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  • The IASLC Lung Cancer Staging Project: A Renewed Call to Participation
    J. Thorac. Oncol. (IF 6.595) Pub Date : 2018-02-22
    Dorothy J. Giroux, Paul Van Schil, Hisao Asamura, Ramón Rami-Porta, Kari Chansky, John J. Crowley, Valerie W. Rusch, Kemp Kernstine

    Over the past two decades, the International Association for the Study of Lung Cancer (IASLC) Staging Project has been a steady source of evidence-based recommendations for the tumor, node, metastasis (TNM) classification for lung cancer published by the Union for International Cancer Control (UICC) and by the American Joint Committee on Cancer (AJCC). The Staging and Prognostic Factors Committee (SPFC) of the IASLC is now issuing a call for participation in the next phase of the project, designed to inform the ninth edition of the TNM classification for lung cancer. Following the case recruitment model for the eighth edition database, volunteer site participants are asked to submit data on patients diagnosed between January 1, 2011 and December 31, 2019 to the project by means of a secure, electronic data capture (EDC) system provided by Cancer Research And Biostatistics (CRAB) in Seattle, WA, USA. Alternatively, participants may transfer existing data sets. The continued success of the IASLC Staging Project in achieving its objectives will depend on the extent of international participation, the degree to which cases are entered directly into the EDC system, and how closely externally submitted cases conform to the data elements for the project.

    更新日期:2018-02-22
  • Potentially Functional variants of ATG16L2 predict radiation pneumonitis and outcomes in patients with non-small cell lung cancer after definitive radiotherapy
    J. Thorac. Oncol. (IF 6.595) Pub Date : 2018-02-15
    Juyi Wen, Hongliang Liu, Lili Wang, Xiaomeng Wang, Ning Gu, Zhensheng Liu, Ting Xu, Daniel R. Gomez, Ritsuko Komaki, Zhongxing Liao, Qingyi Wei

    Introduction Autophagy not only plays an important role in the progression of cancer but also is involved in tissue inflammatory response. However, few published studies have investigated associations between functional genetic variants of autophagy-related genes and radiation pneumonitis (RP) as well as clinical outcomes in patients with non-small cell lung cancer (NSCLC) after definitive radiotherapy. Methods We genotyped nine potentially functional single nucleotide polymorphisms (SNPs) in four autophagy-related genes (ATG2B, ATG10, ATG12 and ATG16L2) in 393 North American NSCLC patients treated by definitive radiotherapy and assessed their associations with RP, local recurrence-free survival (LRFS), progression-free survival (PFS) and overall survival (OS) in multivariable Cox proportional hazards regression analyses. Results We found that the ATG16L2 rs10898880 CC variant genotype had a better LRFS, PFS and OS [adjusted hazards ratio (adjHR) = 0.59, 0.64 and 0.64; 95% confidence interval (95% CI = 0.45-0.79, 0.48-0.84 and 0.48-0.86); and P = 0.0004, 0.002 and 0.003, respectively], but a greater risk of developing severe RP (adjHR = 1.80, 96% CI = 1.04-3.12, P = 0.037), than patients with CC/CT genotypes. Further functional analyses suggested that the ATG16L2 rs10898880 C variant allele modulated the expression of the ATG16L2 gene. Conclusion This is the first report that functional ATG16L2 C variant homozygous genotype may be a predictor of RP, LRFS, PFS, and OS in NSCLC patients after definitive radiotherapy. Additional larger, prospective studies are needed to confirm these findings.

    更新日期:2018-02-15
  • New insights into the molecular characteristics of pulmonary carcinoids and large-cell neuroendocrine carcinomas, and the impact on their clinical management
    J. Thorac. Oncol. (IF 6.595) Pub Date : 2018-02-14
    J.L. Derks, N. Leblay, S. Lantuejoul, A.M. Dingemans, E.J.M. Speel, L. Fernandez-Cuesta

    Carcinoids and large-cell neuroendocrine carcinomas (LCNEC) are rare neuroendocrine lung tumors. Here we provide an overview of the most updated data on the molecular characteristics of these diseases. Recent genomic studies showed that carcinoids generally contain a low mutational burden and few recurrently mutated genes. Most of the reported mutations occur in chromatin-remodeling genes (e.g. MEN1), and few affect genes of the PI3K-AKT-mTOR pathway. Aggressive disease has been related to chromothripsis, DNA-repair gene mutations, loss of OTP/CD44, and upregulation of RET gene expression. In the case of LCNECs, which present with a high mutation burden, two major molecular subtypes have been identified: one with bi-allelic inactivation of TP53 and RB1, a hallmark of small-cell lung cancer (SCLC); and the other one with bi-allelic inactivation of TP53 and STK11/KEAP1, genes that are frequently mutated in non-small cell lung cancer (NSCLC). These data, together with the identification of common mutations in the different components of combined LCNEC-NSCLC tumors, provides further evidence of the close molecular relation of LCNEC with other lung tumor types. In terms of therapeutic options, future studies should explore the association between mTOR pathway mutations and response to mTOR inhibitors in carcinoids. For LCNEC, preliminary data suggest that the two molecular subtypes might have a predictive value for chemotherapy response, but this observation needs to be validated in randomized prospective clinical trials. Finally, DLL3 inhibitors and immunotherapy may provide alternative options for patient-tailored therapy in LCNEC.

    更新日期:2018-02-14
  • Progress in Radiotherapy for Regional and Oligometastatic Disease in 2017
    J. Thorac. Oncol. (IF 6.595) Pub Date : 2018-02-13
    Suresh Senan, Chad G. Rusthoven, Ben J. Slotman, Shankar Siva

    This review highlights key publications and abstracts in the field of radiation oncology for lung cancer in 2017, and attempts to place these in the context of developments for the broader thoracic oncology community.

    更新日期:2018-02-14
  • Training and validating a portable electronic nose for lung cancer screening
    J. Thorac. Oncol. (IF 6.595) Pub Date : 2018-02-06
    Rens van de Goor, Michel van Hooren, Anne-Marie Dingemans, Bernd Kremer, Kenneth Kross

    Introduction Profiling volatile organic compounds in exhaled breath enables the diagnosis of several types of cancer. In this study we investigated if a portable point-of-care version of an electronic nose (Aeonose™) is able to discriminate between lung-cancer patients and healthy controls, based on their volatile organic compound pattern. Methods In this study, we used five e-nose devices to collect breath samples from lung-cancer patients and healthy controls. Sixty lung-cancer patients and 107 controls exhaled through an e-nose for five minutes. Patients were assigned either to a training group for building an artificial neural network model, or to a blinded control group for validating this model. Results For differentiating lung-cancer patients from healthy controls, the results showed a diagnostic accuracy of 83% with a sensitivity of 83%, specificity of 84% and area under the curve of 0.84. Results for the blinded group showed comparable results with sensitivity of 88%, specificity of 86% and diagnostic accuracy of 86%. Conclusion This feasibility study showed that this portable e-nose can properly differentiate between lung-cancer patients and healthy controls. This result could have important implications for future lung cancer screening. Further studies with larger cohorts, including also more early-stage tumor participants, should be performed to increase the robustness of this non-invasive diagnostic tool, and to determine its added value in the diagnostic chain for lung cancer.

