Third CECOG consensus on the systemic treatment of non-small-cell lung cancer

The current third consensus on the systemic treatment of non-small-cell lung cancer (NSCLC) builds upon and updates similar publications on the subject by the Central European Cooperative Oncology Group (CECOG), which has published such consensus statements in the years 2002 and 2005 (Zielinski CC, Beinert T, Crawford J et al. Consensus on medical treatment of non-small-cell lung cancer—update 2004. Lung Cancer 2005; 50: 129-137). The principle of all CECOG consensus is such that evidence-based recommendations for state-of-the-art treatment are given upon which all participants and authors of the manuscript have to agree (Beslija S, Bonneterre J, Burstein HJ et al. Third consensus on medical treatment of metastatic breast cancer. Ann Oncol 2009; 20 (11): 1771-1785). This is of particular importance in diseases in which treatment options depend on very particular clinical and biologic variables (Zielinski CC, Beinert T, Crawford J et al. Consensus on medical treatment of non-small-cell lung cancer—update 2004. Lung Cancer 2005; 50: 129-137; Beslija S, Bonneterre J, Burstein HJ et al. Third consensus on medical treatment of metastatic breast cancer. Ann Oncol 2009; 20 (11): 1771-1785). Since the publication of the last CECOG consensus on the medical treatment of NSCLC, a series of diagnostic tools for the characterization of biomarkers for personalized therapy for NSCLC as well as therapeutic options including adjuvant treatment, targeted therapy, and maintenance treatment have emerged and strongly influenced the field. Thus, the present third consensus was generated that not only readdresses previous disease-related issues but also expands toward recent developments in the management of NSCLC. It is the aim of the present consensus to summarize minimal quality-oriented requirements for individual patients with NSCLC in its various stages based upon levels of evidence in the light of a rapidly expanding array of individual therapeutic option

Molecular pathogenesis of lung cancer and potential translational applications

Molecular studies of lung cancer using individual genes and global approaches of gene analysis have shown several observations that are ready to be translated into clinically useful information to provide new methods of diagnosis, risk assessment, prevention, and treatment. Clinically evident lung cancers have acquired 20 or more clonal genetic alterations, and tumor acquired promoter hypermethylation is a frequent epigenetic mechanism of inactivation of gene expression in lung cancer giving at least another 10-20 lesions. Furthermore, small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) have acquired different genetic and epigenetic lesions. Alterations in 3p tumor suppression genes (TSGs) appear especially early, including those of RASSF1A and SEMA3B at 3p21.3, followed by changes in 9p (p16), 8p, and then multiple other sites. Changes consistent with oxidative damage leading to mitotic recombination are frequently seen. Smoking-damaged, histologically normal epithelium as well as epithelium with preneoplastic/preinvasive changes have thousands of clonal patches containing genetic alterations. Finally, correcting even single genetic abnormalities can reverse the malignant phenotype

Aberrant promoter methylation of multiple genes in non-small cell lung cancers

Aberrant methylation of CpG islands acquired in tumor cells in promoter regions is one method for loss of gene function. We determined the frequency of aberrant promoter methylation (referred to as methylation) of the genes retinoic acid receptor β-2 (RARβ), tissue inhibitor of metalloproteinase 3 (TIMP-3), p16, O-methylguanine-DNA-methyltransferase (MGMT), death-associated protein kinase (DAPK), E-cadherin (ECAD), p14, and glutathione S-transferase P1 (GSTP1) in 107 resected primary non-small cell lung cancers (NSCLCs) and in 104 corresponding nonmalignant lung tissues by methylation-specific PCR. Methylation in the tumor samples was detected in 40% for RARβ, 26% for TIMP-3, 25% for p16, 21% for MGMT, 19% for DAPK, 18% for ECAD, 8% for p14, and 7% for GSTP1, whereas it was not seen in the vast majority of the corresponding nonmalignant tissues. Moreover, p16 methylation was correlated with loss of p16 expression by immunohistochemistry. A total of 82% of the NSCLCs had methylation of at least one of these genes; 37% of the NSCLCs had one gene methylated, 22% of the NSCLCs had two genes methylated, 13% of the NSCLCs had three genes methylated, 8% of the NSCLCs had four genes methylated, and 2% of the NSCLCs had five genes methylated. Methylation of these genes was correlated with some clinicopathological characteristics of the patients. In comparing the methylation patterns of tumors and nonmalignant lung tissues from the same patients, there were many discordancies where the genes methylated in nonmalignant tissues were not methylated in the corresponding tumors. This suggests that the methylation was occurring as a preneoplastic change. We conclude that these findings confirm in a large sample that methylation is a frequent event in NSCLC, can also occur in smoking-damaged nonmalignant lung tissues, and may be the most common mechanism to inactivate cancer-related genes in NSCLC