• Clinical and Translational Epidemiology Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
• Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri; Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri; Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri.
• Department of Medical Oncology, Dana-Farber Cancer Institute, and Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
• Case Western Reserve University School of Medicine, Cleveland, Ohio.
• Clinical and Translational Epidemiology Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
• Clinical and Translational Epidemiology Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
• Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri.
• Information Management Services, Inc., Rockville, Maryland.
• Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
• Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; Broad Institute of MIT and Harvard, Cambridge, Massachusetts; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.

BACKGROUND & AIMS: Interval colorectal cancers (CRCs), cancers diagnosed after a screening/surveillance examination in which no cancer is detected, and before the date of next recommended examination, reflect an unprecedented challenge in CRC detection and prevention. To better understand this poorly characterized CRC variant, we examined the clinical and mutational characteristics of interval CRCs in comparison with screen detected CRCs.

METHODS: We included 1175 CRCs documented in the Prostate, Lung, Colorectal, and Ovarian (PLCO) cancer screening trial and 3661 CRCs in the Nurses' Health Study (NHS) and Health Professionals Follow-up Study (HPFS). Multivariable Cox models were performed to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of death risk. Whole exome sequencing was conducted in 147 PLCO cases and 796 NHS/HPFS cases.

RESULTS: A total of 619 deaths (312 CRC-specific) and 2404 deaths (1904 CRC-specific) were confirmed during follow-up of PLCO and NHS/HPFS, respectively. Compared with screen detected CRCs, interval CRCs had a multivariate-adjusted HR (95% CI) of 1.47 (1.21-1.78) for CRC-specific mortality and 1.27 (1.09-1.47) for overall mortality (meta-analysis combining all 3 cohorts). However, we did not observe significant differences in mutational features between interval and screen detected CRCs (false discovery rate adjusted P > .05).

CONCLUSION: Interval CRCs had a significantly increased risk of death compared with screen detected CRCs that were not explained by established clinical prognostic factors, including stage at diagnosis. The survival disadvantage of interval CRCs did not appear to be explained by differences in the genomic landscape of tumors characterized by whole exome sequencing.