In recent years, the management of lung cancer has been moving towards molecular-guided treatment, and the best example of this new approach is the use of the tyrosine kinase inhibitors (TKIs) erlotinib and gefitinib in patients with mutations in the epidermal growth factor receptor (EGFR). Erlotinib was introduced as a second- and third-line therapy for advanced non-small-cell lung cancer and demonstrated a survival advantage over placebo in unselected patients. Gefitinb did not confer the same advantage but specific subgroups of patients obtained higher response rates. The discovery of EGFR mutations explained the molecular mechanism of sensitivity to TKIs, and several clinical trials have evaluated the efficacy of TKIs in EGFR-mutated patients. New molecular alterations involving different genes have also been described and associated with sensitivity or resistance to TKIs. The identification of molecular predictors of response can allow the selection of patients who will be the most likely to respond to erlotinib and gefitinib.

BACKGROUND Hereditary nonpolyposis colorectal carcinoma (HNPCC) significantly raises the risk of developing colorectal carcinoma (CRC) and other extracolonic tumors. It is defined by the Amsterdam Criteria and is associated with germline mutations in mismatch repair genes, primarily MLH1 and MSH2. The objectives of the current study were to evaluate the presence of CRC (Type I) and other extracolonic tumors (Type II) in families with HNPCC and to analyze the findings for correlations with germline mutations in the MLH1 and MSH2 genes. METHODS Seventy families with an HNPCC diagnosis were analyzed. Denaturing gradient gel electrophoresis and direct sequencing were used for germline mutation analysis in the MLH1 and MSH2 genes. RESULTS Forty‐three of 70 families (61%) presented with HNPCC Type II. In 21 of 30 families that had a complete genetic diagnosis, 16 pathogenic germline mutations (7 MLH1 mutations and 9 MSH2 mutations) and 5 mutations of unknown pathogenecity (all MLH1 mutations) were found. In the remaining nine families, no mutations were detected. Unequivocally pathogenic mutations were far more common in families with HNPCC Type II compared with families that had CRC only (P = 0.01). Families with endometrial carcinoma presented with the greatest probability of mutational detection (P = 0.005). MLH1 was only gene affected in families with HNPCC Type I, whereas mutations in both MLH1 and MSH2 were found in families with HNPCC Type II (P = 0.04). However, the MSH2 gene was more frequently involved in families with HNPCC in which endometrial carcinoma was present (P = 0.005). CONCLUSIONS CRC and endometrial carcinoma were associated with a greater probability of detecting pathogenic mutations in mismatch repair genes, with MSH2 involvement predominating. The results support specific mutational screening strategies, based on observed phenotypes, for families with HNPCC. Cancer 2004. © 2004 American Cancer Society.

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Survival in advanced non-small-cell lung cancer (NSCLC) patients treated with platinum-based chemotherapy is rather variable. Methylation-dependent transcriptional silencing of 14-3-3sigma, a major G2/M checkpoint control gene, could be a predictor of longer survival. A sensitive methylation-specific polymerase chain reaction assay was used to evaluate 14-3-3sigma methylation status in pretreatment serum DNA obtained from 115 cisplatin-plus-gemcitabine-treated advanced NSCLC patients. 14-3-3sigma methylation was observed in all histologic types in 39 patients (34%). After a median follow-up of 9.8 months, median survival was significantly longer in the methylation-positive group (15.1 vs 9.8 months; P = 0.004). Median time to progression was 8 months in the methylation-positive group, and 6.3 months in the methylation-negative group (P = 0.027 by the log-rank test). A multivariate Cox regression model identified only 14-3-3sigma methylation status and ECOG performance status (PS) as independent prognostic factors for survival. In an exploratory analysis, median survival for 22 methylation-positive responders has not been reached, while it was 11.3 months for 29 methylation-negative responders (P = 0.001). Methylation of 14-3-3sigma is a new independent prognostic factor for survival in NSCLC patients receiving platinum-based chemotherapy. It can be reliably and conveniently detected in the serum, thus obviating the need for tumor tissue analysis.