Couture, Félix

Abstract Background: Adhering to 2018 World Cancer Research Fund (WCRF)/American Institute for Cancer Research (AICR) Cancer Prevention Recommendations is reportedly associated with better survival among long-term colon cancer survivors (likely affected by immortal time bias). Thus, it is important to validate survival benefits by assessing adherence shortly after diagnosis, and further investigation is needed to examine its association with chemotherapy outcomes. Methods: Using an NCI-sponsored adjuvant chemotherapy trial conducted in patients with stage III colon cancer (CALGB/SWOG 80702; NCT01150045), we included 1,666 patients who returned valid Willett food frequency questionnaires (FFQ) at chemotherapy initiation and derived WCRF/AICR scores accordingly (higher score suggesting higher adherence). The primary outcome was disease-free survival (time from FFQ completion to recurrence or death), and secondary outcomes were reduced relative dose intensity (RDI; <85% suggesting worse completion) and severe toxicities (grade ≥3 for any chemotherapy-related toxicity). To estimate the associations of WCRF/AICR scores (quartiles) with survival and chemotherapy outcomes, we conducted multivariable Cox proportional hazards regression for disease-free survival and multivariable logistic regression for reduced RDI and severe toxicities. Results: Compared to those in the lowest quartile of the WCRF/AICR score, patients in the highest quartile had significantly better disease-free survival (hazard ratio: 0.75 [0.58, 0.98], Ptrend = 0.02) and lower risk of reduced RDI (odds ratio [OR]: 0.74 [0.54, 1.00], Ptrend = 0.03), but not for severe toxicities (OR: 1.24 [0.93, 1.67], Ptrend = 0.11). Conclusions: In patients with stage III colon cancer, higher adherence to WCRF/AICR recommendations was associated with better survival and chemotherapy completion, but not for severe toxicities. Funding: https://acknowledgments.alliancefound.org Citation Format: En Cheng, Chao Ma, Qian Shi, Anthony F. Shields, Peter T. Campbell, Ardaman P. Shergill, Katherine A. Guthrie, Felix Couture, Philip Kuebler, Pankaj Kumar, Benjamin Tan, Smitha S. Krishnamurthi, Kimmie Ng, Eileen M. O'Reilly, Justin C. Brown, Philip A. Philip, Jeffrey A. Meyerhardt. Associations of WCRF/AICR recommendations with survival and chemotherapy outcomes in colon cancer: CALGB/SWOG 80702 (Alliance) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5038.

163 Background: Being physically inactive is an independent predictor of poor outcomes in patients with stage III colon cancer. Whether physical activity can mitigate the oncologic risk of postoperative MRD is unknown. Methods: We concluded a post hoc analysis of a phase III trial evaluating celecoxib vs. placebo and 3 vs. 6 months of adjuvant chemotherapy in patients with resected stage III colon cancer. Self-reported physical activity was assessed in standardized measures of metabolic equivalent hours per week (MET-h/wk) at 2 timepoints: 1) midway through and 2) 6 months after completing adjuvant chemotherapy, modeled as a time-weighted average. MRD was determined via a clinically validated, tumor-informed circulating tumor DNA (ctDNA) assay (Signatera, Natera, Inc.). Disease-free survival (DFS) and overall survival (OS) were estimated using flexible parametric survival models. Results: Among 763 patients (median follow-up 6.0 years), 24% were highly active (≥18 MET-h/wk) and 32% were inactive (<3 MET-h/wk); 18% were ctDNA positive. Adjusting for covariates, DFS improved in patients who were ctDNA negative and moderately active (Ref: inactive; 3-17.9 MET-h/wk; HR=0.62, 95% CI [0.40-0.97]) or highly active (HR = 0.53 [0.30-0.94]). No benefit was seen among patients who were ctDNA positive (Ref: inactive; moderately active: HR = 1.20 [0.75-1.92]; highly active: HR=0.83 [0.45-1.54]). The interaction was not significant (Pint=0.269). Physical activity did not impact OS regardless of ctDNA status. The interaction of physical activity and adjuvant celecoxib use is shown in Table. Conclusions: Among patients who were ctDNA negative, physical activity was associated with improved DFS, and may demonstrate increased survival benefit alongside adjuvant celecoxib. The additive effects of both interventions were inconclusive among those who were ctDNA positive. Support: U10CA180821, U10CA180882, U24CA196171; https://acknowledgments.alliancefound.org; Natera, Pfizer; NCT01150045. Disease-free survival by physical activity level and celecoxib use, stratified by ctDNA status. 