Tumor Genetic Analyses of Patients with Metastatic Melanoma Treated with the BRAF Inhibitor Dabrafenib (GSK2118436)
- 1 September 2013
- journal article
- Published by American Association for Cancer Research (AACR) in Clinical Cancer Research
- Vol. 19 (17), 4868-4878
- https://doi.org/10.1158/1078-0432.ccr-13-0827
Abstract
Purpose: Dabrafenib is a selective inhibitor of V600-mutant BRAF kinase, which recently showed improved progression-free survival (PFS) as compared with dacarbazine, in metastatic melanoma patients. This study examined potential genetic markers associated with response and PFS in the phase I study of dabrafenib. Experimental Design: Baseline (pretreatment or archival) melanoma samples were evaluated in 41 patients using a custom genotyping melanoma-specific assay, sequencing of PTEN, and copy number analysis using multiplex ligation amplification and array-based comparative genomic hybridization. Nine patients had on-treatment and/or progression samples available. Results: All baseline patient samples had BRAFV600E/K confirmed. Baseline PTEN loss/mutation was not associated with best overall response to dabrafenib, but it showed a trend for shorter median PFS [18.3 (95% confidence interval, CI, 9.1–24.3) vs. 32.1 weeks (95% CI, 24.1–33), P = 0.059]. Higher copy number of CCND1 (P = 0.009) and lower copy number of CDKN2A (P = 0.012) at baseline were significantly associated with decreased PFS. Although no melanomas had high-level amplification of BRAF, the two patients with progressive disease as their best response had BRAF copy gain in their tumors. Conclusions: Copy number changes in CDKN2A, CCND1, and mutation/copy number changes in PTEN correlated with the duration of PFS in patients treated with dabrafenib. The results suggest that these markers should be considered in the design and interpretation of future trials with selective BRAF inhibitors in advanced melanoma patients. Clin Cancer Res; 19(17); 4868–78. ©2013 AACR.Keywords
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This publication has 48 references indexed in Scilit:
- Melanoma: from mutations to medicineGenes & Development, 2012
- Survival in BRAF V600–Mutant Advanced Melanoma Treated with VemurafenibNew England Journal of Medicine, 2012
- NRAS mutation status is an independent prognostic factor in metastatic melanomaCancer, 2011
- Role and therapeutic potential of PI3K‐mTOR signaling in de novo resistance to BRAF inhibitionPigment Cell & Melanoma Research, 2011
- The genomic complexity of primary human prostate cancerNature, 2011
- COT drives resistance to RAF inhibition through MAP kinase pathway reactivationNature, 2010
- A comprehensive catalogue of somatic mutations from a human cancer genomeNature, 2009
- Genomic profiling of malignant melanoma using tiling-resolution arrayCGHOncogene, 2007
- Abnormal structure and expression ofPTEN/MMAC1 gene in human uterine cancersMolecular Carcinogenesis, 2000
- PTEN mutations and microsatellite instability in complex atypical hyperplasia, a precursor lesion to uterine endometrioid carcinoma.1998