Large study of early-onset colorectal cancer patients identifying unique and potentially actionable mutations

Large study of early-onset colorectal cancer patients identifying unique and potentially actionable mutations

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

Some of the mutational characteristics identified in these young colorectal cancer patients deserve further study, especially as they may offer opportunities for precision treatment and underscore the need to genomically profile all patients with early-onset colorectal cancer, he said. said Eric Lander, clinical researcher in hematology/oncology. Saturday at Vanderbilt University Medical Center, at the American Society of Clinical Oncology Annual Meeting.

Lander presented data from a genomic analysis of patients with early-onset colorectal cancer who developed disease before age 50 and patients with mid-onset colorectal cancer who were diagnosed after age 60. patients with stage II to III colorectal cancer and compared the mutational prevalence between early- and mid-onset patients. (Samples were initially taken from patients for ctDNA analysis with Natera’s Signatera test.)

About 10% of colorectal cancer cases occur in people under the age of 50, and the incidence is increasing worldwide. The reasons for this increase are poorly understood, but researchers suspect it is 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 studies and to generate a hypothesis about the mutagenomic exposures that might cause specific alterations in this subset of patients.

Nearly 3,000 patients in the study had early-onset disease and about 10,200 had mid-onset colorectal cancer, which Lander says makes this the largest analysis of its kind. The researchers focused on sporadic colorectal cancers, which comprise 84% of early-onset cases.

While other researchers have explored the genomic basis of early-onset colorectal cancer, Lander’s team uniquely decided to stratify their genomic analyzes according to whether patients had a 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 had low MSS and low TMB. The differences were seen primarily in colon cancer cases, which tended to be low in TMB and MSS in early-onset cases, and high in MSI and high in TMB (20 mutations per megabase or greater) in mid-onset cases. A subset of patients had TMB-high tumors but MSS, and patients with early-onset colorectal cancer were three times more likely to have this molecular profile than those with medium-onset disease.

The majority of clinically significant tumor mutational differences between early- and mid-onset patients were in the MSI-high/TMB-high and MSS/TMB-high subgroups.

For example, early-onset MSI-high/TMB-high 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 found that in this subgroup, 15.8% had HER2 mutations and 13.1% had HER3 mutations.

“We haven’t looked at HER2 amplification, but this is a very unique finding that should be explored in future studies,” he said. “HER2 amplification should be investigated between early-onset and mid-onset disease as this may be a treatment option for which we are not identifying [younger] patients”.

In comparison, medium-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 nearly 65% ​​of early-onset patients, comprising 3.3% of all MSS tumors. POLE-driven tumors tend to be hypermutated, but if doctors aren’t testing patients for TMB, then this mutational status may not be understood. Patients with higher mutational burden tend to do well with immunotherapy.

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

Meanwhile, in the low MSS/TMB cohort, the researchers found some mutational differences between patients with early- and mid-onset colorectal cancer, but none that were clinically relevant. “From this, we could draw the conclusion that patients with early-onset disease are exposed to something or more things earlier in life, leading to a pattern of chromosome instability similar to what middle-onset patients have traditionally experienced,” he said. landers.

This large-scale analysis was limited by the lack of data on race and ethnicity associated with the tumor samples sent to Natera. The researchers also excluded stage IV patients to try to limit confounding factors from prior treatment, did not do germline analysis, and included only US patients. Lander said future studies will include germline analysis and stage IV patients.

In addition, his team is looking at differences in tumor mutational signatures between patients with early- and mid-onset colorectal cancer and will present the data at a future medical conference in July. “This analysis looked at individual genes mutated across ages, but the mutational signatures are actually looking at clusters of mutations,” Lander said. “Maybe it’s not a gene [mutation] but a cluster of mutations that is leading to more early-onset cases.”

These findings support performing NGS testing in all patients with early-onset colorectal cancer, according to Lander. “The findings could really open the door to tailoring therapy for patients with early-onset disease,” she said.

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

Scott pointed out that last year an international multidisciplinary group published the first guidelines for the diagnosis and treatment of early-onset colorectal cancer and recommended that all newly diagnosed patients under the age of 50 should undergo multigene panel testing for germline mutations, MSI testing, and evaluation of somatic mutations in KRAS, BRAF, HER2, NTRK, and NRAS to inform treatment of some of the same genes that Lander’s group flagged as mutated in patients with high-grade colorectal cancer early onset in this study. “The findings of Lander et al. support this recommendation,” Scott said.

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