title: BRAFV600E Mutations in High-Grade Colorectal Neuroendocrine Tumors May Predict Responsiveness to BRAF-MEK Combination Therapy.
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.
  
  
  
  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.
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Chao Family Comprehensive Cancer Center, University of California, Irvine, School of Medicine, Orange, California. sklempner@theangelesclinic.org.
authors.forename: Samuel J
authors.initials: SJ
authors.lastname: Klempner
authors.affiliation: Cancer Treatment Centers of America, Midwestern Regional Medical Center, Zion, Illinois.
authors.forename: Bruce
authors.initials: B
authors.lastname: Gershenhorn
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Chao Family Comprehensive Cancer Center, University of California, Irvine, School of Medicine, Orange, California.
authors.forename: Phu
authors.initials: P
authors.lastname: Tran
authors.affiliation: Department of Pathology, University of California, Irvine, Orange, California.
authors.forename: Thomas K
authors.initials: TK
authors.lastname: Lee
authors.affiliation: Trovagene, Inc., San Diego, California.
authors.forename: Mark G
authors.initials: MG
authors.lastname: Erlander
authors.affiliation: Foundation Medicine, Inc., Cambridge, Massachusetts.
authors.forename: Kyle
authors.initials: K
authors.lastname: Gowen
authors.affiliation: Foundation Medicine, Inc., Cambridge, Massachusetts.
authors.forename: Alexa B
authors.initials: AB
authors.lastname: Schrock
authors.affiliation: Foundation Medicine, Inc., Cambridge, Massachusetts.
authors.forename: Deborah
authors.initials: D
authors.lastname: Morosini
authors.affiliation: Foundation Medicine, Inc., Cambridge, Massachusetts. Albany Medical College, Albany, New York.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Ross
authors.affiliation: Foundation Medicine, Inc., Cambridge, Massachusetts.
authors.forename: Vincent A
authors.initials: VA
authors.lastname: Miller
authors.affiliation: Foundation Medicine, Inc., Cambridge, Massachusetts.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Stephens
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Chao Family Comprehensive Cancer Center, University of California, Irvine, School of Medicine, Orange, California.
authors.forename: Sai-Hong Ignatius
authors.initials: SH
authors.lastname: Ou
authors.affiliation: Foundation Medicine, Inc., Cambridge, Massachusetts.
authors.forename: Siraj M
authors.initials: SM
authors.lastname: Ali
mesh_terms: D000328:Adult; D000368:Aged; D019943:Amino Acid Substitution; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001706:Biopsy; D003062:Codon; D015179:Colorectal Neoplasms / Q000175:diagnosis* / Q000188:drug therapy / Q000235:genetics*; D005260:Female; D006801:Humans; D058990:Molecular Targeted Therapy; D009154:Mutation; D060787:Neoplasm Grading; D009362:Neoplasm Metastasis; D018358:Neuroendocrine Tumors / Q000175:diagnosis* / Q000188:drug therapy / Q000235:genetics*; D000072078:Positron Emission Tomography Computed Tomography; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D016896:Treatment Outcome
chemical_list: D003062:Codon; D047428:Protein Kinase Inhibitors; D048493:Proto-Oncogene Proteins B-raf