title: Multiple Gastrointestinal Polyps in Patients Treated with BRAF Inhibitors.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  Colonic and gastric polyps were identified and 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 β-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.
authors.affiliation: Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania. ravi.amaravadi@uphs.upenn.edu.
authors.forename: Ravi K
authors.initials: RK
authors.lastname: Amaravadi
authors.affiliation: Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Hamilton
authors.affiliation: Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Ma
authors.affiliation: Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Shengfu
authors.initials: S
authors.lastname: Piao
authors.affiliation: Department of Pathology and Cell Biology, Columbia University, New York, New York.
authors.forename: Armando Del
authors.initials: AD
authors.lastname: Portillo
authors.affiliation: Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Nathanson
authors.affiliation: Crown Princess Mary Cancer Centre, Westmead and Blacktown Hospitals, Sydney, New South Wales, Australia. Melanoma Institute Australia and The University of Sydney, New South Wales, Australia.
authors.forename: Matteo S
authors.initials: MS
authors.lastname: Carlino
authors.affiliation: Melanoma Institute Australia and The University of Sydney, New South Wales, Australia.
authors.forename: Georgina V
authors.initials: GV
authors.lastname: Long
authors.affiliation: Vanderbilt-Ingram Cancer Center, Nashville, Tennessee.
authors.forename: Igor
authors.initials: I
authors.lastname: Puzanov
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Xu
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Jennifer J D
authors.initials: JJ
authors.lastname: Morrissette
authors.affiliation: University of Texas, MD Anderson Cancer Center, Houston, Texas.
authors.forename: Kenneth Y
authors.initials: KY
authors.lastname: Tsai
authors.affiliation: Massachusetts General Hospital Cancer Center, Boston, Massachusetts.
authors.forename: Keith T
authors.initials: KT
authors.lastname: Flaherty
authors.affiliation: Vanderbilt-Ingram Cancer Center, Nashville, Tennessee.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Sosman
authors.affiliation: Genentech, Inc., South San Francisco, San Francisco, California.
authors.forename: Grant R
authors.initials: GR
authors.lastname: Goodman
authors.affiliation: Peter MacCallum Cancer Centre and University of Melbourne, Australia, Melbourne, Victoria, Australia.
authors.forename: Grant A
authors.initials: GA
authors.lastname: McArthur
authors.affiliation: Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Anil K
authors.initials: AK
authors.lastname: Rustgi
authors.affiliation: Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: David C
authors.initials: DC
authors.lastname: Metz
authors.affiliation: Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Lynn M
authors.initials: LM
authors.lastname: Schuchter
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Paul B
authors.initials: PB
authors.lastname: Chapman
authors.affiliation: Department of Pathology and Cell Biology, Columbia University, New York, New York.
authors.forename: Antonia R
authors.initials: AR
authors.lastname: Sepulveda
mesh_terms: D018256:Adenomatous Polyps / Q000175:diagnosis / Q000209:etiology* / Q000235:genetics; D000328:Adult; D000368:Aged; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D003062:Codon; D003111:Colonic Polyps / Q000175:diagnosis / Q000209:etiology* / Q000235:genetics; D003113:Colonoscopy; D004195:Disease Models, Animal; D005260:Female; D005773:Gastroscopy; D017491:Genes, APC; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D007211:Indoles / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D008297:Male; D008545:Melanoma / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D016609:Neoplasms, Second Primary / Q000175:diagnosis / Q000209:etiology* / Q000235:genetics; D010091:Oximes / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D049268:Positron-Emission Tomography; D047428:Protein Kinase Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics; D013274:Stomach Neoplasms / Q000175:diagnosis / Q000209:etiology* / Q000235:genetics; D013449:Sulfonamides / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D014057:Tomography, X-Ray Computed; D000077484:Vemurafenib
chemical_list: D000970:Antineoplastic Agents; D003062:Codon; D007093:Imidazoles; D007211:Indoles; D010091:Oximes; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D000077484:Vemurafenib; D048493:Proto-Oncogene Proteins B-raf; C561627:dabrafenib