Citations

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.

Abstract Background Completing adjuvant chemotherapy and reducing toxicities are critical for maximizing survival after a colon cancer diagnosis. Sex, as a biological variable, may affect colon cancer chemotherapy completion, toxicities, and survival differently. Methods From a National Cancer Institute–sponsored trial conducted among patients with stage III colon cancer (Cancer and Leukemia Group B (Alliance)/Southwest Oncology Group 80702), we included 2201 patients receiving the standard adjuvant chemotherapy regimen of fluorouracil, leucovorin, and oxaliplatin. We calculated relative dose intensity to indicate chemotherapy completion and considered reduced relative dose intensity (values &lt;85%) as a clinically significant deviation from standard fluorouracil, leucovorin, and oxaliplatin. Using National Cancer Institute’s Common Terminology Criteria for Adverse Events, we defined severe adverse events (grade ≥3) as the occurrence of any following event, including neutrophil count decrease, nausea, platelet count decrease, hypertension, peripheral neuropathy, diarrhea, fatigue, gastritis, creatinine level increase, gastric ulcer, myocardial ischemia, and cerebral ischemia. The primary survival outcome was disease-free survival (time from enrollment to colon cancer recurrence or death from any cause), and secondary survival outcomes were recurrence-free and overall survival. Results Compared with men, women were at statistically significantly higher risks of experiencing reduced relative dose intensity (adjusted odds ratio = 1.59, 95% CI = 1.29 to 1.96; P &lt; .001) and severe advance events (adjusted odds ratio = 1.72, 95% CI = 1.41 to 2.11; P &lt; .001). Yet, women had statistically significantly better disease-free survival (adjusted hazard ratio = 0.72, 95% CI = 0.59 to 0.87; P &lt; .001) as well as better recurrence-free and overall survival. Conclusions Our findings suggested that women with colon cancer are more likely to have worse chemotherapy completion rates and more severe adverse events, but they have better survival. Sex as a biological variable warrants further consideration in chemotherapy administration and survivorship management after colon cancer diagnosis.

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 .

Abstract Pulmonary large cell neuroendocrine carcinoma (LCNEC) is a rare, aggressive lung tumor marked by significant molecular heterogeneity. In a study of 590 patients across two independent cohorts, we observed comparable overall survival across treatment regimens (chemotherapy, chemoimmunotherapy, immunotherapy) without unexpected adverse events. Genomic analysis identified distinct NSCLC-like (KEAP1, KRAS, STK11 mutations) and SCLC-like (RB1, TP53 mutations) LCNEC subtypes, with 80% aligning with SCLC transcriptional profiles. Serial sampling revealed stable mutational but shifting transcriptomic landscapes over time. NSCLC-like LCNECs showed elevated FGL-1 (a LAG-3 ligand) and SPINK1 expression, while SCLC-like subtypes expressed higher levels of DLL3. Immunofluorescence confirmed FGL-1 in NSCLC-like LCNECs, and H&E slide analyses indicated fewer tumor-infiltrating lymphocytes in LCNECs versus other lung cancers. These findings highlight LCNEC’s distinct immunogenomic profile, supporting future investigations into LAG-3, SPINK1, and DLL3-targeted therapies.

AbstractBackgroundColon cancer patients have inferior overall survival than a matched general population (MGP). It is unknown if physical activity is associated with a reduction in this survival disparity.MethodsData were analyzed from two National Cancer Institute–sponsored postoperative treatment trials in stage III colon cancer, Cancer and Leukemia Group B (CALGB) 89803 and 80702, with 2876 patients who self‐reported physical activity. Physical activity was converted to metabolic equivalents (MET‐hours/week). The MGP was derived from the National Center for Health Statistics and matched on age, sex, and year.ResultsIn CALGB 89803, among patients who were alive at 3 years, those with <3.0 and ≥18.0 MET‐hours/week had subsequent 3‐year overall survival rates that were −17.1% (95% confidence interval [CI], −22.4 to −11.8) and −3.5% (95% CI, −7.7 to 0.3) lower than MGP, respectively. In CALGB 80702, among patients who were alive at 3 years, those with <3.0 and ≥18.0 MET‐hours/week had subsequent 3‐year overall survival rates that were −10.8% (95% CI, −15.4 to −6.9) and −4.4% (95% CI, −7.6 to −1.6) lower than MGP, respectively. In pooled analyses, among patients who were alive and did not have tumor recurrence by year 3 (n = 1908), those with <3.0 and ≥18.0 MET‐hours/week had subsequent 3‐year overall survival rates that were −3.1% (95% CI, −6.2 to −0.3) lower and 2.9% (95% CI, 1.5–4.2) higher than MGP, respectively.ConclusionsPhysical activity is associated with an attenuation of the survival disparity between patients with stage III colon cancer participating in clinical trials and MGP. Colon cancer survivors who are physically active may achieve survival that approximates the MGP.

