Elez, Elena, Ros, Javi, Fernandez, Jose, Villacampa, Guillermo, Kodack, David, Moreno, Ana Belen, Arenillas, Carlota, Li, Shanshan, Dienstmann, Rodrigo, Bernatowicz, Kinga, Fasani, Roberta, Comas, Raquel, Garcia, Ariadna, Gonzalez-Ruiz, Javi, Piris-Gimenez, Alejandro, Nuciforo, Paolo, Perez-Lopez, Raquel, Vivancos, Ana, Smits, Ron, Randon, Giovanni, Graus-Porta, Diana, Cremolini, Chiara, Lonardi, Sara, Pietrantonio, Filippo, Tabernero, Josep, Toledo, Rodrigo, Kerr, Grainne, Montagna, Aldo, Germani, Marco Maria and Intini, Rossana (2022) RNF43 mutations predict response to anti-BRAF/EGFR combinatory therapies in BRAFV600E metastatic colorectal cancer. Nature medicine, 28 (10). pp. 2162-2170. ISSN 1546-170X; 1078-8956

Abstract

Anti-BRAF/EGFR therapy was recently approved for the treatment of metastatic BRAFV600E colorectal cancer (mCRCBRAF-V600E). However, a large fraction of patients do not respond, underscoring the need to identify molecular determinants of treatment response. Using whole-exome sequencing in a discovery cohort of patients with mCRCBRAF-V600E treated with anti-BRAF/EGFR therapy, we found that inactivating mutations in RNF43, a negative regulator of WNT, predict improved response rates and survival outcomes in patients with microsatellite-stable (MSS) tumors. Analysis of an independent validation cohort confirmed the relevance of RNF43 mutations to predicting clinical benefit (72.7% versus 30.8%; P = 0.03), as well as longer progression-free survival (hazard ratio (HR), 0.30; 95% confidence interval (CI), 0.12–0.75; P = 0.01) and overall survival (HR, 0.26; 95% CI, 0.10–0.71; P = 0.008), in patients with MSS-RNF43mutated versus MSS-RNF43wild-type tumors. Microsatellite-instable tumors invariably carried a wild-type-like RNF43 genotype encoding p.G659fs and presented an intermediate response profile. We found no association of RNF43 mutations with patient outcomes in a control cohort of patients with MSS-mCRCBRAF-V600E tumors not exposed to anti-BRAF targeted therapies. Overall, our findings suggest a cross-talk between the MAPK and WNT pathways that may modulate the antitumor activity of anti-BRAF/EGFR therapy and uncover predictive biomarkers to optimize the clinical management of these patients.

Item Type:	Article
Date Deposited:	29 Nov 2022 00:46
Last Modified:	29 Nov 2022 00:46
URI:	https://oak.novartis.com/id/eprint/46673