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Journal of Thoracic Oncology:
doi: 10.1097/JTO.0b013e31828ab04a
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In This Issue

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ROLE OF SELECT GENETIC VARIANTS IN LUNG CANCER RISK IN AFRICAN AMERICANS

The disparities between African Americans and whites in lung cancer incidence and mortality prompted efforts to further understand the underlying biological differences. Spitz and colleagues have previously shown that African Americans with prior emphysema have higher risks of lung cancer compared with white lung cancer patients. The present study, therefore, included a panel of 1440 inflammatory gene variants in a two-phase analysis (discovery and replication), top Genome-Wide Association Studies (GWAS) hits from lung cancer in whites, and 28 single nucleotide polymorphisms (SNPs) from a published gene panel. This study would also evaluate the addition of select genetic hits in improving their risk prediction models for African Americans. The findings revealed 154 significant SNPs in inflammation, and one in REV1 (suggested role in translesion synthesis), and three GWAS hits (2 in the 15q locus and 1 in the HTERT locus) in the discovery set, and one replicated inflammation SNP between IRF4 and EXOC2. This study has demonstrated that incorporating these SNPs into risk-prediction models did not improve the model performance substantially or present any clinical relevance for African American lung cancer cases. The analysis suggested the role of inflammation pathway, smoking-related genes, and TERT and Rev1 in lung cancer development in African Americans.

Spitz MR, Amos CI, Land S, et al. Role of Selected Genetic Variants in Lung Cancer Risk in African Americans. J Thoracic Oncol 2013;8:391-397.

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PATTERNS OF DNA MUTATIONS AND ALK REARRANGEMENT IN RESECTED NODE-NEGATIVE LUNG ADENOCARCINOMA

The genetic mutation profiles of patients with resected lung adenocarcinoma have been extensively assessed, primarily in the advanced or metastatic stage. However, information on the mutation status of patients at early-stage node-negative disease is limited. Yip and colleagues, therefore, conducted a study to examine the patterns of mutations in these diseases. Mutation analysis and fluorescence in situ hybridization were performed on tumors from 204 patients, with resected stage IB lung adenocarcinoma and without neoadjuvant or adjuvant treatments. The study revealed diverse patterns of mutations in these tumors, including KRAS, EGFR, PIK3CA, ALK, PDGFRA, AKT1, BRAF, FGFR1, and HRAS, with at least one of these mutations in a little more than half of the patients. In these early-stage tumors, a high rate (8.8%) of synchronous mutations, either comutations or double mutations, was detected, whereas only 1% harbored an ALK rearrangement. Correlation of mutation status to disease prognosis was established: KRAS and PIK3CA mutations are linked to poorly differentiated tumors, whereas EGFR mutations are linked to well-differentiated tumors. EGFR mutations associated with resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors were also found in 2.5% of the tumors. These findings are useful in providing information about future adjuvant-targeted therapy trials where specific mutations may affect the response to therapy.

Yip PY, Yu B, Cooper WA, et al. Patterns of DNA Mutations and ALK Rearrangement in Resected Node Negative Lung Adenocarcinoma. J Thoracic Oncol 2013;8:408-414.

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THE PROGNOSTIC VALUE OF RATIO–BASED LYMPH-NODE STAGING IN RESECTED NON–SMALL-CELL LUNG CANCER

For patients with non–small-cell lung cancer (NSCLC), lymph-node (LN) staging is currently the strongest prognostic indicator. LN staging for NSCLC in the current tumor, node, metastasis classification is based on the anatomical location of involved LNs, although there is growing evidence establishing the number of metastatic LNs (MLNs) and lymph-node ratio ([LNR], ratio of positive LNs divided by total number of retrieved LNs) as prognostic indicators. This retrospective study aimed to assess the LNR staging for the prognosis of patient with resected NSCLC and to compare its prognostic significance with the MLN staging, and the traditional pN staging. Apart from MLN and LNR, a number of potential factors (age, sex, smoking status, location of tumor, histology, pathology T stage, pN stage, surgical procedure, and chemotherapy) were also evaluated for prognostic value on survival of the 480 NSCLC patients undergoing radical resection between 2006 and 2008. The findings show an association of higher LNR with worse overall survival and disease-free survival in the whole series, and no difference in N2 patients. LNR, smoking status, and chemotherapy are determined as independent predictors for overall survival and disease-free survival in NSCLC patients undergoing radical surgery. LNR, though not proven to be superior to pN staging in this study, would provide more informative prognosis when combined with pN status (N1 patients in this case).

Qiu C, Dong W, Su B, et al. The Prognostic Value of Ratio-Based Lymph Node Staging in Resected Non-Small-Cell Lung Cancer. J Thoracic Oncol 2013;8:429-435.

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Research Watch

EML4-ALK–Positive NSCLC Patient Developed Severe Acute Interstitial Lung Disease after Crizotinib Treatment

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors–associated interstitial lung disease (ILD) has been identified previously. Tamiya and colleagues reported here the first case of crizotinib-associated ILD in an EML4-ALK–positive non–small-cell lung cancer patient. Crizotinib (Xalkori, Pfizer) is generally well-tolerated with pronounced clinical activity, but clinicians should be aware of the possibility of this severe adverse reaction. Because of the high mortality resulting from drug-induced ILD, it is important to determine the prevalence and risk factors of crizotinib-associated ILD.

Tamiya A, Okamoto I, Miyazaki M, et al. Severe Acute Interstitial Lung Disease after Crizotinib Therapy in a Patient with EML4-ALK-Positive Non-Small-Cell Lung Cancer. J Clin Oncol 2013;31:e15-e17.

