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Prognostic and Predictive Importance of p53 and RAS for Adjuvant Chemotherapy in Non–Small-Cell Lung Cancer

Ming-Sound Tsao, Sarit Aviel-Ronen, Keyue Ding, Davina Lau, Ni Liu, Akira Sakurada, Marlo Whitehead, Chang-Qi Zhu, Robert Livingston, David H. Johnson, James Rigas, Lesley Seymour, Timothy Winton, Frances A. Shepherd

From the University Health Network, Princess Margaret Site and Ontario Cancer Institute, University of Toronto, Toronto; National Cancer Institute of Canada Clinical Trials Group and Queen's University, Kingston, Ontario; University of Alberta Hospital, Edmonton, Alberta, Canada; Southwest Oncology Group, San Antonio, TX; Eastern Cooperative Oncology Group, Boston, MA; and Cancer and Leukemia Group B, Chicago, IL

Address reprint requests to Frances Shepherd, MD, Department of Hematology and Oncology, Princess Margaret Hospital, 610 University Avenue, Toronto, Ontario M5G 2M9, Canada; e-mail: frances.shepherd{at}uhn.on.ca

Purpose: p53 and RAS are multifunctional proteins that are critical to cell cycle regulation, apoptosis, cell survival, gene transcription, response to stress, and DNA repair. We have evaluated the prognostic and predictive value of p53 gene/protein aberrations using tumor samples from JBR.10, a North American phase III intergroup trial that randomly assigned 482 patients with completely resected stage IB and II non–small-cell lung cancer (NSCLC) to receive four cycles of adjuvant cisplatin plus vinorelbine or observation alone.

Methods: p53 protein expression was evaluated by immunohistochemistry. Mutations in exons 5 to 9 of the p53 gene were determined by denaturing high-performance liquid chromatography and confirmed by sequencing. RAS mutations were identified by allelic specific oligonucleotide hybridization.

Results: Of 253 patients, 132 (52%) were positive for p53 protein overexpression. Untreated p53-positive patients had significantly shorter overall survival than did patients with p53-negative tumors (hazard ratio [HR] = 1.89; 95% CI, 1.07 to 3.34; P = .03). However, these p53-positive patients also had a significantly greater survival benefit from adjuvant chemotherapy (HR = 0.54; P = .02) compared with patients with p53-negative tumors (HR = 1.40; P = .26; interaction P = .02). Mutations of p53 and RAS genes were found in 124 (31%) of 397 and 117 (26%) of 450 patients, respectively. Mutations in these genes were neither prognostic for survival nor predictive of a differential benefit from adjuvant chemotherapy.

Conclusion: p53 protein overexpression is a significant prognostic marker of shortened survival, and also a significant predictive marker for a differentially greater benefit from adjuvant chemotherapy in completely resected NSCLC patients.

Supported by grants from the Ontario Cancer Research Network (02-MAY-0132), and the Canadian Cancer Society. The JBR.10 trial was supported by the Canadian Cancer Society, the National Cancer Institute of the United States, and GlaxoSmithKline. S.A.-R. is a Fellow of the CIHR Training Program for Clinician Scientists in Molecular Oncologic Pathology (STP-53912) and is also supported by Knudson Research Fellowship (Ontario Cancer Institute) and NCIC Terry Fox Foundation Clinical Research Fellowship.

Presented at the 43rd Annual Meeting of the American Society of Clinical Oncology, June 1-5, 2007, Chicago, IL.

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