    更新日期:2018-02-07
  • EGFR T790M and C797S mutations as mechanisms of acquired resistance to dacomitinib
    J. Thorac. Oncol. (IF 6.595) Pub Date : 2018-02-02
    Yoshihisa Kobayashi, Toshio Fujino, Masaya Nishino, Takamasa Koga, Masato Chiba, Yuichi Sesumi, Shuta Ohara, Masaki Shimoji, Kenji Tomizawa, Toshiki Takemoto, Tetsuya Mitsudomi

    Introduction Dacomitinib is superior to gefitinib in terms of progression-free survival in patients with EGFR-mutant lung cancer in a recent ARCHER 1050 trial. However, despite a marked initial response, lung cancers eventually acquire resistance to these inhibitors. This study aimed to elucidate the mechanisms of acquired resistance to dacomitinib in vitro. Methods Dacomitinib-resistant clones were established by exposure to fixed concentrations of dacomitinib using N-ethyl-N-nitrosurea (ENU) mutagenesis or by chronic exposure to increasing concentrations of dacomitinib without ENU. EGFR secondary mutations were analyzed by Sanger sequencing. Time to resistance in each clone was compared according to the mutational status. EGFR Del19, L858R, and G719A mutations were introduced into Ba/F3 cells using retroviral vectors. Results Chronic exposure to dacomitinib without ENU induced T790M in Ba/F3 cells expressing Del19. ENU mutagenesis resulted in 171 dacomitinib-resistant clones. Among these clones, 90% acquired T790M. However, C797S occurred in 11% (4/35) of L858R-mutant clones and in 24% (12/38) of G719A-mutant clones established using low-dose dacomitinib. Time to resistance was not significantly different between T790M- and C797S-mutant clones in both of L858R clones (p = 0.93) and G719A clones (p = 0.86). Cells expressing Del19 that acquired T790M were sensitive to osimertinib, whereas cells with L858R+C797S mutations were sensitive to gefitinib or erlotinib. Conclusions These in vitro data demonstrate that dacomitinib can directly induce T790M or C797S secondary mutations. Our data suggest the importance of analyzing these secondary mutations because appropriate selection of EGFR inhibitors could overcome acquired resistance to dacomitinib in a subset of lung cancers.

    更新日期:2018-02-02
  • Early mortality in patients undergoing adjuvant chemotherapy for non-small-cell lung cancer
    J. Thorac. Oncol. (IF 6.595) Pub Date : 2018-02-02
    Daniel Morgensztern, Pamela Samson, Saiama N. Waqar, Siddhartha Devarakonda, Clifford Robinson, Ramaswamy Govindan, Varun Puri

    Background Although adjuvant chemotherapy improves survival in patients with completely resected non-small-cell lung cancer (NSCLC), it is also associated with potentially disabling or lethal adverse events. Since there is limited information on the early mortality among patients undergoing adjuvant chemotherapy, we used the National Cancer Data Base (NCDB) to calculate the percentage of deaths within the first 6 months from starting chemotherapy. Methods The NCDB was queried for patients aged 18 or older who were diagnosed with stage IB to IIIA NSCLC between 2004 and 2012 and received multi-agent adjuvant chemotherapy starting within 120 days from the surgical resection with negative surgical margins. Age groups were divided into less than 50, 51-60, 61-70, 71-80 and more than 80 years. Results A total of 19,691 patients met the eligibility criteria, of which 19,398 had a known 6-month mortality status. The median age was 65 years (range 19-89). The 1, 2, 3, 4, 5 and 6-month cumulative mortality rates from initiation of chemotherapy were 0.7%, 1.3%, 1.9%, 2.6%, 3.3% and 4.2% respectively. The 6-month mortality rates for each age group (≤ 50 years, 51-60, 61-70, 71-80, and >80) was 2.6%, 3.1%, 4.1%, 5.3% and 7.6% respectively (p<0.001). Independent factors associated with increased 6-month mortality included age (age 71-80 vs < 50: odds ratio (OR) 1.72, 95% CI 1.16-2.55, p = 0.007, age > 80 vs < 50: OR 2.43; 1.40-4.20, p = 0.002), male gender (OR 1.42; 1.21-1.67, p <0.001), Charlson-Deyo comorbidity score (score 2 vs 0: OR 1.52; CI 1.22-1.89, p < 0.001), type of surgery (pneumonectomy OR 1.38, 1.11-1.73, p=0.004), length of stay after surgery > 6 days (OR 1.21; 1.03-1.41, p = 0.02) and readmission within 30 days from surgery (OR 1.48; 1.15-1.90, p = 0.02). Conclusion Early mortality with the use of adjuvant chemotherapy following complete resection of NSCLC is a clinical concern. The risk is higher in patients older than 70 years, with higher co-morbidity scores and a prolonged length of stay post-operatively.

    更新日期:2018-02-02
  • Immunological Aspects of Cryoablation of Non-Small Cell Lung Cancer: A Comprehensive Review
    J. Thorac. Oncol. (IF 6.595) Pub Date : 2018-01-31
    Daniel Katzman, Shirley Wu, Daniel H. Sterman

    In cryo-immunotherapy, target tumors are treated with cryoablation to generate anti-tumor immune responses. Since immune checkpoint inhibitors have demonstrated that lung cancer can be an immunotherapy responsive disease, there has been renewed interest in the immunological aspects of cryoablation of lung cancer. Herein, we review pre-clinical and clinical trials of cryoablation of primary lung tumors. We examine the magnitude of cryoablation induced anti-tumor immune responses and the synergy between cryoablation and either other immunotherapies or molecular targeted therapies to improve treatment responses in advanced lung cancer. We further discuss a rationale for the addition of cryoablation to immune checkpoint inhibitors for the treatment of advanced lung cancer, which is currently under clinical investigation.

    更新日期:2018-02-02
  • Cannabis Use, Lung Cancer, and Related Issues
    J. Thorac. Oncol. (IF 6.595) Pub Date : 2018-01-31
    Emily Stone, James Jett, Graham Warren, K Michael Cummings

    The cannabis plant and its derivatives have been exploited for centuries for recreational and medicinal purposes with millions of regular users around the world. The recreational use of cannabis is reflective of its neuropsychiatric effects such as anxiolysis and euphoria. However, cannabis appears to have an emerging therapeutic role, especially in chronic disease and as an adjunct to cancer treatment. Increasing evidence supports cannabis in the management of chemotherapy induced nausea and vomiting and for pain management, but studies are limited particularly by difficulties associated with standardized dosing estimates and inability to accurately assess biologic activities of compounds in cannabis and derivative products. Smoking cannabis has not been proven to be a risk factor in the development of lung cancer but the data are limited by small studies, misclassification due to self-reporting of usage, small numbers of heavy cannabis smoking and confounding of risk associated with known causative agents for lung cancer such as parallel chronic tobacco use. Cannabis and its biologically effective derivatives warrant additional research, ideally controlled trials where the CBD and the THC strength and usage are controlled and documented.

    更新日期:2018-02-02
  • Computational analysis of epidermal growth factor receptor mutations predicts differential drug sensitivity profiles towards kinase inhibitors
    J. Thorac. Oncol. (IF 6.595) Pub Date : 2018-01-31
    Sravani Akula, Swapna Kamasani, SreeKanth Sivan, Vijjulatha Manga, Dashavantha Reddy Vudem, Rama Krishna Kancha

    Introduction A significant proportion of lung cancer patients carry mutations in the epidermal growth factor receptor (EGFR) kinase domain. The presence of a deletion mutation in exon 19 or L858R point mutation in the EGFR kinase domain were shown to cause enhanced efficacy of inhibitor treatment in NSCLC patients. Several less frequent (“Uncommon”) mutations in the EGFR kinase domain with potential implications in treatment response were also reported. The role of a limited number of uncommon mutations in drug sensitivity was experimentally verified. However, a huge number of these mutations remain uncharacterized for inhibitor sensitivity/resistance. Methods A large scale computational analysis of clinically reported 298 point mutants of EGFR kinase domain has been performed and drug sensitivity profiles for each mutant towards seven kinase inhibitors has been determined by molecular docking. In addition, the relative inhibitor binding affinity (RIBA) towards each drug as compared to that of the ATP was calculated for each mutant. Results The inhibitor sensitivity profiles predicted in this study for a set of previously characterized mutants correlated well with the published clinical, experimental and computational data. Both the single and compound mutations displayed differential inhibitor sensitivity towards first and next generation kinase inhibitors. Conclusions The present study provides predicted drug sensitivity profiles for a large panel of uncommon EGFR mutations towards multiple inhibitors which may help clinicians in deciding mutant-specific treatment strategies.

