Biological markers in lung cancer: A clinician's perspective

Biological markers are urgently needed to improve the early detection, diagnosis and treatment of lung tumours. Over the past several years various promising biomarkers have emerged in the field of lung cancer. The poor prognosis associated with advanced lung cancer has resulted in attempts to develop lung cancer screening programs. The role of imaging and sputum cytology in lung cancer screening is the focus of much discussion, and efforts to find a suitable blood, sputum or exhaled breath biomarker for the detection of early lung cancer are ongoing. Regarding diagnosis, immunohistochemical profiling is a relatively well established adjunct to microscopic histology as a means of differentiating tumours originating in the lung from metastases from elsewhere. And, in particular in the case of non small cell lung cancer, a precise histological sub-classification of lung tumours is becoming clinically relevant in the choice of anti-tumour therapy, suggesting an increased and defined role for immunohistochemical markers. Molecular changes which correlate with the proposed subclassification of non-small cell lung cancer have also been identified. The treatment of lung cancer is dependant on the stage at the time of diagnosis. In particular, the decision whether or not to operate is dependant on the presence or absence of tumour cells in specific groups of mediastinal lymph nodes. The use of biomarkers can reveal microscopic lymph node metastases which would go unnoticed using conventional histology alone, and can provide early information about the presence of brain metastases. In addition, there is evidence that specific genetic factors predispose tumours to metastasis, which may have a role in the future risk-stratification of patients. Treatment with chemotherapy can be associated with significant toxicity, and is unfortunately not always successful in slowing the progression of lung cancer. The concept of individualized treatment depends on our ability to predict which tumours will respond to which medications. Numerous biomarkers have been suggested to have predictive value in response to chemotherapy, including ERCC-1 for response to cisplatin, beta-tubulin for response to taxanes, and RRM1 for response to gemcitabine. Increasing understanding of the EGFR pathway in NSCLC has led to the development of a class of medications aimed at inhibiting this pathway, including erlotinib, gefitinib and cetuximab. The efficacy of these medications seems to correlate with the presence of mutations in the EGFR gene. It has now been widely accepted that specific activating mutations in EGFR predicts the response of NSCLC to gefitinib and erlotinib. The failure of treatment with EGFR inhibitors also appears to correlate with both specific mutations in EGFR and with mutations in other proteins in the EGFR pathway. The importance of angiogenesis to tumour growth has led to interest in medications which inhibit angiogenesis. The vascular endothelial growth factor (VEGF) and its receptor are of particular interest. Once treatment has been initiated, biomarkers play an important role in patient monitoring. The serum levels of CYFRA-21-1 and CEA, as well serum nucleosome levels, correlate with the tumour's response to therapy. In addition, serum levels of circulating tumour cells, as well as the detection of specific mutations in circulating tumour DNA may be of clinical use in the future. This paper describes the current role of biomarkers in the detection, diagnosis and treatment of lung cancer, and presents data relating to the development of new biomarkers which are emerging as tools in the management of this difficult disease.