Predictive role of repair enzymes in the efficacy of Cisplatin combinations in pancreatic and lung cancer.

Platinum combinations are the mainstay of treatment for non-small cell lung cancer (NSCLC), while for pancreatic cancer platinum combinations are being given to good-performance status patients. These platinum combinations consist of cis- or carboplatin with gemcitabine, while, for non-squamous NSCLC and mesothelioma, of pemetrexed. The combination of gemcitabine and cisplatin is based on gemcitabine-induced increased formation and retention of DNA-platinum adducts, which can be explained by a decrease of excision repair cross-complementing group-1 (ERCC1)-mediated DNA repair.

Impact of epidermal growth factor receptor and KRAS mutations on clinical outcomes in previously untreated non-small cell lung cancer patients: results of an online tumor registry of clinical trials.

Purpose: The impact of epidermal growth factor receptor (EGFR) and KRAS genotypes on outcomes with erlotinib or gefitinib therapy continues to be debated. This study combines patient data from five trials in predominantly Western populations to assess the impact of EGFR and KRAS mutations on first-line therapy with an EGFR-tyrosine kinase inhibitor (TKI) and compare clinical versus molecular predictors of sensitivity.

Experimental Design: Chemotherapy-naïve patients with advanced non-small cell lung cancer and known EGFR mutation status treated with erlotinib or gefitinib monotherapy as part of a clinical trial were eligible for inclusion.

Epigenetic mechanisms of irinotecan sensitivity in colorectal cancer cell lines.

Irinotecan is a topoisomerase-I (Top-I) inhibitor used for the treatment of colorectal cancer. DNA demethylating agents, including 5-azacytidine (5-aza), display synergistic antitumor activity with several chemotherapy drugs. 5-Aza may enhance irinotecan cytotoxicity by at least one of the following mechanisms: (a) Top-I promoter demethylation, (b) activation of genes involved in Top-I transcriptional regulation (p16 or Sp1), and (c) modulation of the cell cycle and apoptosis after DNA damage.

Tissue micro array analysis of ganglioside N-glycolyl GM3 expression and signal transducer and activator of transcription (STAT)-3 activation in relation to dendritic cell infiltration and microvessel density in non-small cell lung cancer.

Background: Tumor immune escape and angiogenesis contribute to tumor progression, and gangliosides and activation of signal transducer and activator of transcription (STAT)-3 are implicated in these processes. As both are considered as novel therapeutic targets, we assessed the possible association of ganglioside GM3 expression and STAT3 activation with suppression of dendritic cell (DC) activation and angiogenesis in non-small cell lung cancer (NSCLC).

Methods: Immunohistochemistry was performed on a tissue array to determine N-glycolyl GM3 (GM3) and phosphorylated STAT3 (pSTAT3) expression in 176 primary NSCLC resections.

Integration of gene dosage and gene expression in non-small cell lung cancer, identification of HSP90 as potential target.

Background: Lung cancer causes approximately 1.2 million deaths per year worldwide, and non-small cell lung cancer (NSCLC) represents 85% of all lung cancers. Understanding the molecular events in non-small cell lung cancer (NSCLC) is essential to improve early diagnosis and treatment for this disease.

Global histone modifications predict prognosis of resected non small-cell lung cancer.

Purpose: Epigenetic modifications may contribute to the development and progression of cancer. We investigated whether epigenetic changes involving multiple histones influence prognosis of non-small-cell lung cancer (NSCLC) patients.

Patients And Methods: We used immunohistochemistry to assess histone 3 lysine 4 dimethylation (H3K4diMe), and acetylation of histone 2A lysine 5 (H2AK5Ac), histone 2B lysine 12, histone 3 lysine 9 (H3K9Ac), and histone 4 lysine 8 in resected tumor samples of 138 NSCLC patients.

Functional analysis of cancer-associated EGFR mutants using a cellular assay with YFP-tagged EGFR intracellular domain.