    更新日期:2018-02-02
  • Differences in longitudinal health utility between stereotactic body radiation therapy and surgery in stage I non-small cell lung cancer
    J. Thorac. Oncol. (IF 6.595) Pub Date : 2018-01-31
    Henri B. Wolff, Leonie Alberts, Elisabeth A. Kastelijn, Birgit I. Lissenberg-Witte, Jos W. Twisk, Frank J. Lagerwaard, Suresh Senan, Sherif Y. El Sharouni, Franz M.N.H. Schramel, Veerle M.H. Coupé

    Introduction There is an ongoing debate on the optimal treatment for stage I non-small cell lung cancer (NSCLC), with increasing evidence for comparable health outcomes after surgery or stereotactic body radiation therapy (SBRT). For clinical decision making, the experienced quality of life, summarized as health utility, is of importance to choose between treatments. In this study, we evaluated differences in longitudinal health utility in stage I NSCLC in the first year after surgical resection versus SBRT, before any recurrence of disease. We also assessed the impact of potential prognostic variables on health utility. Methods Prospectively collected databases containing stage I NSCLC patients treated with either SBRT or surgery were pooled from two large hospitals in the Netherlands. Quality of life data was measured by the QLQ-C30 questionnaire at baseline, and 3, 6 and 12 months after treatment. Health utility (EQ-5D) was calculated from the QLQ-C30 questionnaire using a mapping algorithm. Propensity score matching was used to adjust for selection bias. Treatment effects were estimated for the matched patients using a longitudinal mixed model approach. Results After correction for ECOG score, gender and age, the difference in 1-year averaged health utility between the SBRT and surgery groups was 0.026 (95% CI -0.028 — 0.080). Differences in health utility decreased over time. Conclusions A small, and not statistically significant difference in health utility was found between stage I NSCLC patients treated with either surgery or SBRT. Current analysis strengthens existing evidence that SBRT is an equivalent treatment option for early stage NSCLC. Comparative cost-effectiveness remains to be determined.

    更新日期:2018-02-02
  • Histologic Lung Cancer Incidence Rates and Trends vary by Race/Ethnicity and Residential County
    J. Thorac. Oncol. (IF 6.595) Pub Date : 2018-01-31
    Keisha A. Houston, Khadijah A. Mitchell, Jessica King, Arica White, Bríd M. Ryan

    Introduction Lung cancer incidence is higher among NH blacks compared with NH white and Hispanic populations in the U.S. However, national cancer estimates may not always reflect the cancer burden in terms of disparities and incidence in small geographic areas, especially urban-rural disparities. Moreover, there is a gap in the literature regarding rural-urban disparities in terms of cancer histology. Methods Using population-based cancer registry data—Surveillance, Epidemiology and End Results (SEER) and National Program of Cancer Registries (NPCR)—we present age-adjusted histologic rates and trends by race/ethnicity, and residential county location at the time of first cancer diagnosis. Rate ratios were calculated to examine racial/ethnic differences in rates. Annual percent change (APC) was calculated to measure changes in rates over time. Results We find that declines in squamous cell carcinoma (SCC) are occurring fastest in metropolitan counties, while rates of adenocarcinoma increased fastest in counties non-adjacent to metropolitan areas. Further, while NH black men have increased lung cancer incidence compared with NH white and Hispanic men in all geographic locations, we find that the degree of the disparity increases with increasing rurality of residence. Finally, we report that among women diagnosed at less than 55 years of age, the incidence of SCC and adenocarcinoma was higher for NH blacks compared with NH whites. Conclusions Our results highlight disparities among NH blacks in non-adjacent rural areas. These findings may have significant impact for the implementation of smoking cessation and lung cancer screening programs.

    更新日期:2018-02-02
  • Safety of Combined PD-1 Pathway Inhibition and Intracranial Radiation Therapy in Non-Small Cell Lung Cancer
    J. Thorac. Oncol. (IF 6.595) Pub Date : 2018-01-31
    Harper G. Hubbeling, Emily F. Schapira, Nora K. Horick, Kelly E.H. Goodwin, Jessica J. Lin, Kevin S. Oh, Alice T. Shaw, William A. Mehan, Helen A. Shih, Justin F. Gainor

    Introduction Intracranial metastases are a common cause of morbidity and mortality in patients with advanced non-small cell lung cancer (NSCLC), and are frequently managed with radiation therapy (RT). The safety of cranial RT in the setting of treatment with immune checkpoint inhibitors (ICIs) has not been established. Methods We identified advanced NSCLC patients with brain metastases who received cranial RT and were treated with or without PD-1/PD-L1 inhibitors between August 2013 and September 2016. RT-related adverse events (AEs) were retrospectively evaluated and analyzed according to ICI treatment status, cranial RT type, and timing of RT with respect to ICI. Results Of 163 patients, 50 (31%) patients received ICIs while 113 (69%) were ICI-naive. Overall, 94 (58%), 28 (17%) and 101 (62%) patients received stereotactic radiosurgery (SRS), partial brain irradiation (PBI), and/or whole brain RT (WBRT), respectively. Fifty percent of patient received >1 radiation course. We observed no significant difference in rates of all-grade AEs and grade ≥3 AEs between ICI-naive and ICI-treated patients across different cranial RT types (grade ≥3 AEs: 8% ICI- vs. 9% ICI+ for SRS [P=1.00]; 8% ICI- vs. 10% ICI+ for WBRT [P=0.71]). Additionally, there was no difference in AE rates based on the timing of ICI administration with respect to RT. Conclusions Treatment with ICI and cranial RT was not associated with a significant increase in RT-related AEs, suggesting that use of PD-1/PD-L1 inhibitors in patients receiving cranial RT may have an acceptable safety profile. Nonetheless, additional studies are needed to validate this approach.

