Targeting BRAF Mutations in High-Grade Neuroendocrine Carcinoma of the Colon

J Natl Compr Canc Netw. 2018 Sep;16(9):1035-1040. doi: 10.6004/jnccn.2018.7043.

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.

Trial registration: ClinicalTrials.gov NCT01713972 NCT01885195.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Biopsy
  • Carcinoma, Neuroendocrine / diagnostic imaging
  • Carcinoma, Neuroendocrine / drug therapy*
  • Carcinoma, Neuroendocrine / genetics
  • Carcinoma, Neuroendocrine / pathology
  • Colorectal Neoplasms / diagnostic imaging
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / pathology
  • DNA Mutational Analysis
  • Female
  • Gain of Function Mutation
  • Humans
  • Imidazoles / pharmacology
  • Imidazoles / therapeutic use
  • Magnetic Resonance Imaging
  • Male
  • Middle Aged
  • Neoplasm Grading
  • Oximes / pharmacology
  • Oximes / therapeutic use
  • Positron Emission Tomography Computed Tomography
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use*
  • Proto-Oncogene Proteins B-raf / antagonists & inhibitors*
  • Proto-Oncogene Proteins B-raf / genetics
  • Pyridones / pharmacology
  • Pyridones / therapeutic use
  • Pyrimidines / pharmacology
  • Pyrimidines / therapeutic use
  • Pyrimidinones / pharmacology
  • Pyrimidinones / therapeutic use
  • Sulfonamides / pharmacology
  • Sulfonamides / therapeutic use
  • Treatment Outcome

Substances

  • Imidazoles
  • Oximes
  • Protein Kinase Inhibitors
  • Pyridones
  • Pyrimidines
  • Pyrimidinones
  • Sulfonamides
  • trametinib
  • pazopanib
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • dabrafenib

Associated data

  • ClinicalTrials.gov/NCT01713972
  • ClinicalTrials.gov/NCT01885195