in the neoadjuvant setting is unclear.

Objective: To evaluate the effect of neoadjuvant endocrine therapy (NET) on the response rate and the rate of breast conservation surgery (BCS) for ER+ breast cancer.

Data sources: Based on PRISMA guidelines, a librarian-led search of PubMed and Ovid MEDLINE was performed to identify eligible trials published from inception to May 15, 2015. The search was performed in May 2015.

Study selection: Inclusion criteria were prospective, randomized, neoadjuvant clinical trials that reported response rates with at least 1 arm incorporating NET (n = 20). Two authors independently analyzed the studies for inclusion.

Data extraction and synthesis: Pooled odds ratios (ORs), 95% CIs, and P values were estimated for end points using the fixed- and random-effects statistical model.

Results: The analysis included 20 studies with 3490 unique patients. Compared with combination chemotherapy, NET as monotherapy with aromatase inhibitors had a similar clinical response rate (OR, 1.08; 95% CI, 0.50-2.35; P = .85; n = 378), radiological response rate (OR, 1.38; 95% CI, 0.92-2.07; P = .12; n = 378), and BCS rate (OR, 0.65; 95% CI, 0.41-1.03; P = .07; n = 334) but with lower toxicity. Aromatase inhibitors were associated with a significantly higher clinical response rate (OR, 1.69; 95% CI, 1.36-2.10; P < .001; n = 1352), radiological response rate (OR, 1.49; 95% CI, 1.18-1.89; P < .001; n = 1418), and BCS rate (OR, 1.62; 95% CI, 1.24-2.12; P < .001; n = 918) compared with tamoxifen. Dual combination therapy with growth factor pathway inhibitors was associated with a higher radiological response rate (OR, 1.59; 95% CI, 1.04-2.43; P = .03; n = 355), but not clinical response rate (OR, 0.76; 95% CI, 0.54-1.07; P = .11; n = 537), compared with endocrine monotherapy. The incidence of pathologic complete response was low (<10%).

Conclusions and relevance: Neoadjuvant endocrine therapy, even as monotherapy, is associated with similar response rates as neoadjuvant combination chemotherapy but with significantly lower toxicity, suggesting that NET needs to be reconsidered as a potential option in the appropriate setting. Additional research is needed to develop rational NET combinations and predictive biomarkers to personalize the optimal neoadjuvant strategy for ER+ breast cancer.

Conflict of interest statement

Conflict of Interest Disclosures: None reported.

Figures

Figure 1. Neoadjuvant Hormone Therapy vs Neoadjuvant…
Figure 1. Neoadjuvant Hormone Therapy vs Neoadjuvant Cytotoxic Chemotherapy
Fixed-effects odds ratios (ORs) are calculated using the Mantel-Haenszel test with nonevent as the reference. Error bars represent 95% CI. Different marker sizes indicate the weight given to the specific study.
Figure 2. Neoadjuvant Aromatase Inhibitors (AIs) vs…
Figure 2. Neoadjuvant Aromatase Inhibitors (AIs) vs Neoadjuvant Tamoxifen
Fixed-effects odds ratios (ORs) are calculated using the Mantel-Haenszel test with nonevent as the reference. Error bars represent 95% CI. Different marker sizes indicate the weight given to the specific study.
Figure 3. Neoadjuvant Endocrine Therapy as Monotherapy…
Figure 3. Neoadjuvant Endocrine Therapy as Monotherapy vs Dual Therapy
For comparison of aromatase inhibitors with dual therapy, dual therapy includes tamoxifen, zoledronic acid, everolimus, celecoxib, gefitinib, or lapatinib. Fixed-effects odds ratios (ORs) are calculated using the Mantel-Haenszel test with nonevent as the reference. Error bars represent 95% CI. Different marker sizes indicate the weight given to the specific study. GFI indicates growth factor pathway inhibitor.

