Clinical impact of germline pathogenic variants in high-risk prostate cancer treated with radiotherapy.

Germline pathogenic variants in cancer susceptibility genes, chiefly CHEK2, ATM and BRCA2, define subgroups with distinct outcomes in high-risk prostate cancer.

Pathogenic or likely pathogenic germline variants in cancer susceptibility genes are detected in 5% to 10% of patients with prostate cancer, but their prognostic implications in high-risk disease remain unclear. This retrospective study included 600 men with high-risk prostate cancer genotyped on a 19-gene panel, with time-to-event analyses performed in the 390 patients treated with radiotherapy with curative intent. A pathogenic or likely pathogenic variant was identified in 8.0% of patients (n = 48), with significant enrichment of CHEK2, ATM and BRCA2 compared with non-cancer control cohorts. BRCA1 or BRCA2 carriers had a 10-year overall survival of 19% versus 57% (p = 0.021), a cumulative incidence of biochemical recurrence of 57% versus 28% (p = 0.048), of distant metastases of 57% versus 18% (p = 0.004) and of prostate cancer-specific mortality of 33% versus 4.3% (p = 0.001); CHEK2 carriers had more second primary malignancies (47% versus 15%; p = 0.003) and ATM carriers showed no metastatic progression or cancer-specific death during follow-up.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The useful contribution is the gradient between genes rather than the already established fact that BRCA2 worsens prognosis: an ATM or CHEK2 carrier should not be counselled in the same terms as a BRCA2 carrier, and the second primary malignancy signal in CHEK2 carriers can be used directly to broaden surveillance. The fragility lies in subgroup size, 48 carriers in total at a single centre, which makes the striking cancer-specific mortality differences highly sensitive to a handful of events. The complete absence of progression in ATM carriers should above all be read as lack of power, not as evidence of benign behaviour.

Analysis by Dr Thibaut Benquey