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Customizing Cisplatin Based on Quantitative Excision Repair Cross-Complementing 1 mRNA Expression: A Phase III Trial in Non–Small-Cell Lung Cancer

Manuel Cobo, Dolores Isla, Bartomeu Massuti, Ana Montes, Jose Miguel Sanchez, Mariano Provencio, Nuria Viñolas, Luis Paz-Ares, Guillermo Lopez-Vivanco, Miguel Angel Muñoz, Enriqueta Felip, Vicente Alberola, Carlos Camps, Manuel Domine, Jose Javier Sanchez, Maria Sanchez-Ronco, Kathleen Danenberg, Miquel Taron, David Gandara, Rafael Rosell

From the Hospital Carlos Haya, Malaga; Hospital Lozano Blesa, Zaragoza; Hospital General de Alicante, Alicante; Catalan Institute of Oncology, Hospital Duran i Reynals; Hospital Clinic; Hospital Vall d'Hebron, Barcelona; Hospital Alcorcon; Hospital Puerta de Hierro; Hospital Doce de Octubre; Fundacion Jimenez Diaz’ Autonomous University of Madrid, Madrid; Hospital de Cruces, Barakaldo-Bizkaia; Valencia Institute of Oncology; Hospital Arnau de Vilanova; Hospital General de Valencia, Valencia; Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Badalona, Spain; Response Genetics, Los Angeles; and the University of California Davis Cancer Center, Sacramento, CA

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

Purpose Although current treatment options for metastatic non–small-cell lung cancer (NSCLC) rely on cisplatin-based chemotherapy, individualized approaches to therapy may improve response or reduce unnecessary toxicity. Excision repair cross-complementing 1 (ERCC1) has been associated with cisplatin resistance. We hypothesized that assigning cisplatin based on pretreatment ERCC1 mRNA levels would improve response.

Patients and Methods From August 2001 to October 2005, 444 stage IV NSCLC patients were enrolled. RNA was isolated from pretreatment biopsies, and quantitative real-time reverse transcriptase PCR assays were performed to determine ERCC1 mRNA expression. Patients were randomly assigned in a 1:2 ratio to either the control or genotypic arm before ERCC1 assessment. Patients in the control arm received docetaxel plus cisplatin. In the genotypic arm, patients with low ERCC1 levels received docetaxel plus cisplatin, and those with high levels received docetaxel plus gemcitabine. The primary end point was the overall objective response rate.

Results Of 444 patients enrolled, 78 (17.6%) went off study before receiving one cycle of chemotherapy, mainly due to insufficient tumor tissue for ERCC1 mRNA assessment. Of the remaining 346 patients assessable for response, objective response was attained by 53 patients (39.3%) in the control arm and 107 patients (50.7%) in the genotypic arm (P = .02).

Conclusion Assessment of ERCC1 mRNA expression in patient tumor tissue is feasible in the clinical setting and predicts response to docetaxel and cisplatin. Additional studies are warranted to optimize methodologies for ERCC1 analysis in small tumor samples and to refine a multibiomarker profile predictive of patient outcome.

Supported by Sanofi-aventis. Additional funding was provided by Spanish Ministry of Health grants, through the Red de Centros de Epidemiología y Salud Pública (RCESP) and the Red Temática de Investigación Cooperativa de Centros de Cáncer (CO-010), and by La Fundación Badalona Contra el Cáncer. None of the funding agencies were involved in the design and conduct, data management and analysis, manuscript preparation and review, or authorization for submission.

Terms in blue are defined in the glossary, found at the end of this article and online at www.jco.org.

Presented in part at the 41st Annual Meeting of the American Society for Clinical Oncology, May 13-17, 2005, Orlando, FL, and at the 31st Congress of the European Society of Medical Oncology, September 30-October 3, 2006, Istanbul, Turkey.

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

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