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Marine omega-3 fatty acid intake and survival of stage III colon cancer according to tumor molecular markers in NCCTG Phase III trial N0147 (Alliance).

ABSTRACT: Marine omega-3 polyunsaturated fatty acids (MO3PUFAs) have anticancer properties and may improve colon cancer survival. However, it remains unknown whether the benefit differs by tumor molecular subtype. We examined data from a phase III randomized trial of FOLFOX or FOLFOX + cetuximab among 1,735 stage III colon cancer patients who completed a dietary questionnaire at enrollment. Multivariable hazard ratios and 95% confidence intervals (CIs) were calculated for the association between MO3PUFA and disease-free survival (DFS) and overall survival according to KRAS and BRAFV600E mutations and DNA mismatch repair (MMR) status. Higher MO3PUFA intake was associated with improved 3-year DFS for KRAS wild-type tumors (77% vs. 73%; HR: 0.84; 95% CI: 0.67-1.05) but not KRAS-mutant tumors (64% vs. 70%; HR: 1.30; 95% CI: 0.97-1.73; Pinteraction = 0.02). Similar heterogeneity was found by MMR (Pinteraction = 0.14): higher MO3PUFA was associated with better 3-year DFS for tumors with deficient MMR (72% vs. 67%) but not proficient MMR (72% vs. 72%). No heterogeneity was found by BRAFV600E mutation. Similar findings were obtained for overall survival. In conclusion, we found a suggestive beneficial association between higher MO3PUFA intake and improved survival among stage III colon cancer patients with wild-type KRAS and deficient MMR. Given the relatively small number of cases with tumor molecular assessments, further studies, preferably through pooled analyses of multiples cohorts, are needed to validate our findings.

SUBMITTER: Song M

PROVIDER: S-EPMC6525069 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Marine omega-3 fatty acid intake and survival of stage III colon cancer according to tumor molecular markers in NCCTG Phase III trial N0147 (Alliance).

Song Mingyang M Ou Fang-Shu FS Zemla Tyler J TJ Hull Mark A MA Shi Qian Q Limburg Paul J PJ Alberts Steven R SR Sinicrope Frank A FA Giovannucci Edward L EL Van Blarigan Erin L EL Meyerhardt Jeffrey A JA Chan Andrew T AT

International journal of cancer 20190128 2

Marine omega-3 polyunsaturated fatty acids (MO3PUFAs) have anticancer properties and may improve colon cancer survival. However, it remains unknown whether the benefit differs by tumor molecular subtype. We examined data from a phase III randomized trial of FOLFOX or FOLFOX + cetuximab among 1,735 stage III colon cancer patients who completed a dietary questionnaire at enrollment. Multivariable hazard ratios and 95% confidence intervals (CIs) were calculated for the association between MO3PUFA a ...[more]

PMID: 30623420

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Project description:BackgroundTumor-infiltrating lymphocytes (TILs), tumor budding, and micropapillary architecture may influence tumor growth and metastatic potential, thereby enhancing prognostic stratification. We analyzed these features and their relative contribution to overall outcome and in low (T1-3 N1) and high (T4 and/or N2) risk groups that are used to inform the duration of adjuvant chemotherapy in patients with resected stage III colon cancers.Patients and methodsAmong 1532 patients treated in a phase III adjuvant trial of FOLFOX-based therapy, intraepithelial TIL densities, tumor budding, and micropapillary features were analyzed and quantified in routine histopathological sections with light microscopy. Optimal cut-points were determined in association with disease-free survival (DFS) in training and validation sets. Associations or relative contributions of individual features or combined variables with DFS were determined using multivariable Cox regression models.ResultsTILs, tumor budding, and micropapillary features were shown to differ significantly by T, N risk groups and by mismatch repair (MMR) status. Low TILs, high budding, and their combined variable [hazard ratio = 2.07 (95% CI, 1.50% to 2.88%); Padj < 0.0001], but not micropapillary features, were each significantly associated with poorer DFS in a training data set and confirmed in a validation set. TILs were prognostic in proficient mismatch repair (pMMR) and deficient mismatch repair (dMMR) tumors; budding was prognostic only in pMMR tumors. The percentage relative contribution of budding/TILs to DFS was second only to nodal status overall, was second (24.4%) after KRAS in low-risk patients, and was the most important contributor (45.4%) in high-risk patients.ConclusionsTIL density and tumor budding were each validated as significant prognostic variables and their combined variable provided robust prognostic stratification by T, N risk groups, being the strongest predictor of DFS among high-risk stage III patients. CLINICALTRIALS.Gov identifierNCT00079274.

Project description:Previous studies have suggested the potential importance of three DPYD variants (DPYD*2A, D949V, and I560S) with increased 5-FU toxicity. Their individual associations, however, in 5-FU-based combination therapies, remain controversial and require further systematic study in a large patient population receiving comparable treatment regimens with uniform clinical data. We genotyped 2886 stage III colon cancer patients treated adjuvantly in a randomized phase III trial with FOLFOX or FOLFIRI, alone or combined with cetuximab, and tested the individual associations between functionally deleterious DPYD variants and toxicity. Logistic regressions were used to assess univariate and multivariable associations. All statistical tests were two-sided. In 2594 patients with complete adverse event (AE) data, the incidence of grade 3 or greater 5FU-AEs in DPYD*2A, I560S, and D949V carriers were 22/25 (88.0%), 2/4 (50.0%), and 22/27 (81.5%), respectively. Statistically significant associations were identified between grade 3 or greater 5FU-AEs and both DPYD*2A (odds ratio [OR] = 15.21, 95% confidence interval [CI] = 4.54 to 50.96, P < .001) and D949V (OR = 9.10, 95% CI = 3.43 to 24.10, P < .001) variants. Statistical significance remained after adjusting for multiple variables. The DPYD*2A variant statistically significantly associated with the specific AEs nausea/vomiting (P = .007) and neutropenia (P < .001), whereas D949V statistically significantly associated with dehydration (P = .02), diarrhea (P = .003), leukopenia (P = .002), neutropenia (P < .001), and thrombocytopenia (P < .001). Although two patients with I560S had grade≥3 5FU-AEs; a statistically significant association could not be demonstrated because of its low frequency (P = .48). In the largest study to date, statistically significant associations were found between DPYD variants (DPYD*2A and D949V) and increased incidence of grade 3 or greater 5FU-AEs in patients treated with adjuvant 5-FU-based combination chemotherapy.

Dataset Information

Marine omega-3 fatty acid intake and survival of stage III colon cancer according to tumor molecular markers in NCCTG Phase III trial N0147 (Alliance).

Publications

Marine omega-3 fatty acid intake and survival of stage III colon cancer according to tumor molecular markers in NCCTG Phase III trial N0147 (Alliance).

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