Lung cancer is the leading cause of cancer-related death worldwide. This section will review recent papers regarding the prevention of lung cancer, molecular mechanisms, new diagnostic techniques, translational research and treatments for lung cancer.
Based on a review by Lim W.Y. and Seow A., approximately 40% of the world's population depends on biomass fuels (wood, charcoal, dung, crop residue) for cooking and heating. This burden is particularly high among Asian countries. The authors summarized the biological and epidemiological evidence of biomass fuel emissions on lung cancer development. Among several epidemiologic reports, Lissowska et al.'s case–control study and a pool of seven case–control studies published for the International Lung Cancer Consortium convincingly revealed an increased risk of lung cancer due to wood smoke exposure, with an odds ratio of 1.21–1.31.
Recently, a number of genome-wide association studies identified several chromosomal regions that contain genes associated with the risk of lung cancer in populations of European descent. Bae et al. examined and confirmed the association between single-nucleotide polymorphisms in the 5p15 and 5q25 chromosomal regions and lung cancer risk in a Korean population, findings that have already been identified in Europe. Specifically, re2736100, CLPTM1L rs402710 and rs401681 single-nucleotide polymorphisms in the 5p15 region have been found to be significantly associated with the risk of lung cancer and, therefore, populations harbouring these genetic variants should be strongly advised to stop smoking and receive careful follow up.
Screening and early diagnosis
Screening for lung cancer using chest X-ray has not shown long-term benefits in terms of overall mortality. The increased sensitivity of CT scanning has rekindled the promotion of early detection and has led to several hypothesis-generating studies. However, until the results of the American National Lung Cancer Screening Trial were published, whether screening using CT scanning could reduce lung cancer mortality remained unknown. The findings of the National Lung Cancer Screening Trial were reported in 2011 and revealed that low-dose CT screening reduces mortality due to lung cancer by 20% and all-cause mortality by 6.7% compared with chest radiograph screening. Spiro and Navani reviewed this topic by evaluating the National Lung Cancer Screening Trial as well as other studies. In the Italian DANTE study, it was reported that the CT arm contained more patients with low-stage and resectable diseases, although the effects of screening on lung cancer mortality in this study have not yet been reported. The results of the French DEPISCAN study, which enrolled 1000 males and females who had smoked more than 15 cigarettes per day for 20 years or had quit smoking within the last 15 years and were currently attending general practices, have not yet been reported. The authors emphasized that many pitfalls and shortcomings of CT screening remain to be overcome, including overdiagnosis bias, cost-effectiveness, false-positive findings of multiple noncalcified nodules and the willingness of relevant populations to accept CT scanning, before its success can be confirmed.
The use of endobronchial ultrasound (EBUS)-guided transbronchial needle aspiration (TBNA) to determine lymph node (LN) staging in lung cancer patients has become popular. Schmid-Bindert et al. prospectively evaluated the ability of six ultrasound criteria and a sum score model to predict malignancy in mediastinal LN. The six criteria were as follows: short axis > 1 cm, heterogeneous pattern, round shape, distinct margin, absence of a central hilar structure and medium to high blood flow in the LN. If more than two criteria were present, the LN was classified as exhibiting a high risk of malignancy. Two hundred and eighty-one LN in 145 patients were analysed. Echogenicity performed the best among all the variables, exhibiting high sensitivity, specificity and positive and negative predictive values (78%, 77%, 73% and 80%, respectively). The probability of malignancy based on the number of positive criteria (the sum score) was approximately 80% when all criteria were met and less than 10% when only two criteria or less were met. Accordingly, criteria based on EBUS-TBNA can be helpful for increasing the accuracy of diagnosing LN metastasis.
Recently, two epoch-making update revisions were made in the field of lung cancer: the Tumor, Node, Metastasis system for classifying lung cancer and the new classification of lung adenocarcinoma. Marshall et al. reported that the 7th edition Tumor, Node, Metastasis staging system for lung cancer requires further development because nonanatomic prognostic factors such as age, performance status, histological grade and serum markers are lacking. Moreover, other variables such as the standardized uptake value obtained on fluoro-deoxyglucose positron emission tomography scanning and molecular profiles such as the epidermal growth factor receptor status may need to be prospectively evaluated in the next revision.
