Multiple gastrointestinal polyps in patients treated with BRAF inhibitors
A partir d'échantillons de polypes prélevés dans le côlon et l'estomac de 7 patients atteints d'un mélanome traité à l'aide d'inhibiteurs de BRAF, puis menée à l'aide de modèles murins, cette étude suggère que ces thérapies ciblées sont susceptibles d'augmenter le risque de développer des polypes gastrointestinaux et, en raison du risque de transformation maligne, soulève la question de pratiquer des endoscopies de surveillance chez ces patients
Purpose: BRAF inhibitors (BRAFi) extend survival in BRAF mutant melanoma but can promote the growth of Ras mutant neoplasms. This study determined if gastrointestinal polyps found in BRAFi-treated patients harbored Ras mutations. Experimental Design: Colonic and gastric polyps were resected from BRAFi-treated melanoma patients. Next generation sequencing (NGS) was performed on polyps. The ability of BRAFi to promote polyp formation was functionally characterized in Apc Min +/- mice. MAPK and beta catenin pathway activity was assessed by immunohistochemistry in mouse and human polyps. Results: 14 patients treated with BRAFi underwent endoscopy to assess for polyps. Seven out of 7 patients >40 years of age and treated for >2 years were found to have colonic tubular adenomas with 4 out of the 7 patients having 5 or more polyps.No patient had adenocarcinoma. One patient presented with bleeding from hyperplastic gastric polyps that recurred 6 months after BRAFi rechallenge. NGS performed on polyps found no mutations in MAPK pathway genes, but found APC mutations in all tubular adenomas. A significant increase in the number of polyps was observed in BRAFi-treated compared to control-treated Apc Min +/- mice (20.8 ± 9.2 v. 12.8 ± 0.1; p=0.016). No polyps were observed in BRAFi-treated wild type mice. Conclusion: BRAF inhibitors may increase the risk of developing hyperplastic gastric polyps and colonic adenomatous polyps. Due to the risk of gastrointestinal bleeding and the possibility of malignant transformation, further studies are needed to determine whether or not endoscopic surveillance should be recommended for patients treated with BRAF inhibitors.