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GEFITINIB-INDUCED GASTRIC PERFORATION IN METASTATIC LUNG CANCER

This was the first reported case of gefitinib-induced gastric perforation for metastatic lung cancer because of tumor necrosis after treatment. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors–sensitive mutation (exon 19 deletion) was found in both the primary tumor of lung origin and at the metastatic site. This severe complication should be monitored when treating patients with drug-sensitive EGFR mutations, with the use of imaging to detect possible gastrointestinal changes.

Chung WP, Song HL, Ho C L, Chiu NT, Su WC. Gastric perforation secondary to regression of lung adenocarcinoma after gefitinib treatment. J Clin Oncol 2013;31:e6–e8.

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NONINVASIVE [11C]ERLOTINIB POSITRON EMISSION TOMOGRAPHY FOR ASSESSMENT OF EGFR MUTATION

Bahce and colleagues assessed whether quantification and imaging of tumor uptake of [11C]erlotinib in patients with non–small-cell lung cancer (NSCLC) using positron emission tomography was possible. They also determined whether the level of tracer uptake corresponded with the presence of activating tumor EGFR mutations. The quantitative measure of [11C]erlotinib uptake (i.e., volume of distribution) was found to be significantly higher in NSCLC tumors with EGFR exon 19 deletions, than in those without activating EGFR mutations. This finding supports the use of noninvasive [11C]erlotinib positron emission tomography in identifying NSCLC patients who could benefit from tyrosine kinase inhibitor treatment.

Bahce I, Smit EF, Lubberink M, et al. Development of [11C]erlotinib Positron Emission Tomography for In Vivo Evaluation of EGF Receptor Mutational Status. Clin Cancer Res 2013;19:183-193.

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NEXT-GENERATION SEQUENCING DETECTS EGFR MUTATION IN BRONCHOALVEOLAR LAVAGE AND PLEURAL FLUIDS

Compared with Sanger sequencing, this sensitive EGFR next-generation sequencing assay can detect mutation in these biological samples with low number of tumor cells, but large number of normal cells and inflammatory elements. The finding would extend the epidermal growth factor receptor (EGFR) testing to patients with limited amount of materials for molecular diagnosis. Therefore, specific therapies will be available for these patients, who otherwise would be directed to rebiopsies or nontargeted treatments.

Buttitta F, Felicioni L, Del Grammastro M, et al. Effective Assessment of EGFR Mutation Status in Bronchoalveolar Lavage and Pleural Fluids by Next-Generation Sequencing. Clin Cancer Res 2013; doi: 10.1158/1078-0432.ccr-12-1958.

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News in Brief

President Obama Signed the Recalcitrant Cancer Research Act Into Law

The bill (originally known as the Pancreatic Cancer Research and Education Act) mandates that the National Cancer Institute prioritize efforts in pancreatic cancer, lung cancer, and other recalcitrant cancers (5-year survival rate <50%), and make comprehensive scientific plans to improve outcomes.

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LUNG CANCER MORTALITY ON THE GLOBAL AND NATIONAL SCALE

On the basis of the Global Burden of Diseases, Injuries, and Risk Factors Study 2010, topping the global ranking of cancer mortality, deaths from trachea, bronchus, and lung cancers increased dramatically (by 48%; eighth to fifth on causes of death ranking worldwide). Other increases include liver cancer (by 63%; 24th to 16th), and colorectal cancer (by 46%; 21st to 19th). However, overall U.S. cancer death rates dropped by 1.8% per year for men, 1.4% for women, and 1.8% for children from 2000 to 2009, according to the 2013 Annual Report to the nation on the status of cancer. The report also showed increased incidence rates for certain human papillomavirus–related cancers.

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ESOPHAGEAL CANCER SCREENING: RAPID AND DETAILED IMAGING FROM A PILL-SIZED DEVICE

Researchers at the Wellman Center for Photomedicine at Massachusetts General Hospital have developed a novel imaging system encapsulated in a pill-sized device to screen for Barrett’s esophagus, a precancerous condition. After being swallowed down the esophagus, it provides three-dimensional images of microscopic structures of the esophagus lining from a small capsule attached to a flexible tether. Compared with conventional endoscopy, additional advantages of using the new device are short procedure (approximately 6 minutes) and no sedation, trained personnel, special equipment, and setting are required. This inexpensive and low-risk device would allow broader screening and potential prevention of esophagus cancer.

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AMERICAN CANCER SOCIETY UPDATED GUIDELINES ON LUNG CANCER SCREENING

The American Cancer Society (ACS) released these guidelines, concluding sufficient evidence supporting annual lung cancer screening, using low-dose computed tomography in specific high-risk groups: 55- to 74–year-olds with a history of smoking. The guidelines also include ACS acknowledgment of concerns such as relatively high level of false-positive findings, and ACS outline of recommendations to clinicians in identification of patients for screening, and discussion about different aspects of screening with them.

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BOEHRINGER INGELHEIM’S AFATINIB NDA ACCEPTED BY U.S. FDA WITH PRIORITY REVIEW STATUS

Afatinib is under review for the treatment of patients with locally advanced or metastatic non–small-cell lung cancer with an EGFR mutation. The Food and Drug Administration target action date for afatinib will be in the third quarter of 2013. Afatinib has demonstrated superiority compared with the best–in-class chemotherapy (pemetrexed/cisplatin), with 11.1 months progression-free survival versus 6.9 months in the comparator arm. Patients treated with afatinib also showed better management of disease-related symptoms and better overall quality of life. Adverse events were expected with EGFR inhibitors, and were manageable, and reversible. Afatinib was also submitted to the European Medicines Agency for Marketing Authorisation review in 2012.

© 2013International Association for the Study of Lung Cancer

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