    更新日期:2018-02-02
  • Association of PD-L1 expression with tumor-infiltrating immune cells and mutation burden in high-grade neuroendocrine carcinoma of the lung
    J. Thorac. Oncol. (IF 6.595) Pub Date : 2018-01-31
    Hye Sook Kim, Jeong Hyeon Lee, Soo Jeong Nam, Chan-Young Ock, Jae-Woo Moon, Chong Woo Yoo, Geon Kook Lee, Ji-Youn Han

    Background The immune microenvironment of high-grade neuroendocrine carcinoma (HGNEC) of the lung, including programmed death-ligand 1 (PD-L1) expression, has not been well characterized. Methods Based on immunohistochemistry (IHC) results, PD-L1 expression on tumor cells (TC) and tumor-infiltrating immune cells (IC) were scored as follows: TC0 and IC0 were defined as PD-L1 expression <1%, TC1 and IC1 as ≥1% but <10%, TC2 and IC2 as ≥10% but <50%, and TC3 and IC3 as ≥50%. Phosphatase and tensin homolog (PTEN) IHC was scored as either lost or retained expression. The Ion AmpliSeq Comprehensive Cancer Panel was used to identify mutations in all coding exons of 409 cancer-related genes. Results A total of 192 patients with large-cell neuroendocrine carcinoma (LCNEC; n = 72) and small cell lung cancer (SCLC; n=120) were studied. The prevalence of PD-L1 expression on TC was 15.1% (29/192). IC infiltration and PD-L1 expression on IC were observed in 34.4% (66/192) and 31.3% (60/192) of patients, respectively. The prevalence of IC infiltration and PD-L1 expression on IC were more strongly correlated with LCNEC than with SCLC (57.6% vs. 23.3%, P<.01; 45.8% vs. 22.5%, P<.01), and high nonsynonymous mutations (P=.05 and .04). PTEN loss was found in 9.5% (18/189) of patients and showed no correlation with PD-L1 expression. Progression-free survival was better in patients with IC infiltration than in those without IC infiltration (median 11.3 vs. 6.8 months, P<.01) and in patients with PD-L1 expression of IC1/2/3 compared to those with IC0 (median 11.3 vs. 7.0 months, P=.03). Conclusion These findings suggest that the PD-1/PD-L1 pathway is activated in the microenvironment of pulmonary HGNEC and correlated with a higher mutation burden.

    更新日期:2018-02-02
  • The role of systemic therapy in the management of stage I large cell neuroendocrine carcinoma of the lung
    J. Thorac. Oncol. (IF 6.595) Pub Date : 2018-01-31
    Lara Kujtan, Varsha Muthukumar, Kevin F. Kennedy, John Russell Davis, Ashiq Masood, Janakiraman Subramanian

    Introduction The optimal treatment strategy for resected stage I large cell neuroendocrine carcinoma of the lung (LCNEC) remains unknown. In this analysis, we evaluate the impact of systemic chemotherapy on patients with stage I LCNEC who have undergone surgical resection. Methods The study population included patients who underwent surgical resection for LCNEC and had pathologic stage I disease. We compared overall survival between patients who underwent surgical resection alone, and those who underwent surgical resection plus chemotherapy. Overall survival (OS) was estimated using the Kaplan-Meier method, and comparisons were analyzed using multivariable Cox models and propensity score matched analyses. Results From 2004 to 2013, 1232 patients underwent surgical resection for stage I LCNEC in the NCDB, including 957 (77.7%) patients who underwent surgical resection alone and 275 (22.3%) who received both surgery plus systemic chemotherapy. Five-year survival was significantly improved in patients who received chemotherapy (hazard ratio (HR) =0.54, 95% confidence interval (CI) 0.43-0.68, p<0.001; 5-year survival, 64.5% versus 48.4%). Multivariable Cox modeling confirmed the survival benefit from chemotherapy for patients with resected stage I LCNEC (HR 0.54, 95% CI 0.43-0.68, p <0.0001). The survival benefit was further confirmed by propensity matched analysis. In addition, older (age > 70 years), comorbid white patients who underwent sublobar resections for tumors >20mm have worse survival outcomes. Conclusion In this largest reported retrospective study of resected stage I LCNEC patients, survival was improved in patients who received chemotherapy, in both stage IA and stage IB LCNEC.

    更新日期:2018-02-02
  • Updated Molecular Testing Guideline for the Selection of Lung Cancer Patients for Treatment With Targeted Tyrosine Kinase Inhibitors : Guideline From the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology
    J. Thorac. Oncol. (IF 6.595) Pub Date : 2018-01-25
    Neal I. Lindeman, Philip T. Cagle, Dara L. Aisner, Maria E. Arcila, Mary Beth Beasley, Eric Bernicker, Carol Colasacco, Sanja Dacic, Fred R. Hirsch, Keith Kerr, David J. Kwiatkowski, Marc Ladanyi, Jan A. Nowak, Lynette Sholl, Robyn Temple-Smolkin, Benjamin Solomon, Lesley H. Souter, Erik Thunnissen, Ming S. Tsao, Christina B. Ventura, Murry W. Wynes, Yasushi Yatabe

    Context In 2013, an evidence-based guideline was published by the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology to set standards for the molecular analysis of lung cancers to guide treatment decisions with targeted inhibitors. New evidence has prompted an evaluation of additional laboratory technologies, targetable genes, patient populations, and tumor types for testing. Objective To systematically review and update the 2013 guideline to affirm its validity; to assess the evidence of new genetic discoveries, technologies, and therapies; and to issue an evidence-based update. Design The College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology convened an expert panel to develop an evidence-based guideline to help define the key questions and literature search terms, review abstracts and full articles, and draft recommendations. Results Eighteen new recommendations were drafted. The panel also updated 3 recommendations from the 2013 guideline. Conclusions The 2013 guideline was largely reaffirmed with updated recommendations to allow testing of cytology samples, require improved assay sensitivity, and recommend against the use of immunohistochemistry for EGFR testing. Key new recommendations include ROS1 testing for all adenocarcinoma patients; the inclusion of additional genes (ERBB2, MET, BRAF, KRAS, and RET) for laboratories that perform next-generation sequencing panels; immunohistochemistry as an alternative to fluorescence in situ hybridization for ALK and/or ROS1 testing; use of 5% sensitivity assays for EGFR T790M mutations in patients with secondary resistance to EGFR inhibitors; and the use of cell-free DNA to “rule in” targetable mutations when tissue is limited or hard to obtain.

    更新日期:2018-01-25
  • Progress in the Management of Advanced Thoracic Malignancies in 2017
    J. Thorac. Oncol. (IF 6.595) Pub Date : 2018-01-11
    Roberto Ferrara, Laura Mezquita, Benjamin Besse

    The treatment paradigm of non-small cell lung cancer (NSCLC) underwent a major revolution during the course of 2017. Immune checkpoint inhibitors (ICIs) brought remarkable improvements in response and overall survival (OS) both in unselected pretreated patients and in untreated patients with PD-L1 expression ≥50%. Furthermore, compelling preliminary results were reported for new combinations of anti-PD-1/PD-L1 agents with chemotherapy or anti-CTLA4 inhibitors. The success of the ICIs appeared to extend to patients with small cell lung cancer (SCLC), mesothelioma or thymic tumors. Furthermore, in SCLC, encouraging activity was reported for an experimental target therapy (Rova T) and a new chemotherapeutic agent (lurbinectedin). For oncogene-addicted NSCLC, next-generation tyrosine kinase inhibitors (such as osimertinib or alectinib) have demonstrated increased response rates and progression-free survival compared to first-generation TKIs in both EGFR-mutated and ALK-rearranged NSCLC patients. However, due to the lack of mature OS data and considering the high efficacy of these drugs in NSCLC patients previously exposed to first or second-generation TKIs, definitive conclusions cannot yet be drawn concerning the best treatment sequence. In addition, new oncogenes such as mutant BRAF, MET and HER2, and RET rearrangements have joined the list of potential targetable drivers. In conclusion, the field of thoracic oncology is on the verge of a breakthrough which will open up many promising new therapeutic options for physicians and patients. The characterization of predictive biomarkers of sensitivity or resistance to immunotherapy, and the identification of the optimal therapeutic combinations (for ICIs) and treatment sequence (for oncogene-addicted NSCLC) represent the toughest upcoming challenges in the domain of thoracic oncology.