3-yr event # at risk Adjusted HR (95% CI) P-value Pint ctDNA Negative 0.258 Inactive + placebo 23 182 Ref Active + placebo 17 132 0.74 (0.43-1.28) 0.283 Inactive + celecoxib 23 167 0.92 (0.57-1.48) 0.720 Active + celecoxib 10 146 0.40 (0.22-0.79) 0.007 ctDNA Positive 0.221 Inactive + placebo 26 33 Ref Active + placebo 15 20 0.96 (0.50-1.84) 0.903 Inactive + celecoxib 34 54 0.62 (0.37-1.05) 0.076 Active + celecoxib 14 29 0.34 (0.18-0.64) 0.001 ctDNA, circulating tumor DNA; HR, hazard ratio; CI, confidence interval. Active = ≥9 MET-h/week, inactive = <9 MET-h/week. Celecoxib use defined by assignment in CALGB/SWOG 80702. Models adjusted by T and N stage, age, sex, race, assigned cycles of fluorouracil, leucovorin, and oxaliplatin, KRAS and BRAF status, BMI, and Western diet.

LBA3509 Background: Systemic inflammation has been implicated in colon cancer progression. We examined whether intake of a proinflammatory diet is associated with survival among patients (pts) with stage III colon cancer. Methods: This prospective cohort study was nested within a randomized phase III trial of adjuvant therapy in pts with stage III colon cancer who had undergone curative-intent resection. EDIP score – a validated tool to classify the inflammatory nature of diets – was derived as a cumulative exposure using data from food-frequency questionnaires completed within 6 weeks of randomization and 14-16 months (mo) after randomization. Cox proportional hazards regression was used to assess the associations of EDIP with disease-free survival (DFS) and overall survival (OS). Results: Of 1625 included pts, the mean (SD) age was 60.9 (10.5) years (yrs). Compared to pts in the lowest EDIP quintile, pts in the highest quintile (a more inflammatory diet) were younger (58.7 ± 10.8 vs 61.3 ± 9.5 yrs old) and more likely to be female (64.0% vs 48.9%) and have worse performance status (ECOG 1-2: 35.7% vs 19.4%). Pts in the highest quintile were less likely to be White (76.6% vs 92.0 %) and more likely to be Black (15.4% vs 3.7%). Baseline aspirin use, assigned chemotherapy (3 mo vs 6 mo), and assigned pharmacotherapy (celecoxib vs placebo) were not significantly different across EDIP quintiles. Compared with pts in the lowest EDIP quintile, pts in the highest quintile had significantly worse OS (multivariable hazard ratio [HR] 1.87, 95% confidence interval [CI] 1.26-2.77, P trend =0.01), but not DFS (HR 1.36, 95% CI 0.99-1.86, P trend =0.22). Diet and physical activity jointly influenced OS. Those with lower EDIP scores (quintiles 1-4, 80% of the study population) and higher physical activity (≥9 MET-h/wk) had the best OS (HR 0.37, 95% CI 0.25-0.53) compared with pts in the highest EDIP quintile (20% of the study population) and lower physical activity (<9 MET-h/wk) ( P interaction <0.001). The association between higher EDIP and OS was consistent when analyzed by celecoxib and placebo treatment arms ( P interaction 0.54). The relationship between EDIP and OS did not differ significantly according to aspirin use, with HR 1.60 (95% CI 0.71-3.60) among aspirin users and HR 2.01 (95% CI 1.27-3.16) among aspirin non-users ( P interaction 0.06). Conclusions: Our findings suggest that greater intake of a proinflammatory dietary pattern is associated with worse OS in pts with stage III colon cancer. Regular physical activity may attenuate the association, and further investigation of diet and physical activity intervention is warranted. Support: U10CA180821, U10CA180882, U24CA196171, U10CA180863, CCS 707213, UG1CA233234, U10CA180820, U10CA180868, U10CA180888; https://acknowledgments.alliancefound.org. Pfizer; ClinicalTrials.gov Identifier: NCT01150045.

