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