Title |
Next generation sequencing of exceptional responders with BRAF-mutant melanoma: implications for sensitivity and resistance
|
---|---|
Published in |
BMC Cancer, February 2015
|
DOI | 10.1186/s12885-015-1029-z |
Pubmed ID | |
Authors |
Jennifer Wheler, Roman Yelensky, Gerald Falchook, Kevin B Kim, Patrick Hwu, Apostolia M Tsimberidou, Philip J Stephens, David Hong, Maureen T Cronin, Razelle Kurzrock |
Abstract |
Patients with BRAF mutation-positive advanced melanoma respond well to matched therapy with BRAF or MEK inhibitors, but often quickly develop resistance. 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. 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. 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. |
X Demographics
Geographical breakdown
Country | Count | As % |
---|---|---|
United States | 1 | 50% |
Unknown | 1 | 50% |
Demographic breakdown
Type | Count | As % |
---|---|---|
Members of the public | 2 | 100% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
Netherlands | 1 | 3% |
United States | 1 | 3% |
Austria | 1 | 3% |
Unknown | 35 | 92% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Researcher | 12 | 32% |
Student > Bachelor | 3 | 8% |
Other | 3 | 8% |
Student > Ph. D. Student | 3 | 8% |
Student > Master | 3 | 8% |
Other | 4 | 11% |
Unknown | 10 | 26% |
Readers by discipline | Count | As % |
---|---|---|
Agricultural and Biological Sciences | 9 | 24% |
Biochemistry, Genetics and Molecular Biology | 7 | 18% |
Medicine and Dentistry | 6 | 16% |
Business, Management and Accounting | 1 | 3% |
Pharmacology, Toxicology and Pharmaceutical Science | 1 | 3% |
Other | 2 | 5% |
Unknown | 12 | 32% |