AR negative triple negative or “quadruple negative” breast cancers in African American women have an enriched basal and immune signature

Melissa Davis,Rachel Martini,Sejong Bae,William Grizzle,Raymond Hughley,Lisa Newman,Balasubramanyam Karanam,Shweta Tripathi,Windy Colomb,Clayton Yates,Qinghua He,Aamir Ahmad

doi:10.1371/journal.pone.0196909

Abstract

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.

Highlights

Among women in the United States, breast cancer is the second most common cancer
Androgen Receptor (AR) expression in breast cancers differs between AA and White patients and among molecular subtypes
Whole-genome expression data from primary breast cancers were obtained from public databases, screened for samples annotated for race information, and analyzed for associations with AR-status among breast cancer subtypes and racial groups (S1A Fig)

Summary

Introduction

Among women in the United States, breast cancer is the second most common cancer. AfricanAmerican (AA) women have historically had lower incidence rates relative to White women; recent statistics indicate that incidence rates for AA women have converged with those of White women [1]. Breast cancer is currently divided into four molecular subtypes by the presence or absence of hormone receptors [(i.e., estrogen (ER) and progesterone (PR)], along with human epidermal growth factor receptor 2 (HER2). This classification influences treatment options and correlates with clinical outcomes such as overall survival (OS) and/or recurrence-free survival [3, 4]. Including AR staining, along with the current standard ER, PR, and HER2 markers has been suggested [5, 8, 9] This is especially applicable for TNBC patients, since determining AR status would correlate to the sensitivity of these tumors to AR-targeted therapies such as Bicalutamide and Enzalutamide [10, 11]. Since AA women typically have the most aggressive forms of breast cancer, there is a need to measure the expression of AR in AA patients across all breast cancer subtypes and determine its relationship to clinical outcomes, in TNBC-QNBC patients

Methods

Results

Conclusion