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

Boscolo Bielo, L.;Napolitano, S.;Avallone, A.;Pietrantonio, F.;Bordonaro, R.;Maiello, E.;Pisconti, S.;Tamburini, E.;Lotesoriere, C.;Tortora, G.;Zaniboni, A.;Blasi, L.;Antonuzzo, L.;Berardi, R.;Tagliaferri, P.;Cremolini, C.;Lonardi, S.;Garufi, C.;Pinto, C.;Ongaro, E.;Santabarbara, G.;Scartozzi, M.;De Falco, V.;De Stefano, A.;Cardone, C.;Iacovucci, A.;Bosco, M. F.;Russo, A. E.;Latiano, T. P.;Nisi, C.;Messina, M.;Salmistraro, N.;Sartore-Bianchi, A.;Siena, S.;Zampino, M. G.;Fazio, N.;Normanno, N.;Febbraro, A.;Guerrera, L. P.;Parente, P.;De Vita, F.;Martinelli, E.;Troiani, T.;Curigliano, G.;Ciardiello, F.;Martini, G.;Ciardiello, D.

2025-01-01

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Abstract

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 < 0.0001]; 33.8% pretreated patients had TMB with ≥10 mutations per megabase compared with 9.7% patients before first-line anti-EGFR treatment. Higher mutational load correlated with 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 < 0.0001), but not in anti-EGFR-naïve samples (beta 1.2, P = 0.4). Conclusion: These findings might support the investigation of immunotherapy in patients with mCRC pretreated with EGFR inhibitors with high mutational load.