Lung adenocarcinomas exhibit a wide spectrum of clinical, molecular and histological features. The European Respiratory Society and the American Thoracic Society sponsored a new classification study that presented several modifications to the 2004 World Health Organization criteria for the diagnosis of resected adenocarcinoma. Kadara et al. reviewed recent advances in the molecular pathology of lung adenocarcinoma with an emphasis on genomics and DNA alterations. Lung adenocarcinomas exhibit unique genomic aberrations compared with lung squamous cell carcinomas. Mutations in the K-ras, epidermal growth factor receptor and Her2/Neu oncogenes occur almost exclusively in adenocarcinomas. An increased gene dosage and protein expression of thyroid transcriptional factor-1/NK2 homeobox 1 are prevalent in patients with lung adenocarcinoma. The ALK fusion gene, the cMet amplification, the ROS-1 rearrangement and the RET fusion gene were recently identified as being powerful driver oncogenes in this tumour type. The authors ultimately suggested that comprehensive analyses of early molecular events in the pathogenesis of lung adenocarcinoma will undoubtedly reveal biomarkers that can aid prevention through the use of personalized strategies in the future.
Interestingly, a case of large-cell neuroendocrine carcinoma with the epidermal growth factor receptor mutation that may have transformed from an adenocarcinoma was recently reported. This suggests that not only adenocarcinoma, but also other histological types of lung cancer, may need to be evaluated for the epidermal growth factor receptor mutation status because the treatment strategy is dependent on the molecular profile.
Chen et al. reviewed biomarkers and transcriptome profiling in patients with lung cancer. Although accumulated studies have suggested that biomarkers can be used in the clinical setting, none are routinely used in clinical practice, except for EGFR-activating mutations. The authors indicated that large-scale prospective trials are urgently needed to validate previously identified biomarkers. The expression of excision repair cross-complementation group 1 is known to be a favourable prognostic marker in patients who have undergone surgery for non-small-cell lung cancer, but a poor predictive marker for cisplatin response. Tseden-Ish M. et al. assessed the prognostic role of excision repair cross-complementation group 1 expression, single-nucleotide polymorphisms, excision repair cross-complementation group 1 and class III β tubulin in patients with lung cancer who underwent surgery followed by adjuvant chemotherapy. They revealed that the excision repair cross-complementation group 1 expression and the AA/CA genotype at C8092A are correlated with good prognoses.
The epithelial-to-mesenchymal transition contributes to the development of various malignant features in cancer cells, including motile, invasive, anti-apoptotic and stem-like phenotypes.[18, 19] According to Sato M. et al.'s review, epithelial-to-mesenchymal transition may occur during lung cancer development. Numerous studies have reported that the loss of E-cadherin is quite common and correlates with poor prognoses in patients with lung cancer. In addition, it has been shown that the expression of molecules involved in epithelial-to-mesenchymal transition correlates with the clinicopathological features of non-small-cell lung cancer. Targeting the epithelial-to-mesenchymal transition pathway appears to be a very promising therapeutic strategy for treating lung cancer because epithelial-to-mesenchymal transition is involved in most of the important malignant properties of cancer cells.
Giroux Leprieur et al. investigated factors associated with long-term survival (>2 years) among patients with advanced non-small-cell lung cancer and identified new factors, including the administration of maintenance therapy, surgery, a time to first progression of the tumour of >3 months and a performance status of 0–1 at first progression of the tumour. Therefore, assessing these factors may identify populations of patients with non-small-cell lung cancer that are likely to exhibit prolonged life expectancies.
Malignant pleural mesothelioma exhibits a poor prognosis. Although treatment with a combination of pemetrexed and cisplatin has been approved, the overall survival of patients with malignant pleural mesothelioma has not been dramatically prolonged. Consequently, new effective molecular targeted drugs are urgently required. One study reported that SU6668, a multiple tyrosine kinase inhibitor, exhibited antitumour effects against human malignant pleural mesothelioma cells and revealed prolonged survival in an orthotopic implantation model of human malignant pleural mesothelioma. These findings suggest that SU6668 is a useful therapeutic candidate to target human malignant pleural mesothelioma.