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Phospho-Akt Overexpression in Non-small Cell Lung Cancer Confers Significant Stage-Independent Survival Disadvantage* FREE TO VIEW

Odile David, MD; Helena LeBeau, HT(ASCP); Arnold R. Brody, PhD; Mitchell Friedman, MD, FCCP; James Jett, MD, FCCP
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*From the Department of Pathology (Drs. David and Brody, and Ms. LeBeau) and the Section of Pulmonary, Critical Care, and Environmental Medicine (Dr. Friedman), Tulane University School of Medicine, New Orleans, LA; and the Division of Pulmonary Medicine (Dr. Jett), Mayo Clinic, Rochester, MN.

Correspondence to: Odile David, MD, Assistant Professor of Pathology, Tulane University School of Medicine, 1430 Tulane Ave, SL79, New Orleans, LA 70112; e-mail: odavid@tulane.edu

Chest. 2004;125(5_suppl):152S. doi:10.1378/chest.125.5_suppl.152S-a
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Akt is a signal transduction protein that, when activated at the cytoplasmic membrane, plays a central role in inhibiting apoptosis in a variety of cell types, including human cancer cells, from many different sites of origin. In cell lines derived from human non-small cell lung cancers (NSCLCs), Akt has been shown to confer chemoresistance by the inhibition of apoptosis in response to many different chemotherapeutic agents including platinum-based agents, which are often the first-line therapy for NSCLCs. Less than 50% of patients with NSCLC treated with chemotherapy have clinical evidence of a response.

To determine whether the overexpression of activated Akt (pAkt) may be correlated with survival, we studied tumors from 61 patients with NSCLC (diagnosed in 1991 and 1992 at the Mayo Clinic) in three tissue microarrays constructed by the Mayo Clinic Core Laboratory. All patients were observed for a period of 10 years or until death. Thirteen of the 61 patients were still alive after 10 years. The arrays were studied at Tulane University, where they were stained with antibodies against pAkt, p53, and Ki-67. Each spot was scored by multiple pathologists, all of whom were blinded to the clinical information. Patients were divided by staining score into the following two groups: pAkt group 1 patients demonstrated weak-to-absent pAkt staining in all tissue represented in the array (some patients had more than one spot); and pAkt group 2 patients demonstrated unequivocally strong staining in at least one spot. Staining was predominantly cytoplasmic. p53 and Ki-67 staining was interpreted as a percentage of tumor nuclei staining positively. Low staining for each of these proteins was designated at ≤ 20%, and high staining was designated at > 20%.

There was a statistically significant difference in survival between the 14 patients with strong pAkt staining compared to the 47 patients with weak-to-absent pAkt staining both by log rank testing (p = 0.0416) and Breslow analysis (p = 0.0446). Only 1 of the 14 patients in pAkt group 2 was alive after 10 years. Interestingly, the staining for pAkt in this patient’s tumor was predominantly nuclear. The significance of this finding is unclear. Twelve of the 47 patients in pAkt group 1 were alive after 10 years. The difference in survival time with respect to pAkt status was also statistically significant, even after accounting for stage of disease at diagnosis (p = 0.004). The mean survival time for patients in pAkt group 2 was 36.4 months compared to 57.0 months for patients in pAkt group 1. Interestingly, patients in pAkt group 2 tended to receive diagnoses at lower stages of disease than did those in pAkt group 1. Neither p53 nor Ki-67 staining was a statistically significant prognostic factor.

We conclude that the overexpression of pAkt is an independent prognostic factor. Further studies of human NSCLCs are warranted to drive the development of targeted tumor-specific antineoplastic therapies.

Abbreviations: pAkt = activated Akt; NSCLC = non-small cell lung cancer





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