RNF43 mutations predict response to anti-BRAF/EGFR combinatory therapies in BRAFV600E metastatic colorectal cancer
Elena Élez, Javier Ros, J. Fernández, Guillermo Villacampa, Ana Belén Moreno-Cárdenas, Carlota Arenillas, Kinga Bernatowicz, R. Comas, Shanshan Li, David P. Kodack, Roberta Fasani, Ariadna García, Javier Gonzalo‐Ruiz, Alejandro Piris‐Giménez, Paolo Nucíforo, Gráinne Kerr, Rossana Intini, Aldo Montagna, Marco Maria Germani, Giovanni Randon, Ana Vivancos, Ron Smits, Diana Graus, Raquel Pérez-López, Chiara Cremolini, Sara Lonardi, Filippo Pietrantonio, Rodrigo Dienstmann, Josep Tabernero, Rodrigo A. Toledo
Abstract
Abstract Anti-BRAF/EGFR therapy was recently approved for the treatment of metastatic BRAF V600E colorectal cancer (mCRC BRAF-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 mCRC BRAF-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- RNF43 mutated versus MSS- RNF43 wild-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-mCRC BRAF-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.