References

    1. Dunnwald LK, Rossing MA, Li CI. Hormone receptor status, tumor characteristics, and prognosis: a prospective cohort of breast cancer patients. Breast Cancer Res. 2007;9(1):R6.
    1. Burstein HJ, Prestrud AA, Seidenfeld J, et al. American Society of Clinical Oncology American Society of Clinical Oncology clinical practice guideline: update on adjuvant endocrine therapy for women with hormone receptor-positive breast cancer. J Clin Oncol. 2010;28(23):3784–3796.
    1. 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(5):778–785.
    1. Bardia A, Baselga J. Neoadjuvant therapy as a platform for drug development and approval in breast cancer. Clin Cancer Res. 2013;19(23):6360–6370.
    1. Mauri D, Pavlidis N, Ioannidis JPA. Neoadjuvant versus adjuvant systemic treatment in breast cancer: a meta-analysis. J Natl Cancer Inst. 2005;97(3):188–194.
    1. Mustacchi G, Ceccherini R, Milani S, et al. Italian Cooperative Group GRETA Tamoxifen alone versus adjuvant tamoxifen for operable breast cancer of the elderly: long-term results of the phase III randomized controlled multicenter GRETA trial. Ann Oncol. 2003;14(3):414–420.
    1. Gazet JC, Ford HT, Coombes RC, et al. Prospective randomized trial of tamoxifen vs surgery in elderly patients with breast cancer. Eur J Surg Oncol. 1994;20(3):207–214.
    1. Mathew J, Asgeirsson KS, Jackson LR, Cheung KL, Robertson JFR. Neoadjuvant endocrine treatment in primary breast cancer: review of literature. Breast. 2009;18(6):339–344.
    1. Monnier A. Clinical management of adverse events in adjuvant therapy for hormone-responsive early breast cancer. Ann Oncol. 2007;18(suppl 8):viii, 36–44.
    1. 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(4):406–412.
    1. Llombart-Cussac A, Guerrero Á, Galán A, et al. Phase II trial with letrozole to maximum response as primary systemic therapy in postmenopausal patients with ER/PgR[+] operable breast cancer. Clin Transl Oncol. 2012;14(2):125–131.
    1. Hille U, Soergel P, Länger F, Schippert C, Makowski L, Hillemanns P. Aromatase inhibitors as solely treatment in postmenopausal breast cancer patients. Breast J. 2012;18(2):145–150.
    1. Dixon JM, Renshaw L, Dixon J, Thomas J. Invasive lobular carcinoma: response to neoadjuvant letrozole therapy. Breast Cancer Res Treat. 2011;130(3):871–87.
    1. Olson JA, Jr, Budd GT, Carey LA, et al. Improved surgical outcomes for breast cancer patients receiving neoadjuvant aromatase inhibitor therapy: results from a multicenter phase II trial. J Am Coll Surg. 2009;208(5):906–914.
    1. Dixon JM, Renshaw L, Macaskill EJ, et al. Increase in response rate by prolonged treatment with neoadjuvant letrozole. Breast Cancer Res Treat. 2009;113(1):145–151.
    1. Krainick-Strobel UE, Lichtenegger W, Wallwiener D, et al. Neoadjuvant letrozole in postmenopausal estrogen and/or progesterone receptor positive breast cancer: a phase IIb/III trial to investigate optimal duration of preoperative endocrine therapy. BMC Cancer. 2008;8:62.
    1. 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(6):802–808.
    1. Salmon RJ, Alran S, Malka I, et al. Breast Group of the Institut Curie Estrogen receptors evolution in neoadjuvant aromatase inhibitor (AI) therapy for breast cancer in elderly women: stability of hormonal receptor expression during treatment. Am J Clin Oncol. 2006;29(4):385–388.
    1. Miller WR, White S, Dixon JM, Murray J, Renshaw L, Anderson TJ. Proliferation, steroid receptors and clinical/pathological response in breast cancer treated with letrozole. Br J Cancer. 2006;94(7):1051–1056.
    1. Cappelletti V, Celio L, Bajetta E, et al. Prospective evaluation of estrogen receptor-β in predicting response to neoadjuvant antiestrogen therapy in elderly breast cancer patients. Endocr Relat Cancer. 2004;11(4):761–770.
    1. Milla-Santos A, Milla L, Calvo N, et al. Anastrozole as neoadjuvant therapy for patients with hormone-dependent, locally-advanced breast cancer. Anticancer Res. 2004;24(2C):1315–1318.
    1. Eiermann W, Paepke S, Appfelstaedt J, et al. Letrozole Neo-Adjuvant Breast Cancer Study Group Preoperative treatment of postmenopausal breast cancer patients with letrozole: a randomized double-blind multicenter study. Ann Oncol. 2001;12(11):1527–1532.
    1. Smith IE, Dowsett M, Ebbs SR, et al. IMPACT Trialists Group 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(22):5108–5116.
    1. 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(18):3808–3816.
    1. Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA Group Preferred Reporting Items for Systematic Reviews and Meta-analyses: the PRISMA statement. Int J Surg Lond Engl. 2010;8(5):336–341.
    1. Mantel N, Haenzel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst. 1959;22(4):719–748.
    1. Higgins JPT, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327(7414):557–560.
    1. Jadad AR, Moore RA, Carroll D, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials. 1996;17(1):1–12.
    1. Quenel-Tueux N, Debled M, Rudewicz J, et al. Clinical and genomic analysis of a randomised phase II study evaluating anastrozole and fulvestrant in postmenopausal patients treated for large operable or locally advanced hormone-receptor-positive breast cancer. Br J Cancer. 2015;113(4):585–594.
