Feliciano, Elizabeth M. Cespedes

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 < .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

Abstract Chronic inflammation is a well-established carcinogenic pathway for colorectal cancer (CRC), but the role of inflammation in CRC prognosis is not well understood. Since cytokines are central in extensive biological networks to regulate inflammation, it is of great importance to investigate inflammatory cytokines and CRC survival. Among an NCI-sponsored adjuvant chemotherapy trial for patients with stage III colon cancer conducted between 2010 and 2015 (CALGB/SWOG 80702), we collected serum samples from 1,498 participants at a median of 1.6 months (interquartile [IQR]: 1.3-1.9 months) after surgery. IL-6, TNFR2, and hsCRP were assayed as biomarkers of chronic inflammation and were categorized into quintiles. The primary outcome was disease-free survival, defined as time from randomization to recurrence or death from any cause. Secondary outcomes included overall survival and time to recurrence. We estimated the associations of inflammatory biomarkers with survival using multivariable Cox proportional hazards regression. Of 1,498 participants (median follow-up: 5.9 years), mean age was 61.3 years, 82.2% were White, 55.5% were male, and 387 experienced recurrence or death. Medians (IQRs) of biomarkers were 2.6mg/L (1.2-5.6mg/L) for IL-6, 2.9×103pg/mL (2.3-3.6×103pg/mL) for TNFR2, and 2.6mg/L (1.2-5.6mg/L) for hsCRP. Compared to the lowest quintile (Q1), the highest quintile (Q5) in inflammatory biomarkers was significantly associated with worse disease-free survival (hazard ratios were 1.52 [95% CI, 1.08-2.15] for IL-6, 1.76 [95% CI, 1.22-2.54] for TNFR2, and 1.66 [95% CI, 1.17-2.35] for hsCRP). Similar patterns were observed for overall survival and time to recurrence. Our findings suggest that higher levels of inflammation after diagnosis were significantly associated with worse survival among those with stage III colon cancer, and reducing inflammation may be considered as a potential intervention to improve CRC survival. ‬‬ Associations of Inflammatory Biomarkers with Survival after Adjustment for Clinicopathologic Factors Q1 Q2 Q3 Q4 Q5 P for Trend Disease-free survival IL-6 1.00 1.14 (0.80-1.62) 1.37 (0.97-1.94) 1.44 (1.02-2.03) 1.52 (1.08-2.15) 0.02 TNFR2 1.00 1.21 (0.84-1.74) 1.43 (0.99-2.05) 1.56 (1.09-2.25) 1.76 (1.22-2.54) 0.002 hsCRP 1.00 1.34 (0.95-1.90) 1.62 (1.15-2.29) 1.26 (0.88-1.80) 1.66 (1.17-2.35) 0.04 Overall survival IL-6 1.00 1.44 (0.91-2.29) 1.56 (0.98-2.48) 1.48 (0.93-2.34) 1.68 (1.07-2.65) 0.09 TNFR2 1.00 1.57 (0.94-2.63) 1.88 (1.13-3.13) 1.92 (1.15-3.20) 2.31 (1.39-3.84) 0.003 hsCRP 1.00 1.27 (0.81-2.00) 1.72 (1.11-2.65) 1.22 (0.77-1.92) 1.73 (1.12-2.69) 0.06 Time to recurrence IL-6 1.00 1.34 (0.92-1.95) 1.48 (1.01-2.16) 1.55 (1.06-2.27) 1.54 (1.05-2.26) 0.07 TNFR2 1.00 1.14 (0.78-1.67) 1.28 (0.87-1.87) 1.48 (1.01-2.16) 1.54 (1.04-2.27) 0.02 hsCRP 1.00 1.27 (0.87-1.83) 1.64 (1.14-2.36) 1.21 (0.82-1.77) 1.55 (1.07-2.26) 0.12 Citation Format: En Cheng, Shi Qian, Anthony F. Shields, Elizabeth M. Cespedes Feliciano, Andrew B. Nixon, Ardaman P. Shergill, Katherine A. Guthrie, Felix Couture, Philip Kuebler, Pankaj Kumar, Dequincy Lewis, Benjamin Tan, Eileen M. O'Reilly, Justin C. Brown, Philip A. Philip, Bette J. Caan, Jeffrey A. Meyerhardt. Associations of inflammatory biomarkers with survival among patients with stage III colon cancer (CALGB/SWOG 80702 [Alliance]) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 682.