Association of obesity with DNA mismatch repair status and clinical outcome in patients with stage II or III colon carcinoma participating in NCCTG and NSABP adjuvant chemotherapy trials

Abstract

Purpose: Although the importance of obesity in colon cancer risk and outcome is recognized, the association of body mass index (BMI) with DNA mismatch repair (MMR) status is unknown.

Patients and methods: BMI (kg/m(2)) was determined in patients with TNM stage II or III colon carcinomas (n = 2,693) who participated in randomized trials of adjuvant chemotherapy. The association of BMI with MMR status and survival was analyzed by logistic regression and Cox models, respectively.

Results: Overall, 427 (16%) tumors showed deficient MMR (dMMR), and 630 patients (23%) were obese (BMI ≥ 30 kg/m(2)). Obesity was significantly associated with younger age (P = .021), distal tumor site (P = .012), and a lower rate of dMMR tumors (10% v 17%; P < .001) compared with normal weight. Obesity remained associated with lower rates of dMMR (odds ratio, 0.57; 95% CI, 0.41 to 0.79; P < .001) after adjusting for tumor site, stage, sex, and age. Among obese patients, rates of dMMR were lower in men compared with women (8% v 13%; P = .041). Obesity was associated with higher recurrence rates (P = .0034) and independently predicted worse disease-free survival (DFS; hazard ratio [HR], 1.37; 95% CI, 1.14 to 1.64; P = .0010) and overall survival (OS), whereas dMMR predicted better DFS (HR, 0.59; 95% CI, 0.47 to 0.74; P < .001) and OS. The favorable prognosis of dMMR was maintained in obese patients.

Conclusion: Colon cancers from obese patients are less likely to show dMMR, suggesting obesity-related differences in the pathogenesis of colon cancer. Although obesity was independently associated with adverse outcome, the favorable prognostic impact of dMMR was maintained among obese patients.

Fig 1.

Percentage of resected colon carcinomas (n = 2,693) showing deficient DNA mismatch repair (dMMR; n = 427) in patients treated in randomized trials of fluorouracil-based adjuvant chemotherapy. Data are shown for (A) percentage of dMMR tumors in normal-weight (153 of 879; 17%) and obese (65 of 630; 10%) patients and (B) stratified by sex within these body mass index categories.

Fig 2.

Prognostic impact of obesity versus normal weight status on (A) overall survival and (B) disease-free survival rates in patients with stage II and III colon carcinoma who participated in fluorouracil-based adjuvant chemotherapy trials. HR, hazard ratio.

Fig 3.

Prognostic impact of deficient mismatch repair (dMMR) versus proficient MMR (pMMR) status for overall survival in (A) normal-weight and (B) obese patients with stage II and III colon cancers. HR, hazard ratio.