Growing clinical evidence for the interaction of the p53 genotype and response to induction chemotherapy in advanced non-small cell lung cancer

doi:10.1016/j.jtcvs.2007.10.072

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Growing clinical evidence for the interaction of the p53 genotype and response to induction chemotherapy in advanced non–small cell lung cancer

Daniela Kandioler, MD^a^,b^,_*, Georgios Stamatis, MD^c, Wilfried Eberhardt, MD^d, Sonja Kappel, PhD^b, Sabine Zöchbauer-Müller, MD^e, Irene Kührer, MD^e, Martina Mittlböck, PhD^f, Ronald Zwrtek, MD^g, Clemens Aigner, MD^h, Christoph Bichler, JD^b, Victoria Tichy, JD^b, Marcus Hudec, PhDⁱ, Thomas Bachleitner, MD^a, Adelheid End, MD^h, Michael Rolf Müller, MD^h, Erich Roth, PhD^b, Walter Klepetko, MD^h

^a Division of Surgery, Medical University of Vienna, Austria
^b Division of Surgical Research, Medical University of Vienna, Austria
^c Division of Thoracic Surgery, Ruhrland Klinik, Essen-Heidhausen, Germany
^d Division of Internal Medicine, University of Essen, Germany
^e Division of Internal Medicine, Medical University of Vienna, Austria
^f Section of Clinical Biometrics, Medical University of Vienna, Austria
^g Division of Surgery, Landesklinikum St Pölten, Austria
^h Division of Thoracic Surgery, Medical University of Vienna, Austria
ⁱ Department of Scientific Computing, University of Vienna, Austria

Received for publication May 2, 2007; revisions received September 26, 2007; accepted for publication October 22, 2007.

^_* Address for reprints: Daniela Kandioler, MD, MBA, Division of Surgery, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria. (Email: Daniela.Kandioler{at}meduniwien.ac.at).

Objective: The objective of this study is to establish clinical evidencethat the p53 genotype can serve as a predictive marker for responseto cisplatin-based induction therapy.

Methods: Patients with advanced non–small cell lung cancer whohad received neoadjuvant chemotherapy in the context of a prospectivephase II trial were analyzed for the p53 genotype of their tumors.Response to induction therapy was then correlated to the p53genotype as assessed by complete direct DNA sequencing. Patientshad received 3 cycles of cisplatin and etoposide, and 1 cycleof simultaneous radiochemotherapy. All 3 treatment componentsmediate their cytotoxic effect through induction of apoptosis,which is suggested to require an intact p53 gene. In addition,the results from a previously published hypothesis-finding studyare updated to demonstrate the consistency of clinical resultsand summarize currently available clinical evidence.

Results: In the phase II trial, 35 patients underwent resection afterinduction chemotherapy, allowing a pathohistologic responseassessment. The presence of a mutant p53 genotype was highlyindicative of resistance to induction chemotherapy (P < .002).The sensitivity of a mutant p53 genotype to identify nonresponderswas 94% (71.3–99.9 confidence interval). A normal p53gene was significantly associated with radical resection (P< .004) and survival advantage (P = .02).

Conclusion: This is the second clinical evaluation demonstrating a significantrelation between p53 genotype and response to induction therapyin non–small cell lung cancer. We conclude that the p53genotype should be evaluated as a predictive marker for responseto induction therapy in prospective randomized protocols.

Abbreviations and Acronyms IHC = immunohistochemistry; NSCLC= non–small cell lung cancer

General Thoracic Surgery

Growing clinical evidence for the interaction of the p53 genotype and response to induction chemotherapy in advanced non–small cell lung cancer