Melanoma remains a highly morbid disease in the United States. With a relatively young age of onset, the toll of melanoma in terms of "life-years lost" is second only to breast cancer among the major solid tumor malignancies. Despite advances in early detection, the number of deaths from melanoma has continued to rise. Current treatment options for metastatic melanoma are largely ineffective with dismal 5-year survival rates of only 3%-14%% for distant metastatic disease (stage IV). In addition, the only commonly used serologic marker of disease activity in the US, serum lactate dehydrogenase, has a poor sensitivity to detect disease progression leading clinicians to rely on expensive imaging studies to monitor disease. Overall, the annual estimated cost of treating melanoma in the United States is over $3.1 billion. Beginning in 2002 activating mutations in the serine-threonine kinase BRAF were identified at high rates in primary and metastatic melanoma, and subsequent in-vitro and animal model experiments demonstrated BRAF to be an oncogene in melanoma. The V600E substitution is a mutation hotspot, accounting for greater than 90% of the mutations identified in melanoma. In mid 2009 preliminary results from a clinical trial of PLX4032, a second generation small molecule inhibitor of the BRAFV600E protein, showed responses in the majority of patients carrying the BRAF V600E mutation. Currently, enrollment into clinical trials with PLX4032 is restricted to patients in whom a tumor biopsy can be obtained, and in which the mutation is detected. Based on our clinical trial experience, tumor genotyping currently takes 1-2 weeks or longer if there are difficulties obtaining a metastatic tumor specimen for genotyping. In addition, we and others have found that multiple metastases from individual patients may be discordant for the BRAF mutation (i.e. one tumor is mutant, a second tumor from the same patient is wild-type). Genotyping of a single tumor biopsy from individual patients, therefore, may inadvertently render some patients ineligible for a BRAF inhibitor who might otherwise derive benefit. To overcome these limitations we have developed a rapid, highly sensitive approach to detect mutant BRAF DNA in patient blood samples. Our Preliminary Data demonstrate that this approach is feasible in melanoma patients, as the results of blood-based testing are highly associated with the BRAF genotype of the tumor. The current proposal seeks to further optimize our methodology, and rigorously demonstrate its utility as a molecular diagnostic tool. In addition, we will test the utility of blood-based detection of BRAF DNA as a biomarker of disease activity. Using a blood sample to genotype a patient's solid tumor is a highly innovative approach in cancer medicine and has potential to change clinical practice not only in melanoma but also in the care of patients with other solid tumors such as thyroid, colon, ovarian and lung cancers which have significant rates of BRAF mutation.
Recently, a mechanism-based therapeutic agent targeting the mutant BRAF kinase has shown effectiveness in metastatic melanoma patients whose tumors have the mutation. We have developed a rapid, highly sensitive approach to detect mutant BRAF DNA in patient blood samples. The current proposal seeks to rigorously demonstrate the clinical utility of these assays as molecular diagnostic tools that have the potential to change the clinical practice in melanoma and potentially in other solid tumors in which mechanism-based therapies may be applied.
|Chang, Gregory A; Tadepalli, Jyothirmayee S; Shao, Yongzhao et al. (2016) Sensitivity of plasma BRAFmutant and NRASmutant cell-free DNA assays to detect metastatic melanoma in patients with low RECIST scores and non-RECIST disease progression. Mol Oncol 10:157-65|