Faculty Collaboration Database

Next generation sequencing of exceptional responders with BRAF-mutant melanoma: implications for sensitivity and resistance. BMC Cancer 2015 Feb 18;15:61

Date

04/18/2015

Pubmed ID

25886620

Pubmed Central ID

PMC4340232

DOI

10.1186/s12885-015-1029-z

Scopus ID

2-s2.0-84924056275 (requires institutional sign-in at Scopus site)   22 Citations

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.

CONCLUSION: 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.

Author List

Wheler J, Yelensky R, Falchook G, Kim KB, Hwu P, Tsimberidou AM, Stephens PJ, Hong D, Cronin MT, Kurzrock R

Author

Razelle Kurzrock MD Center Associate Director, Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adult
Drug Resistance, Neoplasm
Female
High-Throughput Nucleotide Sequencing
Humans
Male
Melanoma
Middle Aged
Mutation
Pilot Projects
Protein Kinase Inhibitors
Proto-Oncogene Proteins B-raf
Skin Neoplasms
Treatment Outcome
Young Adult