Genetic variants in the one-carbon metabolism pathway to predict outcome in patients with metastatic colorectal cancer (mCRC): Data from TRIBE and FIRE-3 phase III trials

Abstract

Background: One‐carbon metabolism (1CM) comprises the folate and the methionine cycles and is involved in nucleotide synthesis and methylation. 1CM is known to be crucial in CRC development and progression. However, the impact of its genetic variants on prognosis in mCRC patients has not been clarified yet. We hypothesized that single nucleotide polymorphisms (SNPs) in genes related to the 1CM pathway may predict first‐line treatment outcomes in mCRC patients. Methods: Genomic DNA from blood samples of patients enrolled in two independent randomized phase III trials, TRIBE and FIRE‐3, was genotyped through the OncoArray, a custom array manufactured by Illumina, including approximately 530K SNP markers. The impact on outcome of SNPs in six genes of the 1CM pathway (MTHFR, MTR, MTRR, MAT2A, SHMT, TYMS) was analyzed. Results: A total of 451 patients were included. TRIBE FOLFIRI/bevacizumab (bev) arm served as discovery cohort (N=215, mPFS/OS: 9.7/26.2 months), FIRE‐3 FOLFIRI/ bev arm as validation (N=107, mPFS/OS: 11.5/31.4 months) and FOLFIRI/cetuximab arm as control (N=129, mPFS/OS: 12.8/49.8 months). In the discovery cohort, the overall population carrying the SHMT rs1979277 A/A variant showed a shorter median PFS (8.1 vs 10.3 months) compared to patients with any G alleles both in univariate (HR 2.13; 95%CI, 1.19‐3.79; P=0.007) and in multivariable analysis (HR 2.03; 95%CI, 1.10‐3.73; P=0.023). Additionally, A/A carrier showed a shorter median OS (18.0 vs 27.9 months) both in univariate (HR 1.74; 95%CI, 1.00‐3.01; P=0.045) and in multivariable analysis (HR 2.14; 95%CI, 1.17‐3.90; P=0.013). These findings were validated in overall patients in FIRE‐3 bev cohort in median OS (24.9 vs 36 months) both in univariate (HR 2.18; 95%CI, 0.96‐4.96; P=0.049) and in multivariable analysis (HR 3.61; 95%CI, 1.47‐8.86; P=0.005). No significant association was observed in the control arm. Conclusions: Our results suggest for the first time that SNPs in the SHMT gene may have a prognostic and predictive value in mCRC patients. These findings may provide novel perspectives on the role of 1CM signaling in CRC and possibly contribute to open novel therapeutic options.