Background: Although the androgen receptor (AR) is frequently co-expressed with ER and PR in hormone receptor-positive (HR+)/HER2- breast cancer, the biological significance of detectable AR alterations (ARalt) in metastatic disease (MBC) remains poorly understood. The primary objective of this study was to evaluate the association of ARalt status with clinical outcomes among women with HR+/HER2- MBC.

Methods: Retrospective review was performed on patients with HR+/HER2- MBC treated at an academic institution, for whom genotyping information was available. ARalt status was determined using Guardant360, a 73-gene next-generation sequencing assay that detects both AR mutations and amplifications in circulating tumor DNA. Women with positive or unknown HER2 status and triple-negative breast cancer were excluded from analysis, as were cases of male breast cancer. Time-to-progression on the therapy initiated immediately following Guardant testing was compared based on ARalt status, excluding patients treated with androgen-directed therapies given potential for confounding. Cumulative incidence plots were generated and analyzed by Gray’s test, and propensity score-adjusted competing risk models were generated with the probability of treatment as a function of age at metastatic diagnosis, presence of visceral metastasis, presence of de novo metastases, as well as number of prior therapies. Additional analysis was performed to assess progression stratified by treatment type (endocrine or non-endocrine based).

Results: Among women with HR+/HER2- MBC (n=222), 16 patients (7%) had detectable ARalt (12 point mutations, 4 amplifications). No baseline differences were observed between women with ARalt and those without AR alterations (ARwt), with respect to age at primary or metastatic diagnosis, menopause status, time to onset of metastasis or de novo metastatic disease, presence of visceral metastases, or number of endocrine/chemotherapies received prior to Guardant testing. ARalt tumors had a higher frequency of detected mutations (14% vs. 5%, p<0.01), and frequently co-altered genes included TP53, PIK3CA, ERBB2, SMAD4, and NF1. Genes with a tendency towards co-alteration in ARalt but not in ARwt included MAP2K2, ARAF1, MAPK1, SMAD4, MYC, ROS1, TERT, and NRAS. In a multivariable model adjusting for age, de novo metastases, visceral metastases, and number of prior therapies, ARalt status was associated with a higher rate of progression (HR 2.5; 95% CI 1.2-5.0, p=0.01), particularly among patients treated with endocrine-based therapies following Guardant testing (HR 4.2, 95% CI 2.4-7.2, p<0.0005) but was not statistically different in women treated with non-endocrine based therapies (HR 1.6; 95% CI 0.5-4.9, p=0.4).

Conclusions: ARalt tumors demonstrate a higher rate of progression on endocrine-based therapy as compared to ARwt tumors, highlighting a potential role of AR in mediating resistance to endocrine therapy in HR+/HER2- disease. Further translational investigations are warranted to determine whether ARalt/HR+/HER2- disease represents a unique biological subtype that predominantly relies on AR signaling and may thus benefit from blockade with AR antagonists.

Table 1. Multivariable competing risks model for endocrine progression.

CovariatePFS
Multivariable
HR95% CIP-value
Positive ARalt status 4.17 2.43-7.17 <0.01 
Age at metastatic dx 1.00 0.97-1.02 0.89 
De novo metastases    
Yes 1.77 0.96-3.26 0.07 
No [ref]   
Visceral metastases    
Yes 1.25 0.72-2.16 0.43 
No [ref]   
No. of prior therapies 1.06 0.93-1.21 0.98 
    
CovariatePFS
Multivariable
HR95% CIP-value
Positive ARalt status 4.17 2.43-7.17 <0.01 
Age at metastatic dx 1.00 0.97-1.02 0.89 
De novo metastases    
Yes 1.77 0.96-3.26 0.07 
No [ref]   
Visceral metastases    
Yes 1.25 0.72-2.16 0.43 
No [ref]   
No. of prior therapies 1.06 0.93-1.21 0.98 
    

Citation Format: Charles Dai, Andrzej Niemierko, Neelima Vidula, Laura M Spring, Seth A Wander, Arielle J Medford, Katherine A Hesler, Giuliana Malvarosa, Jeffrey Peppercorn, Dejan Juric, Steven J Isakoff, Beverly Moy, Leif W Ellisen, Aditya Bardia. Molecular alterations in the androgen receptor and associated clinical outcomes in hormone receptor-positive/HER2- metastatic breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS17-02.