Biomarker Associations with Efficacy of Abiraterone Acetate and Exemestane in Postmenopausal Patients with Estrogen Receptor–Positive Metastatic Breast Cancer

Abstract

Purpose: Abiraterone may suppress androgens that stimulate breast cancer growth. We conducted a biomarker analysis of circulating tumor cells (CTCs), formalin-fixed paraffin-embedded tissues (FFPETs), and serum samples from postmenopausal estrogen receptor (ER) þ breast cancer patients to identify subgroups with differential abiraterone sensitivity. Methods: Patients (randomized 1:1:1) were treated with 1,000 mg/d abiraterone acetate þ 5 mg/d prednisone (AA), AA þ 25 mg/d exemestane (AAE), or exemestane. The biomarker population included treated patients (n ¼ 293). The CTC population included patients with !3 baseline CTCs (n ¼ 104). Biomarker [e.g., androgen receptor (AR), ER, Ki-67, CYP17] expression was evaluated. Cox regression stratified by prior therapies in the metastatic setting (0/1 vs. 2) and setting of letrozole/anastrozole (adjuvant vs. metastatic) was used to assess biomarker associations with progression-free survival (PFS).Results: Serum testosterone and estrogen levels were lowered and progesterone increased with AA. Baseline AR or ER expression was not associated with PFS in CTCs or FFPETs for AAE versus exemestane, but dual positivity of AR and ER expression was associated with improved PFS [HR, 0.41; 95% confidence interval (CI), 0.16-1.07; P ¼ 0.070]. For AR expression in FFPETs obtained <1 year prior to first dose (n ¼ 67), a trend for improved PFS was noted for AAE versus exemestane (HR, 0.56; 95% CI, 0.24-1.33; P ¼ 0.19).Conclusions: An AA pharmacodynamic effect was shown by decreased serum androgen and estrogen levels and increased progesterone. AR and ER dual expression in CTCs and newly obtained FFPETs may predict AA sensitivity.

Androgen receptor expression in circulating tumor cells of patients with metastatic breast cancer

“…These studies have shown that mBC patients can derive clinical benefit from AR-targeted therapies, although the reported outcomes were quite modest with clinical benefit rates (CBR) at 6 months (responses and stable disease lasting longer than 6 months) around 20-30% and response rates of 6-8%. 3,10,[12][13][14][15] Collectively, these data show that AR-targeting drugs are only active in a subset of patients, stressing the need for biomarkers to identify these patients. Additionally, there is a 35% discrepancy rate between AR-expression in primary breast cancer and metastatic tissue 16 rendering it questionable whether assessment of AR expression on primary tumor tissue is appropriate to select mBC patients for AR-targeting drugs.…”

“…All studies performed in mBC so far, included patients based on immunohistochemical (IHC) determination of the AR status on primary or metastatic tumor tissues. These studies have shown that mBC patients can derive clinical benefit from AR‐targeted therapies, although the reported outcomes were quite modest with clinical benefit rates (CBR) at 6 months (responses and stable disease lasting longer than 6 months) around 20–30% and response rates of 6–8% . Collectively, these data show that AR‐targeting drugs are only active in a subset of patients, stressing the need for biomarkers to identify these patients.…”

AR Signaling in Breast Cancer

“…Eligibility required sensitivity to an aromatase inhibitor (AI) prior to disease progression and AR positivity was reportedly balanced between treatment arms, including abiraterone plus prednisone, versus abiraterone with exemestane versus exemestane alone with primary end point of PFS. Abiraterone either in combination with prednisone or with exemestane did not improve PFS, compared to exemestane [150,151]. Another phase II clinical trial assessed the safety and efficacy of abiraterone plus prednisone in molecular apocrine AR-positive metastatic breast cancer with a primary endpoint of CBR at 6 months.…”

A review of estrogen receptor/androgen receptor genomics in male breast cancer

“…Notably, AR is highly expressed in male breast cancers (Zhou et al 2014) and has been found to be indicative of good outcome in male breast (Shaaban et al 2012) and poor outcome in hormone-refractory prostate cancer (Buhmeida et al 2006). These discordant results may be indicative of inherent differences between breast and prostate cancer or they may highlight the importance of treatment setting in these studies as ERα/AR dual positivity has recently been shown to be associated with improved outcome (Li et al 2016). A recent study by Johansson and coworkers examining the gene expression profiles of MBC identified two novel subgroups using unsupervised hierarchical clustering, that are associated with different clinical and biological features (Johansson et al 2012).…”