    更新日期:2018-01-11
  • The addition of chemotherapy to radiation therapy improves survival in elderly patients with stage III non-small cell lung cancer
    J. Thorac. Oncol. (IF 6.595) Pub Date : 2018-01-08
    Eric D. Miller, James L. Fisher, Karl E. Haglund, John C. Grecula, Meng Xu-Welliver, Erin M. Bertino, Kai He, Peter G. Shields, David P. Carbone, Terence M. Williams, Gregory A. Otterson, Jose G. Bazan

    Introduction Elderly patients represent the majority of lung cancer diagnoses but are poorly represented in clinical trials. We evaluated the overall survival (OS) of elderly patients with stage III non-small cell lung cancer (NSCLC) treated with definitive radiation compared to those treated with definitive chemoradiation. Methods We conducted a comparative effectiveness study of radiation therapy vs. chemoradiation in elderly (≥70 years old) patients with stage III NSCLC not treated surgically diagnosed from 2003-2014 using the National Cancer Database. Two cohorts were evaluated: patients treated with definitive (≥59.4 Gy) radiation (n=5,023) and patients treated with definitive chemoradiation (n=18,206). Chemoradiation was further defined as concurrent (radiation and chemotherapy started within 30 days of each other) or sequential (radiation started>30 days after chemotherapy). We compared OS between the treatment groups using the Kaplan-Meier method and Cox proportional hazards regression before and after propensity score matching (PSM). Results Treatment with chemoradiation was associated with improved OS compared to radiation before PSM (HR=0.66, 95%CI 0.64-0.68, p<.001) and after PSM (HR=0.67, 95%CI 0.64-0.70, p<.001). Relative to concurrent chemoradiation, sequential chemoradiation was associated with a 9% reduction in the risk of death (HR=0.91, 95%CI 0.85-0.96, p=.002). Conclusions We found that definitive chemoradiation resulted in a survival advantage compared to definitive radiation in elderly patients. Sequential chemotherapy and radiation was superior to concurrent chemoradiation. While prospective trials are needed, this analysis suggests that chemoradiation should strongly be considered for elderly patients and the optimal sequencing of chemotherapy and radiation remains an unanswered question for this patient population.

    更新日期:2018-01-08
  • Brief Report: Tivantinib in Combination with Erlotinib Versus Erlotinib Alone for EGFR Mutant NSCLC: An Exploratory Analysis of the Phase 3 MARQUEE Study
    J. Thorac. Oncol. (IF 6.595) Pub Date : 2017-12-27
    Giorgio V. Scagliotti, Dale Shuster, Sergey Orlov, Joachim von Pawel, Frances A. Shepherd, Jeffrey S. Ross, Qiang Wang, Brian Schwartz, Wallace Akerley

    Introduction This exploratory subgroup analysis of the MARQUEE study evaluated the efficacy and safety of erlotinib plus tivantinib in patients with epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC). Methods Patients with advanced, non-squamous, EGFR and mesenchymal-epithelial transition (MET) inhibitor-naive NSCLC, previously treated with 1 to 2 lines of systemic therapy, were randomized to oral erlotinib (150 mg once daily) plus tivantinib (360 mg twice daily) or to erlotinib plus placebo. The primary endpoint was overall survival. Results Among 1,048 patients enrolled, 109 (10.4%) had EGFR-mutant disease. Erlotinib plus tivantinib improved progression-free survival (PFS) in this subpopulation; median PFS was 13.0 months for erlotinib plus tivantinib (n=56) and 7.5 months for erlotinib plus placebo (n=53) (hazard ratio [HR]=0.49, 95% confidence interval [CI]: 0.31-0.77). Deaths occurred in 73 (67%) patients, and median overall survival was 25.5 months in the erlotinib plus tivantinib arm versus 20.3 months in the erlotinib plus placebo arm (HR=0.68, 95% CI: 0.43-1.08). Common adverse events included diarrhea, rash, and asthenia. Neutropenia and febrile neutropenia were more common with erlotinib plus tivantinib. Conclusions Erlotinib plus tivantinib was tolerable and showed improved efficacy over erlotinib monotherapy in previously treated EGFR-mutant NSCLC.

    更新日期:2017-12-27
  • Excellent Outcomes with Radiosurgery for Multiple Brain Metastases in Oncogene-Addicted Non-Small-Cell Lung Cancer
    J. Thorac. Oncol. (IF 6.595) Pub Date : 2017-12-19
    Tyler P. Robin, D. Ross Camidge, Kelly Stuhr, Sameer K. Nath, Robert E. Breeze, Jose Pacheco, Arthur K. Liu, Laurie E. Gaspar, W Thomas Purcell, Robert C. Doebele, Brian D. Kavanagh, Chad G. Rusthoven

    Introduction Patients with brain metastases (BM) arising from EGFR-mutated and ALK-rearranged NSCLC have a favorable prognosis compared to non-oncogene-addicted NSCLC, emphasizing the importance of minimizing toxicities, such as the cognitive sequelae of whole brain radiation therapy (WBRT). Nevertheless, while radiosurgery without WBRT is the preferred strategy for 1-3 BM, this paradigm remains controversial for patients with multiple BM. Methods We reviewed the cases of patients with oncogene-addicted NSCLC presenting to our cancer center between 2008 and 2017 and included only patients treated to ≥4 BM in a single radiosurgery session. Results We identified 35 patients with a median follow-up of 4.1 years. Number of BM treated in a single radiosurgery session ranged from 4-26, and in total over all courses, ranged from 4-47. Median survival was 3.0 years (4.2 for ALK, 2.4 for EGFR) from the diagnosis of BM, and survival was equivalent regardless of number of radiosurgery courses, number of BM treated in total, or number of BM treated in a single radiosurgery session. Mean hippocampal and whole-brain doses were exceedingly low even for patients treated to >10 BM (1.2 and 0.8 Gy, respectively). Radiosurgery was reasonably well tolerated and five-year freedom from neurologic death was 84%. Five-year freedom from WBRT was 97%. Conclusions The utilization of radiosurgery for multiple BM is controversial, yet patients with EGFR-mutated and ALK-rearranged NSCLC may be uniquely suited to benefit from this approach. These results support single and multiple courses of radiosurgery without WBRT for oncogene-addicted NSCLC patients with ≥4 BM.

    更新日期:2017-12-19
  • Prognostic Model for Resected Squamous-Cell Lung Cancer: External Multicenter Validation and Propensity Score Analysis exploring the Impact of Adjuvant and Neoadjuvant Treatment
    J. Thorac. Oncol. (IF 6.595) Pub Date : 2017-12-18
    Sara Pilotto, Isabella Sperduti, Giovanni Leuzzi, Marco Chiappetta, Felice Mucilli, Giovanni Battista Ratto, Filippo Lococo, Pierluigi Filosso, Lorenzo Spaggiari, Silvia Novello, Michele Milella, Antonio Santo, Aldo Scarpa, Maurizio Infante, Giampaolo Tortora, Francesco Facciolo, Emilio Bria

    Introduction We developed one of the first clinicopathological prognostic nomograms for resected squamous cell lung cancer (SQLC). Herein, we validate the model in a larger multicenter cohort and we explore the impact of adjuvant/neoadjuvant treatment (ANT). Methods Resected SQLC patients from January 2002 to December 2012 in six institutions were eligible. To each patient was assigned a prognostic score based on those clinicopathological factors included in the model (age, T-descriptor according to TNM 7th edition, lymph nodes, grading). Kaplan-Meier analysis for disease-free/cancer-specific/overall survival (DFS/CSS/OS) was performed according to three-class risk model. Harrell’s C-statistics were adopted for model validation. The effect of ANT was adjusted with propensity score (PS). Results Data from 1,375 patients was gathered (median age: 68 years; male: 86.8%; T-descriptor 1-2/3-4: 71.7%/24.9%; nodes negative/positive: 53.4%/46.6%; grading 1-2/3: 35.0%/41.1%). Data for survival analysis was available for 1,097 patients. With a median follow-up of 55 months, patients at low risk had a significantly longer DFS versus intermediate (HR 1.67, 95% CI 1.40-2.01) and high risk (HR 2.46, 95% CI 1.90-3.19), as well as for CSS (HR 2.46, 95% CI 1.80-3.36; HR 4.30, 95% CI 2.92-6.33) and OS (HR 1.79, 95% CI 1.48-2.17; HR 2.33, 95% CI 1.76-3.07). A trend in favor of ANT was observed for intermediate/high risk patients, particularly for CSS (p=0.06; 5-year CSS 72.7% versus 60.8%). Conclusions A model based on a combination of easily available clinicopathological factors effectively stratifies resected SQLC patients in three-risk classes.

