In a phase III trial reported in JAMA Oncology, Cynthia X. Ma, MD, PhD, and colleagues found that neither neoadjuvant fulvestrant nor anastrozole plus fulvestrant improved the endocrine-sensitive disease (ESD) rate vs anastrozole alone among postmenopausal patients with phase II to III estrogen receptor (ER)-rich, HER2-negative breast cancer.
Study Details
In the open-label U.S. multicenter trial, 1,298 evaluable patients enrolled between February 2014 and November 2018 were randomly assigned to receive anastrozole (n = 434), fulvestrant (n = 430) or anastrozole plus fulvestrant (n = 434) for 6 months preoperatively. The primary endpoint was rate of ESD at 6 months, defined as pathologic complete response or ypT1-2N0/N1mic/Ki67 2.7% or less residual disease. Tumor Ki67 was assessed at week 4 and optionally at week 12; if it was greater than 10% at either time point, patients were switched to neoadjuvant chemotherapy or immediate surgery. The trial was designed to determine if fulvestrant or anastrozole plus fulvestrant improved the ESD rate by ≥ 10% over anastrozole alone.
Cynthia X. Ma, MD, PhD
Key Findings
ESD rates were 18.7% (95% confidence interval [CI] = 15.1%–22.7%) in the anastrozole group, 22.8% (95% CI = 18.9%–27.1%), in the fulvestrant group (difference = 4.1% vs anastrozole, P = .98), and 20.5% (95% CI = 16.8%–24.6%) in the combination group (difference = 1.8% vs anastrozole, P < .99); neither fulvestrant-containing regimen improved the ESD rate by ≥ 10% or greater vs anastrozole (P = .98 and P > .99). Compared to the anastrozole group, neither the fulvestrant group nor the combination group had significantly improved rates of ESD or week 4 Ki67 suppression.
The rate of week 4 or 12 Ki67 level > 10% was 25.1% in the anastrozole group, 24.2% in the fulvestrant group, and 15.7% in the combination group. Among 167 patients switching to neoadjuvant chemotherapy due to week 4 or 12 Ki67 level > 10%, pathologic complete response (n = 8) or residual cancer burden class I (n = 17) occurred in 25 (15.0%).
PAM50 subtyping from RNA sequencing of baseline biopsies was available for 753 patients (58%) and identified as luminal A in 394 patients, luminal B in 304, and nonluminal in 55. Combination treatment was associated with greater week 4 Ki67 suppression than anastrozole alone in luminal B tumors (median = −90.4% vs −76.7%, P < .001), but not luminal A tumors. Of 55 nonluminal tumors, 36 (65.5%) had week 4 or week 12 Ki67 level > 10%.
The investigators concluded, “In this randomized clinical trial, neither fulvestrant nor anastrozole plus fulvestrant significantly improved the 6-month ESD [rate] over anastrozole in ER-rich/[HER2]-negative breast cancer. Aromatase inhibition remains the standard-of-care neoadjuvant endocrine therapy. Differential neoadjuvant endocrine therapy response by PAM50 subtype in exploratory analyses warrants further investigation.”
Cynthia X. Ma, MD, PhD, of Washington University School of Medicine in St. Louis, is the corresponding author for the JAMA Oncology article.
Disclosure: The study was supported by the National Cancer Institute, Breast Cancer Research Foundation, and others. For full disclosures of the study authors, visit jamanetwork.com.
