Association of germline HSD3B1 (c.1100) genotype with tumoral and clinical outcomes in breast and endometrial cancers.

Abstract

10587 Background: A germline single-nucleotide polymorphism in HSD3B1 results in adrenal-permissive (c.1100 C) and adrenal-restrictive (c.1100 A) phenotypes with respect to androgen synthesis. In pre- and post-menopausal patients with breast cancer (n=3548 and 7871) and endometrial cancer (n=1588 and 8439), we annotated samples as adrenal permissive (CC/AC) or restrictive (AA) based on HSD3B1 variant status and then examined tumoral characteristics and clinical outcomes. Methods: We utilized tumors from the Caris Life Sciences Precision Oncology Alliance database and inferred germline HSD3B1 c.1100 genotype using variant allele frequencies (VAFs): c.1100 C VAF of 0% defined the AA genotype, VAF of 40-60% defined the AC genotype, and VAF of 100% defined the CC genotype. We explored associations of each HSD3B1genotypes with other genomic (WES) and transcriptomic (RNA-seq) features, as well as with survival outcomes. To performed consider menopausal status we used the patient’s age at the time of biopsy (>55 indicating post-menopausal). Results: In breast cancer (BC) and endometrial cancer (EC), the permissive HSD3B1genotype had greater mRNA expression of the estrogen receptor ( ESR1) and co-alterations of the TP53 (p<0.0001). In post-menopausal ECs, the permissive genotype was associated with increased alterations in the PI-3-kinase pathway ( PTEN, PIK3CA, PIK3R1, p<0.0001). In pre-menopausal HER2+ BCs, the restrictive genotype was associated with worse survival (HR=1.40, 95% CI = 1.05-1.85, p=0.027) and exhibited increases in hallmark GSEA signatures including epithelial-to-mesenchymal transition. Post-menopausal basal BCs with the permissive genotype had numerically higher PD-L1 protein expression (50% vs 13%) and less PI-3-kinase alterations ( PTEN, PIK3R1, p<0.01). Post-menopausal clear cell ECs with the restrictive genotype exhibited worse survival (HR=1.60, 95% CI=1.07-2.38, p=0.03) and were 3-fold more likely to be TMB-high or MSI-high (p<0.05). Distinctly, post-menopausal endometrioid ECs of the restrictive genotype were less likely to be TMB- or MSI-high (p<0.05). Conclusions: Breast and endometrial cancers can be classified as adrenal-permissive or -restrictive based on HSD3B1 c.1100 genotype. This classification distinguishes clinical outcomes and tumoral features, particularly when stratifying by menopausal status. Importantly, these genotypes are differentially associated with druggable pathways (PI-3-kinase) and markers of immune sensitivity (PD-L1, TMB, MSI). [Table: see text]