    更新日期:2017-12-18
  • Stromal PD-L1+regulatory T cells and PD-1+CD8+ T cells define the response of different subsets of non-small-cell lung cancer to PD-1/PD-L1 blockade immunotherapy
    J. Thorac. Oncol. (IF 6.595) Pub Date : 2017-12-18
    Si-Pei Wu, Ri-Qiang Liao, Hai-Yan Tu, Wen-Jun Wang, Zhong-Yi Dong, Shu-Mei Huang, Wei-Bang Guo, Lan-Ying Gou, Hui-Wen Sun, Qi Zhang, Zhi Xie, Li-Xu Yan, Jian Su, Jin-Ji Yang, Wen-Zhao Zhong, Xu-Chao Zhang, Yi-Long Wu

    Introduction Inhibition of programmed cell death-1 (PD-1) and its ligand PD-L1 using an immune checkpoint inhibitor has emerged as a promising immunotherapy for non-small-cell lung cancer (NSCLC). The correlation of PD-L1 expression in tumor cells with treatment outcomes has been reported in many pivotal trials; however, the relation remains unclear. Here, we demonstrate that the patients with both high density of PD-1+CD8 and PD-L1+CD4+CD25+ (PD-1hiPD-L1hi) regulatory T cells (Tregs) have a better response to PD1/PD-L1 blockade. Methods and experimental design: In our study, between April 1, 2014 and May 30, 2017, 73 NSCLC peripheral blood samples and fresh tumor specimens were collected for study. Of these, 42 large (10mm3) fresh tumor specimens were obtained from surgical, and checked the immunology biomarker including PD-L1, PD-1, CD8, CD4, and CD25 expression in tumor cells and TILs by flow cytometry, IHC and IF. Moreover, 31 mall biopsy specimens from patients who received immunotherapy (pembrolizumab or nivolumab) were detected by IHC and IF. The correlation between flow cytometry and IF detected for TILs’ density was evaluated by Spearman’s rank correlation test, and the primary end point was progression-free survival (PFS). For the PD-1/PD-L1 blockade assay, the TILs and PB mononuclear CD8+ T cells were cultured (1×105 per well) with anti-PD-1 (clone MIH4), anti-PD-L1 (clone MIH1). The cytotoxic activity of TILs in killing NSCLC cells after stimulation by anti-PD-1 and PD-L1 was measured by a conventional 51Cr release assay. Results We first identified a population of high PD-L1 expressing CD25+ CD4+ T cells (PD-L1hi Tregs) in the tumor microenvironment. The frequency of PD-L1hi Tregs was higher in tumor tissues (mean, 48.6 ± 14.3% in CD25+CD3+CD4+T cells) than in blood (mean, 35.4 ± 10.2% in CD25+CD3+CD4+T cells) and normal tissues (mean, 38.6 ± 9.7% in CD25+CD3+CD4+T cells) (P<0.05), as determined by flow cytometry. The frequency of PD-L1hi Tregs was positively correlated with PD-1+ CD8in Tregs.In addition, the TILs from these patients (PD-1hiPD-L1hi) showed PD-1/PD-L1 pathway dependence and could induce a greater killing effect of TILs by PD-1/PD-L1 blockade treatment. The PD-L1 positive NSCLC patients with PD-1hiPD-L1hiTILs showed a better clinical outcome than those with low frequency of PD-1hi CD8 or PD-L1hi Tregs (Median PFS=Not reach vs 2 months). Conclusions Our findings suggested that the density of PD-L1+CD4+CD25+Tregs in the tumor microenvironment can serve as a diagnostic factor to supplement PD-L1 expression in tumor cells and predict the response to PD-1/PD-L1 blockade immunotherapy in NSCLC.

    更新日期:2017-12-18
  • Influence of Ground-Glass Opacity and the Corresponding Pathological Findings on Survival in Patients with Clinical Stage I Non-Small Cell Lung Cancer
    J. Thorac. Oncol. (IF 6.595) Pub Date : 2017-12-13
    Keiju Aokage, Tomohiro Miyoshi, Genichiro Ishii, Masahiro Kusumoto, Shogo Nomura, Shinya Katsumata, Keigo Sekihara, Kenta Tane, Masahiro Tsuboi

    Introduction The aim was to clarify the influence on patient prognosis of ground glass opacity (GGO) component in each new tumor-node-metastasis stage and propose grouping reflecting the prognosis more accurately. Methods We examined the data of 1290 patients who underwent lung cancer resection from 2003 to 2011. The demographics and overall survival of patients with adenocarcinoma with and without GGO, squamous cell carcinoma, and the others, were compared according to clinical stage (c-stage) from 0 to IB. In adenocarcinoma, we examined the distribution of histological subtypes of adenocarcinoma with and without GGO in each c-stage. Results Each c-stage differentiated overall survival well. However, prognosis of the patients with adenocarcinoma with GGO was considerably favorable compared to the others in c-stage IA2 and IA3, whereas not in IB. In c-stage 0 to IA3, patients showing adenocarcinoma in situ, minimally invasive adenocarcinoma, and invasive lepidic predominant adenocarcinoma accounted for about 50% of the total numbers of patients with adenocarcinoma with GGO (0: 16/21, IA1: 113/143, IA2: 80/157, IA3: 45/94). In c-stage IB, 20% of adenocarcinomas with GGO showed invasive solid predominant adenocarcinoma (IB: 7/38). Most of adenocarcinomas without GGO were in c-stage IA2 to IB, and the distribution of the histological subtype was similar at each c-stage. Invasive acinar and solid predominant adenocarcinomas were more common in adenocarcinoma without GGO. Conclusions Clinical T classification considering GGO component may offer further accurate prognosis for patients with lung cancer less than 3cm in invasive diameter.

