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Large Study of Early-Onset Colorectal Cancer Patients IDs Unique, Potentially Actionable Mutations

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CHICAGO – Whole-exome sequencing analysis of a large cohort of patients who developed colorectal cancer before they were 50 years old revealed unique genomic alterations that were distinct from the aberrations seen in older patients.

Some of the mutational features identified in these younger colorectal cancer patients deserve further study, especially since they might offer opportunities for precision treatment and underscore the need to genomically profile all early-onset colorectal cancer patients, said Eric Lander, a hematology/oncology clinical fellow at Vanderbilt University Medical Center, at the American Society of Clinical Oncology's annual meeting on Saturday.

Lander presented data from a genomic analysis of early-onset colorectal cancer patients who developed the disease before age 50 and of average-onset colorectal cancer patients who were diagnosed after age 60. Researchers conducted whole-exome sequencing analysis on tumor biopsy samples taken from 13,200 patients with stage II to III colorectal cancer and compared the mutational prevalence between early- and average-onset patients. (The samples were initially taken from patients for ctDNA analysis with Natera's Signatera assay.)

Around 10 percent of colorectal cancer cases occur in those younger than 50 years old and the incidence is rising around the world. The reasons for this increase are poorly understood, but researchers suspect it's likely due to a combination of genomic and environmental factors. Lander and colleagues set out to identify driver mutations unique to early-onset disease for future study and to generate a hypothesis about mutagenomic exposures that may be causing specific alterations in this subset of patients.

Nearly 3,000 patients in the study had early-onset disease and approximately 10,200 had average-onset colorectal cancer, which Lander said makes this the largest analysis of its type. The researchers focused on sporadic colorectal cancers, which comprise 84 percent of early-onset cases.

While other researchers have explored the genomic underpinnings of early-onset colorectal cancer, Lander's team uniquely decided to stratify their genomic analyses according to whether patients had high or low tumor mutation burden (TMB) and had high microsatellite instability (MSI-high) or were microsatellite stable (MSS). Regardless of age, most rectal cancer patients were MSS and TMB-low. Differences were seen primarily in colon cancer cases, which tended to be TMB-low and MSS in early-onset cases, and MSI-high and TMB-high (20 mutations per mega base or higher) in average-onset cases. A subset of patients had TMB-high but MSS tumors, and early-onset colorectal cancer patients were three times more likely to have this molecular profile than those with average-onset disease.

Most of the clinically meaningful tumor mutational differences between early-onset and average-onset patients were in the MSI-high/TMB-high and MSS/TMB-high subgroups.

For example, MSI-high/TMB-high early-onset patients tended to have a higher prevalence of alterations in KRAS, CTNNB1, PIK3CA, and HER2/3, as well as more mutations in the WNT and PI3K oncogenic pathways. Lander highlighted that in this subgroup 15.8 percent had HER2 mutations and 13.1 percent had HER3 mutations.

"We didn't look at HER2 amplification, but this is a really unique finding that should be explored in future studies," he said. "HER2 amplification should be investigated between early-onset and average-onset disease as this might be a therapeutic option that we're not identifying for [younger] patients."

In comparison, average-onset patients with MSI-high/TMB-high tumors tended to have more BRAF and RNF43 mutations and RTK-RAS pathway mutations.

In the MSS/TMB-high cohort, POLE mutations were present in almost 65 percent of early-onset patients, comprising 3.3 percent of all MSS tumors. POLE-driven tumors tend to be hypermutated, but if clinicians aren't testing patients for TMB, then this mutational state may be missed. Patients with higher mutational burden tend to fare well with immunotherapy.

In comparison, average-onset patients who were MSS/TMB-high tended to have mutations in BRAF, RNF43, and ACVR2A.

Meanwhile, in the MSS/TMB-low cohort, researchers found some mutational differences between early- and average-onset colorectal cancer patients, but none that were clinically relevant. "From this, we might draw the conclusion that patients with early-onset disease are being exposed to something or multiple things earlier in life, leading to a similar chromosomal instability pathway of disease as average-onset patients have traditionally experienced," Lander said. 

This large-scale analysis was limited by the lack of race and ethnicity data associated with tumor samples submitted to Natera. Researchers also excluded stage IV patients to try to limit confounders from prior treatment, didn't do germline analysis, and included only US patients. Lander said that future studies will include germline analysis and stage IV patients.

Additionally, his team is examining differences in tumor mutational signatures between early-onset and average-onset colorectal cancer patients and will present the data at a future medical conference in July. "This analysis looked at single genes being mutated between ages, but mutational signatures are actually looking at clusters of mutations," Lander said. "Perhaps it's not one gene [mutation] … but a cluster of mutations that's leading to more early-onset cases."

These findings support performing NGS testing in all early-onset colorectal cancer patients, in Lander's view. "The findings might really open the door for personalization of therapy for patients with early-onset disease," he said.

In reviewing the data from this study, Aaron Scott, a gastrointestinal oncologist and researcher at the University of Arizona Cancer Center, said that Lander's group identified attractive targets for treatment of early-onset colorectal cancer, "but it is yet to be determined if these are actionable." He noted that the unique mutations identified in younger patients in this study also point to KRAS inhibitors and PI3K inhibitors as potential options. While some of these treatments are being investigated in metastatic colorectal cancer, Tukysa (tucatinib) is approved for RAS-wild type HER2-positive advanced disease, and neoadjuvant immunotherapy is recommended in treatment guidelines for MSI-high rectal cancer. 

Scott pointed out that last year a multidisciplinary international group issued the first guidelines for diagnosing and treating early-onset colorectal cancer and recommended that all newly diagnosed patients younger than 50 years old should have multi-gene panel testing for germline mutations, MSI testing, and assessment of somatic mutations in KRAS, BRAF, HER2, NTRK, and NRAS for informing treatment — some of the same genes that Lander's group flagged as mutated in early-onset colorectal cancer patients in this study. "The results from Lander et al. support this recommendation," Scott said.