Prognostic Implications of Cell Cycle, Apoptosis, and Angiogenesis Biomarkers in Non–Small Cell Lung Cancer: A Review

Abstract

Lung cancer is the leading cause of cancer death in the U.S. with survival restricted to a subset of those patients able to undergo surgical resection. However, even with surgery, recurrence rates range from 30% to 60%, depending on the pathologic stage. With the advent of partially effective, but potentially toxic adjuvant chemotherapy, it has become increasingly important to discover biomarkers that will identify those patients who have the highest likelihood of recurrence and who thus might benefit most from adjuvant chemotherapy. Hundreds of papers have appeared over the past several decades proposing a variety of molecular markers or proteins that may have prognostic significance in non^small cell lung cancer. This review analyzes the largest and most rigorous of these studies with the aim of compiling the most important prognostic markers in early stage non^small cell lung cancer. In this review, we focused on biomarkers primarily involved in one of three major pathways: cell cycle regulation, apoptosis, and angiogenesis. Although no single marker has yet been shown to be perfect in predicting patient outcome, a profile based on the best of these markers may prove useful in directing patient therapy. The markers with the strongest evidence as independent predictors of patient outcome include cyclin E, cyclin B1, p21, p27, p16, survivin, collagen XVIII, and vascular endothelial cell growth factor.

Expression of Bcl-2 predicts outcome in locally advanced non-small cell lung cancer patients treated with cisplatin-based concurrent chemoradiotherapy

“…The most frequently investigated apoptosis-related protein in NSCLC is p53 [13,[20][21][22]. The effect of abnormal p53 status on the response and survival of locally advanced NSCLC patients treated with RT or CRT has shown conflicting results [13,[20][21][22].…”

“…The effect of abnormal p53 status on the response and survival of locally advanced NSCLC patients treated with RT or CRT has shown conflicting results [13,[20][21][22]. While some reports suggested the correlation between mutation or high expression of p53 and poor survival or low response to treatment, others demonstrated no significant negative impact on outcome in patients with abnormal p53 status [13,[20][21][22].…”

“…The effect of abnormal p53 status on the response and survival of locally advanced NSCLC patients treated with RT or CRT has shown conflicting results [13,[20][21][22]. While some reports suggested the correlation between mutation or high expression of p53 and poor survival or low response to treatment, others demonstrated no significant negative impact on outcome in patients with abnormal p53 status [13,[20][21][22]. In terms of Bax, although one article reported a correlation between low expression of Bax and poor outcome in resected advanced NSCLC among small number of studies, the prognostic significance of Bax has not been demonstrated in locally advanced NSCLC patients treated with CRT or RT [21,23].…”

“…In the present study, high expression of Bcl-2 was an independent prognostic factor of better OS in multivariate analysis, along with significant association with high response rate to CCRT. It is somewhat unexpected finding since high Bcl-2 expression is normally associated with decreased apoptotic activity leading to poor response to chemotherapy or RT [21]. In terms of prognostic significance of Bcl-2 expression in both resectable and unresectable NSCLC, conflicting results have been reported [21,[29][30][31][32][33][34].…”

“…It is somewhat unexpected finding since high Bcl-2 expression is normally associated with decreased apoptotic activity leading to poor response to chemotherapy or RT [21]. In terms of prognostic significance of Bcl-2 expression in both resectable and unresectable NSCLC, conflicting results have been reported [21,[29][30][31][32][33][34]. Several studies showed a better outcome in patients with high Bcl-2 expression, while others suggested the role of high Bcl-2 as a marker of poor prognosis.…”