Phosphorylated Bcl-2 and Mcl-1 as prognostic markers in small cell lung cancer.

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.