Predictive value of DNA repair gene alterations for the response to platinum-based chemotherapy and immunotherapy in advanced solid tumors patients: Results from a single center molecular screening program

Homologous recombination DNA repair deficiency is associated with sensitivity to platinum in certain cancer types, including breast, ovarian, pancreatic, and prostate. We aimed to characterize the antitumor activity of platinum-based therapies in patients (pts) with unselected advanced solid tumors for who a DNA repair gene alteration (DNA-RGA) was identified through a tumor molecular screening program (TMSP). All comers pts from the TMSP of Institut Bergonié, Bordeaux, France, were reviewed. Each DNA-RGA identified was classified as pathogenic (P), probably pathogenic (PP), unknown pathogenecity (UP) according to OncoKB and/or ClinVAR databases and defined 3 pts groups. Between January 2018 and May 2020, 662 pts were screened. 199 tumor DNA-RGA were found in 121 (27.7%) pts. The most frequent mutations were : ATM (N=40), POLE (N=23), BAP1 (N=19), BRCA2 (N=16), PMS2 (N=9), ATR (N=9), MSH2 (N=8) and BRCA1 (N=8). 96 pts received platinum-based chemotherapy in the advanced setting, mostly lung cancer pts (N=28). Platinum was carboplatin in 46 (48%) of the pts. No difference in overall response rate (ORR) under platinum regimen was observed between the 3 (P,PP,UP) pts groups. Median progression free survival (PFS) was 8.4 months (IC95% : 7 – 9.4). The only predictor of worst PFS in Cox regression model was the existence of a P alteration compared to the UP group: HR=2.11 (95%CI = 1.2 – 3.7), P = 0.0094. The UP group had a better 6-months PFS compared to the P/PP group: 81% vs 60%, p=0.0382. 48/96 pts received a immune checkpoint inhibitor (ICI) alone or in combination. Interestingly we observed a trend in an increased ORR to ICI according to the DNA-RGA status : 1/11, 5/16, 9/20 pts (p=0.14; Chi-2 test for trend in proportions: p=0.04) in the UP, PP and P group respectively. The same trend was observed on PFS with a 6-months PFS of 11, 44 and 50% in the UP, PP and P groups respectively (p=0.37). P/PP DNA-RGA impacted the PFS but not the ORR to platinum in advanced solid tumors pts. Though the limited population size, this exploratory study paves the way for further investigations evaluting DNA-RGA as biomarkers of response to ICI.