Genetic variants in immunogenic cell death (ICD) relating genes to predict outcome in metastatic colorectal cancer (mCRC): Data from FIRE-3, TRIBE and MAVERICC trials.

Abstract

187 Background: ICD is an immune response against dead-cell antigens from cancer cells treated with cytotoxic and/or targeted therapies. Oxaliplatin (OHP) and cetuximab (Cet) are distinct drugs to elicit ICD, while most other anticancer agents kill cancer cells in a nonimmunogenic manner. We hypothesized that genetic variants in ICD-related genes could predictive efficacy of OHP and/or Cet in mCRC. Methods: We analyzed data of mCRC patients enrolled in three 1st-line randomized trials [FIRE-3: FOLFIRI+Cet vs FOLFIRI+bevacizumab (Bev), TRIBE: FOLFOXIRI+Bev vs FOLFIRI+Bev and MAVERICC: FOLFOX+Bev vs FOLFIRI+Bev]. Genomic DNA from blood samples was genotyped through the OncoArray, a custom array manufactured by Illumina. Candidate 14 SNPs in five ICD-related genes ( CALR, HMGB1, ANXA1, LRP1 and P2RX7) were tested for association with progression-free survival (PFS) and overall survival (OS), using Cox proportional hazards model. We tested treatment-by-SNP interactions in the following cohorts: combined TRIBE and MAVERICC (OHP-containing treatment vs non-OHP-containing treatment), and FIRE-3 (FOLFIRI+Cet vs FOLFIRI+Bev). An interaction p-value (i p) < 0.05 was considered significant. Results: Totally, 890 patients’ SNPs were available (FIRE-3: n = 236, TRIBE: n = 324, and MAVERICC: n = 330). In the combined TRIBE and MAVERICC cohorts [the reference of hazard ratio (HR) is non-OHP-containing treatment], a significant interaction was observed in ANXA1 rs1050305 (A/A: HR 0.96, Any G: HR 2.62, i p < 0.01), LRP1 rs1466535 (G/G: HR 1.39, Any A: HR 0.91, i p = 0.02), P2RX7 rs2230911 (C/C: HR 0.98, Any G: HR 1.76, i p = 0.03) and P2RX7 rs208294 (C/C: HR 1.82, Any T: HR 0.93, i p < 0.01) on OS. For PFS, that was observed in CALR rs110222 (G/G: HR 1.30, Any A: HR 0.87, i p = 0.02), HMGB1 rs1045411 (C/C: HR 0.85, Any T: HR 1.30, i p = 0.04) and HMGB1 rs1360485 (T/T: HR 0.81, Any C: HR 1.40, i p < 0.01). However, in the FIRE-3 cohort, no significant interactions were observed in any SNPs. Conclusions: Our results showed for the first time that SNPs in ICD-related genes may predict efficacy of OHP-containing treatment in mCRC. But the predictive values for Cet efficacy was not evident.