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Abstract
Introduction. Current selection of patients with metastatic colorectal cancer (mCRC) for anti-EGFR monoclonal antibody therapy involves testing for KRAS, NRAS, and BRAFp.V600 mutations, as well as microsatellite instability (MSI) and HER2 (ERBB2) amplification. However, data from the Valentino and PARADIGM studies indicate that multigene next-generation sequencing (NGS) and stricter patient selection based on comprehensive molecular profiling can more accurately predict the efficacy of anti-EGFR therapy.
Aim. To evaluate the incidence of mutations potentially associated with resistance to anti-EGFR therapy ("hyper-selection" mutations) in patients with left-sided, RAS/BRAF-wild-type mCRC enrolled in a prospective study, and to compare these findings with a retrospective cohort.
Materials and Methods. A prospective phase III clinical trial (NCT06226857) included patients with morphologically confirmed left-sided mCRC and no activating KRAS/NRAS/BRAFp.V600 mutations, as determined by PCR. Pre-treatment FFPE tumor samples were analyzed using the NGS-based "Solo-Test Driver" panel (38 genes + MSI). Based on NGS results, patients were stratified into treatment groups according to the presence of abnormalities in hyper-selection genes (HSG). Data were compared with a prior retrospective NGS analysis. The study is registered with ClinicalTrials.gov (NCT06226857).
Results. As of publication, 134 samples were analyzed by NGS. In total, 31 patients (23.1 %) were classified as HSG-positive. The most frequent genetic alterations were found in TP53 (77.6 %), PIK3CA (12.7 %), and KRAS (11.2 %). Clinically significant mutations in KRAS, NRAS, or BRAFgenes were detected in 24 samples (18 %). The frequencies of individual biomarkers did not differ statistically from the retrospective cohort, with the exception of RAS/BRAF p.V600 data, a discrepancy likely attributable to differences in patient screening methodologies.
Conclusion. The NGS results from this prospective study demonstrate a high incidence (18 %) of biomarkers indicative of potential primary resistance to anti-EGFR therapy. Resistance was most commonly due to rare RAS mutations, and less frequently to alterations outside the canonical RAS/BRAFp.V600 pathway.
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