Does Age at Diagnosis Impact Clinical and Molecular Features of Colorectal Cancer?

Colorectal cancers diagnosed in early adulthood are genetically and clinically distinct, and potentially more aggressive, than colorectal tumors diagnosed at older ages, according to the results of a large analysis of four patient cohorts. The findings were published in the journal Cancer.

Among patients younger than 50 years old, colorectal tumors harbor different genetic mutations and histologic features than those seen in older patients, including synchronous metastases, microsatellite instability, and fewer BRAF V600 mutations, the researchers reported.

“Both BRAF V600 mutations and microsatellite instability are important molecular alterations in colon cancer because they are both things that we can target with specific treatments, and our study helps highlight which groups of patients may be more likely to have these targetable alterations,” said senior study coauthor Jonathan M. Loree, MD, of BC Cancer in Vancouver, British Columbia, Canada.

Patients younger than 30 years at the time of diagnosis had even more distinct molecular and histologic profiles, including a higher frequency of CTNNB1 mutations, the team found.

“Specific to patients younger than 30 years of age, we noted lower rates of APC mutations and an increased prevalence of signet-ring histology in comparison to other patients age 30–50,” Loree told Cancer Network.

“These are actually both findings that are associated with a poor prognosis. APC mutations have previously been shown to be associated with a better outcome, and similarly, signet-ring histology tends to be a more aggressive histologic feature. As such, our findings suggest that patients aged 18–29 might have more aggressive disease biologies than those aged 30 to 50,” said Loree.

A higher prevalence of CTNNB1 mutations in young patients has also been described for other cancers, including endometrial cancer and pediatric medulloblastoma, Loree noted.

“Taking this into context with the differences in APC and MAPK pathway mutations, both of which are key hallmarks of colon cancer development, suggests that cancers which develop in young patients may have very different pathogenesis than cancers which develop in the rest of the population,” Loree said.

The study was a “timely” one, commented Valentine N. Nfonsam, MD, MS, FACS, associate professor in the Department of Surgery, Division of General Surgery, Section of Surgical Oncology at the University of Arizona College of Medicine in Tucson, Arizona.

“The authors did a great job in the molecular characterization of the early-onset colorectal cancer and established a clear uniqueness of the molecular features seen in young patients with colorectal cancer, especially in the MAPK and WNT pathways,” Nfonsam said. “The findings in this study accentuate those from previous studies which showed that early-onset colorectal cancers presented at a more advanced stage and had more aggressive molecular features, including mucinous and signet-ring morphology.”

The study also bolstered earlier evidence of racial disparities in early-onset colorectal cancer incidence: a greater proportion of patients younger than 30 years were Hispanic (P = .0015).

That came as a surprise, Loree said.

“According to the 2018 American Cancer Society statistics, this overrepresentation was not seen when you look at all age groups together,” he noted.

There were relatively few African Americans represented in the study, particularly in the analyzed University of Texas MD Anderson Cancer Center (MDACC) patient cohort, which represented a large proportion of the study cohorts, Nfonsam cautioned.

“The MDACC cohort used for this particular study had very few African Americans and more Hispanic patients,” noted Nfonsam, whose team separately reported on ethnic disparities in early- and late-onset colorectal cancer last year. Their analysis of the National Cancer Institute’s Surveillance, Epidemiology, and End Results database found an overall decrease in late-onset colorectal cancer rates overall among whites, but increasing incidence rates in early-onset cases among whites, and both early- and late-onset colorectal cancer among Hispanics.

The higher incidence of early-onset colorectal cancer in Hispanics might be attributed to increasing obesity rates, socioeconomic status and inadequate access to quality healthcare, cultural factors, or a lack of “proper awareness and education” about screening and diagnosis, Nfonsam speculated.

“I think the biggest limitation of the study is the sample size, which shrinks even more when subgroup analysis is performed,” Nfonsam said. “Overall, this is a well-done study that seeks to answer very important clinical and molecular questions on early-onset colorectal cancer, especially with the current increasing incidence. It reinforces the expediency of implementing the new and more robust screening guidelines proposed by the American Cancer Society that take into consideration the unique clinical and molecular features of early-onset colorectal cancer.”

The study team is now investigating treatment-outcome associations with identified molecular differences in early-onset colorectal cancer, and is exploring whether the findings can be used to better target and personalize colorectal cancer treatment.