3624 Background: Increasing chemotherapy completion and reducing chemotherapy adverse events (AE) are critical to improve survival after colon cancer diagnosis. Sex, as a biological variable, may impact chemotherapy treatment differently, and thus further investigation is needed to examine sex differences in chemotherapy completion and adverse events among patients with colon cancer. Methods: Among an NCI-sponsored trial conducted among patients with stage III colon cancer (CALGB/SWOG 80702), all patients received standard adjuvant chemotherapy FOLFOX (fluorouracil, leucovorin, and oxaliplatin). To signal chemotherapy completion, we utilized relative dose intensity (RDI) calculated as the ratio of the delivered dose intensity to planned dose intensity; and reduced RDI (RDI <85%) was considered as a clinically significant deviation from standard FOLFOX. From clinicians’ records of NCI’s Common Terminology Criteria for Adverse Events (CTCAE), we primarily focused on clinically significant AE such as neutrophils decrease, nausea, platelets decrease, hypertension, peripheral neuropathy, diarrhea, fatigue, gastritis, creatinine increase, gastric ulcer, myocardial ischemia, and cerebral ischemia; and severe AE was defined as the occurrence of any above AE with CTCAE grade ≥3. Using multivariable logistic regression that adjusted for body surface area (BSA) and other clinicopathological confounders, we estimated adjusted odds ratios (OR) for the associations of sex with reduced RDI and severe AE. Results: Of 2201 patients, mean (standard deviation [SD]) age was 60.9 (10.9) years, 1019 (46.3%) were female, 1750 (79.5%) were White, 172 (7.8%) were Hispanic, 964 (43.8%) experienced reduced RDI, and 1156 (52.5%) had severe adverse events. Compared to males, females were at significantly higher risks of experiencing reduced RDI (OR [95% CI]: 1.57 [1.27-1.93], P <0.001) and severe AE (OR [95% CI]: 1.73 [1.41-2.12], P <0.001). Conclusions: Our findings suggested females are more likely than men to experience reduced RDI and severe AE during colon cancer chemotherapy. Clinical Impact: In the era of precision medicine, sex (as a biological variable) should be considered in optimizing colon cancer chemotherapy to improve completion and reduce toxicities. Clinical trial information: NCT01150045 .

Observational studies have demonstrated that aspirin and/or PTSG2 inhibitor (e.g., celecoxib) use, before or after colon cancer (CC) diagnosis, is associated with a lower risk of recurrence. However, a randomized trial of adjuvant celecoxib therapy in stage III CC did not show improved survival compared to placebo treatment. We therefore hypothesized that immune microenvironment features may identify patient subgroups with stronger survival benefits from anti-inflammatory celecoxib treatment. Drawing from an NCI-Intergroup trial (Cancer and Leukemia Group B [now Alliance for Clinical Trials in Oncology]/SWOG 80702) for patients with stage III resected CC that compared 3 versus 6 months of adjuvant fluorouracil, leucovorin, and oxaliplatin ± 3 years of celecoxib, we conducted tissue-based tumor microenvironment profiling on 1,098 resected tumors using a custom 9-plex, T-cell multiplex immunofluorescence assay coupled with digital image analysis and supervised machine learning. The Kaplan-Meier method was used to describe disease-free survival, based on T cell density, and log-rank testing was performed. Cox proportional hazards models were used to examine unadjusted and adjusted associations between T cell density and disease-free survival (DFS). Two-sided P values ≤0.05 were considered statistically significant. We found that higher CD3+ T cell density was associated with longer DFS with an adjusted hazard ratio (HR) of 0.69 (95% confidence interval [CI] 0.52-0.91) for patients with densities in the highest tertile as compared the lowest tertile (P=0.01). T cell subset analysis showed that stromal regulatory T helper cells (HR 0.42 comparing highest to lowest tertile, CI 0.31-0.58, P&lt;0.001) and stromal memory cytotoxic T cells (HR 0.55 comparing highest to lowest tertile, CI 0.42-0.74, P&lt;0.001) were most strongly associated with longer DFS. Compared to the placebo group, adjuvant celecoxib use associated with improved