Phosphorylated Bcl-2 and Mcl-1 as prognostic markers in small cell lung cancer
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Rajasree P. Chowdry1, Gabriel L. Sica2,3, Sungjin Kim2,4,7, Zhengjia Chen2,4, Aaron Goodman1, Diane Alexis2, Xingming Deng2,5, Taofeek K. Owonikoko2,6
1Department of Medicine, Emory University School of Medicine Atlanta, GA, USA
2Winship Cancer Institute of Emory University, Atlanta, GA, USA
3Department of Pathology, Emory University, Atlanta, GA, USA
4Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, GA, USA
5Department of Radiation Oncology, Emory University School of Medicine Atlanta, GA, USA
6Department of Hematology and Medical, Emory University School of Medicine Atlanta, GA, USA
7Current affiliation: Cedars-Sinai Medical Center, Los Angeles, CA, USA
Taofeek K. Owonikoko, e-mail: [email protected]
Keywords: small cell lung cancer, carcinoid, Bcl-2, Mcl-1, survival
Received: October 23, 2015 Accepted: February 09, 2016 Published: February 18, 2016
Background: We hypothesized that the activated phosphorylated forms of proapoptotic Bcl-2 family of proteins is most relevant to small cell lung cancer (SCLC) biology. We therefore characterized pBcl-2 and pMcl-1 in pulmonary neuroendocrine tumors to better elucidate the role of these proteins in SCLC.
Methods: We analyzed archival samples of pulmonary carcinoid, SCLC and large-cell neuroendocrine carcinoma (LCNEC) by immunohistochemistry (IHC). Association of protein expression with age, gender, smoking status, tumor type, stage and survival was assessed by Wilcoxon rank-sum test, Kruskal-Wallis test, Spearman rank correlation, and Cox regression model.
Results: We employed 77 cases: carcinoid (21%), SCLC (53%) and LCNEC (26%); median age of 61.5 years, 75% Caucasians and 60% female. Carcinoid had lower median expression of Bcl-2 [0 (0 - 100) vs. 90 (0 - 300); p<0.001] and pBcl-2 [12.5 (0 - 255) vs. 190 (0 - 300); p<.001] compared to SCLC and LCNEC. On univariate analyses, high nuclear pBcl-2 expression was associated with adverse features (smoking, malignant histology, higher stage) and higher risk of progression (PFS HR: 1.45; 95% CI:1.13-1.85; p=0.004) and death (OS HR: 1.32; 95% CI: 0.99-1.75;p=0.054). High cytoplasmic Mcl-1 immunoscore was significantly associated with male gender (p-value= 0.009), and higher risk of progression (HR: 1.31 (1.02-1.68); p=0.036). On multivariable analysis, pBcl-2 remained significantly associated with PFS both by intensity (HR: 1.54; 1.08-2.20; p=0.016) and immunoscore (HR: 1.41; 0.99-2.02; p=0.058).
Conclusions: pBcl-2 and pMcl-1 showed stronger correlation with adverse prognostic features in SCLC and should be considered superior biomarkers for patient selection for therapy.
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