Comprehensive characterization of androgen receptor expression in breast cancer.
Authors: Jayachandran Priya , Deshmukh Sachin , Wu Sharon , Enriquez Kathryn Therese , Kang Irene , Xiu Joanne , Farrell Alex Patrick , Battaglin Francesca , Mittal Pooja , Lu Janice M. , Soni Shivani , Zhang Wu , Millstein Joshua , Ma Cynthia X. , Graff Stephanie L. , Radovich Milan , Lenz Heinz-Josef , Spicer Darcy V. , Sledge George W. , Roussos Torres Evanthia T. 
Published: June 2023

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Background: The androgen receptor ( AR) is a hormone-regulated transcription factor that plays an important role in breast cancer (BC) pathogenesis. While estrogen receptor inhibitors are well-studied in BC, the role of AR on prognosis and therapy is less well-known. Here we aim to characterize the clinicopathologic and molecular features of AR expression in BC. Methods: 27,169 BC samples were tested by NGS (592, NextSeq; WES, NovaSeq), WTS (NovaSeq) (Caris Life Sciences, Phoenix, AZ). Microsatellite-instability (MSI) was tested by IHC and NGS. Tumor mutational burden (TMB) totaled somatic mutations per tumor (high≥10 mt/MB). Tumors with AR-high(H) and AR-low(L) 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 tissue collection or 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<0.05). Results: Median AR expression was higher in lobular compared to ductal carcinoma (2.2-fold) and in HR+/HER2- compared to TNBC (13.9-fold). Compared to AR-L, AR-H BC had higher frequency of PIK3CA (50.6% vs 12.7%), CDH1 (20% vs 2.2%), ESR1 (12.8% vs 1.4%), MAP3K1 (9.4% vs 1.4%), GATA3 (11.2% vs 2.7%), AKT1 (5.7% vs 1.4%), NF1 (8.6% vs 3.6%), ARID1A (6.9 vs 3.6), SPEN (2.8% vs 1.5%), and PTEN (7.9% vs 6.2%) mutations and TMB high (9.5% vs 7.7%), but lower frequency of dMMR/MSI-H (0.6% vs 1.7%) and PD-L1 (18.7% vs 45.3%) positivity (all p<0.05). AR-H tumors also showed enrichment of the IL2-STAT5 pathway (NES: 1.33, FDR: 0.24). Further, AR-H BC had higher expression of immune checkpoint genes ( CD274, PDCD1LG2, LAG3, HAVCR2, FOXP3, FC: 1.1-1.4, all p<0.05) and T cell inflamed scores (32.5% vs 26.2%, p<0.05). AR-H BC had increased immune cell infiltration of B cells (6% vs 4%), M2 Mφ (5% vs 2%), and NK cells (3% vs 2%), but decreased infiltration of M1 Mφ (2% vs 3%) (all p<0.05). AR-H BC had upregulation of M2 Mφ related genes ( ARG1, IL10, CCL17, CXCR1, FC: 1.2-1.8, all p<0.05) and downregulation of M1 Mφ related genes ( CCL2, CCL5, CXCL9, CXCL10, FC: 1-1.5, all p<0.05). AR-H BC was associated with improved OS compared to AR-L BC (mOS: 1843 vs 1096 days; HR 0.6, 95% CI 0.5-0.7, p<0.00001), and with doxorubicin (2294 vs 2054 days; HR 0.7, 95% CI 0.5-0.9, p<0.001) , paclitaxel (2239 vs 1967 days; HR 0.7, 95% CI 0.5-0.9, p<0.001) and trastuzumab (inf vs 2351 days; HR 0.6, 95% CI 0.4-0.9, p<0.01) treatment. Conclusions: Our data suggest a strong association between AR expression and increased mutations in several cancer related genes, immune checkpoint markers, the IL2-STAT5 pathway, differential immune cell infiltration, and improved overall survival.