Neuroendocrine tumors (NETs) of the gastrointestinal tract occur at an approximate incidence of 6.2 per 100,000 worldwide, and are the second most prevalent gastrointestinal tract tumor behind colorectal cancer (CRC).1 Many factors, including site of origin, stage, and biological features, influence treatment decisions.2 Metastatic, high-grade, poorly differentiated neuroendocrine carcinomas (NECs) are typically aggressive tumors characterized by a Ki-67 level of >20% and a mitotic index of >20 mitoses per 10 high-powered field, and are generally treated with chemotherapy regimens used for small cell lung cancer.3–5 Despite treatment, prognosis for high-grade NEC remains poor, with a median survival of <1 year,6,7 underlining the need to develop effective targeted therapies that can produce durable responses.
Targetable genetic features of high-grade NECs have not been comprehensively described. In a recent case series, Klempner et al2 reported BRAF mutations in 9% of 108 total cases of colorectal NEC, and described 2 cases of treatment-refractory high-grade rectal NECs harboring BRAFV600E mutations. BRAFV600E mutation has been identified in both solid and hematologic malignancies, including adenocarcinoma of the colon and lung, papillary thyroid cancer, melanoma, and hairy cell leukemia.8 In BRAFV600E-mutated melanoma, combined BRAF and MEK inhibition has shown superiority to BRAF monotherapy and has proven to be an effective treatment for metastatic disease.9 In the Klempner et al2 study, 2 patients with metastatic high-grade rectal NEC with BRAFV600E mutations were treated with combined BRAF/MEK inhibition after experiencing disease progression through treatment with platinum-based regimens. Both patients had excellent and durable partial responses to therapy of 7 and 9 months, respectively, at the time of writing. However, the use of combination BRAF/MEK inhibition in patients with colonic or small bowel NEC has not been described. This report presents 2 cases of NEC, which demonstrate both the promises and limitations of BRAF inhibition in gastrointestinal NEC, and highlight the need for ongoing preclinical and clinical research to optimize patient selection for these treatments.
The authors wish to thank NCCN and Novartis for their support.
Dr. Roychowdhury has disclosed the he serves on the advisory board for Incyte Corporation. Dr. Shah has disclosed the she has served as an advisory board member for Novartis Pharmaceuticals Corporation. The remaining authors have disclosed that they have no financial interests, arrangements, affiliations, or commercial interests with the manufacturers of any products discussed in this article or their competitors.
NCT01713972 was approved and funded in part by the NCCN Oncology Research Program from general research support provided by Novartis. NCT01885195 was sponsored by Novartis.
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. Corcoran RB André T Yoshino T Efficacy and circulating tumor DNA (ctDNA) analysis of the BRAF inhibitor dabrafenib (D), MEK inhibitor trametinib (T), and anti-EGFR antibody panitumumab (P) in patients (pts) with BRAF V600E–mutated (BRAFm) metastatic colorectal cancer (mCRC) [abstract]. Ann Oncol 2016; 27( Suppl 6): Abstract 455O.
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