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14-3-3 Methylation in Pretreatment Serum Circulating DNA of Cisplatin-Plus-Gemcitabine-Treated Advanced Non–Small-Cell Lung Cancer Patients Predicts Survival: The Spanish Lung Cancer Group

From the Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Badalona; Autonomous University of Madrid, Madrid; Hospital Arnau de Vilanova, Valencia; Hospital de Castellon, Castellon; Hospital General de Valencia, Valencia; Hospital General de Alicante, Alicante, Spain

Address reprint requests to Rafael Rosell, MD, Chief, Medical Oncology Service, Scientific Director of Oncology Research, Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Ctra Canyet, s/n 08916 Badalona (Barcelona), Spain; e-mail: rrosell{at}ico.ses.es

PURPOSE: Survival in patients with advanced non–small-cell lung cancer (NSCLC) who are treated with platinum-based chemotherapy is rather variable. Methylation-dependent transcriptional silencing of 14-3-3, a major G₂-M checkpoint control gene, could be a predictor of longer survival.

PATIENTS AND METHODS: A sensitive methylation-specific polymerase chain reaction assay was used to evaluate 14-3-3 methylation status in pretreatment serum DNA obtained from 115 cisplatin-plus-gemcitabine–treated advanced NSCLC patients.

RESULTS: 14-3-3 methylation was observed in all histologic types of 39 patients (34%). After a median follow-up of 9.8 months, median survival was significantly longer in the methylation-positive group (15.1 v 9.8 months; P = .004). Median time to progression was 8 months in the methylation-positive group and 6.3 months in the methylation-negative group (log-rank test, P = .027). A multivariate Cox regression model identified only 14-3-3 methylation status and Eastern Cooperative Oncology Group performance status as independent prognostic factors for survival. In an exploratory analysis, median survival for 22 methylation-positive responders has not been reached, whereas survival was 11.3 months for 29 methylation-negative responders (P = .001).

CONCLUSION: Methylation of 14-3-3 is a new independent prognostic factor for survival in NSCLC patients receiving platinum-based chemotherapy. It can be reliably and conveniently detected in the serum, thus obviating the need for tumor tissue analysis.

Supported in part by the Spanish Ministry of Health grants provided through Red Tematica de Investigacion Cooperativa de Centros de Cancer (CO-010) and Red de Centros de Epidemiologia y Salud Publica (RCESP), and by funding from La Fundacio Badalona Contra el Cancer and from La Fundacion Carvajal. The sponsors of this study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.

The study reported in this article is original and was not reported or presented elsewhere at the time of submission.

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

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