Prognostic and predictive value of androgen receptor expression in postmenopausal women with estrogen receptor-positive breast cancer: results from the Breast International Group Trial 1-98

Abstract

Background: The androgen receptor (AR) is an emerging prognostic marker and therapeutic target in breast cancer. AR is expressed in 60-80% of breast cancers, with higher prevalence among estrogen receptor-positive (ER+) tumors. Androgen treatment inhibits ER signaling in ER+/AR+ breast cancer cell lines, and AR expression is associated with improved survival for this subtype in epidemiologic studies. However, whether AR expression modifies the efficacy of selective ER modulators or aromatase inhibitors for ER+ cancers remains unclear.

Methods: We evaluated the prognostic and predictive value of AR expression among 3021 postmenopausal ER+ breast cancer patients in the Breast International Group (BIG) trial 1-98. The BIG 1-98 study was a four-armed, double-blind, phase III randomized clinical trial that compared 5 years of tamoxifen or letrozole monotherapy, or sequences of 2 years and 3 years treatment with one drug and then the other. AR expression was measured by immunohistochemistry and the percentage of AR-positive nuclei was quantified. The association between AR expression and prognosis was evaluated using Cox proportional hazards models. Continuous AR-by-treatment interactions were assessed using Subpopulation Treatment Effect Pattern Plots (STEPP).

Results: Eighty-two percent of patients had AR+ (≥ 1%) tumors. Patients with AR+ cancers were more likely to have smaller, lower-grade tumors, with higher expression of ER and PR. AR expression was not associated with breast cancer-free interval (BCFI) (415 events) over a median 8.0 years of follow-up (p = 0.12, log-rank test). In multivariable-adjusted models, AR expression was not associated with BCFI (HR = 1.07, 95% CI 0.83-1.36, p = 0.60). The letrozole versus tamoxifen monotherapy treatment effect did not significantly differ for AR+ tumors (HR = 0.63, 95% CI 0.44-0.75, p = 0.003) and AR- tumors (HR = 0.39, 95% CI 0.21-0.72, p = 0.002) (p-heterogeneity = 0.16). STEPP analysis also suggested no heterogeneity of the treatment effect across the continuum of AR expression.

Conclusions: AR expression was not associated with prognosis, nor was there heterogeneity of the letrozole versus tamoxifen treatment effect by AR expression. These findings suggest that AR expression may not be an informative biomarker for the selection of adjuvant endocrine therapy for postmenopausal women with ER+ breast cancers.

Trial registration: ClinicalTrials.gov , NCT00004205, Registered 27 January 2003-Retrospectively registered, https://clinicaltrials.gov/ct2/show/study/NCT00004205 .

Keywords: Androgen receptor; BIG 1–98; Breast cancer; Letrozole; Tamoxifen.

Fig. 1

Flow diagram of participant inclusion

Fig. 2

Kaplan-Meier estimate of breast cancer-free interval by tumor AR expression. AR expression is defined as ≥ 1% positive, < 1% negative. P value from log-rank test is 0.12

Fig. 3

Kaplan-Meier estimate of breast cancer-free interval by cross-classified AR expression and treatment in monotherapy population. AR expression is defined as ≥ 1% positive, < 1% negative

Fig. 4

Subpopulation Treatment Effect Patten Plot (STEPP) analysis of the letrozole versus tamoxifen treatment effect. Treatment effect is defined as the 5-year BCFI in the monotherapy population (n = 1753). Plots show treatment effects in subpopulations denoted by median AR expression on the x-axis. Treatment effects are shown as a 5-year cumulative incidences (%), b 5-year cumulative incidence differences (95% CI) [Let. – Tam.], and c hazard ratios (95% CI) [Let.:Tam.]