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Identification of Clinically Actionable Genomic Alterations in Colorectal Cancer Patients From the VA National Precision Oncology Program (NPOP)


 

Purpose

Colorectal cancer (CRC) is the fourth most common cancer at VA and the third leading cause of cancer-related death in the USA. The VA National Precision Oncology Program (NPOP) was established in 2016 with the goal of implementing standardized, streamlined methods for molecular testing of veterans with cancer and has enabled comprehensive genomic profiling (CGP) and precision medicine as part of routine cancer care. Obtaining CGP of predictive biomarkers in cancer tissue, including mutations in genes (e.g., KRAS, NRAS and BRAF), tumor mutation burden (TMB) and microsatellite instability status (MSI) can be used to support treatment decisions with targeted and immunotherapies.

Methods

In this study we describe the frequencies of these clinical biomarkers in colon adenocarcinoma (COAD), rectal adenocarcinoma (READ), and other colon or rectum histologies (CROT); and compare these frequencies to a published cohort of metastatic CRC using Chi-square test (Yaeger et al., 2018).

Results

A total of 1802 patients with CRC were included in this study. COAD was the most frequent disease site (76.9%) followed by READ (19.1%). Approximately 52.9% of COAD patients harbored at least one highly actionable biomarker (defined as having an FDA-approved indication) including NRAS/ KRAS/BRAF wildtype (38.0%), TMB-H (12.9%), BRAF V600E (9.7%), MSI-H (8.9%), and NTRK fusion or rearrangement (0.3%). About 52.0% of patients with READ had these biomarkers, while this rate was (16.4%) in CROT. Among patients with COAD and READ, those with BRAF V600E mutations were more likely to be older, White, not Hispanic or Latino, and lived in urban areas compared to those without BRAF V600E. Relative to those with NRAS/KRAS/BRAF mutations, patients with NRAS/KRAS/BRAF wildtype were frequently younger. Relative to the frequency of biomarkers from a cBioPortal cohort of metastatic CRC, the frequency of NRAS wildtype was significantly lower in patients with COAD and READ tested through NPOP.

Consulsions

In this cohort, ~53 % of patients with COAD and 52% of patients with READ have highly actionable biomarkers and are potentially eligible for FDAapproved targeted therapies. Future studies examining cancer outcomes with regard to the use of targeted therapies in the setting of actionable gene alterations, TMB, and MSI are warranted.

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