Tumor genetic analyses of patients with metastatic melanoma treated with the BRAF inhibitor dabrafenib (GSK2118436)

Katherine L. Nathanson*, Anne Marie Martin, Bradley Wubbenhorst, Joel Greshock, Richard Letrero, Kurt D'Andrea, Steven O'Day, Jeffrey R. Infante, Gerald S. Falchook, Hendrik Tobias Arkenau, Michael Millward, Michael P. Brown, Anna Pavlick, Michael A. Davies, Bo Ma, Robert Gagnon, Martin Curtis, Peter F. Lebowitz, Richard Kefford, Georgina V. Long

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

123 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)4868-4878
Number of pages11
JournalClinical Cancer Research
Volume19
Issue number17
DOIs
Publication statusPublished - 1 Sep 2013
Externally publishedYes

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