Relevance of circulating mutant BRAF DNA in melanoma

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DESCRIPTION (provided by applicant): The high frequency of BRAF oncogene mutations coupled with the critical role of its gene product in the pathogenesis of metastatic melanoma have led to the development of BRAF inhibitor therapies that are currently undergoing clinical trials. We are participating in two such trials, (one at our institution testing BAY 43-9006, and the other collaborating with Memorial Sloan-Kettering Cancer Center testing 17-AAG) which require that the patients undergo biopsy of their metastatic lesion for sequencing of the BRAF gene to be eligible for participation. As a result, many patients are ineligible for BRAF inhibitors due to inaccessibility of their metastases. Thus, there is an urgent need to develop a simple mechanism for BRAF genotyping to improve selection of patients who are eligible for anti-BRAF therapies. We have developed a new, sensitive, specific, DNA-based, fluorescent assay to detect mutant BRAF alleles in the peripheral blood and tumor specimens of melanoma patients. In our preliminary analyses, we were able to detect mutant BRAF alleles in 13/23 (57%) patient blood specimens. The objective of our proposal is to define the clinical utility of this innovative assay in well-defined patient cohorts. In Aim 1, we will compare the frequency of detection of mutant BRAF alleles in the peripheral blood of melanoma patients with lymph node metastases (Stage III) to those with metastases to visceral sites (Stage IV). In addition, we will determine the association between detection of mutant BRAF alleles in the blood and disease burden based on well-established, standard clinical measures such as pattern of tumor spread and the number of metastatic sties. In Aim 2, we will determine the level of concordance between mutational BRAF status in the blood and corresponding tumor tissues from the patients analyzed in Aim 1. We foresee our project as a critical step in establishing the utility of this peripheral blood assay in selecting melanoma patients eligible to receive BRAF inhibitor therapy, and, potentially, in monitoring response to treatment.