The predictive value of neuroendocrine markers and p53 for response to chemotherapy and survival in patients with advanced non-small cell lung cancer

Abstract

Background: A minority of patients (30–40%) with advanced non-small cell lung cancer (NSCLC) have objective responses to chemotherapy. Therefore, defining molecular features that determine resistance or response to chemotherapy would have important implications in this disease. Several studies have suggested that patients whose tumors have neuroendocrine features may be more responsive to chemotherapy. In addition, increased expression of p53 may play a role in chemotherapy resistance in patients with NSCLC. Methods: The objective of this study was to analyze retrospectively, the correlation between marker expression and response to chemotherapy and survival using immunohistochemistry for neuroendocrine markers and p53. Ninety patients with unresectable stage III or IV NSCLC, treated with platinum based combination chemotherapy were evaluated. The pathological specimens were obtained prior to chemotherapy. Results: There was no statistically significant correlation between any individual marker and response to chemotherapy. However, patients with tumors with increased expression of p53 were more likely to have progressive disease following chemotherapy (P=0.02). Similarly, patients with tumors lacking neuroendocrine expression and with increased expression of p53 were more likely to have progressive disease when compared to patients with tumors with normal p53 expression and neuroendocrine differentiation (P=0.03). Normal expression of p53 along with the presence of neuroendocrine differentiation was a favorable factor for both survival (P=0.05) and time to disease progression (P=0.04) in the multivariate analysis. Conclusion: The presence of neuroendocrine markers alone was not predictive of response to chemotherapy and did not impact on the survival of this group of patients with advanced stage NSCLC. The normal expression of p53 together with neuroendocrine differentiation seems to impact favorably on overall survival time and time to disease progression without significant improvement in response to chemotherapy.

Introduction

Lung cancer is the leading cause for cancer-related mortality for both men and women in the United States. It is estimated that there were 157,400 deaths from lung cancer in the year 2001, accounting for 28.4% of all cancer deaths [1]. Lung cancer is classified into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). SCLC is distinctive secondary to its high response rate to combination chemotherapy. The response rates to chemotherapy for patients with NSCLC are relatively low when compared to SCLC. Identification of subsets of patients with chemotherapy responsive disease is critical to offering appropriate therapy.

It is clear from both clinical and in vitro data that SCLC has distinct neuroendocrine (NE) properties [2]. Some NSCLCs also express neuroendocrine markers. A number of studies suggest that this subset of patients with NSCLC with neuroendocrine differentiation may have increased sensitivity to chemotherapy [3], [4], [5], [6], [7], [8], [9], [10].

p53 is a 53 kD nuclear phosphoprotein, the product of a 20 kb gene (TP53) localized on the short arm of chromosome 17. Abnormal expression of p53 and p53 mutations occur in about 60% of tumors and are some of the most frequent abnormalities in NSCLC [11], [12]. It has been demonstrated in vitro that apoptotic mechanisms induced by chemotherapy and ionizing radiation require wild-type p53 expression [13], [14]. Further, adenovirus-mediated transfer of the wild-type p53 into spheroid tumor culture of human NSCLC cell line with homozygous deletion of p53 markedly increased cisplatin sensitivity [15]. Kawasaki et al. reported a positive correlation between p53 over-expression and chemotherapy resistance in patients with advanced NSCLC [16]. Rusch et al. reported a statistically significant inverse association between aberrant p53 expression and pathological response for patients receiving neoadjuvant chemotherapy for stage IIIA NSCLC. Only three of 20 patients (15%) whose tumors exhibited a high level of p53 expression prior to chemotherapy had a major pathological response compared with 14 of 32 (44%) for those with low p53 expression (P=0.04) [17]. Rosell et al. found an association between p53 gene mutations and poor response to paclitaxel in data generated by a phase II trial of single-agent paclitaxel in advanced NSCLC [18]. However, other reports suggest that there are other factors that may affect the role of p53 in chemotherapy responsiveness [19], [20]. The objective of the trial was to determine the impact of neuroendocrine and p53 expression upon response to platinum based chemotherapy and survival in patients with advanced NSCLC.