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.

doi:10.1016/j.esmoop.2025.105877

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.

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.. - In: ESMO OPEN. - ISSN 2059-7029. - ELETTRONICO. - 10:(2025), pp. 105877.1-105877.8. [10.1016/j.esmoop.2025.105877]