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Predictive Utility of Circulating Methylated DNA in Serum of Melanoma Patients Receiving Biochemotherapy

From the Department of Molecular Oncology, John Wayne Cancer Institute at Saint John’s Health Center; Angeles Clinic and Research Institute, Santa Monica; Department of Biostatistics, UCLA School of Medicine, Los Angeles, CA

Address reprint requests to Dave S.B. Hoon, PhD, Department of Molecular Oncology, John Wayne Cancer Institute, 2200 Santa Monica Blvd, Santa Monica, CA 90404; e-mail: hoon{at}jwci.org

PURPOSE: Currently, no validated blood-based assays accurately predict treatment response or outcome in melanoma patients. We hypothesized that methylation of tumor-related genes detected in serum DNA could predict disease outcome and therapeutic response in patients receiving concurrent biochemotherapy (BC) for metastatic melanoma.

PATIENTS AND METHODS: American Joint Committee on Cancer stage IV melanoma patients (N = 50) had blood drawn before administration of BC. Patients (n = 47) were classified as BC responders or nonresponders. Responders (n = 23) demonstrated a complete or partial response following BC; nonresponders (n = 24) demonstrated progressive disease. Hypermethylation of Ras association domain family 1 (RASSF1A), retinoic acid receptor-ß2 (RAR-ß2), and O⁶-methylguanine DNA methyltransferase (MGMT) genes were assessed by methylation-specific polymerase chain reaction.

RESULTS: Circulating methylated RASSF1A was significantly less frequent for responders (three of 23 patients; 13%) than nonresponders (10 of 24 patients; 42%; P = .028). Patients with RASSF1A, RAR-ß2, or at least one serum methylated gene had significantly worse overall survival than patients with no methylated genes (log-rank, P = .013, .021, and .01, respectively). Methylated RASSF1A was the only factor that significantly correlated with overall survival and BC response (risk ratio, 2.38; 95% CI, 1.16 to 4.86; P = .018; odds ratio = 0.21; 95% CI, 0.05 to 0.90; P = .036).

CONCLUSION: Detection of circulating methylated DNA in serum can predict response to BC and disease outcome.

Supported by National Institutes of Health, National Cancer Institute Project II Grants No. P0 CA029605 and CA012582, and R33-CA100314.

Presented at the 41st Annual Meeting of the American Society of Clinical Oncology, Orlando, Florida, May 13-17, 2005 (T.M., ASCO Merit Award).

Authors’ disclosures of potential conflicts of interest are found at the end of this article.

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