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Journal of Thoracic Oncology:
doi: 10.1097/JTO.0000000000000112
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In This Issue

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A Prospective, Molecular Epidemiology Study of EGFR Mutations in Asian Patients with Advanced Non– Small-Cell Lung Cancer of Adenocarcinoma Histology (PIONEER)

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The PIONEER trial was conducted to evaluate epidermal growth factor receptor (EGFR) mutations in Asian patients with advanced lung adenocarcinoma. Patients were 20 years of age or more and had stage IIIB/IV adenocarcinoma with no prior treatment. The primary endpoint was EGFR mutation status in tumor samples. The frequency of the mutation was compared between demographic/clinical subgroups. Of the 1482 patients, 43.4% were female, 52.6% never-smoker, and 97.8% had tumors with evaluable EGFR mutations. Of these, 51.4% were EGFR positive and 48.6% EGFR negative. It is the first prospective study that confirmed such a high EGFR mutation incidence in Asian patients with lung adenocarcinoma. A statistically significant association was determined between mutation frequency and sex (female 61.1% versus male 44.0%), country (India 22% versus others 47.2%–64.2%), smoking status (never-smokers 60.7%), pack-years (higher as pack-years decreased), ethnicity, disease stage, and histology. The correlation with ethnicity and pack-years smoked were also significant in multivariate analysis whereas sex was not, after adjusting for smoking status. The authors concluded that the findings of high mutation frequency in demographic/clinical subgroups warrant mutation assessment for all Asian patients with stage IIIB/IV adenocarcinoma, including males and smokers. (p. 154)

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The International Association Study Lung Cancer (IASLC) Strategic Screening Advisory Committee (SSAC) Response to the USPSTF Recommendations

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In response to the draft recommendations from the United States Preventive Services Task Force on low-dose computed tomography (CT) screening for lung cancer, The International Association for the Study of Lung Cancer Strategic Screening Advisory Committee recommended a few current issues to be considered for the implementation of lung cancer screening. First, the cost effectiveness of screening is important for the success of screening programs and could be further improved by including smoking cessation counseling. Data on cost effectiveness will be available from the NLST and NELSON trial. Volume measurement guidelines in CT imaging analysis of suspicious lung nodules to differentiate between benign and malignant lesions will potentially improve the management of the screening. In addition to the NLST selection criteria (age 55–74 years, ≥30 pack-years), the application of risk-prediction models, such as the one developed from the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial data, could improve the sensitivity and positive predictive value of low-dose CT without compromising its specificity and mortality reduction. The committee discredited upper age limit (e.g., 80 years by the United States Preventive Services Task Force) as an accurate criterion for comorbidity in patient selection and suggested revisions as a better definition becomes available. Fitness evaluation was, however, recommended before and during the screening program to ensure the individual is well enough go through follow-up tests and treatment as a result of the screening, and not interfering with the treatment outcome. Harms from overdiagnosis, nodule discovery, and workup should be minimized and could be achieved through careful fitness evaluation, less-invasive procedures of workup of nodules, and adherence to low-dose protocols. (p. 141)

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EGFR Mutation and Brain Metastasis in Pulmonary Adenocarcinomas

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This study explored the relationship between epidermal growth factor receptor (EGFR) mutation status and brain metastases at diagnosis, as well as the prognostic significance of EGFR mutations in the development of brain metastasis in patients with surgically resected lung adenocarcinomas. In 138 patients with EGFR mutations of 314 analyzed, mutations occurred with statistically higher frequency in patients with brain metastases (64.7% brain metastases; 39.8% no metastases; 40.2% extracranial metastases; p = 0.005). EGFR mutation status was associated strongly with brain metastasis (adjusted odds ratio = 3.83, p = 0.001) whereas no association was observed between EGFR mutation and extracranial metastases (adjusted odds ratio = 1.73, p = 0.079). Further analysis in patients with brain metastases (n=51) demonstrated that EGFR mutation was significantly linked to extended tumor spread, that is, higher number of brain metastases (p = 0.029), but not the size of brain metastases.

