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 BRAFV600E 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 BRAFV600E. 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 BRAFV600E is an oncogenic driver responsive to BRAF–MEK combination therapy in this molecular subset.
SIGNIFICANCE: BRAFV600E 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 BRAFV600E 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); 1–7. ©2016 AACR.
- Received October 1, 2015.
- Revision received March 31, 2016.
- Accepted April 1, 2016.
- ©2016 American Association for Cancer Research.