GERMLINE pathogenic variants (PV) are found in approximately 8–12% of patients presenting with metastatic hormone-sensitive prostate cancer (mHSPC). A recent study from the Hospital Universitario De Torrejón in Madrid, Spain found that patients with mHSPC and germline PVs had a worse survival outcome.
The genetic basis of prostate cancer is not fully understood, however, 35% of cases are linked to hereditary factors, with only 6% due to high-penetrance autosomal dominant mutations. The remaining cases are associated with common low-risk variants, such as single nucleotide polymorphisms.
High-penetrance variants are more frequent in advanced prostate cancer, with about 12% of advanced cases involving mutations in cancer predisposition genes, often linked to syndromes like hereditary breast and ovarian cancer syndrome, or specific to prostate cancer, like the G84E variant on the HOXB13 gene. Mutations in BRCA2, CHEK2, ATM, and BRCA1 are common, with BRCA2 mutations associated with aggressive tumours and poorer survival outcomes.
Genetic analysis was performed through next-generation sequencing on 34 patients who had been diagnosed with mHSPC and were engaged in treatment. Of these patients, six were found to possess a germline PV and the 33-month follow-up revealed a significant difference in overall survival (OS) between these two patient groups.
The researchers concluded that germline PV presence is a significant prognostic factor for OS in mHSPC. Additionally, BRCA2 mutation is an independent prognostic factor for both time to castration-resistant prostate cancer and OS, associated with poor outcomes. However, given the small cohort involved in the study, larger studies are needed to confirm these findings and allow definitive conclusions to be drawn.
Katie Wright, EMJ
Reference
Custodio-Cabello S et al. Prognostic value of germline mutations in metastatic hormone-sensitive prostate cancer (mHSPC). Urol Oncol. 2024;DOI:10.1016/j.urolonc.2024.05.010.
