title: Next generation sequencing of exceptional responders with BRAF-mutant melanoma: implications for sensitivity and resistance.
abstract: BACKGROUND
  Patients with BRAF mutation-positive advanced melanoma respond well to matched therapy with BRAF or MEK inhibitors, but often quickly develop resistance.
  
  
  METHODS
  Tumor tissue from ten patients with advanced BRAF mutation-positive melanoma who achieved partial response (PR) or complete response (CR) on BRAF and/or MEK inhibitors was analyzed using next generation sequencing (NGS) assay. Genomic libraries were captured for 3230 exons in 182 cancer-related genes plus 37 introns from 14 genes often rearranged in cancer and sequenced to average median depth of 734X with 99% of bases covered >100X.
  
  
  RESULTS
  Three of the ten patients (median number of prior therapies = 2) attained prolonged CR (duration = 23.6+ to 28.7+ months); seven patients achieved either a PR or a short-lived CR. One patient who achieved CR ongoing at 28.7+ months and had tissue available close to the time of initiating BRAF inhibitor therapy had only a BRAF mutation. Abnormalities in addition to BRAF mutation found in other patients included: mutations in NRAS, APC and NF1; amplifications in BRAF, aurora kinase A, MYC, MITF and MET; deletions in CDKN2A/B and PAX5; and, alterations in RB1 and ATM. Heterogeneity between patients and molecular evolution within patients was noted.
  
  
  CONCLUSIONS
  NGS identified potentially actionable DNA alterations that could account for resistance in patients with BRAF mutation-positive advanced melanoma who achieved a PR or CR but whose tumors later progressed. A subset of patients with advanced melanoma may harbor only a BRAF mutation and achieve a durable CR on BRAF pathway inhibitors.
authors.affiliation: Department of Investigational Cancer Therapeutics - a Phase I Clinical Trials Program, Unit 455, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA. jjwheler@mdanderson.org.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Wheler
authors.affiliation: Foundation Medicine, 150 Second Street, Cambridge, MA, 02141, USA. ryelensky@foundationmedicine.com.
authors.forename: Roman
authors.initials: R
authors.lastname: Yelensky
authors.affiliation: Department of Investigational Cancer Therapeutics - a Phase I Clinical Trials Program, Unit 455, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA. gfalchoo@mdanderson.org.
authors.forename: Gerald
authors.initials: G
authors.lastname: Falchook
authors.affiliation: Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA. kkim@mdanderson.org.
authors.forename: Kevin B
authors.initials: KB
authors.lastname: Kim
authors.affiliation: Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA. phwu@mdanderson.org.
authors.forename: Patrick
authors.initials: P
authors.lastname: Hwu
authors.affiliation: Department of Investigational Cancer Therapeutics - a Phase I Clinical Trials Program, Unit 455, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA. atsimber@mdanderson.org.
authors.forename: Apostolia M
authors.initials: AM
authors.lastname: Tsimberidou
authors.affiliation: Foundation Medicine, 150 Second Street, Cambridge, MA, 02141, USA. pstephens@foundationmedicine.com.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Stephens
authors.affiliation: Department of Investigational Cancer Therapeutics - a Phase I Clinical Trials Program, Unit 455, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA. dshong@mdanderson.org.
authors.forename: David
authors.initials: D
authors.lastname: Hong
authors.affiliation: Foundation Medicine, 150 Second Street, Cambridge, MA, 02141, USA. mcronin@foundationmedicine.com.
authors.forename: Maureen T
authors.initials: MT
authors.lastname: Cronin
authors.affiliation: Center for Personalized Cancer Therapy, Moores Cancer Center, The University of California San Diego, 3855 Health Sciences Drive, La Jolla, CA, 92093, USA. rkurzrock@mail.ucsd.edu.
authors.forename: Razelle
authors.initials: R
authors.lastname: Kurzrock
mesh_terms: D000328:Adult; D019008:Drug Resistance, Neoplasm; D005260:Female; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics; D008875:Middle Aged; D009154:Mutation; D010865:Pilot Projects; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000235:genetics; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D047428:Protein Kinase Inhibitors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf