Abstract PR18: Prognostic role of androgen receptor in triple-negative breast cancer: A global multi-institutional experience
Authors: Bhattarai Shristi , Klimov Sergey , Mittal Karuna , Krishnamurthi Uma , Li Xiaoxian Bill , Wali Deepika , Wetherilt Ceyda Sonmez , Riaz Ansa , Aleskandarany Mohammad A. , Green Andrew R. , Ellis Ian O. , Gupta Meenakshi , McCullough Lauren E. , Manne Upender , Agboola Johnson , Baskovich Brett , Janssen Emiel A. , Callagy Grace , Mehta Anurag , Shet Tanuja , Emad Rakha A. , Rida Padmashree C.G. , Aneja Ritu 
Published: August 2020

Background: African American (AA) triple-negative breast cancer (TNBC) patients experience worse clinical outcomes and exhibit 40% higher mortality rate than their European Americans (EAs) counterparts. There are currently no distinctions in inherent tumor biology between the ethnically distinct TNBC patients that serve as risk-predictive markers allowing new tailored treatments. Recently, androgen receptor (AR) has emerged as a new target for treating TNBC. However, the prognostic value of AR in TNBC remains controversial. To reconcile conflicting reports about the impact of AR loss on prognosis of TNBC and uncover the molecular pathways that may underlie the racial disparity in outcomes among AR-negative TNBCs, we determined the prognostic value of AR in diverse TNBC cohorts. Since loss of AR is associated with worse clinical outcome and African and AA women are more prone to aggressive disease course, we hypothesized that AR loss may underlie the global disparate burden in TNBC.

Methods: We evaluated AR expression in well-annotated formalin-fixed, paraffin-embedded TNBC resection samples (n=1351) obtained from multiple hospitals from US, UK, Norway, Ireland, Nigeria and India. Samples with ≥1% nuclei staining positive for AR were deemed to be AR-positive. Associations between AR status, clinicopathologic variables and overall survival (OS) were evaluated. We performed gene set enrichment analysis for AR low and high group in AA and EA TNBCs. In vitro experiments were performed to examine whether AR loss increased the metastatic potential of TNBC cells.

Results: We observed a significant difference in AR expression among EA and AA TNBCs (p=0.02) with AR loss associated with women of African ancestry (&gt;90%, p&lt;0.05). AR loss was significantly associated with poor OS in TNBC patients from US cohort (p=0.0324; n=316 for AR-negative, n=104 for AR-positive) and Nigerian cohort (p=0.0251; AR-negative=164, AR-positive=16). AR-negative was associated with poor OS in adjuvant-treated high Ki67 (&gt;14%) (HR=1.72; p=0.095) AA TNBC (n=98) when compared to EA TNBCs (n=80). Furthermore, AR status retained its significant prognostic value (HR=1.549, p=0.036) after controlling for age, grade, Ki67, race and chemotherapy status. Gene set enrichment analysis revealed that Wnt/β-catenin signaling was the top-enriched gene ontology in the AR-low TNBC subgroup. Moreover, β-catenin protein levels are higher in AA AR-low TNBCs compared with AA AR-high TNBCs (p&lt;0.05), suggesting Wnt signaling upregulation in AA women with AR-negative TNBC. In TNBC cell lines, loss of AR was significantly associated with higher cell proliferation, migration and invasion (p&lt;0.05).

Conclusion: Our study suggests a striking association of AR loss in TNBC with women of African ancestry. Our data offer compelling evidence that oncogenic Wnt/β-catenin signaling may link AR loss to more aggressive disease course and represent actionable biology in AA AR-negative TNBCs for whom no targeted treatments are currently on the horizon.

This abstract is also being presented as Poster C102.

Citation Format: Shristi Bhattarai, Sergey Klimov, Karuna Mittal, Uma Krishnamurthi, Xiaoxian Bill Li, Deepika Wali, Ceyda Sonmez Wetherilt, Ansa Riaz, Mohammad A. Aleskandarany, Andrew R. Green, Ian O. Ellis, Meenakshi Gupta, Lauren E. McCullough, Upender Manne, Johnson Agboola, Brett Baskovich, Emiel A. Janssen, Grace Callagy, Anurag Mehta, Tanuja Shet, Rakha A. Emad, Padmashree C.G. Rida, Ritu Aneja. Prognostic role of androgen receptor in triple-negative breast cancer: A global multi-institutional experience [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr PR18.