Racial disparities in breast cancer chiefly reside in the lesser-known quadruple-negative breast cancer

Abstract Background: Triple-negative breast cancer (TNBC) is a notoriously hard to treat and aggressive breast cancer (BC) subtype. Androgen receptor-positive (AR+) TNBC is characterized by AR overexpression and sensitivity to AR antagonists. In contrast, basal-like TNBC lacking AR expression, also known as quadruple-negative breast cancer (QNBC), is refractory to AR antagonists. Women of African descent are predisposed to TNBC. Moreover, QNBC differences between African American (AA) and European American (EA) patients have been noted, with the former expressing distinct basal and immune signatures and having worse outcomes. Although AR testing is not part of standard BC diagnosis and the QNBC subtype is usually reported as TNBC, QNBC may have distinct biological and clinical characteristics. In this study, we examined the prevalence and clinical characteristics of QNBC.Methods: We immunohistochemically evaluated AR expression in formalin-fixed paraffin-embedded TNBC samples (n=760) from our multi-institutional cohorts across the US and Nigeria. Samples with ≥1% AR-positive nuclei were deemed AR-positive. Descriptive statistics were generated for clinicopathological characteristics. Kaplan-Meier (KM) survival analyses were performed to compare overall survival (OS) between patient groups with a different AR status. Multivariable Cox regression analysis was conducted to select the covariates (a≥0.20 removal criterion). AR mRNA levels in patients with BC were evaluated using RNA-seq data retrieved from The Cancer Genome Atlas (TCGA). The Cancer Proteome Atlas (TCPA) BRCA dataset was used to assess AR protein levels.Results: We found an association between African ancestry and AR loss. QNBC accounted for 92.1% of BCs in Africans, 82.4% in AAs, and only 39.8% in EAs. Similarly, analyses of RNA-seq data from TCGA revealed that tumors in AAs with TNBC (n=32) had lower AR mRNA levels than their EA counterparts (n=67). Consistently, AR protein levels in TNBC tumors were lower in AAs than in EAs. Univariate analyses revealed a significant association between QNBC status and high tumor grade (grade 3: 83.02% vs. 66.41%, p<0.001) and high expression of the proliferation marker Ki-67 (≥14%: 85.41 vs. 75.51%, p=0.022) in patients from our multi-institutional cohorts. Race-wise associations showed a non-significant trend of QNBCs in AAs toward higher tumor grade (85.65% vs. 80.27%, p=0.196) and Ki67 expression levels (87.77% vs. 81.06%, p=0.113) compared with QNBCs in EAs. Compared with EAs with QNBC, a higher proportion of AAs with QNBC aged ≤56 (59.17% AAs vs. 45.7 EAs, p=0.011) and had tumors >2 cm (60.88% AAs vs. 45.65% EAs, p=0.075). KM survival analyses indicated that patients with QNBC had worse outcomes than those with TNBC, with significant differences in women of African descent (p<0.05). Furthermore, a race-wise comparison uncovered that while AA and EA patients with TNBC displayed similar OS, AAs with QNBCs had worse OS than their EA counterparts (p=0.03). Finally, we stratified samples in the TCGA BC dataset (n=920) according to AR mRNA levels into AR-low (n=243) and AR-high groups (n=677) and found that among patients in the AR-low subgroup, AAs (n=90) had significantly worse OS than EAs (n=153; p=0.008). No significant differences in OS were observed within the AR-high group (p=0.93).Conclusion: Our findings suggest a strong association between AR loss and African descent. These data offer compelling evidence to support that racial BC disparities in the US lie within the QNBC subgroup rather than the TNBC subtype. These findings also suggest that the widening BC mortality gap between AAs and EAs essentially whittles down to a failure to characterize the QNBC subtype. Citation Format: Shristi Bhattarai, Geetanjali Saini, Manali Rupji, Justin Luningham, Ravi C. Turaga, Uma Krishnamurti, Xiaoxian (Bill) Li, Johnson Agboola, Murtala Abubakar, Haruna A. Nggada, Abidemi Omonisi, Saad A. Ahmed, Luciane Cavalli, Ritu Aneja. Racial disparities in breast cancer chiefly reside in the lesser-known quadruple-negative breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-07-31.