Association of inherited steroidogenic genotype with body composition changes after androgen signaling inhibition (ASI) in men with biochemical recurrent (BCR), hormone-sensitive prostate cancer (HSPC).
Authors: Neha Venkatesh, Rebecca Tidwell, Yao Yu, Ana Aparicio, Amado J. Zurita, Sumit Kumar Subudhi, Bilal Ahmed Siddiqui, Justin R. Gregg, Paul Gettys Corn, Pavlos Msaouel, Efstratios Koutroumpakis, Jennifer Leigh McQuade, Daniel Frigo, Patrick Glen Pilié, Christopher Logothetis, Chad Huff, Andrew Warren Hahn
Journal: Journal of Clinical Oncology (2024)

108 Background: ASI is reported to cause adverse changes in body composition, including a loss of muscle mass and increased adiposity and weight. Clinically, interpatient body composition changes are heterogeneous, but there are no predictive biomarkers to identify those at-risk for body composition morbidity. Herein, we test the hypothesis that inherited variants in steroidogenic genes are associated with differential change in body composition after exposure to ASI. Methods: Men with BCR after definitive localized therapy and no prior systemic therapy who received 8 months of LHRH analog (LHRHa) +/- an ASI were eligible if they had: 1) cross-sectional CT imaging of L3 available prior to and after treatment, and 2) nucleated cells available for germline DNA next-generation sequencing (NGS). Cardiometabolic co-morbidities were retrospectively extracted from the electronic medical record at treatment initiation. Body composition was measured using Voronoi Data Analysis Facilitation Suite and normalized for height. Germline DNA whole exome or genome sequencing was performed with a focus on variants in steroidogenic genes. Body composition measures were compared between groups using the non-parametric Kruskal-Wallis test. Results: Body composition was measured at baseline and after 8 months in 162 men. After 8 months of LHRHa +/- ASI, median skeletal muscle mass (SMMi) loss was 6.6% (IQR -10.3, -3.0), skeletal muscle density (SMD) loss was 3.4% (IQR -9.6, 5.5), subcutaneous adipose tissue (SATi) gain was 12.3% (IQR 1.2, 21.7), and visceral adipose tissue (VATi) loss was 3.1% (IQR -12.3, 12.2). For the 150 patients with germline NGS available, HSD3B1 rs104703 was associated with a difference in VATi before (63.0 cm 2 /m 2 vs. 77.9 for AA vs. AC + CC genotype, p=0.05) and after 8 months of ASI (61.3 vs. 73.4 for AA vs AC + CC genotype, p=0.01), and AKR1C3 rs12529 was associated with a difference in VATi after ASI (59.4 vs. 70.7 for CC vs. GC + GG, p=0.04). Notably, SRD5A2 rs523349 correlated with a differential % change in SMD after exposure to ASI (-1.3% for CC vs. -7.1% for GC + GG, p=0.04), and it was maintained in a multivariable analysis incorporating cardiometabolic co-morbidities and prior receipt of LHRHa defined by a directed acyclic graph. Time to testosterone recovery after discontinuation of ASI was not associated with genotypes in steroidogenic genes. Conclusions: In men with BCR HSPC, 8 months of LHRHa +/- ASI induced notable losses of skeletal muscle and increase subcutaneous adipose tissue. Inherited polymorphisms in steroidogenic genes are associated with differences in body composition, and SRD5A2 is associated with differential skeletal muscle toxicity. These findings suggest that polymorphisms in germline DNA may contribute to the body composition toxicity observed with LHRHa +/- ASI.