Tumor-intrinsic chemosensitivity assessed by KELIM and prognosis byBRCAstatus in patients with advanced ovarian carcinomas

Objective Treatment of high-grade serous ovarian carcinomas relies on surgery and chemotherapy, potentially followed by bevacizumab and/or poly (ADP-ribose) polymerase inhibitors (PARPi). The modeled CA-125 ELIMination rate constant K (KELIM) is a pragmatic indicator of tumor primary chemosensitivity. Although it is well established that BRCA mutations are associated with platinum sensitivity, the relationship between BRCA status and KELIM score has yet to be elucidated. This study aimed to evaluate the interactions between BRCA and KELIM, and their respective prognostic values. Methods We retrospectively collected data from 743 patients with high-grade serous ovarian carcinomas included in a French nationwide registry ( NCT03275298 ) treated with neoadjuvant platinum-based chemotherapy followed by surgery. We analyzed the interactions between BRCA and KELIM, and their impacts on progression-free survival and overall survival. Results BRCA -mutated (BRCA m) patients had higher standardized KELIM than BRCA -wild type ( BRCA wt) tumors (median 1.16 vs 1.06, respectively; p=0.001). The prognostic value of the KELIM score was independent of BRCA in multivariate analyses. KELIM score and BRCA could be combined to define three prognostic groups: (1) an unfavorable prognostic group with both BRCA wt and unfavorable KELIM (median progression-free survival 12.0 months); (2) an intermediate prognostic group with either BRCA m and unfavorable KELIM, or BRCA wt and favorable KELIM (median progression-free survival of 16.0 and 18.8 months, respectively; HR 0.64 compared with the unfavorable group, p<0.001); and (3) a favorable prognostic group with both BRCA m and favorable KELIM (median progression-free survival 28.8 months; HR 0.37 compared with the unfavorable group, p<0.001). Conclusions The KELIM score provides complementary prognostic information with respect to BRCA, and discriminates different prognoses within BRCA m or BRCA wt patients. Patients with both BRCA wt/unfavorable KELIM have a poor prognosis, underscoring the urgent need for novel therapeutic strategies.