Multiple gastrointestinal polyps in patients treated with BRAF inhibitors

Ravi K. Amaravadi*, Kathryn E. Hamilton, Xiaohong Ma, Shengfu Piao, Armando Del Portillo, Katherine L. Nathanson, Matteo S. Carlino, Georgina V. Long, Igor Puzanov, Xiaowei Xu, Jennifer J D Morrissette, Kenneth Y. Tsai, Keith T. Flaherty, Jeffrey A. Sosman, Grant R. Goodman, Grant A. McArthur, Anil K. Rustgi, David C. Metz, Lynn M. Schuchter, Paul B. ChapmanAntonia R. Sepulveda

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

Purpose: BRAF inhibitors (BRAFi) extend survival in BRAFmutant 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 identified and resected from BRAFi-treated melanoma patients. Nextgeneration sequencing (NGS) was performed on polyps. The ability of BRAFi to promote polyp formation was functionally characterized in Apc Min+/- mice. MAPK and b-catenin pathway activity was assessed by immunohistochemistry in mouse and human polyps. Results: Fourteen 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. 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 with control-treated Apc Min+/- mice (20.8±9.2 vs 12.8±0.1; P=0.016). No polyps were observed in BRAFi-treated wild-type mice. Conclusions: BRAFi 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 BRAFi.

Original languageEnglish (US)
Pages (from-to)5215-5221
Number of pages7
JournalClinical Cancer Research
Volume21
Issue number23
DOIs
StatePublished - Dec 1 2015

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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