Molecular Features of Androgen-Receptor Low, Estrogen Receptor-Negative Breast Cancers in the Carolina Breast Cancer Study

Abstract

Purpose: Androgen receptor (AR) expression is absent in 40-90% of estrogen receptor (ER)-negative breast cancers. The prognostic value of AR in ER-negative patients and therapeutic targets for patients absent in AR remains poorly explored. Methods: We used an RNA-based multigene classifier to identify AR-low and AR-high ER-negative participants in the Carolina Breast Cancer Study (CBCS; n=669) and The Cancer Genome Atlas (TCGA; n=237). We compared AR-defined subgroups by demographics, tumor characteristics, and established molecular signatures [PAM50 risk of recurrence (ROR), homologous recombination deficiency (HRD), and immune response]. Results: AR-low tumors were more prevalent among Black (relative frequency difference (RFD) = +7%, 95% CI = 1% to 14%) and younger (RFD = +10%, 95% CI = 4% to 16%) participants in CBCS and were associated with HER2-negativity (RFD = -35%, 95% CI = -44% to -26%), higher grade (RFD = +17%, 95% CI = 8% to 26%), and higher risk of recurrence scores (RFD = +22%, 95% CI = 16.1% to 28%), with similar results in TCGA. The AR-low subgroup was strongly associated with HRD in CBCS (RFD = +33.3%, 95% CI = 23.8% to 43.2%) and TCGA (RFD = +41.5%, 95% CI = 34.0% to 48.6%). In CBCS, AR-low tumors had high adaptive immune marker expression. Conclusion: Multigene, RNA-based low AR expression is associated with aggressive disease characteristics as well as DNA repair defects and immune phenotypes, suggesting plausible precision therapies for AR-low, ER-negative patients.

Androgen Receptor Is Expressed in the Majority of Breast Cancer Brain Metastases and Is Subtype-Dependent

“…A study of 101 primary TNBCs found that qRT-PCR detected AR expression in 34% of cases compared to 15% of cases using IHC (i.e., ≥1% using AR441 antibody), with 75% concordance between the two methods; this study found that AR mRNA expression was associated with shorter distant metastases free survival, which is consistent with previous studies employing IHC in TNBC [22]. Another study of 872 primary ER-negative breast cancers found that mRNA expression of AR had a strong correlation (R = 0.68, p < 0.001) with AR reverse phase protein assay, and AR mRNA expression was associated with lower grade disease and lower risk of recurrence [23]. Interestingly, this study also showed that AR mRNA expression was associated with HER2+ status, which is consistent with our finding that HER2+ BrM have highest expression of AR by IHC.…”