A subgroup analysis in 133 surgically resected patients was performed to assess prognostic significance of EGFR mutation for the risk of brain metastasis. The findings showed that EGFR-mutated tumor posed a significant higher risk of recurrence of brain metastasis (hazard ratio = 4.49, p = 0.026) after adjustment by pathologic N stage. To conclude, this is the first study to suggest a significant association between EGFR mutation and a higher possibility of brain metastases in patients with pulmonary adenocarcinomas at initial diagnosis and after surgery. EGFR mutations could be useful for early detection of brain metastases, but its predictive value should be evaluated in further studies. (p. 195)

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BRIEF REPORT

HIP1-ALK, A Novel Fusion Protein Identified in Lung Adenocarcinoma
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In addition to the five fusion proteins anaplastic lymphoma kinase (ALK)-EML4, -TFG, -KIF5B, -KCL1, and -PTPN3 reported to be involved in ALK overexpression and activation in non–small-cell lung cancer, a novel fusion gene, huntingtin interacting protein 1 (HIP1)–ALK, was discovered by Hong and colleagues. Reverse transcriptase polymerase chain reaction and immunohistochemistry were used in the detection of this fusion gene and protein expression, respectively. It was localized to the cytoplasm, mainly in the submembrane area. HIP1 is essential for clathrin trafficking and cell survival in relation to its epsin N-terminal homology domain. The coiled-coil domain of HIP1 and the juxtamembrane of ALK on the fusion protein demonstrated potential constitutive dimerization and aberrant activation of the ALK tyrosine kinase activity, which could indicate strong transforming potential. This case report presented HIP1–ALK as a novel diagnostic and therapeutic candidate for lung adenocarcinoma, which warrants further studies.

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RESEARCH WATCH

Integrative and Comparative Genomic Analysis of Lung Squamous Cell Carcinomas in East Asian Patients

The authors set out to investigate somatic genome abnormalities in lung squamous cell carcinomas (SCC) in Korean patients to determine therapeutically actionable targets and conduct comparative analyses in lung SCC. DNA from 104 SCC samples and paired normal tissues from Korean patients were subject to whole-exome sequencing and analyses of copy number and transcriptome (subset of samples). Clinical significance of the genetic mutations was evaluated. A high frequency of mutation (average 261 somatic exonic mutations/tumor) was found, with a signature of cigarette smoke exposure. Statistically significant mutations were demonstrated in seven genes: TP53, RB1, PTEN, NFE2L2, KEAP1, MLL2, and PIK3CA. The finding of comparative analysis revealed a similar mutation pattern between Korean and North American lung SCC samples, as opposed to the differences in lung adenocarcinoma between the two groups. Moreover, a recurrent FGFR3-TACC3 fusion in lung SCC was found to be a potential actionable target. This study indicated new strategy in identifying new genomic candidate targets toward tailoring treatments for lung SCC.

Kim Y, Hammerman PS, Kim J, et al. Integrative and Comparative Genomic Analysis of Lung Squamous Cell Carcinomas in East Asian Patients. J Clin Oncol, doi:10.1200/jco.2013.50.8556 (2013).

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Prosurfactant Protein B as a Biomarker for Lung Cancer Prediction

On the basis of preliminary studies that demonstrated the potential of prosurfactant protein B (pro-SFTPB) as a blood biomarker for non–small-cell lung cancer, this study aimed to evaluate its predictive potential for patients with lung cancer. The pro-SFTPB measured in 2485 enrollees of the Pan-Canadian Early Detection of Lung Cancer Study was used to assess its predictive value together with other known lung cancer risk factors via multivariable logistic regression models. The data were externally validated with a case-control study design in samples from the Carotene and Retinol Efficacy Trial. The results indicated an odd ratio of 2.220 (p < 0.001) for pro-SFTPB after adjustment for known lung cancer risk factors, including smoking history and family history. The areas under the receiver operating characteristic curve were 0.741 with pro-SFTPB and 0.669 without pro-SFTPB (p < 0.001), and 0.683 with pro-SFTPB in the Carotene and Retinol Efficacy Trial study. The findings suggest pro-SFTPB as an independent predictive biomarker of lung cancer, which could be included in current lung cancer risk-prediction models.

