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Cancer Discov. 2016 Jun;6(6):594-600. doi: 10.1158/2159-8290.CD-15-1192. Epub 2016 Apr 5.

BRAFV600E Mutations in High-Grade Colorectal Neuroendocrine Tumors May Predict Responsiveness to BRAF-MEK Combination Therapy.

Author information

1
Division of Hematology-Oncology, Department of Medicine, Chao Family Comprehensive Cancer Center, University of California, Irvine, School of Medicine, Orange, California. sklempner@theangelesclinic.org.
2
Cancer Treatment Centers of America, Midwestern Regional Medical Center, Zion, Illinois.
3
Division of Hematology-Oncology, Department of Medicine, Chao Family Comprehensive Cancer Center, University of California, Irvine, School of Medicine, Orange, California.
4
Department of Pathology, University of California, Irvine, Orange, California.
5
Trovagene, Inc., San Diego, California.
6
Foundation Medicine, Inc., Cambridge, Massachusetts.
7
Foundation Medicine, Inc., Cambridge, Massachusetts. Albany Medical College, Albany, New York.

Abstract

Neuroendocrine tumors comprise a heterogeneous group of malignancies with a broad spectrum of clinical behavior. Poorly differentiated tumors follow an aggressive course with limited treatment options, and new approaches are needed. Oncogenic BRAF V600E (BRAF(V600E)) substitutions are observed primarily in melanoma, colon cancer, and non-small cell lung cancer, but have been identified in multiple tumor types. Here, we describe the first reported recurrent BRAF(V600E) mutations in advanced high-grade colorectal neuroendocrine tumors and identify a BRAF alteration frequency of 9% in 108 cases. Among these BRAF alterations, 80% were BRAF(V600E) Dramatic response to BRAF-MEK combination therapy occurred in two cases of metastatic high-grade rectal neuroendocrine carcinoma refractory to standard therapy. Urinary BRAF(V600E) circulating tumor DNA monitoring paralleled disease response. Our series represents the largest study of genomic profiling in colorectal neuroendocrine tumors and provides strong evidence that BRAF(V600E) is an oncogenic driver responsive to BRAF-MEK combination therapy in this molecular subset.

SIGNIFICANCE:

BRAF(V600E) is an established oncogenic driver, but significant disparities in response exist among tumor types. Two patients with treatment-refractory high-grade colorectal neuroendocrine tumors harboring BRAF(V600E) exhibited rapid and durable response to combined BRAF-MEK inhibition, providing the first clinical evidence of efficacy in this aggressive tumor type. Cancer Discov; 6(6); 594-600. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 561.

PMID:
27048246
PMCID:
PMC5008024
DOI:
10.1158/2159-8290.CD-15-1192
[Indexed for MEDLINE]
Free PMC Article

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