DFS for patients with low but not high stromal CD3+ T cell density (adjusted HRs of 0.45 [CI 0.31-0.65] for lowest tertile and 1.13 [CI 0.73-1.74] for highest tertile; Pinteraction=0.01). This association was also seen when the analysis was restricted to microsatellite stable tumors (HR 0.50 [CI 0.32-0.80] for lowest density tertile and 1.50 [CI 0.87-2.59] for highest density tertile; Pinteraction=0.01). T cell subset analysis showed that DFS benefit for celecoxib use most strongly associated with stromal memory helper T cell density (HR 0.38 [CI 0.26-0.56] for lowest density tertile and 1.26 [CI 0.80-1.97] for highest density tertile; Pinteraction&lt;0.001). Together, these results show that while higher T cell infiltration is associated with improved DFS, lower T cell infiltration is associated with improved DFS for patients treated with celecoxib. This unexpected finding may inform immunomodulatory treatment strategies for CC. Citation Format: Yasutoshi Takashima, Chao Ma, Qian Shi, Andressa Dias Costa, Tyler Twombly, Juha P. Väyrynen, Melissa Zhao, Ardaman Shergill, Pankaj Kumar, Felix Couture, Philip Kuebler, Smitha Krishnamurthi, Benjamin Tan, Eileen M. O'Reilly, Anthony F. Shields, Shuji Ogino, Charles S. Fuchs, Jeffrey A. Meyerhardt, Jonathan A. Nowak. Prognostic and predictive role of T cell infiltration in stage III colon cancer (CC) treated with celecoxib: CALGB/SWOG 80702 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5858.

LBA14 Background: CALGB/SWOG 80702 previously showed that the addition of celecoxib to standard adjuvant chemotherapy with FOLFOX did not significantly improve disease-free survival (DFS) in patients with stage III colon cancer. Here, we evaluated the prognostic and predictive value of ctDNA in identifying a subpopulation of patients who may benefit from celecoxib. Methods: In the subset of patients with adequate biospecimens who participated in CALGB/SWOG 80702, a randomized phase III trial of 3 versus 6 months of adjuvant 5-FU, leucovorin, oxaliplatin (FOLFOX) +/- celecoxib, ctDNA assessment was performed using a clinically validated, tumor-informed 16-plex mPCR-NGS assay (Signatera(TM), Natera, Inc.) after surgery and before the start of adjuvant therapy (baseline). The Kaplan-Meier method was used to describe the distribution of survival time based on ctDNA positivity and log-rank testing was performed. Cox proportional hazards models were used to examine unadjusted associations between ctDNA positivity and disease-free (DFS) and overall survival (OS). Two-sided P values equal to or less than 0.05 were considered statistically significant, except for interaction P values (tested with a likelihood ratio). Results: In total, 1,011 of the 2,526 patients who participated in 80702 had ctDNA testing results from baseline; 189 were ctDNA positive (18.7%). ctDNA positivity associated with male sex, higher T stage, and N2 (versus N1) stage. ctDNA positivity was significantly associated with worse DFS (hazard ratio [HR] 6.52 [95% confident interval (CI) 5.09-8.34; p<0.0001] and OS (HR 6.28 [95% CI 4.63-8.51; p<0.0001]). Three-year DFS was 86.6% in ctDNA-negative cases and 36.8% in ctDNA-positive cases. Among patients who were ctDNA negative, celecoxib use was not significantly associated with worse DFS as compared to placebo (HR 0.75 [95% CI 0.54-1.05; p=0.095]) with a three-year DFS of 87.7% versus 85.5%, respectively. Among ctDNA-positive patients, celecoxib significantly improved DFS compared to placebo (HR 0.59 [95% CI 0.42-0.85; p=0.004]) with a three-year DFS of 44.1% versus 26.6% (P interaction = 0.25). Similar results were seen for overall survival with a hazard ratio of 0.86 (95% CI 0.56-1.33; p=0.49) for ctDNA negative cases and 0.63 (95% CI 0.41-0.96; p=0.028) for ctDNA-positive cases for celecoxib versus placebo (P interaction = 0.28). Conclusion: In a randomized phase III adjuvant therapy trial for stage III colon cancer, ctDNA was highly prognostic of DFS and OS. ctDNA positivity also appeared predictive of the benefit of adjuvant celecoxib for DFS and OS. These results suggest a potential role for ctDNA in determining which patients should consider celecoxib in addition to standard FOLFOX adjuvant therapy. Clinical trial information: NCT01150045 .