    更新日期:2017-12-14
  • Brief Report: Phase 2 Study of the HSP-90 inhibitor AUY922 in Previously Treated and Molecularly Defined Patients with Advanced Non-Small Cell Lung Cancer
    J. Thorac. Oncol. (IF 6.595) Pub Date : 2017-12-13
    Enriqueta Felip, Fabrice Barlesi, Benjamin Besse, Quincy Chu, Leena Gandhi, Sang-We Kim, Enric Carcereny, Lecia V. Sequist, Paal Brunsvig, Christos Chouaid, Egbert F. Smit, Harry J.M. Groen, Dong-Wan Kim, Keunchil Park, Emin Avsar, Sebastian Szpakowski, Mikhail Akimov, Edward B. Garon

    Introduction In this phase 2 study, we evaluated the activity of AUY922 in pretreated stage IV NSCLC patients. Methods Patients with advanced NSCLC were divided into molecularly defined strata based on mutations in EGFR, ALK, KRAS, or wild-type for all three. All patients must have received > 2 prior lines of therapy, except a fifth stratum for less pretreated EGFR cohort (EGFR < 2). In EGFR mutant and ALK-rearranged strata, prior platinum therapy was not required. Patients with EGFR mutation must have received an EGFR TKI unless patients have de novo resistance (eg: T790M or exon 20 insertions). Eligible patients received weekly intravenous AUY922 70 mg/m2. Primary objective was to estimate efficacy (complete/partial response (CR/PR) or in absence of CR/PR a stable disease [SD]) at 18 weeks, by RECIST. Results A total of 153 patients from 21 global centers were enrolled from October, 2010 to November, 2014. Investigator-assessed ORR and SD at 18 weeks were 31.8% and 9.1% in ALK-rearranged stratum; 17.1% and 8.6% in EGFR-mutant stratum; 9.7% and 22.6% in EGFR < 2 stratum; 0% and 7.1% in KRAS mutant stratum, and 8.8% and 8.8% in wild type stratum. Biomarker data showed activity of AUY922 in EGFR-mutant patients with exon 19 deletion, T790M mutation, and exon 20 insertion. Most common (≥ 40%) all-causality AEs were diarrhea, nausea, and decreased appetite. Visual-related disorders were reported in 79.7% of patients (majority were grade 1/2). Thirty-five (22.9%) patients reported night-blindness. Conclusion AUY922 is active in patients with NSCLC, particularly among patients with ALK rearrangements and EGFR mutations.

    更新日期:2017-12-14
  • Brief report: Geographic variation in EGFR mutation frequency in lung adenocarcinoma may be explained by interethnic genetic variation
    J. Thorac. Oncol. (IF 6.595) Pub Date : 2017-12-13
    Lars Soraas, Justin Stebbing

    Our understanding of the etiology of EGFR mutant lung cancer remains incomplete. One persistent finding in the literature is the geographic variation in the frequency of EGFR mutations in lung adenocarcinoma. We investigated the association between two biomarkers of East Asian ancestry, the genetic polymorphisms EDAR V370A and ABCC11 G180A, and the frequency of EGFR mutations in lung adenocarcinoma patients in a range of countries. The Pearson’s linear correlation between the frequency of EGFR mutations and the EDAR polymorphism was 0.92 (P < 2.2 x 10-10) and for the ABCC11 polymorphism it was 0.72 (P < 1.6 x 10-4). These results suggest that the variation in the measured frequency of EGFR mutations in lung adenocarcinoma can be explained, at least in part, by interethnic genetic variation. To improve our understanding of this disease, studies exploring the genetic polymorphism(s) that cause these interethnic differences, as well as the mechanisms of actions through which they work, are warranted.

    更新日期:2017-12-14
  • PD-1 modulates radiation-induced cardiac toxicity through cytotoxic T lymphocytes
    J. Thorac. Oncol. (IF 6.595) Pub Date : 2017-12-13
    Shisuo Du, Lin Zhou, Gregory S. Alexander, Kyewon Park, Lifeng Yang, Nadan Wang, Xinliang Ma, Yajing Wang, Adam P. Dicker, Bo Lu

    Introduction Combined immune checkpoint blockade has led to rare autoimmune complications, such as fatal myocarditis. Recent approvals of several anti-PD1 drugs for lung cancer treatment prompted ongoing clinical trials that directly combine PD-1 inhibitors with thoracic radiotherapy for locally advanced lung cancer. Overlapping toxicities from either modality have the potential to increase the risk for radiation-induced cardiotoxicity (RICT), which is well documented among patients with HD and breast cancer. Methods To investigate cardiotoxicity without the compounding pulmonary toxicity from thoracic RT, we developed a technique to deliver cardiac irradiation (CIR) in a mouse model, concurrently with PD-1 blockade to determine the presence of cardiac toxicity, using physiologic testing and mortality as end points along with histological analysis. Results We observed an acute mortality of 30% within two weeks following CIR+anti-PD1, compared with 0% from CIR+IgG (p= 0.023). Physiological testing demonstrated a reduced left ventricular ejection fraction (P<0.01) by echocardiogram. Tissue analyses revealed increased immune cell infiltrates within cardiac tissue. Depletion of CD8+ lymphocytes with anti-CD8 antibody reversed the acute mortality suggesting that the toxicity is CD8+ cell-mediated. To validate these findings using clinically relevant fractionated radiotherapy regimen, we repeated the study by delivering five daily fractions of 6Gy (fCIR). Similar mortality, cardiac dysfunction, and histological changes were observed in mice receiving fractionated radiotherapy with concurrent anti-PD-1. Conclusions This study provides strong preclinical evidence that RICT is modulated by the PD-1 axis and that PD-1 blockade should be administered with careful radiotherapy planning with an effort of reducing cardiac dose.

    更新日期:2017-12-14
  • Brief Report: PD-L1 expression of tumor cells, macrophages, and immune cells in non-small cell lung cancer patients with malignant pleural effusion
    J. Thorac. Oncol. (IF 6.595) Pub Date : 2017-12-12
    Yen-Han Tseng, Hsiang-Ling Ho, Chiung-Ru Lai, Yung-Hung Luo, Yen-Chiang Tseng, Jacqueline Whang-Peng, Yi-hsuan Lin, Teh-Ying Chou, Yuh-Min Chen

    Introduction Weather we could use IHC stain of PD-L1 on cells of pleural effusion to predict immunotherapy treatment response have not been reported. Methods We retrospectively enrolled patients who had undergone malignant pleural effusion drainage and had effusion cell block specimens from 2014-2016. IHC staining for PD-L1 was performed with tumor cells, immune cells, and macrophage of all cell block specimens. The immunoactivity was defined as 0 for absence of staining; 1+ for faint; 2+ for moderate; 3+ for intense membranous staining. Patients’ clinicopathological characteristics were also collected. Results PD-L1 expression of pleural effusion tumor cells was associated with the PD-L1 expression of macrophages (p=0.003) and immune cells (p<0.001). However, the PD-L1 expression of immune cells was not associated with that of macrophages. The PD-L1 expression of tumor cells was correlated with gender (p=0.012), smoking status (p=0.032), and ECOG performance status (p=0.017). The PD-L1 expression of immune cells was associated with the overall survival of patients (p=0.004). Conclusions These results suggested that there might be an immune interaction between pleural effusion tumor cells and macrophages. The low intensity of PDL1 expression in immune cells is associated with the poor survival of lung cancer patients with malignant pleural effusion.