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.

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 Obesity is a chronic, relapsing, progressive disease of excess adiposity that increases the risk of developing at least 13 types of cancer. This report provides a concise review of the current state of the science regarding metabolic and bariatric surgery and obesity pharmacotherapy related to cancer risk. Meta-analyses of cohort studies report that metabolic and bariatric surgery is independently associated with a lower risk of incident cancer than nonsurgical obesity care. Less is known regarding the cancer-preventive effects of obesity pharmacotherapy. The recent approval and promising pipeline of obesity drugs will provide the opportunity to understand the potential for obesity therapy to emerge as an evidence-based cancer prevention strategy. There are myriad research opportunities to advance our understanding of how metabolic and bariatric surgery and obesity pharmacotherapy may be used for cancer prevention.

ImportanceThe association of chronic inflammation with colorectal cancer recurrence and death is not well understood, and data from large well-designed prospective cohorts are limited.ObjectiveTo assess the associations of inflammatory biomarkers with survival among patients with stage III colon cancer.Design, Setting, and ParticipantsThis cohort study was derived from a National Cancer Institute–sponsored adjuvant chemotherapy trial Cancer and Leukemia Group B/Southwest Oncology Group 80702 (CALGB/SWOG 80702) conducted between June 22, 2010, and November 20, 2015, with follow-up ending on August 10, 2020. A total of 1494 patients with plasma samples available for inflammatory biomarker assays were included. Data were analyzed from July 29, 2021, to February 27, 2022.ExposuresPlasma inflammatory biomarkers (interleukin 6 [IL-6], soluble tumor necrosis factor α receptor 2 [sTNF-αR2], and high-sensitivity C-reactive protein [hsCRP]; quintiles) that were assayed 3 to 8 weeks after surgery but before chemotherapy randomization.Main Outcomes and MeasuresThe primary outcome was disease-free survival, defined as time from randomization to colon cancer recurrence or death from any cause. Secondary outcomes were recurrence-free survival and overall survival. Hazard ratios for the associations of inflammatory biomarkers and survival were estimated via Cox proportional hazards regression.ResultsOf 1494 patients (median follow-up, 5.9 years [IQR, 4.7-6.1 years]), the median age was 61.3 years (IQR, 54.0-68.8 years), 828 (55.4%) were male, and 327 recurrences, 244 deaths, and 387 events for disease-free survival were observed. Plasma samples were collected at a median of 6.9 weeks (IQR, 5.6-8.1 weeks) after surgery. The median plasma concentration was 3.8 pg/mL (IQR, 2.3-6.2 pg/mL) for IL-6, 2.9 × 103pg/mL (IQR, 2.3-3.6 × 103pg/mL) for sTNF-αR2, and 2.6 mg/L (IQR, 1.2-5.6 mg/L) for hsCRP. Compared with patients in the lowest quintile of inflammation, patients in the highest quintile of inflammation had a significantly increased risk of recurrence or death (adjusted hazard ratios for IL-6: 1.52 [95% CI, 1.07-2.14];P = .01 for trend; for sTNF-αR2: 1.77 [95% CI, 1.23-2.55];P &amp;lt; .001 for trend; and for hsCRP: 1.65 [95% CI, 1.17-2.34];P = .006 for trend). Additionally, a significant interaction was not observed between inflammatory biomarkers and celecoxib intervention for disease-free survival. Similar results were observed for recurrence-free survival and overall survival.Conclusions and RelevanceThis cohort study found that higher inflammation after diagnosis was significantly associated with worse survival outcomes among patients with stage III colon cancer. This finding warrants further investigation to evaluate whether anti-inflammatory interventions may improve colon cancer outcomes.Trial RegistrationClinicalTrials.gov Identifier:NCT01150045