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Next generation sequencing of exceptional responders with BRAF-mutant melanoma: implications for sensitivity and
Jennifer Wheler1, Roman Yelensky2, Gerald Falchook3
1Department 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.
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.
Insights
Advanced melanoma patients on BRAF/MEK inhibitors develop resistance. Next-generation sequencing (NGS) revealed additional DNA alterations causing resistance, though some patients with only BRAF mutations achieved durable responses.
Area of Science:
- Oncology
- Genomics
- Cancer Research
Background:
- Advanced melanoma patients with BRAF mutations respond to targeted therapies.
- Acquired resistance to BRAF or MEK inhibitors is a significant clinical challenge.
Purpose of the Study:
- To identify genomic alterations associated with resistance to BRAF/MEK inhibitors in advanced melanoma.
- To investigate molecular heterogeneity and evolution in treatment-resistant melanoma.
Main Methods:
- Tumor tissue from ten advanced melanoma patients was analyzed using next-generation sequencing (NGS).
- NGS targeted 3230 exons in 182 cancer genes and 37 introns in 14 rearrangement-prone genes.
Main Results:
- Three patients achieved prolonged complete response (CR), one with only a BRAF mutation.
- Seven patients experienced partial response (PR) or short-lived CR.
- Additional mutations (NRAS, APC, NF1), amplifications (BRAF, MYC), deletions (CDKN2A/B), and other alterations were identified.
Conclusions:
- NGS identified actionable DNA alterations potentially driving resistance in advanced melanoma.
- A subset of patients with BRAF-mutated melanoma and only the BRAF mutation may achieve durable responses to targeted therapy.
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