Abstract Background Inflammation and insufficient physical inactivity contribute to individual-level risk of disease recurrence and death in stage III colon cancer. The extent to which increased inflammatory risk can be offset by sufficient physical activity remains unknown. Methods This cohort study was nested within the Cancer and Leukemia Group B (now part of the Alliance for Clinical Trials in Oncology) and Southwest Oncology Group randomized trial. Inflammatory burden was quantified by high-sensitivity C-reactive protein, interleukin-6, and soluble tumor necrosis factor-α receptor 2 after recovery from tumor resection. Physical activity was measured during and after postoperative chemotherapy. The primary endpoint was disease-free survival. Results The 3-year disease-free survival rate was 88.4% among patients with low inflammation and sufficient physical activity (referent group for all comparisons), 84.9% with low inflammation and insufficient physical activity (absolute risk difference = −3.5 percentage points, 95% confidence interval [CI] = −11.3 to 4.3; P = .38), 78.0% with intermediate inflammation and insufficient physical activity (absolute risk difference = −10.4 percentage points, 95% CI = −17.4 to −3.3; P = .007), and 79.7% with high inflammation and insufficient physical activity (absolute risk difference = −8.7 percentage points, 95% CI = −15.7 to −1.6; P = .022). In contrast, the 3-year disease-free survival rate was 87.3% among patients with intermediate inflammation and sufficient physical activity (absolute risk difference = −1.1 percentage points, 95% CI = −7.5 to 5.3; P = .74) and 84.4% with high inflammation and sufficient physical activity (absolute risk difference = −4.0 percentage points, 95% CI = −12.3 to 4.3; P = .34). Conclusion In this observational study of stage III colon cancer patients, physical activity was associated with improved disease-free survival despite high inflammation. Patients with intermediate or high inflammation who were physically active had disease-free survival rates that were not statistically significantly different from those with low inflammation.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. Observational studies have associated aspirin or cyclooxygenase 2 (COX-2) inhibitor usage either before or after colorectal cancer diagnosis with lower risk of recurrence and suggest that PIK3CA mutational status is predictive of better response to COX-2 inhibition. To prospectively test whether adding the COX-2 inhibitor celecoxib to standard adjuvant chemotherapy reduces the risk of recurrence and improves survival, the National Cancer Institute sponsored the CALGB/SWOG 80702 trial (ClinicalTrials.gov identifier: NCT01150045 ) for patients with stage III resected colon cancer. Although the primary hypothesis for all patients did not show a statistically significant improvement in disease-free survival (DFS) with celecoxib, subgroup analysis by PIK3CA mutational status was a preplanned study. PIK3CA gain-of-function mutations were detected in 259 of 1,197 tumors with available whole-exome sequencing data. When stratified by PIK3CA status, patients with PIK3CA gain-of-function mutations treated with celecoxib exhibited improved DFS (adjusted hazard ratio [HR], 0.56 [95% CI, 0.33 to 0.96]) compared with PIK3CA wildtype patients (adjusted HR, 0.89 [95% CI, 0.70 to 1.14]), although the interaction test was nonsignificant ( Pinteraction = .13). Overall survival was similarly improved for patients with PIK3CA gain-of-function mutations (adjusted HR, 0.44 [95% CI, 0.22 to 0.85]) compared with PIK3CA wildtype patients (adjusted HR, 0.94 [95% CI, 0.68 to 1.30]; Pinteraction = .04). Although the test for heterogeneity in DFS did not reach statistical significance, the results suggest potential utility of PIK3CA to consider selective usage of COX-2 inhibitors in addition to standard treatment for stage III colon cancer.

