Outcomes of Patients with Metastatic Castration-Resistant Prostate Cancer According to Somatic Damage DNA Repair Gene Alterations

Abstract

(1) Background: In literature, approximately 20% of mCRPC present somatic DNA damage repair (DDR) gene mutations, and their relationship with response to standard therapies in mCRPC is not well understood. The objective was to evaluate outcomes of mCRPC patients treated with standard therapies according to somatic DDR status. (2) Methods: Eighty-three patients were recruited at Caen Cancer Center (France). Progression-free survival (PFS) after first-line treatment was analyzed according to somatic DDR mutation as primary endpoint. PFS according to first exposure to taxane chemotherapy and PFS2 (time to second event of disease progression) depending on therapeutic sequences were also analyzed. (3) Results: Median first-line PFS was 9.7 months in 33 mutated patients and 8.4 months in 50 non-mutated patients (p = 0.9). PFS of first exposure to taxanes was 8.1 months in mutated patients and 5.7 months in non-mutated patients (p = 0.32) and significantly longer among patients with ATM/BRCA1/BRCA2 mutations compared to the others (10.6 months versus 5.5 months, p = 0.04). PFS2 was 16.5 months in mutated patients, whatever the sequence, and 11.7 months in non-mutated patients (p = 0.07). The mutated patients treated with chemotherapy followed by NHT had a long median PFS2 (49.8 months). (4) Conclusions: mCRPC patients with BRCA1/2 and ATM benefit from standard therapies, with a long response to taxanes.

BRCA-deficient metastatic prostate cancer has an adverse prognosis and distinct genomic phenotype

“…It is worth noting that our data should not be considered conclusive due to the small number of patients that received chemotherapy, with the heterogeneity of the cohort being a limitation of this study. Furthermore, prior studies have provided conflicting data regarding docetaxel efficacy and DDR alterations 42 , 43 and this issue warrants further evaluation.…”

Cell-Free DNA Sequencing Reveals Gene Variants in DNA Damage Repair Genes Associated with Prognosis of Prostate Cancer Patients

“…Similarly, Neviere et al recently identified mutations in several DDR genes (ATM, BRCA1/2, FANC-C/-F/-G/-M, CHEK1/2, CDK12, MRE11A, PALB2 and BLM) in mCRPC patients; patients with DDR gene mutations showed somewhat better overall and progression-free survival than patients without these mutations, but the differences were not significant [ 41 ].…”

“…Defects in BRCA2 and ATM are strongly associated with poor clinical outcomes, i.e., shorter progression-free survival [ 21 ]. However, a recent study has reported that mCRPC patients with somatic mutations in BRCA1/2 and ATM benefit from standard therapies and have a longer progression-free survival (long response to taxane therapy) than patients without these mutations [ 41 ]. Comparably, Kaur et al showed that mCRPC patients with mutations in the BRCA1/2 or ATM gene who are treated with taxanes as the first-line therapy show a longer progression-free survival than patients without these alterations [ 50 ].…”