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Clin Cancer Res. 2015 Dec 1;21(23):5215-21. doi: 10.1158/1078-0432.CCR-15-0469. Epub 2015 Jul 22.

Multiple Gastrointestinal Polyps in Patients Treated with BRAF Inhibitors.

Author information

1
Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania. ravi.amaravadi@uphs.upenn.edu.
2
Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
3
Department of Pathology and Cell Biology, Columbia University, New York, New York.
4
Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania.
5
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.
6
Melanoma Institute Australia and The University of Sydney, New South Wales, Australia.
7
Vanderbilt-Ingram Cancer Center, Nashville, Tennessee.
8
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
9
University of Texas, MD Anderson Cancer Center, Houston, Texas.
10
Massachusetts General Hospital Cancer Center, Boston, Massachusetts.
11
Genentech, Inc., South San Francisco, San Francisco, California.
12
Peter MacCallum Cancer Centre and University of Melbourne, Australia, Melbourne, Victoria, Australia.
13
Memorial Sloan Kettering Cancer Center, New York, New York.

Abstract

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 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.

PMID:
26202952
PMCID:
PMC4668213
DOI:
10.1158/1078-0432.CCR-15-0469
[Indexed for MEDLINE]
Free PMC Article

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