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Mortality Risk Significantly Greater With Interval CRC Than Screen-detected CRC

Key findings

  • This study compared clinical and mutational characteristics of interval colorectal cancer (CRC) and screen-detected CRCs within the Prostate, Lung, Colorectal, and Ovarian cancer screening trial of flexible sigmoidoscopy, and two other studies
  • Individuals with interval CRCs had a significantly increased risk of death compared to those with screen-detected CRCs (CRC-specific mortality, HR=1.47); overall mortality, HR=1.27, after adjusting for established clinical prognostic factors
  • However, survival disadvantage of interval CRCs did not appear to be explained by differences in the genomic landscape of tumors characterized by whole exome sequencing
  • More tailored colonoscopic screening/surveillance strategies are needed, and more research is warranted to determine whether and how interval cancers exhibit a more aggressive biological profile

Interval colorectal cancer (CRC)—diagnosed after a screening or surveillance exam in which no cancer is detected, and before the date of the next recommended exam—represents 5% to 6% of all CRC cases in the U.S. Some interval CRCs presumably arise from lesions overlooked on endoscopy. Still, some may differ biologically from typical CRCs.

Massachusetts General Hospital researchers report in Gastroenterology that they found no genetic differences between interval CRCs and screen-detected CRCs. However, individuals with interval cancers were at significantly higher risk of death than those with screen-detected cancers.

The authors are Keming Yang, MD, PhD, a postdoc research fellow in the Clinical and Translational Epidemiology Unit of the Department of Medicine at Massachusetts General Hospital, Andrew T. Chan, MD, MPH, chief of the Unit, vice chief for clinical research in the Division of Gastroenterology, director of Cancer Epidemiology at the Mass General Cancer Center, and Daniel K. Podolsky professor of Medicine at Harvard Medical School, and colleagues.


Three prospective cohorts served as data sources:

  • The multicenter, randomized Prostate, Lung, Colorectal, and Ovarian (PLCO) trial of cancer screening with flexible sigmoidoscopy (FS), which enrolled 154,900 men and women ages 55 to 74 between 1993 and 2001 (reports of CRCs were collected from 1993 to 2014)
  • The Nurses' Health Study (NHS), which enrolled 121,700 female registered nurses ages 30 to 55 years in 1976 (reports of CRCs were collected from 1984 to 2014)
  • The Health Professionals Follow-up Study (HPFS), which enrolled 51,529 male health professionals ages 40 to 75 in 1986 (reports of CRCs were collected from 1984 to 2014)

Incidence of CRC

Screen-detected CRCs were defined as those diagnosed within 12 months of a positive FS or colonoscopy screening. Interval CRCs were those appearing within 48 months in a segment of the colon that had been previously endoscopically screened.

The study team documented:

  • 1,175 CRCs in the PLCO trial (246 screen-detected, 182 interval, and 747 others)
  • 3,661 CRCs in NHS/HPFS (494 screen-detected, 514 interval, and 2,653 others)

Highlighting the potentially more rapid and aggressive behavior of interval CRCs, a higher percentage of them were diagnosed at stage IV:

  • PLCO—17% of interval CRCs were stage IV vs. 4% of screen-detected CRCs
  • NHS/HPFS—13% vs. 7%

Survival and Interval CRC

In multivariable analyses, the risk of death was consistently higher for individuals with interval CRCs in comparison to screen-detected CRCs:

  • CRC-specific mortality—HR, 1.57 in PLCO, 1.45 in NHS/HPFS, and 1.47 when combined through meta-analysis
  • Overall mortality—HR, 1.38 in PLCO, 1.24 in NHS/HPFS, and 1.27 when combined

When analyses were confined to patients with stage IV CRCs:

  • CRC-specific mortality—HR, 2.08 in meta-analysis
  • Overall mortality—HR, 2.06 in meta-analysis

Whole-Exome Sequencing

Thinking that the increased mortality in interval CRC might be associated with specific genetic alterations, the researchers performed whole-exome sequencing on pairs of tumor tissue and adjacent normal tissue (147 pairs from PLCO, 796 from NHS/HPFS).

They found no significant differences between interval CRCs and screen-detected CRCs concerning mutational signature.

Indications for Future Work

The survival discrepancy in this study was not explained by established clinical prognostic factors, either, as the multivariable analyses adjusted for age at diagnosis, year of diagnosis, sex, family history of CRC, tumor location, grade, and stage.

There is a need to develop more tailored colonoscopic screening/surveillance strategies, and more research is warranted to determine whether and how interval cancers exhibit a more aggressive biological profile.

greater risk of CRC-specific mortality for interval CRC than screen-detected CRC

greater risk of overall mortality for interval CRC than screen-detected CRC

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