AbstractBackgroundOne in three patients with stage III colon cancer will experience tumor recurrence. It is uncertain whether physical activity during and after postoperative chemotherapy for stage III colon cancer improves overall survival after tumor recurrence.MethodsA prospective cohort study nested within a randomized multicenter trial of patients initially diagnosed with stage III colon cancer who experienced tumor recurrence (N = 399) was conducted. Postoperative physical activity before tumor recurrence was measured. Physical activity energy expenditure was quantified via metabolic equivalent task hours per week (MET‐h/week). The primary end point was overall survival after tumor recurrence. Multivariable flexible parametric survival models estimated relative and absolute effects with two‐sided hypothesis tests.ResultsCompared with patients expending <3.0 MET‐h/week of physical activity (comparable to <1.0 h/week of brisk walking), patients with ≥18.0 MET‐h/week of physical activity (comparable to 6 h/week of brisk walking) had a 33% relative improvement in overall survival time after tumor recurrence (hazard ratio, 0.67; 95% CI, 0.42–0.96). The overall survival rate at 3 years after tumor recurrence was 61.3% (95% CI, 51.8%–69.2%) with <3.0 MET‐h/week of physical activity and 72.2% (95% CI, 63.1%–79.6%) with ≥18 MET‐h/week of physical activity (risk difference, 10.9 percentage points; 95% CI, 1.2–20.8 percentage points).ConclusionsHigher postoperative physical activity is associated with improved overall survival after tumor recurrence in patients initially diagnosed with stage III colon cancer. These data may be relevant to patients who, despite optimal postoperative medical therapy, have a high risk of tumor recurrence.

Abstract Purpose: To assess whether higher plasma 25-hydroxyvitamin D [25(OH)D] is associated with improved outcomes in colon cancer and whether circulating inflammatory cytokines mediate such association. Experimental Design: Plasma samples were collected from 1,437 patients with stage III colon cancer enrolled in a phase III randomized clinical trial (CALGB/SWOG 80702) from 2010 to 2015, who were followed until 2020. Cox regressions were used to examine associations between plasma 25(OH)D and disease-free survival (DFS), overall survival (OS), and time to recurrence (TTR). Mediation analysis was performed for circulating inflammatory biomarkers of C-reactive protein (CRP), IL6, and soluble TNF receptor 2 (sTNF-R2). Results: Vitamin D deficiency [25(OH)D &lt;12 ng/mL] was present in 13% of total patients at baseline and in 32% of Black patients. Compared with deficiency, nondeficient vitamin D status (≥12 ng/mL) was significantly associated with improved DFS, OS, and TTR (all Plog-rank&lt;0.05), with multivariable-adjusted HRs of 0.68 (95% confidence interval, 0.51–0.92) for DFS, 0.57 (0.40–0.80) for OS, and 0.71 (0.52–0.98) for TTR. A U-shaped dose–response pattern was observed for DFS and OS (both Pnonlinearity&lt;0.05). The proportion of the association with survival that was mediated by sTNF-R2 was 10.6% (Pmediation = 0.04) for DFS and 11.8% (Pmediation = 0.05) for OS, whereas CRP and IL6 were not shown to be mediators. Plasma 25(OH)D was not associated with the occurrence of ≥ grade 2 adverse events. Conclusions: Nondeficient vitamin D is associated with improved outcomes in patients with stage III colon cancer, largely independent of circulation inflammations. A randomized trial is warranted to elucidate whether adjuvant vitamin D supplementation improves patient outcomes.