Melanoma remains a highly morbid disease in the United States. With a relatively young age of onset, the tollof melanoma in terms of 'life-years lost' is second only to breast cancer among the major solid tumormalignancies. Despite advances in early detection, the number of deaths from melanoma has continued torise. Five-year survival rates are dismal, with only 3%-14%% of patients with distant metastatic disease (stageIV) achieving that milestone. In addition, the only commonly used serologic marker of disease activity in theUS, serum lactate dehydrogenase, has a poor sensitivity to detect disease progression leading clinicians torely on expensive imaging studies to monitor disease. Overall, the annual estimated costof treating melanomain the United States is over $3.1 billion. Beginning in 2002 activating mutations in the serine-threonine kinaseBRAF were identified at high rates in primary and metastatic melanoma, and subsequent in-vitro and animalmodel experiments demonstrated BRAF to be an oncogene in melanoma. The V600E substitution is amutation hotspot, accounting for greater than 90% of the BRAF mutations identified in melanoma. Earlier thismonth the results of a Phase III randomized trial of Vemurafenib, a second generation small molecule inhibitorof the BRAFV600E protein, demonstrated improved disease-free and overall survival at 6 months. The trial waslimited to patients with metastatic melanoma tumors that had the BRAFV600E as determined by genotyping of abiopsy specimen. Thus, knowledge of the BRAF genotype of a patient's metastatic melanomas will be anessential step for proper therapeutic decision-making. Based on our clinical trial experience, tumor genotypingoften takes 1-2 weeks or longer if there are difficulties obtaining a metastatic tumor specimen for analysis. Inaddition, we and others have found that multiple metastases from individual patients may be discordant for theBRAF mutation (i.e. one tumor is mutant, a second tumor from the same patient is wild-type). Genotyping of asingle tumor biopsy from individual patients, therefore, may inadvertently render some patients ineligible for aBRAF inhibitor who might otherwise derive benefit. We have patented and licensed a highly sensitiveapproach to detect mutant BRAF DNA in patient blood samples. Our Preliminary Data demonstrate that thisapproach is feasible in melanoma patients, as the results of blood-based testing are highly associated with theBRAF genotype of the tumor. In the current proposal we will work with our industry collaborator, Molecular MDto further optimize our blood-based methodology, and rigorously demonstrate its utility as both a moleculardiagnostic biomarker of metastatic melanoma genotype and response-predictive biomarker that candifferentiate between patients that will have a longer versus shorter duration of progression-free survival whileunder treatment with the new agents that inhibit mutant BRAF.
/Relevance The goal of this proposal is to bring robust, blood-based molecular biomarkers for metastatic melanoma to the clinic with the support of Molecular MD Corporation. We are proposing to develop blood-based detection of BRAFmutant and NRASmutant DNA as both molecular diagnostic biomarkers of metastatic melanoma tumor genotype, as well as response-predictive biomarkers that can differentiate between patients that will have a longer versus shorter duration of progression-free survival while under treatment with the new agents that target mutant BRAF in melanoma.
| 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 |