Sin DD, Tammemagi CM, Lam S, et al. Pro-Surfactant Protein B as a Biomarker for Lung Cancer Prediction. J Clin Oncol, doi:10.1200/jco.2013.50.6105 (2013).

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NEWS IN BRIEF

FDA Grants Regular Approval to Crizotinib for ALK-Positive Non– Small-Cell Lung Cancer
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Crizotinib was granted “accelerated approval” in 2011, meaning that the manufacturer needed to perform confirmatory randomized studies for full approval. As a result of superior progression-free survival and overall response rate over chemotherapy, crizotinib (Xalkori) is being granted full approval by the Food and Drug Administration for the treatment of patients with anaplastic lymphoma kinase–positive metastatic non–small-cell lung cancer. In an open-label, active-controlled, multinational and randomized trial, 347 patients with progressive disease after platinum-based chemotherapy with anaplastic lymphoma kinase expression detected by an Food and Drug Administration–approved fluorescence in situ hybridization test were enrolled. Median progression-free survival and overall response rate were 7.7 months and 65%, respectively, for the crizotinib-treated patients versus 3.0 months and 20%, respectively, for those receiving chemotherapy. No difference in overall survival was found in both arms. The rate for common adverse events, including nausea and diarrhea, were 25% or higher, and severe adverse events, including pneumonia and pulmonary embolism, were found in 37% of crizotinib-treated patients.

Photo source: www.cancer.gov

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Smoking After Cancer Diagnosis Increases Risk of Death

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According to a study published in American Association for Cancer Research’s journal Cancer Epidemiology, Biomarkers & Prevention, data from the Shanghai Cohort Study demonstrated that men who continued to smoke after cancer diagnosis increased their risk of death compared with those who quit smoking postdiagnosis. This prospective study evaluated the link between lifestyle and risk of cancer in a population of middle-aged and older men in Shanghai, China. When assessing the men who were smokers at diagnosis, a 76% increase in risk of death from all causes was observed in those continued to smoke postdiagnosis versus those who quit. The increase in risk of death varied with different cancers in smokers who continued smoking: 2.36-fold for lung cancer, 2.95-fold for bladder cancer, and 2.31-fold for colorectal cancer. The findings confirm the effect of postdiagnosis smoking on cancer survival and underscore the importance of tobacco control in cancer survivorship, by implementing smoking cessation counseling from physicians to patients at diagnosis and treatment to achieve better outcomes.

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GLOBOCAN 2012: Cancer Incidence, Mortality, and Prevalence Worldwide
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The latest data on global cancer incidence, mortality, and prevalence have been published by The International Agency for Research on Cancer. According to GLOBOCAN 2012, 14.1 million new cancer cases and 8.2 million cancer-related deaths were estimated in 2012, compared with 12.7 million and 7.6 million, respectively, in 2008. Lung cancer is the most commonly diagnosed worldwide (1.8 million, 13.0% of all cancers), 58% of which occurr in less-developed regions. This is followed by breast cancer (1.7 million, 11.9%), and colorectal cancer (1.4 million, 9.7%). Lung cancer is still the most common cancer in men worldwide (1.2 million, 16.7% of the total), with the highest age-standardized rates in Central and Eastern Europe (53.5 per 100,000), and Eastern Asia (50.4 per 100,000), whereas the lowest rates are in Middle and Western Africa (2.0 and 1.7 per 100,000, respectively). In women, the incidence rates are relatively lower: the highest rates are in Northern America (33.8) and Northern Europe (23.7) whereas the lowest are in Middle and Western Africa (1.1 and 0.8, respectively). Lung cancer is the most common cause of cancer death (1.6 million, 19.4%), followed by liver (0.8 million, 9.1%) and stomach (0.7 million, 8.8%).

Photo source: Ferlay J et al. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11.

Copyright © 2013 by the International Association for the Study of Lung Cancer

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