Prognostic significance of ABCB1 in stage I lung adenocarcinoma

Abstract

Cancer stem cell (CSC) properties have been recently proposed to explain tumor carcinogenesis and multidrug resistance in several human cancers, including non-small cell lung cancer (NSCLC). The present study examined the protein expression of three CSC-associated markers, namely ATP binding cassette subfamily B member 1 (ABCB1), aldehyde dehydrogenase 1 family member A1 (ALDH1A1) and cluster of differentiation (CD) 44, by immunohistochemistry in 194 NSCLC patients who underwent complete resection of NSCLC tumors. The association between the expression of these proteins and patient prognosis was evaluated to clarify the prognostic significance of CSC-associated markers in NSCLC patients. Positive staining for ABCB1 demonstrated a trend toward worse survival compared with negative staining in stage I-III NSCLC. Negative staining for ALDH1 or CD44 exhibited a trend toward worse survival compared with positive staining in stage I-III NSCLC. It was observed that patients with stage I lung adenocarcinoma (ADC) showing positivity for ABCB1 expression had significantly poorer survival than those with negative ABCB1 staining (P=0.03). Furthermore, stage I ADC patients with wild-type epidermal growth factor receptor (EGFR) who exhibited positive staining for ABCB1 had significantly shorter disease-free survival (DFS) compared with patients with negative staining for ABCB1 (P<0.01). Analyses by univariate and multivariate Cox proportional hazards models revealed that ABCB1-positive staining was significantly associated with DFS and was an independent prognostic factor (hazard ratio, 3.49; P<0.05) in these patients. These results suggest that ABCB1 protein expression is useful for predicting prognosis and selecting patients for post-operative therapy in stage I lung ADC patients, particularly those harboring wild-type EGFR.

Keywords: ABCB1; EGFR; lung adenocarcinoma; prognosis.

Figure 1.

IHC staining for ALDH1A1, CD44 and ABCB1 from different patients. IHC staining for (A) ABCB1, (B) ALDH1A1 and (C) CD44 protein expression in tumor cells. Scores 0, 1, 2 and 3 correspond to negative, weak, moderate and strong staining, respectively (magnification, ×20). IHC, immunohistochemical; ABCB1, ATP binding cassette subfamily B member 1; ALDH1A1, aldehyde dehydrogenase 1 family member A1; CD, cluster of differentiation.

Figure 2.

Kaplan-Meier analyses of OS in adenocarcinoma patients. OS curves of patients with positive or negative expression of (A) ALDH1A1, (B) CD44 and (C) ABCB1. The significance of the differences in OS between subgroups was analyzed by the log-rank test. OS, overall survival; ABCB1, ATP binding cassette subfamily B member 1; ALDH1A1, aldehyde dehydrogenase 1 family member A1; CD, cluster of differentiation.

Figure 3.

Kaplan-Meier analyses of OS and DFS in stage I adenocarcinoma patients based on ABCB1 expression. (A) Wild-type EGFR patients with positivity for ABCB1 expression exhibited significantly poorer OS than those with ABCB1-negative staining (P=0.047). (B) Cases with positive ABCB1 expression exhibited poorer DFS than those that were negative for ABCB1 (P=0.098). (C) Wild-type EGFR patients with positive ABCB1 expression exhibited significantly poorer DFS than those with negativity for ABCB1 (P<0.01). The significance of differences in OS or DFS was analyzed by the log-rank test. OS, overall survival; DFS, disease-free survival; ABCB1, ATP binding cassette subfamily B member 1; EGFR, epidermal growth factor receptor.