ERBB3 expression in racially diverse patients with castration-sensitive prostate cancer and its association with a unique AR activity signature.

Abstract

23 Background: Despite successful clinical management of castration sensitive prostate cancer (CSPC), the 5-year survival rate for men with castration-resistant prostate cancer (CRPC) is only 32%. This number is even more striking in the context of racial disparities where prostate cancer mortality rates for Black/African American (AA) men are two to four times higher than those in every other racial and ethnic group in the US. Identification of molecular expression and activity patterns that vary by racial group may provide a key to addressing outcomes related to survival disparities, as current treatments have not been developed with attention to the inclusion of diverse patient populations. Developing a biomarker in CSPC to stratify patients who will progress on standard-of-care therapy could guide intelligent intensification of therapeutic strategies and improve survival, particularly in high-risk patient populations. Methods: Targeted deep sequencing was performed as routine care for treatment naïve patients in the UI cohort (n=30), and immunostaining was performed in racially diverse tissue microarray (n=149). Bioinformatics analyses were utilized to identify signaling pathways associated with biomarker overexpression in the UI cohort, consolidated publicly available RNA-seq datasets (n=664), and a racially diverse Gene Expression Omnibus dataset (n=68). Results: We identified ERBB3 overexpression (OE) in racially diverse CSPC patient populations, where it was associated with advanced disease at diagnosis. At the protein level, HER3 expression was negatively correlated with intraprostatic androgen in Black/AA men. Bioinformatics analyses showed a positive correlation between ERBB3 expression and the Androgen Response pathway despite low intraprostatic androgen and stable expression of androgen receptor (AR) transcript in Black/AA men. Clinically, ERBB3 OE is associated with high pre-treatment serum PSA in Black/AA men and is positively correlated with a clinically adaptable AR signature score. Preliminary outcomes data suggest Black/AA men with ERBB3 OE have a shorter time to disease progression. Conclusions: In diverse CSPC patient populations, ERBB3 OE was associated with high AR signaling and serum PSA despite low intraprostatic androgen, suggesting ERBB3 OE as a prospective biomarker for ligand-independent AR activation. In this context, ERBB3 OE could stratify patients for intensification of therapy in castration-sensitive disease and emphasizes the importance of biomarker-directed clinical trials with diverse populations.