While the incidence of colorectal cancer (CRC) has dropped significantly among older adults in recent years — a trend attributed to regular screening colonoscopies and lower smoking rates — the opposite is true for people born between 1981 and 1996, who have double the risk compared with people born in 1950.

There’s an urgent need to identify more-effective therapies for those younger people: Approximately 58% of patients age 50 or under have advanced, distant disease at the time of diagnosis, and only 14% of that group will survive five years.

A novel study led by medical oncologists Deepak Vadehra, DO, and Sarbajit Mukherjee, MD, MS, of the Gastrointestinal Center at Roswell Park Comprehensive Cancer Center is shedding light on factors that may affect treatment response in younger people with CRC. That information could guide the development of new treatments for younger patients, who typically have poorer outcomes.

“This idea arose from my wanting to investigate the question of what factors at the metabolic level may be influencing the rise in young-onset colorectal cancer,” says Dr. Vadehra, Co-Leader of the Adolescent/Young Adult (AYA) Translational Research Group at Roswell Park and first author of the study.

“Our concept is a novel look at metabolic dysregulation. We used a unique bioinformatics-based approach that used the transcriptomic data to identify metabolic dysregulation. This identified affected pathways that may be clinically impactful and allow for targeting of those pathways, and may give signals that could explain the reason for the poor outcomes in young-onset CRC.”

Dr. Vadehra discussed the results of the study as part of the Clinical Science Symposium session on Molecular Basis for Young-Onset Colorectal Cancer at the American Society of Clinical Oncology (ASCO) 2023 Annual Meeting in Chicago.

Working with data from a total of 857 patients who had either colon adenocarcinoma or colorectal cancer, the investigators compared the transcriptional profiles of patients over 50 against those of patients 50 or younger.

Transcriptional profiling helps determine the degree to which genes influence the behavior of cells. The research team used this method to identify differences in metabolic flux and transcriptional dysregulation — processes that interfere with the normal functioning of various genes.

The team retrieved data from The Cancer Genome Atlas (TCGA) for 397 patients with colon adenocarcinoma and from the Oncology Research Information Exchange Network (ORIEN) for 460 patients with colorectal cancer. Along with age, the groups were categorised by race, gender, tumour stage and body mass index (BMI).

In younger patients, the data showed enriched NRAS and MYC oncogenes. Mutations of both oncogenes are associated with the proliferation and metastasis of colorectal cancer. Younger patients also were found to have enriched metabolic pathways for amino acids and lipids, which can contribute to the development and progression of cancer, and enriched cellular processes.

The investigators found that older patients had upregulated pathways that increase both steroid hormone metabolism and kynurenine metabolism, which can contribute to the growth of cancer cells.

But patients over 50 also had upregulated pathways associated with response to CTLA-4 and PD-L1 treatments — immune checkpoint inhibitors — which are sometimes used for the treatment of metastatic colon cancer. This may indicate that older patients are more responsive to those therapies than younger patients.

The study was a collaborative effort with colleagues from the University of Kentucky, Moffitt Cancer Center, The James Cancer Hospital of The Ohio State University and the University of Oklahoma Health Sciences Center. Dr. Mukherjee is Co-Leader of the Gastrointestinal Translational Research Group at Roswell Park; Spencer Rosario, PhD, of the Department of Biomedical Informatics at Roswell Park was responsible for the transcriptome-based metabolic analysis that made the study unique.

The team hopes the results of their study will help future studies zero in on new ways of treating colorectal cancer in younger patients.

Source: Roswell Park Comprehensive Cancer Center