Impact of Epidermal Growth Factor Receptor and KRAS Mutations on Clinical Outcome in Resected Non-Small Cell Lung Cancer Patients

Surgery yields best results for non-small cell lung cancer (NSCLC) patients. Epidermal growth factor receptor (EGFR) and its downstream factor Kirsten rat sarcoma viral oncogene homolog (KRAS) are variably mutated in NSCLC. Such mutations predict clinical response to tyrosine kinase inhibitors. This study evaluated incidence and correlation of EGFR and KRAS mutations with clinicopathologic parameters and outcome in resected stage I to III NSCLC.

EGFR and KRAS mutations are frequent in adenocarcinomas and are not prognostic factors for survival. EGFR mutations could be used to identify patients suitable for adjuvant treatment with targeted therapy resulting in potentially improved outcomes.


EGFR-TKI resistance due to BIM polymorphism can be circumvented by in combination with HDAC inhibition

BIM (BCL2L11) is a BH3-only pro-apoptotic member of the Bcl-2 protein family. BIM upregulation is required for apoptosis induction by EGFR tyrosine kinase inhibitors (EGFR-TKIs) in EGFR-mutant forms of non-small cell lung cancer (NSCLC). Notably, a BIM deletion polymorphism occurs naturally in 12.9% of East Asian individuals, impairing the generation of the pro-apoptotic isoform required for the EGFR-TKIs gefitinib and erlotinib and therefore conferring an inherent drug resistant phenotype. We investigated whether the histone deacetylase (HDAC) inhibitor vorinostat could circumvent EGFR-TKI resistance in EGFR mutant NSCLC cell lines that also harbored the BIM polymorphism.

Our results show how HDAC inhibition can epigenetically restore BIM function and death sensitivity of EGFR-TKI, in cases of EGFR mutant NSCLC where resistance to EGFR-TKI is associated with a common BIM polymorphism.


Cox-2 in non-small cell lung cancer: A meta-analysis

We investigated the prognostic value of cyclooxygenase-2 (COX-2) for survival of patients with non-small cell lung cancer (NSCLC). Our meta-analysis shows that the COX-2 expression status is an independent prognostic factor in NSCLC, and this tendency applies to SCC, ADC and stage I NSCLC.


TIMP-2 modulates cancer cell transcriptional profile and enhances E-cadherin/beta-catenin complex expression in A549 lung cancer cells

Tissue Inhibitor of Metalloproteinase 2 (TIMP-2) plays an essential role in regulating matrix remodeling, cell growth, differentiation, angiogenesis and apoptosis in vitro and in vivo. We have recently shown that TIMP-2-mediated inhibition of tumor growth is independent of matrix metalloproteinase-mediated mechanisms, and is a consequence of modulating both the tumor cells and the tumor microenvironment. In the current study we aim to identify the molecular pathways associated with these effects.

We show that TIMP-2 promotes an anti-tumoral transcriptional profile in vitro and in vivo, including upregulation of E-cadherin, in A549 lung cancer cells.


SUVmax may help indicate progression-free survival in stage I NSCLC patients treated with SBRT

SUVmax (Maximum Standardized Uptake Value) may be a significant and clinically independent marker to indicate progression-free survival in stage I non-small cell lung cancer (NSCLC) patients treated with stereotactic body radiation therapy (SBRT), according to research being presented at the 2013 Cancer Imaging and Radiation Therapy Symposium.

SUVmax is measured via PET/CT scan after patients have been injected with radioactive sugar (glucose). Quantifying the SUV of suspicious lesions can aid the identification of early stage tumors because cells that take in greater than normal amounts of radioactive glucose have a higher likelihood of being tumor cells. The highest concentration of radioactive glucose represents SUVmax. Previous studies have been able to correlate SUVmax to the growth rate of tumors, which indicates that tumors with higher SUVmax will more likely be more rapidly growing and will therefore be tumors that are more difficult to treat, may recur or may metastasize more frequently.


Phase 3 Trial of Whole Brain Radiation Therapy and Stereotactic Radiosurgery Alone Versus WBRT and SRS With Temozolomide or Erlotinib for Non-Small Cell Lung Cancer and 1 to 3 Brain Metastases

A phase 3 Radiation Therapy Oncology Group (RTOG) study subset analysis demonstrated improved overall survival (OS) with the addition of stereotactic radiosurgery (SRS) to whole brain radiation therapy (WBRT) in non-small cell lung cancer (NSCLC) patients with 1 to 3 brain metastases. Because temozolomide (TMZ) and erlotinib (ETN) cross the blood-brain barrier and have documented activity in NSCLC, a phase 3 study was designed to test whether these drugs would improve the OS associated with WBRT + SRS.

The addition of TMZ or ETN to WBRT + SRS in NSCLC patients with 1 to 3 brain metastases did not improve survival and possibly had a deleterious effect. Because the analysis is underpowered, these data suggest but do not prove that increased toxicity was the cause of inferior survival in the drug arms.


Hierarchical modeling identifies novel lung cancer susceptibility variants in inflammation pathways among 10,140 cases and 11,012 controls

Recent evidence suggests that inflammation plays a pivotal role in the development of lung cancer. In this study, we used a two-stage approach to investigate associations between genetic variants in inflammation pathways and lung cancer risk based on genome-wide association study (GWAS) data.