Background: The presence of EGFR kinase domain mutations in a subset of NSCLC patients correlates with the response to treatment with the EGFR tyrosine kinase inhibitors gefitinib and erlotinib. Although most EGFR mutations detected are short deletions in exon 19 or the L858R point mutation in exon 21, more than 75 different EGFR kinase domain residues have been reported to be altered in NSCLC patients. The phenotypical consequences of different EGFR mutations may vary dramatically, but the majority of uncommon EGFR mutations have never been functionally evaluated.

EGFR and K-ras mutation analysis in non-small cell lung cancer: comparison of paraffin embedded versus frozen specimens.

Background: Mutational analysis of the Epidermal Growth Factor Receptor (EGFR) and K-ras genes to select non-small cell lung cancer (NSCLC) patients for treatment with novel EGFR tyrosine kinase inhibitors is an appealing possibility currently under investigation. Although frozen tumor tissue would probably be the optimal source for analysis, the most common source of tumor material is fixed and paraffin embedded (FPE) archival specimens. Here, we evaluate how different procedures of tissue sample processing and preservation may affect the outcome of EGFR and K-ras mutation analysis.

Genetic heterogeneity in patients with multiple neoplastic lung lesions: a report of three cases.

Introduction: It is important to determine the relation among the various lesions in patients presenting with multiple malignant lung tumors to define the best treatment approach. A better understanding of the molecular alterations present in the different lesions may help in defining this relation.

Methods: We performed a detailed molecular analysis of several tumor specimens obtained from three patients presenting with multiple lung lesions.

Response to erlotinib in first-line treatment of non-small-cell lung cancer in a white male smoker with squamous-cell histology.

Erlotinib, a potent inhibitor of the tyrosine-kinase (TK) activity of human epidermal growth factor receptor (HER1/EGFR), produces significant survival and quality of life benefits in patients with previously treated advanced-stage non-small-cell lung cancer. Although the survival benefit from erlotinib was observed in varied subgroups of patients, the radiographic responses were more common in certain patient subgroups, such as women, never-smokers, patients with adenocarcinoma histology, patients of Asian ethnicity, and patients with presence of HER1/EGFR TK domain mutations. Herein, we describe a white male former smoker with advancedstage squamous cell non-small-cell lung cancer, who responded to first-line erlotinib.

Erlotinib for frontline treatment of advanced non-small cell lung cancer: a phase II study.

Purpose: Erlotinib has proven activity in pretreated patients with advanced non-small cell lung cancer (NSCLC). We evaluated erlotinib in the frontline treatment of advanced NSCLC and assessed biological predictors of outcome.

Experimental Design: In this phase II study, chemotherapy-naive patients with stage IIIB/IV NSCLC received oral erlotinib (150 mg/d) until disease progression or unacceptable toxicity occurred.

Predictive factors for outcome in a phase II study of gefitinib in second-line treatment of advanced esophageal cancer patients.

Purpose: The efficacy of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) gefitinib was assessed in a phase II study in patients with advanced esophageal cancer. Several biologic features were investigated as potential markers of gefitinib activity.

Patients And Methods: Patients with advanced esophageal cancer, who had failed one line of prior chemotherapy, were administered gefitinib 500 mg/d.

Enhanced cytotoxicity induced by gefitinib and specific inhibitors of the Ras or phosphatidyl inositol-3 kinase pathways in non-small cell lung cancer cells.

In this study, we have characterized a panel of NSCLC cell lines with differential sensitivity to gefitinib for activating mutations in egfr, pik3ca, and k-ras, and basal protein expression levels of PTEN. The egfr mutant NSCLC cell line H1650 as well as the egfr wild type cell lines H292 and A431 were highly sensitive to gefitinib treatment, indicating that other factors determine gefitinib-sensitivity in egfr wild type cells. Activating k-ras mutations were specifically detected in gefitinib-resistant cells, suggesting that the occurrence of k-ras mutations is correlated with resistance to EGFR antagonists.