Characteristics of long-term survivors of untreated lung cancer

Abstract

Non-small cell lung cancer (NSCLC) is a malignant tumor with poor prognosis. Although the prognostic variables determining short-term survival have been well described, relatively little attention has been paid to factors associated with long-term survival. In search of these factors we studied the expression of several molecular markers in NSCLC. Only tumor samples of patients with squamous cell carcinomas and stage III tumors with a postoperative survival of at least 5 years and those of patients who died within 2 years after resection were selected for this study. The expression of several parameters including oncogene and suppressor gene products, proliferative, apoptotic, angiogenic and resistance-related factors were investigated and the differences in these two extreme populations were determined by the Wilcoxon rank sum test. Factors involved in proliferation (ras, fos, erbB-1, jun, cyclin A) were downregulated whereas factors involved in apoptosis (p53, bcl-2, CD95) were upregulated in the long survival group. Direct measurement of parameters of proliferation (cell cycle analysis by flow cytometry, PCNA index) revealed a lower proliferative activity in tumors of the long survivors compared to short survivors. In conclusion, tumors of the long survival group are characterized by a downregulation of factors involved in proliferation and an upregulation of factors involved in apoptosis. These tumors may grow more slowly and this may influence long-term survival of patients with NSCLC.

Introduction

Lung cancer consists of a heterogeneous group of tumors with distinct biological and clinical characteristics. There are four major subtypes of lung cancer: squamous cell carcinoma, adenocarcinoma, large cell carcinoma (referred to as non-small cell lung cancer—NSCLC) and small cell lung cancer. The only hope for the significant survival of those patients with NSCLC is tumor resection. However, in more than 70% of all patients suffering from lung cancer, the tumor is inoperable at the time of diagnosis. Furthermore, even with treatment, more than 85–90% of the patients die shortly following their diagnosis.

However, it has become apparent that a number of patients with locally advanced tumors have continued to live for prolonged periods, and in some cases, appear to be cured by operation alone.

Although the prognostic variables determining short-term survival have been well described [1], [2], [3], [4], [5], [6], [7], relatively little attention has been paid to factors associated with long-term survival. In an attempt to identify these factors, we investigated the expression of several markers in tumors of patients with a long and a short survival after resection of locally advanced stage III NSCLC. The evaluated biomarkers were chosen according to our own experience, and they are among the most often reported ones in the literature as of prognostic importance: oncogenes (fos, ras, jun, erbB-1, erbB-2), tumor suppressor genes (p53, Rb), markers of angiogenesis (VEGF, VEGFR-1, bFGF, FGFR-1, TSP), resistance-related factors (P-170, GST, MT, TS, MGMT, Cat, HSP-70), markers of cell proliferation (cyclin A, PCNA-index, S-phase fraction) and markers of apoptosis (fas/CD95, bcl-2, apoptotic index (AI)).