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

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.

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 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 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.