Are Early-Onset Colorectal Cancers More Aggressive?

Early-onset colorectal cancer (EO-CRC) is not biologically different from, or more aggressive than, average-onset CRC (AO-CRC), according to a comparative analysis.

“EO-CRCs are more commonly left-sided and present with rectal bleeding and abdominal pain but are otherwise clinically and genomically indistinguishable from AO-CRCs,” wrote Andrea Cercek, MD, of Memorial Sloan Kettering Cancer Center in New York City, and colleagues in the Journal of the National Cancer Institute.

More aggressive treatment based on age is not necessary or effective, they added.

The authors noted that obesity, diabetes, and a Western diet have been established as risk factors in older individuals, yet are not definitively associated with the increasing incidence of EO-CRC. However, they suggested that external or environmental factors “are likely to be driving earlier CRC development, and further investigations, using appropriately matched control populations, are necessary.”

Cercek and team compared clinical, somatic, and germline characteristics of 687 AO-CRC patients (ages 50 and older) with 759 EO-CRC patients (ages 35 to 49), all of whom were treated during the same time frame (2014-2019) at Memorial Sloan Kettering. The EO-CRC cohort was further stratified by age at diagnosis (151 at ≤35 years, and 608 at 36-49 years).

Rectal bleeding was more common in the early-onset subgroups (≤35 years: 41.1%, 36-49 years: 41.0%) compared with the average-onset cohort (25.9%), as was abdominal pain (37.1%, 34.0%, and 26.8%, respectively), left-sided tumors (80.8%, 83.7%, and 63.9%, respectively), and rectal cancer (33.7%, 33.7%, and 22.6%, respectively).

Anemia was more common among patients in the AO-CRC cohort (14.6%) compared with the EO-CRC subgroups (≤35 years: 2.0%, 36-49 years: 3.6%).

Among patients ≤35 years, the prevalence of germline mutations was particularly high (23.3%) compared with the AO-CRC group (14.1%).

This finding underlines the importance of germline testing and genetic counseling in young adults, noted Cathy Eng, MD, of Vanderbilt-Ingram Cancer Center in Nashville, and Howard Hochster, MD, of Rutgers Cancer Institute in New Brunswick, New Jersey, in an accompanying commentary.

“In turn, pediatricians, family care physicians, and/or primary care providers should carefully review the family history of their young patients with family members,” they suggested.

Somatic mutation analyses of microsatellite stable (MSS) CRC found that the most common alterations in early-onset cancers were APC (78.7%), TP53 (82.1%), KRAS (42.5%), SMAD4 (15.5%), PIK3CA (14.9%), FBXW7 (8.9%), SOX9 (7.7%), TCF7L2 (7.2%), and BRAF (5.5%). However, after adjusting for confounders, the authors determined that the genetic makeup of the tumors was essentially equivalent.

Among patients with MSS tumors with metastatic disease, the use and type of chemotherapy was comparable among the three cohorts, with the majority of patients in each receiving fluoropyrimidine plus oxaliplatin with or without bevacizumab (Avastin) as first-line therapy. Radiographic response to first-line chemotherapy was 71.9% for patients ≤35 years, 61.8% for those ages 36-49, and 66.5% for AO-CRC patients. There was no statistically significant difference in median overall survival between the groups — 46.9 months for patients ≤35 years, 56.4 months for patients 36-49 years, and 54.5 months for patients with AO-CRC.

There was an association between age ≤35 and worse outcomes, but it was not statistically significant (HR 1.43, 95% CI 0.99-2.07, P=0.06), Cercek and colleagues noted.

This study highlights the importance of the lack of genomic and biological differences in the disease, Cercek and colleagues suggested, particularly since initial reports described EO-CRC as a potentially different and more aggressive entity, and led many physicians to pursue more intense treatments.

“Our results demonstrate that clinical outcomes and response to chemotherapy are the same and that aggressive treatment regimens based solely on age at CRC diagnosis are not warranted,” they concluded. “Further research should be focused on evaluating diverse populations and identifying potential environmental risk factors that are contributing to this shift in incidence to better distinguish the young population at risk and improve outcomes in this disease.”

“Areas of additional exploration and development include evaluating the role of the microbiome on carcinogenesis extending from antibiotic exposure, as well as the possible link between obesity and dysbiosis in the development of CRC,” the editorialists noted.