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Cell Cycle Regulators and Outcome of Adjuvant Cisplatin-Based Chemotherapy in Completely Resected Non–Small-Cell Lung Cancer: The International Adjuvant Lung Cancer Trial Biologic Program

Martin Filipits, Robert Pirker, Ariane Dunant, Sylvie Lantuejoul, Katharina Schmid, Anh Huynh, Vincent Haddad, Fabrice André, Rolf Stahel, Jean-Pierre Pignon, Jean-Charles Soria, Helmut H. Popper, Thierry Le Chevalier, Elisabeth Brambilla

From the Departments of Medicine I and Clinical Pathology, Medical University of Vienna, Vienna; Institute of Pathology, Medical University of Graz, Graz, Austria; Biostatistics and Epidemiology Unit, Department of Medicine, Institut Gustave Roussy, Villejuif; L'Institut National de la Santé et de la Recherche Médicale U823, Université Joseph Fourier, Department of Pathology, Grenoble Hospital, Grenoble, France; and Department of Internal Medicine, University Hospital of Zurich, Zurich, Switzerland

Address reprint requests to Martin Filipits, PhD, Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, Borschkegasse 8a, A-1090 Vienna, Austria; e-mail: martin.filipits{at}meduniwien.ac.at

Purpose: The International Adjuvant Lung Cancer Trial (IALT) demonstrated that adjuvant cisplatin-based chemotherapy improves the survival of patients with completely resected non–small-cell lung cancer (NSCLC). The purpose of our study was to determine whether cell cycle regulators are of prognostic and/or predictive value in patients who were enrolled onto the IALT.

Patients and Methods: Expression of p27^Kip1, p16^INK4A, cyclin D1, cyclin D3, cyclin E, and Ki-67 was immunohistochemically assessed in tumor specimens obtained from 778 IALT patients. Prognostic and predictive analyses were based on Cox models adjusted for clinical and pathologic parameters.

Results: There was a relationship between p27^Kip1 status and benefit of cisplatin-based chemotherapy (test for interaction, P = .02). Among patients with p27^Kip1-negative tumors, cisplatin-based chemotherapy resulted in longer overall survival compared with controls (adjusted hazard ratio [HR] for death = 0.66; 95% CI, 0.50 to 0.88; P = .006). In patients with p27^Kip1-positive tumors, overall survival was not different between patients treated with cisplatin-based chemotherapy and controls (adjusted HR for death = 1.09; 95% CI, 0.82 to 1.45; P = .54). The other cell cycle regulators and Ki-67 did not predict benefit of adjuvant cisplatin-based chemotherapy. None of these biomarkers was significantly associated with overall survival of the patients in the total study population.

Conclusion: NSCLC patients with p27^Kip1-negative tumors benefit from adjuvant cisplatin-based chemotherapy after complete tumor resection. Before establishing p27^Kip1 as a routine marker for selection of patients for adjuvant chemotherapy, the predictive value of p27^Kip1 has to be confirmed in patients from other trials.

Supported by the Austrian Federal Ministry of Education, Science and Culture (Grant No. GZ 200.062/2-VI/1/2002), the Austrian Science Fund (Grant No. P15377), Programme Hospitalier de Recherche Clinique, Cancéropôle Rhône-Alpes, Institute of Pathology Graz, and an unrestricted research grant from Eli-Lilly.

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

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