Abstract P1-03-22: Comprehensive characterization of the androgen receptor in male breast cancer

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Abstract Background: Male breast cancer (BC) accounts for less than 1% of new BC cases annually. Androgen receptor (AR), a member of steroid and nuclear receptor superfamily is emerging as an important factor in pathobiology of BC. While the estrogen receptor (ER) is well-studied in BC, the role of the AR is less understood, particularly in male patients. Here, we aimed to characterize the molecular and immunological features of AR gene expression in male BC. Methods: 191 samples from male breast cancer patients were tested by NGS (592, NextSeq; WES, NovaSeq) and WTS (NovaSeq; Caris Life Sciences, Phoenix, AZ). MSI was tested by IHC and NGS. Tumor mutational burden (TMB) totaled somatic mutations per tumor (high>10 mt/MB). Immune cell fractions were calculated by deconvolution of WTS: Quantiseq. Tumors with AR-high(H) and AR-low(L) RNA expression were classified as above or below the 50th percentile, respectively. Real world overall survival (OS) and treatment-associated survival was obtained from insurance claims and calculated from tissue collection 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: AR-H male BC had lower frequency of TP53 mutations (20% AR-L vs 7% AR-H, p=0.02) compared to AR-L male BC tumors. AR-H had numerically higher frequency of PIK3CA (34.8% vs 27.2%) and CHEK2 (3.7% vs 1.1%), but lower frequency of BRCA2 (7.1% vs 13.6%) and PTEN (2.3% vs 6.9%) compared to AR-L, all p = 0.1-0.2. AR-H male BC had lower frequency of TMB-high (3.45% vs 12.22%) and PD-L1 positivity (5.08% vs 18.57%), all p<0.05. Analysis of inferred immune cells revealed that AR-H had higher infiltration of NK cells (3.58% vs 2.56%), dendritic cells (2.43% vs 1.98%), and B cells (5.93% vs 5.26%), all p<0.05. AR-H had higher T-cell inflamed score (19 vs -72) and MAPK activation score (-0.24 vs -1.6) but lower IFNg score (-0.38 vs -0.33), all p<0.05. AR-H had higher expression of immune checkpoint genes (CD274, FOXP3, HAVCR2, LAG3; FC: 1.3-1.5) and stem cell-related genes (CD34, CD44, POU5F1, KLF4, ALDH2; FC: 1.2-1.4) compared to AR-L male BC, all p<0.05. AR-H male BC had higher AR protein (IHC) expression (100% vs 86.8%, q<0.05) and numerically higher frequency of AR-fusion variant (3.2% vs 0%, p=0.08) compared to AR-L male BC. AR-H male BC had worse OS (mOS: 35.9 vs 92.4 month; HR 1.6, 95% CI 1.0-2.5, p = 0.043) compared to AR-L BC. When analyzed by TP53 mutation status, AR-H with TP53-wt had numerically better survival (mOS: 35.6 vs 25.7 months, HR 0.52, 95% CI 0.20-1.35, p=0.17) compared to TP53-mt. Similarly, AR-L with TP53-wt had numerically better survival (mOS: 48.3 vs 23.2 months, HR 0.58, 95% CI 0.22-1.33, p=0.18) compared to TP53-mt. Conclusions: Our analysis suggests a strong association between AR expression and TP53 mutations, TMB-H, and PD-L1 positivity, immune cell infiltration, immune checkpoint and stem cell-related gene. Also, T cell inflamed and IFNy score were inversely related. Further exploration of specific alterations and immune-oncology markers associated with AR expression may help in clinical trial design for male patients with BC. Citation Format: Priya Jayachandran, Sachin Kumar Deshmukh, Sharon Wu, Jennifer R. Ribeiro, Irene Kang, Joanne Xiu, Francesca Battaglin, Darcy V. Spicer, Daphne B. Stewart, Shivani Soni, Wu Zhang, Janice Lu, Karam Ashouri, Joshua Millstein, William Flood, Jose P. Leone, Dario Trapani, Maryam Lustberg, Stephanie L. Graff, George W. Sledge Jr., Heinz-Josef Lenz, Evanthia T. Roussos Torres. Comprehensive characterization of the androgen receptor in male breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P1-03-22.

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