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.
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.
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.
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.
The authors.
This manuscript was partly supported by the National Cancer Institute (grant number P30CA014089), the Gloria Borges WunderGlo Foundation-The Wunder Project, the Dhont Family Foundation, the San Pedro Peninsula Cancer Guild, the Daniel Butler Research Fund, the Call to Cure Research Fund, and the Fong Research Project.
F. Loupakis: Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Amgen; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Bayer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Sanofi; Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Research grant / Funding (institution), Travel / Accommodation / Expenses: Merck Serono. S. Stintzing: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Amgen; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Bayer; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Lilly; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Merck KGaA; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Sanofi; Honoraria (self), Travel / Accommodation / Expenses: Sirtex Medical; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy, Travel / Accommodation / Expenses: Takeda. F. Battaglin: Travel / Accommodation / Expenses: Amgen; Travel / Accommodation / Expenses: Bayer. M.D. Berger: Travel / Accommodation / Expenses: Astellas Pharma; Research grant / Funding (institution): Merck KGaA. C. Cremolini: Honoraria (self): Amgen; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Roche; Advisory / Consultancy: Lilly; Research grant / Funding (self), Research grant / Funding (institution): Merck. A. Falcone: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Amgen; Honoraria (self), Advisory / Consultancy: Lilly; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Merck; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Servier; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Bayer; Advisory / Consultancy: Bristol-Myers Squibb; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Sanofi. V. Heinemann: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Amgen; Honoraria (self), Advisory / Consultancy: Baxalta; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Celgene; Honoraria (self): Lilly; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Merck; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Honoraria (self), Advisory / Consultancy: Sanofi; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: SERVIER; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Sirtex Medical; Honoraria (self): Taiho Pharmaceutical; Advisory / Consultancy, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Advisory / Consultancy: Halozyme; Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Research grant / Funding (institution): Shire. H.J. Lenz: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Bayer; Honoraria (self): Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Merck Serono; Advisory / Consultancy: Pfizer; Travel / Accommodation / Expenses: CARIS. All other authors have declared no conflicts of interest.