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Next generation sequencing of exceptional responders with BRAF-mutant melanoma: implications for sensitivity and resistance.
- Source :
-
BMC cancer [BMC Cancer] 2015 Feb 18; Vol. 15, pp. 61. Date of Electronic Publication: 2015 Feb 18. - Publication Year :
- 2015
-
Abstract
- Background: Patients with BRAF mutation-positive advanced melanoma respond well to matched therapy with BRAF or MEK inhibitors, but often quickly develop resistance.<br />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.<br />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.<br />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.
- Subjects :
- Adult
Drug Resistance, Neoplasm
Female
Humans
Male
Melanoma genetics
Middle Aged
Pilot Projects
Protein Kinase Inhibitors therapeutic use
Skin Neoplasms genetics
Treatment Outcome
Young Adult
High-Throughput Nucleotide Sequencing methods
Melanoma drug therapy
Mutation
Proto-Oncogene Proteins B-raf genetics
Skin Neoplasms drug therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1471-2407
- Volume :
- 15
- Database :
- MEDLINE
- Journal :
- BMC cancer
- Publication Type :
- Academic Journal
- Accession number :
- 25886620
- Full Text :
- https://doi.org/10.1186/s12885-015-1029-z