Targeting BRAF mutations in high-grade neuroendocrine carcinoma of the colon

Jarred Burkart, Dwight Owen, Manisha H. Shah, Sherif R.Z. Abdel-Misih, Sameek Roychowdhury, Robert Wesolowski, Sigurdis Haraldsdottir, Julie W. Reeser, Eric Samorodnitsky, Amy Smith, Bhavana Konda*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

16 Citations (Scopus)

Abstract

Mutations in the RAS/RAF/MEK/ERK pathway leading to constitutive activation and uncontrolled cellular growth have been identified in various human malignancies, making this pathway a target for potential therapeutics. The activating BRAFV600E mutation is one well-characterized oncogenic mutation that has been described and targeted with clinical success in various malignancies, including melanoma and hairy cell leukemia. Although BRAF-directed treatments have yielded clinical benefit in a subset of tumor types, such as melanoma, thyroid cancer, and lung cancer, BRAF inhibition fails to confer a clinical benefit in colon cancer. Identification of patients for whom BRAF inhibition may produce clinically meaningful outcomes is imperative. The incidence of BRAF mutations in neuroendocrine carcinoma (NEC) is estimated to be 5% to 10%. A recent case series demonstrated benefit in targeting the BRAFV600E mutation in metastatic high-grade rectal NECs. Combination BRAF and MEK inhibition is known to yield improved outcomes compared with BRAF inhibition alone in melanoma. This report presents 2 patients with high-grade colorectal NECs who had different responses to treatment with combined BRAF/MEK inhibition after experiencing disease progression through first-line platinum-based chemotherapy. One patient experienced an excellent initial response to therapy before ultimately experiencing progression, and in the other patient initially had stable disease before eventually experiencing progression. These cases highlight the complicated role BRAF mutations play in gastrointestinal NECs, and the need for further research to identify not only patients who may benefit from BRAF-directed therapies but also strategies to avoid development of resistance.

Original languageEnglish
Pages (from-to)1035-1040
Number of pages6
JournalJNCCN Journal of the National Comprehensive Cancer Network
Volume16
Issue number9
DOIs
Publication statusPublished - 1 Sept 2018

Bibliographical note

Funding Information:
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. Correspondence: Bhavana Konda, MD, MPH, Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, 460 West 10th Avenue, Columbus, OH 43210. Email: [email protected]

Publisher Copyright:
© JNCCN—Journal of the National Comprehensive Cancer Network.

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