Vitamin C Might Have Clinical Benefit Against KRAS- and BRAF-mutated CRC
Key findings
- This was the first study of prospectively collected data that examined how dietary vitamin C intake after diagnosis of colorectal cancer (CRC) related to CRC-specific and all-cause mortality according to KRAS or BRAF mutation status
- Data on 2,096 patients with incident stage I to III CRC were drawn from the Nurses' Health Study (n=1,333) and the Health Professionals Follow-up Study (n=763)
- Higher total vitamin C intake after CRC diagnosis was associated with lower CRC-specific mortality in patients with a KRAS or BRAF mutation (adjusted HR, 0.74; P for trend <0.05) but not in those with both KRAS and BRAF wild-type
- There was a dose-response relationship between post-diagnosis vitamin C intake and both CRC-specific mortality and all-cause mortality
- The findings support previous laboratory data showing a benefit of vitamin C against KRAS/BRAF-mutant CRC and suggest the effect may extend to dietary vitamin C intake, but the optimal dose could not be determined from this analysis
About 50% of colorectal cancers (CRC) harbor an activating KRAS or BRAF mutation. In mice, high-dose vitamin C (4 g/kg intraperitoneal injection) has been shown to kill KRAS- and BRAF-mutant CRC cells through increased uptake of its metabolite dehydroascorbate, which depletes antioxidant levels and increases reactive oxygen species within the cells.
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Now, after integrating dietary and tumor molecular data from two large, prospective cohorts, Harvard researchers have demonstrated the benefit of vitamin C may extend to dietary intake by patients who have KRAS- or BRAF-mutated CRC. Their report appears in the British Journal of Cancer.
The authors are Shuji Ogino, MD, PhD, chief of the Program in Molecular Pathological Epidemiology in the Department of Pathology at Brigham and Women's Hospital and professor in the Department of Epidemiology at Harvard T.H. Chan School of Public Health, Mingyang Song, MBBS, ScD, a researcher in the Clinical and Translational Epidemiology Unit and Division of Gastroenterology at Massachusetts General Hospital and associate professor of Epidemiology and Nutrition at Harvard T.H. Chan School of Public Health, and colleagues.
Methods
The data sources for the analyses were:
- The Nurses' Health Study (NHS), which enrolled 121,701 women ages 30 to 55 in 1976
- The Health Professionals Follow-up Study (HPFS), which enrolled 51,529 men ages 40 to 75 in 1986
Participants in both studies completed questionnaires at enrollment and every two years to update information, including self-reports of newly diagnosed diseases.
Detailed data about diet were collected every four years, starting in 1980 for the NHS and 1986 for the HPFS, and those years were the baselines for this analysis. Total vitamin C intake was assessed by summing the estimated intakes from diet, vitamin C supplements, and multivitamins.
2,096 patients with incident stage I to III CRC were identified from baseline through June 1, 2016, for the NHS (n=1,333) and through January 31, 2016, for the HPFS (n=763). Physicians blinded to exposure data reviewed medical records to confirm the diagnosis of CRC and collect data on the tumor stage.
Vitamin C and Mortality
Total vitamin C intake after diagnosis was not associated with CRC-specific mortality or all-cause mortality, whether in the overall cohort, among individuals with both KRAS and BRAF wild-type, or among individuals with either mutant type.
Vitamin C and Mortality by Mutation Status
The association between post-diagnosis total vitamin C intake and CRC-specific mortality differed by KRAS or BRAF mutation status (P for interaction = 0.04). Per 400 mg/day increment in vitamin C intake:
- All 703 individuals with KRAS/BRAF data available—adjusted HR (aHR), 0.92 (P for trend = 0.39)
- 351 individuals without KRAS/BRAF mutation—aHR, 1.07 (P for trend = 0.52)
- 352 individuals with either KRAS or BRAF mutation—aHR, 0.74 (P for trend <0.05)
The association between all-cause mortality and post-diagnosis vitamin C did not differ significantly by KRAS/BRAF mutation.
Among patients with KRAS/BRAF mutation, those with the highest quartile of vitamin C showed lower CRC-specific and all-cause mortality than those whose intake was in quartiles 1 to 3 (P>0.05).
SLC2A1 Expression and KRAS/BRAF Mutations
Using The Cancer Genome Atlas (TCGA) database, the researchers obtained data on KRAS mutation status, BRAF mutation status, and SLC2A1 mRNA expression from 460 patients with stage I to III CRC. SLC2A1 is the primary gene responsible for vitamin C uptake.
Expression of SLC2A1 proved to be significantly higher in tumors with KRAS/BRAF mutations than those without (P=0.02), showing tumors with these mutations are enriched with dehydroascorbate.
Optimal Dose Unknown
Phase 1 and phase 2 clinical trials have found high-dose intravenous vitamin C (1.5 g/kg) is well tolerated in cancer patients. However, dietary intake may not provide the plasma concentrations achievable with intravenous administration.
This study did not provide data on higher doses, so further research is needed before recommendations can be made about using vitamin C to treat CRC with KRAS/BRAF mutations.
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