Genomic profiling of high tumor mutational load in microsatellite-stable colorectal cancer uncovers MAPK signaling pathway alterations following anti-EGFR therapy

Background Translational studies have provided evidence that targeted therapies and chemotherapy might induce a status of adaptive mutability with an increase in the tumor mutational load. Patients and methods We conducted an analysis of pathogenic variants (PVs) detected by liquid biopsy (LBx)-based comprehensive genomic profiling in patients with chemo-refractory microsatellite-stable metastatic colorectal cancer (mCRC) pretreated with anti-epidermal growth factor receptor (EGFR) within the VELO and CAVE-2 GOIM studies compared with anti-EGFR naïve mCRC included in the CAPRI-2 GOIM trial. Results Overall, 559 patients with available samples for LBx analysis were included. EGFR pretreated tumors had significant enrichment for PVs in the MAPK signaling pathway with a median tumor mutational burden (TMB) [6 interquartile range (IQR 4-11) versus 4 (IQR 3-9), P KRAS (q = 0.07), BRAFV600 (q = 0.01), ERBB2 AMP (q = 0.06) and EGFR ECD (q = 0.07) PVs. Such association was not observed in patients naïve to anti-EGFR drugs. MAPK mutations were associated with higher TMB in anti-EGFR pretreated samples (beta = 4.0, P P = 0.4). Conclusion These findings might support the investigation of immunotherapy in patients with mCRC pretreated with EGFR inhibitors with high mutational load.