Abstract

We immunohistochemically examined specimens of 215 surgically resected non-small cell lung cancers (NSCLCs) for p27KIP1 protein (p27) expression and the growth fraction determined by the Ki-67 labeling index (LI). The NSCLCs analyzed showed considerable heterogeneity in both p27 and Ki-67 LIs; 25 of 207 (13%) lacked p27 expression (p27 LI < 5%), and 116 of 215 (54%) showed a high Ki-67 LI (>30%). The p27 LI was not significantly associated with the Ki-67 LI. A chi2 test showed that loss of p27 expression was inversely correlated with smoking (P = 0.01) and that a high Ki-67 LI was significantly associated with male gender, squamous cell carcinoma histology, and smoking (P < 0.0001 each). Prognostic values of p27 and Ki-67 expression were evaluated in 109 tumors of postsurgical pathological stages I and II. Patients with tumors lacking p27 expression survived for a significantly shorter time than patients with tumors expressing p27 (5-year survival rates, 38% and 68%, respectively; P = 0.02). Patients with tumors having a high Ki-67 LI survived for a significantly shorter time than patients with tumors having a low Ki-67 LI (5-year survival rates, 48% and 78%, respectively; P = 0.005). Multivariate analysis showed that loss of p27 expression tended to be an unfavorable prognostic factor (P = 0.054), whereas a high Ki-67 LI was a significant and independent unfavorable prognostic factor (P = 0.004). When analyzed by cell types, loss of p27 expression was a significant and independent unfavorable prognostic factor in squamous cell carcinomas (P = 0.01), whereas a high Ki-67 LI was a significant and independent unfavorable prognostic factor in nonsquamous cell carcinomas (P = 0.007). We further evaluated the importance of p27 expression in clinical outcome in combination with the Ki-67 LI and ras p21 protein (ras) expression, which we previously reported as an important prognostic factor in NSCLCs. Patients with tumors lacking p27 expression and having a high Ki-67 LI survived for a significantly shorter time than those with tumors expressing p27 and having a high Ki-67 LI (5-year survival rates, 17% and 52%, respectively; P = 0.003). Patients with p27-negative and ras-positive tumors survived for a significantly shorter time than those with both p27- and ras-positive tumors (5-year survival rates, 0% and 38%, respectively; P < 0.0001). These results indicate the pivotal roles of p27 and Ki-67 expression in the clinical outcome of NSCLCs.