In this study, 5.9% of Dutch patients with metastatic prostate cancer (mPCa) carried a germline pathogenic variant (gPV) in a DNA damage-repair (DDR) gene. Consistent with international data, gPVs in CHEK2, ATM and BRCA2 were significantly more common in mPCa patients than in reference populations, supporting their association with metastatic disease. Several clinical factors increased the likelihood of detecting a gPV: a personal history of another primary cancer, a first- or second-degree relative with breast cancer diagnosed before age 50, pancreatic cancer in close relatives and Jewish ancestry. Patients with at least one risk factor had an estimated gPV probability of 7.9%, compared with 4.2% in those without risk factors. Given this relatively low prevalence, routine germline testing in all mPCa patients – currently recommended in international guidelines – may warrant reassessment within the Dutch healthcare context. A total of 46 families were identified with a high- or moderate-risk DDR gPV. These findings have important implications for relatives, particularly women, as BRCA1, BRCA2 and PALB2 variants substantially increase breast and ovarian cancer risk and trigger cascade testing. For moderate-risk genes such as ATM and CHEK2, Dutch recommendations advise cascade testing only when relevant cancers already exist within the family. In our cohort, 58% of families with an ATM or CHEK2 gPV met these criteria. The prevalence of BRCA2 gPVs (1.16%) was lower than in other mPCa cohorts, possibly due to prior cascade testing or differences in ancestral backgrounds. Tumour testing may also identify some gPVs earlier, although it can occasionally miss germline variants. This is the largest European study to date evaluating germline variants in mPCa using a focused hereditary breast cancer gene panel, reducing ambiguity linked to broader panels. Despite the cohort size, the number of gPV carriers was modest, underscoring the need for larger European studies. Overall, CHEK2, ATM and BRCA2 gPVs were enriched in Dutch mPCa patients, and clinicians should prioritise testing in those with identified risk factors.
Prevalence of germline pathogenic variants in patients with metastatic prostate cancer
Reviewed by Asih H Ansari
Prevalence of germline pathogenic variants in 779 patients with metastatic prostate cancer.
