Molecular and immunological characterization of androgen receptor expression in different breast cancer subtypes.
Authors: Jayachandran Priya , Deshmukh Sachin Kumar , Wu Sharon , Ribeiro Jennifer , Kang Irene , Xiu Joanne , Farrell Alex Patrick , Battaglin Francesca , Spicer Darcy V. , Soni Shivani , Zhang Wu , Ashouri Karam , Millstein Joshua , Ma Cynthia X. , Graff Stephanie L. , Radovich Milan , Sledge George W. , Lenz Heinz-Josef , Roussos Torres Evanthia T. 
Published: June 2024

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Background: While estrogen receptor (ER) is well-studied in breast cancer (BC), the role of androgen receptor (AR) in prognosis and therapy response is less understood. Here, we aimed to characterize the clinicopathologic and molecular features of AR gene expression in BC subtypes. Methods: 10,728 BC samples were tested by NGS (592, NextSeq; WES, NovaSeq) and WTS (NovaSeq; Caris Life Sciences, Phoenix, AZ). MSI was tested by IHC and NGS. TMB-high was designated as >10 somatic mutations/MB. Tumors with AR-high(H) and AR-low(L) RNA expression were classified by top and bottom quartile, respectively. Real world overall survival (OS) and treatment-associated survival was obtained from insurance claims and calculated from treatment start to last contact using Kaplan-Meier estimates. Statistical significance was determined by chi-square and Mann-Whitney U test with p-values adjusted for multiple comparisons ( q<.05). Results: Lobular carcinoma had higher AR expression (2.37-fold) and AR positivity by IHC (93.6% vs 63.6%) compared to ductal carcinoma ( q<.05). Luminal A (LumA) had higher AR expression and IHC positivity compared to HER2-enriched, basal-like, and normal-like tumors ( q<.05). AR-H tumors were significantly ( p<.05) enriched for PIK3CA mutations in LumA (60.3% vs 29.8%), LumB (48.1% vs 23.2%), HER2-enriched (51.2% vs 39.3%), and basal-like (23.8% vs 8.3%); CDH1 mutations in LumA (26% vs 10.3%) and normal-like (55.5% vs 4.8%); MAP3K1 in LumA (17.1% vs 5.3%); ESR1 in LumB (17.9% vs 10.7%); and NF1 in HER2-enriched (19.3% vs 7.1%). AR-H had higher immune infiltration for LumA (B cells, M2 Mφ, neutrophils, NK cells, DC), LumB (B cells, M2 Mφ, neutrophils, NK cells, CD4+ T cells, DC), basal-like (NK cells, CD4+ T cells), and normal-like (NK cells, DC; q<.05) than AR-L. Conversely, AR-H HER2-enriched tumors had lower immune infiltration (B cells, M1 and M2 Mφ, NK cells, CD8+ T cells, DC) and fewer TMB-high (15.1% vs 23.2%), dMMR/MSI-high (0.3% vs 2%), and PD-L1+ tumors (15% vs 40.8%; p<.05) compared to AR-L (all q<.05). Post-doxorubicin survival was longer for patients with AR-H tumors; however, opposing trends were observed for patients with LumB (75.5 vs 56.3 m; p=.081) and HER2-enriched tumors (47.9 vs 65.2 m; p.071). AR-H was associated with longer post-dox survival in patients with LumB PIK3CA-mt tumors (81.7 vs 39.3 m; p=.036), but shorter post-dox survival in HER2-enriched PIK3CA-wt (50.4 vs 70.4 m) and PIK3CA-mt cohorts (40.8 vs 58.0 m; p=.18). Conclusions: Findings from our updated analysis based on PAM50 designation suggest a strong association between AR and PIK3CA mutations across subtypes and suggest that distinct AR-associated alterations in the immune microenvironment require further study. Exploration of specific mutations and immune-oncology markers associated with AR-H may aid in molecularly selected clinical trial design for advanced BC patients.