Germline Variation in HSD3B1 as a Novel Biomarker in Prostate Cancer
Abstract
In lay terms, we assessed the clinical impact of inheriting a variant allele (form) of the HSD3B1 gene that enables prostate cancer cells to make their own derivative of testosterone that can drive disease progression, despite castration. We have demonstrated in three independent groups of men treated with androgen deprivation therapy (ADT) that men possessing the variant HSD3B1 allele have worse clinical outcomes (i.e. likelihood of disease progression, metastasis (spread to the bones or other distant sites), and death). Moreover, men who have two copies of the variant allele tend to have profound resistance to ADT. In a fourth cohort of men who received ADT for biochemical failure after initialradiation therapy, we again found that the variant allele predicts for large differences in time to metastasis. Taken together, these results indicate that HSD3B1 genotype is a powerful genetic biomarker of resistance to ADT and can be used to identify men who might benefit from escalated treatment. Identification of these men has potential ramifications for guiding clinicians in augmenting standard ADT with highly-potent inhibitors of the androgen axis or chemotherapy. To investigate this further, we analyzed data from the landmark CHAARTED randomized trial. We found that inheritance of at least one copy of the variant HSD3B1 allele is associated with early development of castration-resistant disease and shorter overall survival in Caucasian patients with low-volume metastatic prostate cancer. These results represent the first prospective validation of HSD3B1 as a biomarker in prostate cancer. In summary, our findings suggest that design and analysis of future studies should consider accounting for HSD3B1 genotype, given the differences in outcomes it portends.
Document Details
- Document Type
- Technical Report
- Publication Date
- Dec 01, 2020
- Accession Number
- AD1125003
Entities
People
- Jason Hearn
Organizations
- University of Michigan