Characterizing a group of people at high-risk for developing lung cancer
Menezes, Ravi Jose
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Background . In the United States, it is estimated that lung cancer will be diagnosed in over 213,000 individuals in 2007, and be the leading cause of cancer death, with 160,930 deaths. Prognosis for lung cancer patients is strongly correlated with the stage of the disease at the time of diagnosis. Five-year survival rates vary considerably, currently at 60-70% for early stage vs. less than 5% for late stage. Unfortunately, approximately 70% of cases exhibit metastases upon detection. Since there has been little change in lung cancer survival rates over the past 20 to 30 years, there is much interesting in developing effective tests for early diagnosis of lung cancer. Examining the molecular and morphological changes that occur premalignantly can not only result in the development of new biomarkers, but also in a new understanding of the way the disease arises and how to intervene. Objectives . The main objective was to characterize a group at-risk for lung cancer, with a focus on the baseline biopsies and short-term followup changes. Associations between key biomarkers and histology, followup changes, and risk factors will be examined. Exploratory analyses will be carried out by examining the expression of a receptor involved in a key chemopreventive pathway the biopsies and some lung tumor samples. Methods . In this study, immunohistochemical methods were used to examine the expression of the p53 and Bcl-2 proteins in 369 mostly pre-malignant baseline biopsies obtained from 106 individuals who underwent autofluorescence bronchoscopy in a surveillance clinic for individuals at-risk for lung cancer. Expression of vitamin D receptor, which mediates the affects of the chemopreventive agent calcitriol, was examined in a subset of these biopsies as well as squamous cell carcinoma and adenocarcinoma samples from lung cancer patients. Associations between marker expression and patient level (e.g. smoking status, cancer history, asbestos exposure) and biopsy level characteristics (e.g. histology, changes upon followup) were examined. Results . Over 70% of the patients in the group had a prevalent premalignant lesions at baseline. The rates of histological change in metaplastic lesions that were rebiopsied were significantly different than the rates for dysplasia (p=0.01), with metaplasias more likely to persist or progress. Similarly, patients with metaplasia at baseline generally returned for followup with metaplastic or worse lesions. p53 and Bcl-2 expression were associated with current smoking and asbestos exposure, while p53 was associated with histological grade. Neither biomarker was associated with histological progression observed at followup. VDR expression was present in bronchial biopsies and lung tumor tissue, and cytoplasmic expression decreased with increasing histological grade. Conclusions . Metaplasia should be considered a lesion of interest in the prospective analysis of high-risk individuals. The presence of nuclear VDR expression in various histological grades indicates the potential for the use of calcitriol as a chemopreventive agent against the development of lung cancer. Further studies, involving additional markers and longer followup times, are warranted.