Real-World Outcomes of DNA Damage Repair Altered Metastatic Castration-Resistant Prostate Cancer: Insights from FFPE-Based Genomic Profiling.

Germline or somatic alterations in DNA damage repair genes, dominated by BRCA2, ATM and BRCA1.

Germline or somatic DNA damage repair gene variants are found in about one-quarter of patients with metastatic prostate cancer, yet their prognostic and predictive value remains debated. This retrospective single-centre study analysed 287 patients treated between 2017 and 2022, comparing outcomes on taxane chemotherapy and on next-generation hormonal therapy according to repair status. Sixty-three patients (21.9%) were mutated, mainly for BRCA2 (12.5%), ATM (3.1%) and BRCA1 (1.39%), and a family history of breast, ovarian or prostate cancer strongly predicted this status (47.0% vs 14.0%, p = 0.0001). BRCA1/2- or ATM-mutated patients treated with first-line taxanes had longer median overall survival without reaching significance (70 vs 36 months; p = 0.30), whereas the mutated subgroup showed a trend to shorter progression-free survival on next-generation hormonal therapy (12 vs 18 months; p = 0.04), with no difference on third-line cabazitaxel. Formalin-fixed paraffin-embedded tissue remained evaluable for sequencing up to 180 months after collection.

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

The authors' conclusion of preferential taxane benefit in BRCA1/2- or ATM-altered carriers rests on a non-significant overall survival difference (p = 0.30) in a retrospective single-centre subgroup: the 70 versus 36 months gap is striking but cannot support a treatment sequencing decision, and cautious reading is required. What is directly usable in the cancer genetics clinic is rather the predictive value of a family history of breast, ovarian or prostate cancer, 47.0% versus 14.0%, a simple argument for prioritising testing. The most solid methodological point here is in fact the usability of archival paraffin blocks up to 180 months, concrete information for laboratory archive retrieval; note however that germline and somatic status are not separated in the outcome analysis, which precludes any conclusion specific to germline carriers.

Analysis by Dr Thibaut Benquey