    1. Alba E, Calvo L, Albanell J, et al. GEICAM 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(12):3069–3074.
    1. 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(3):581–590.
    1. 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(2):244–254.
    1. 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(3):853–861.
    1. Masuda N, Sagara Y, Kinoshita T, et al. Neoadjuvant anastrozole versus tamoxifen in patients receiving goserelin for premenopausal breast cancer (STAGE): a double-blind, randomised phase 3 trial. Lancet Oncol. 2012;13(4):345–352.
    1. Cataliotti L, Buzdar AU, Noguchi S, et al. Comparison of anastrozole vs 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(10):2095–2103.
    1. Miller WR, Dixon JM, Cameron DA, Anderson TJ. Biological and clinical effects of aromatase inhibitors in neoadjuvant therapy. J Steroid Biochem Mol Biol. 2001;79(1–5):103–107.
    1. Harper-Wynne CL, Sacks NPM, Shenton K, et al. Comparison of the systemic and intratumoral effects of tamoxifen and the aromatase inhibitor vorozole in postmenopausal patients with primary breast cancer. J Clin Oncol. 2002;20(4):1026–1035.
    1. Hojo T, Kinoshita T, Imoto S, et al. Use of the neo-adjuvant exemestane in post-menopausal estrogen receptor-positive breast cancer: a randomized phase II trial (PTEX46) to investigate the optimal duration of preoperative endocrine therapy. Breast. 2013;22(3):263–267.
    1. 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(17):2342–2349.
    1. Kuter I, Gee JMW, 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(1):237–246.
    1. 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(16):2630–2637.
    1. Chow LW-C, Yip AY-S, Loo WT-Y, Lam C-K, Toi M. Celecoxib anti-aromatase neoadjuvant (CAAN) trial for locally advanced breast cancer. J Steroid Biochem Mol Biol. 2008;111(1–2):13–17.
    1. 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(1):66.
    1. 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(6):383–391.
    1. Smith IE, Walsh G, Skene A, et al. A phase II placebo-controlled trial of neoadjuvant anastrozole alone or with gefitinib in early breast cancer. J Clin Oncol. 2007;25(25):3816–3822.
    1. 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(10):1050–1057.
    1. 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):164–172.
    1. Regan MM, Neven P, Giobbie-Hurder A, et al. BIG 1-98 Collaborative Group; International Breast Cancer Study Group (IBCSG) Assessment of letrozole and tamoxifen alone and in sequence for postmenopausal women with steroid hormone receptor-positive breast cancer: the BIG 1-98 randomised clinical trial at 8.1 years median follow-up. Lancet Oncol. 2011;12(12):1101–1108.
    1. Howell A, Cuzick J, Baum M, et al. ATAC Trialists’ Group Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years’ adjuvant treatment for breast cancer. Lancet. 2005;365(9453):60–62.
    1. Pagani O, Regan MM, Walley BA, et al. TEXT SOFT Investigators; International Breast Cancer Study Group Adjuvant exemestane with ovarian suppression in premenopausal breast cancer. N Engl J Med. 2014;371(2):107–118.
    1. Hug V, Thames H, Clark J. Chemotherapy and hormonal therapy in combination. J Clin Oncol. 1988;6(1):173–177.
    1. Bear HD, Anderson S, Smith RE, et al. Sequential preoperative or postoperative docetaxel added to preoperative doxorubicin plus cyclophosphamide for operable breast cancer: National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J Clin Oncol. 2006;24(13):2019–2027.
    1. Finn RS, Crown JP, Lang I, et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet Oncol. 2015;16(1):25–35.
    1. Turner NC, Ro J, André F, et al. PALOMA3 Study Group Palbociclib in hormone-receptor-positive advanced breast cancer. N Engl J Med. 2015;373(3):209–219.
    1. Sparano JA, Gray RJ, Makower DF, et al. Prospective validation of a 21-gene expression assay in breast cancer. N Engl J Med. 2015;373(21):2005–2014.
    1. Sgroi DC, Carney E, Zarrella E, et al. Prediction of late disease recurrence and extended adjuvant letrozole benefit by the HOXB13/IL17BR biomarker. J Natl Cancer Inst. 2013;105(14):1036–1042.
    1. Dowsett M, Smith IE, Ebbs SR, et al. IMPACT Trialists Group Prognostic value of Ki67 expression after short-term presurgical endocrine therapy for primary breast cancer. J Natl Cancer Inst. 2007;99(2):167–170.
    1. . Fulvestrant and/or Anastrozole in Treating Postmenopausal Patients With Stage II-III Breast Cancer Undergoing Surgery. NCT01953588. . Accessed January 15, 2016.
    1. . A Study of Neoadjuvant Letrozole + GDC-0032 Versus Letrozole + Placebo in Post-Menopausal Women With Breast Cancer (LORELEI) NCT02273973. . Accessed January 15, 2016.
    1. . A Phase II Randomized Study Evaluating the Biological and Clinical Effects of the Combination of Palbociclib With Letrozole as Neoadjuvant Therapy in Post-Menopausal Women With Estrogen-Receptor Positive Primary Breast Cancer. NCT02296801. . Accessed January 15, 2016.
    1. 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). Presented at: San Antonio Breast Cancer Symposium; December 11, 2015; San Antonio, TX. Abstract S6-05.

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