There is increasing evidence that Androgen Receptor (AR) expression has prognostic usefulness in Triple negative breast cancer (TNBC), where tumors that lack AR expression are considered “Quadruple negative” Breast Cancers (“QNBC”). However, a comprehensive analysis of AR expression within all breast cancer subtypes or stratified by race has not been reported. We assessed AR mRNA expression in 925 tumors from The Cancer Genome Atlas (TCGA), and 136 tumors in 2 confirmation sets. AR protein expression was determined by immunohistochemistry in 197 tumors from a multi-institutional cohort, for a total of 1258 patients analyzed. Cox hazard ratios were used to determine correlations to PAM50 breast cancer subtypes, and TNBC subtypes. Overall, AR-negative patients are diagnosed at a younger age compared to AR-positive patients, with the average age of AA AR-negative patients being, 49. AA breast tumors express AR at lower rates compared to Whites, independent of ER and PR expression (p<0.0001). AR-negative patients have a (66.60; 95% CI, 32–146) odds ratio of being basal-like compared to other PAM50 subtypes, and this is associated with an increased time to progression and decreased overall survival. AA “QNBC” patients predominately demonstrated BL1, BL2 and IM subtypes, with differential expression of E2F1, NFKBIL2, CCL2, TGFB3, CEBPB, PDK1, IL12RB2, IL2RA, and SOS1 genes compared to white patients. Immune checkpoint inhibitors PD-1, PD-L1, and CTLA-4 were significantly upregulated in both overall “QNBC” and AA “QNBC” patients as well. Thus, AR could be used as a prognostic marker for breast cancer, particularly in AA “QNBC” patients.

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We propose a genetic epidemiologic metric derived from sequencing tumor cells and matched "normal" cells (typically peripheral blood mononuclear cells); this metric can be used to evaluate the relevance of germline pathogenic variants (GPVs) in tumor-suppressor genes to the development of individual cancer types (Table S1 in the Supplementary Appendix, available with the full text of this letter at NEJM.org). According to Knudson's two-hit hypothesis, a tumor that is attributable to a GPV requires biallelic inactivation of a tumor-suppressor gene. Biallelic but not monoallelic inactivation of BRCA1 or BRCA2 is accompanied by genomic hallmarks of deficiency in homologous recombination repair. 1,2 These genomic hallmarks include mutational signatures (i.e., patterns of somatic nucleotide changes caused by distinct mutagenic processes that can be detected by tumor genome sequencing). 1 Therefore, the presence or absence of biallelic inactivation as determined by tumor sequencing can establish whether BRCA1/2 GPVs contributed to the cancer. In a recent study, gene-panel sequencing was used to determine the zygosity status of BRCA1/2 in 17,000 tumors. 2 We propose that the fraction of tumors harboring a BRCA1/2 GPV and a second hit (Fig. 1) is the excess risk that can be attributed to the GPV across tumor types.Jonsson et al. 2 found that tumors in breast, ovarian, prostate, and pancreatic cancers that have established associations with BRCA1/2 GPVs (the established set) have a higher

Purpose: Recently, we have demonstrated that triple-negative breast tumors (TNBC) that lack the expression of androgen receptor are quadruple-negative tumors (QNBC) and have increased aggressiveness. Additionally, we determined that this is due to a unique gene signature in the QNBC subtype. However, whether this gene signature is associated with a unique miRNA expression and differential in African American (AA) women compared to Caucasian (CA) women has not been determined. Therefore, the purpose of this study is to determine the miRNA expression in presence or absence of androgen receptor in both African American and Caucasian QNBC patients. Methods: miRNA level 3 sequencing files were originally downloaded on June 01 2016 from TCGA for 925 breast cancer patients. The miRNA sequence files (RPKM) and gene expression files (FPKM UQ) were obtained for normal and tumor samples for these patients. Median value of AR FPKM UQ was used as cut-off and divided patient group as AR(+ve/-ve). Log2 fold change values were calculated by comparing AR-negative and AR-positive patients. P-value was calculated using two-tail t-test. GSE19783 (mRNA, miRNA data) was also obtained and was used as validating dataset. Results: Out of 925 patients, 101 patients have TNBC. Among TNBC patients, 107 are QNBC and 8 patients are AR +ve TNBC. Reads per million for 1046 miRNAs were considered for this study.40 miRNAs showed differential expression in QNBC. (p-value and lt 0.05). All BC patients were organized based on race (CA/AA), stage (I/II/III, IV) and subtype (Luminal, Her2type, TNBC).We have found that hsa-mir-452 and hsa-mir-937 expression was high in AR-negative, hsa-mir-190b expression was low in AR -ve African American women. miRNAs expression was changed in QNBC and correlated to AR (hsa-mir-577, hsa-mir-135b and hsa-mir-18a). hsa-mir-375 expression was low in QNBC.hsa-mir-150, hsa-mir-181a-2, hsa-mir-500a, hsa-let-7d, hsa-mir-92a-1, hsa-mir-92a-2, hsa-mir-20a, hsa-mir-17, hsa-mir-30a, hsa-mir-210, hsa-mir-455, hsa-mir-130a are expression was changed in African American women with QNBC. Hsa-mir-3607 is low in African American women, irrespective of AR expression. These results are in process of validation using independent dataset. Discussion/Conclusion: Standard treatment of breast cancer relies on reliable assessment by IHC analysis of ER, PR, and HER2. Our results suggest that the heterogeneity of TNBC is at least partially associated with the presence or absence of AR expression, suggesting that QNBC should be considered as a clinically relevant breast cancer subtype. IHC analysis of AR appears to be a practical assay to determine the most aggressive TNBC subtypes and identifies tumors that could benefit from available targeted therapies. miRNA isoform or novel miRNA needs to be discovered to further investigate the gene regulation for QNBC patients. Citation Format: Anusha Angajala, Raymond Hughley, Windy DeanColomb, Shweta Tripathi, Ming Tan, Clayton Yates. Identification of differentially expressed microRNAs in African American women with quadruple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4769.