    更新日期:2017-12-14
  • Preclinical Evidence for Combined Use of Aromatase Inhibitors and NSAIDs as Preventive Agents of Tobacco-Induced Lung Cancer
    J. Thorac. Oncol. (IF 6.595) Pub Date : 2017-12-09
    Laura P. Stabile, Mariya Farooqui, Beatriz Kanterewicz, Shira Abberbock, Brenda F. Kurland, Brenda Diergaarde, Jill M. Siegfried

    Introduction A hormonal role in non-small cell lung cancer (NSCLC) development is well documented. We previously showed that the aromatase inhibitor (AI) anastrozole decreased the development of tobacco carcinogen-induced lung tumors in a murine lung cancer prevention model and that aromatase and estrogen receptor (ER) were expressed in pulmonary inflammatory cells. Methods We utilized a tobacco carcinogen-induced lung tumor mouse model [4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanone (NNK)] to determine whether an AI combined with non-steroidal anti-inflammatory drugs (NSAIDs) results in greater lung tumor prevention effects than single agent treatment. Results Combination of anastrozole (0.1mg/kg/day) with aspirin (25mg/kg/day) following NNK exposure resulted in significantly fewer and smaller lung tumors compared to single agent treatments, accompanied by maximum decreases in circulating β-estradiol (E2) and IL-6, tumor infiltrating macrophages and tumoral Ki67, P-MAPK, P-STAT3 and IL-17A expression. Preneoplasia arising after combination treatment showed the lowest Sox-2 expression, suggesting an inhibitory effect on proliferative capacity in the airways by blocking both E2 and inflammation. Anastrozole combined with ibuprofen instead of aspirin also showed enhanced anti-tumor effects. Moreover, male mice treated with NNK that received E2 in the drinking water showed greater levels of pulmonary macrophages and inflammatory markers compared to control, confirming an E2 effect on inflammation in the microenvironment. Conclusions Our results suggest a benefit to joint targeting of the estrogen and inflammatory pathways for NSCLC prevention. Combining AIs with NSAIDs reduces circulating E2, pro-inflammatory cytokines, and macrophage recruitment in the lung microenvironment following tobacco exposure. This strategy could be particularly effective in women who have underlying pulmonary inflammatory diseases.

    更新日期:2017-12-14
  • Incidental anterior mediastinal nodular lesions on chest CT in asymptomatic subjects
    J. Thorac. Oncol. (IF 6.595) Pub Date : 2017-12-09
    Soon Ho Yoon, Seung Ho Choi, Chang Hyun Kang, Jin Mo Goo

    Hypothesis To investigate the prevalence and characteristics of nodular lesions in the anterior mediastinum that had been incidentally found on screening chest CT in asymptomatic subjects. Methods We included 56,358 consecutive participants (mean age, 52.4±10.5 years; male-female, 35,306:21,052) who underwent a baseline low-dose chest CT scan for health checkups from 2006 through 2013. After confirming the presence of anterior mediastinal nodular lesion, their CT findings, confirmatory diagnosis and interval CT scan were reviewed. The standardized prevalence ratio for thymic epithelial tumor (TET) was calculated based on the Korean cancer statistics for 2014. Results Of the 56,358 participants, 413 had lesions (0.73%; 95%CI, 0.66-0.80%); the prevalence increased with age (P<0.001) and a history of malignancy (P=0.005). 85.2% of the lesions were smaller than 2 cm, 61.3% were round, and 80.2% had CT attenuation higher than 20 Hounsfield units. Among 51 proven cases, 39 lesions (76.9%) were benign and 12 (23.1%) were malignant. The standardized prevalence ratio for TET was 2.04 (95%CI, 1.01–3.42). Among 11 resected TETs, 5 were carcinomas, 10 were stage I-II, and all were completely resected without recurrence. Among the 237 unconfirmed cases with a follow-up CT scan, 82.2% were stable, 8.9% increased, and the other 8.9% decreased. Conclusions The prevalence of incidental nodular lesion was 0.73%. Most lesions had CT features that were indistinguishable from TETs, but a considerable portion of the lesions was suspected to be benign. Incidental TETs were more prevalent than clinically detected tumors, were early-stage cancer, and showed favorable outcomes.

    更新日期:2017-12-14
  • Predictive performance of four programmed cell death ligand 1 assay systems on nivolumab response in previously treated patients with non-small cell lung cancer
    J. Thorac. Oncol. (IF 6.595) Pub Date : 2017-12-09
    Daichi Fujimoto, Yuki Sato, Keiichiro Uehara, Kaori Ishida, Junya Fukuoka, Takeshi Morimoto, Hayato Kawachi, Ryobu Mori, Munehiro Ito, Shunsuke Teraoka, Kazuma Nagata, Atsushi Nakagawa, Kojiro Otsuka, Yukihiro Imai, Keisuke Tomii

    Introduction Nivolumab has demonstrated efficacy against metastatic non-small cell lung cancer (NSCLC). Four programmed cell death ligand 1 (PD-L1) immunohistochemistry (IHC) assay systems are available for identification of responders among patients with NSCLC, and these assays show some differing characteristics. Accordingly, in this study, we evaluated the ability of these assays to identify responders to nivolumab therapy. Methods We retrospectively analyzed patients with previously treated advanced NSCLC, who received nivolumab between January 2016 and September 2016. Specimens were stained using four PD-L1 IHC assays (28-8, 22C3, SP142, and SP263). We classified patients as strongly positive (≥ 50% tumor proportion score [TPS]), weakly positive (1–49% TPS), or negative (< 1% TPS). Results Forty patients with NSCLC and their specimens were analyzed. Analytical comparisons demonstrated good concordance of PD-L1-stained tumor cells among the 28-8, 22C3, and SP263 assays (weighted κ coefficient: 0.64–0.71), whereas the SP142 assay showed lower concordance with other assays (weighted κ coefficient: 0.39–0.55). Progression-free survival in patients showing strongly positive PD-L1 staining classified by 28-8, 22C3, and SP263 assays was significantly longer than that in patients who were negative for PD-L1 staining. Predictive performance of response to nivolumab, as assessed by receiver operating characteristic analysis, was also equivalent among the 28-8, 22C3, and SP263 assays (area under the curve [AUC]: 0.75–0.82), whereas the SP142 assay exhibited lower predictive performance (AUC: 0.68). Conclusions The 28-8, 22C3, and SP263 PD-L1 IHC assays showed equivalent predictive performance, whereas the SP142 assay showed lower predictive performance.

    更新日期:2017-12-14
  • RANKL signaling sustains primary tumor growth in genetically engineered mouse models of lung adenocarcinoma
    J. Thorac. Oncol. (IF 6.595) Pub Date : 2017-12-06
    Julien Faget, Caroline Contat, Nadine Zangger, Solange Peters, Etienne Meylan

    Hypothesis Non-small cell lung cancer (NSCLC) is the leading cause of cancer mortality. Recent retrospective clinical analyses suggest that blocking the receptor activator of NF-κB (RANK) signaling pathway inhibits the growth of NSCLC and might represent a new treatment strategy. Methods RANK and RANKL expression in human lung adenocarcinoma was interrogated from publicly available gene expression datasets. Several genetically engineered mouse models were used to evaluate treatment efficacy of RANK-Fc to block RANKL, with primary tumor growth measured longitudinally using micro-computed tomography. A combination of RANKL blockade with cisplatin was tested to mirror an ongoing clinical trial. Results In human lung adenocarcinoma datasets, RANKL expression was associated with decreased survival and KRAS mutation, with the highest levels in tumors with co-occurring KRAS and LKB1 mutations. In KrasLSL-G12D/WT, KrasLSL-G12D/WT; Lkb1Flox/Flox and KrasLSL-G12D/WT; p53Flox/Flox mouse models of lung adenocarcinoma, we monitored an impaired progression of tumors upon RANKL blockade. Despite elevated expression of RANKL and RANK in immune cells, treatment response was not associated with major changes in the tumor immune microenvironment. Combined RANK-Fc with cisplatin revealed increased efficacy compared to single agents in p53- but not in Lkb1-deficient tumors. Conclusions RANKL blocking agents impair the growth of primary lung tumors in several mouse models of lung adenocarcinoma, and suggest that patients with KRAS mutant lung tumors will benefit from such treatments.

    更新日期:2017-12-14
  • A Phase II Study of Trastuzumab Emtansine in HER2-positive Non-Small-Cell Lung Cancer
    J. Thorac. Oncol. (IF 6.595) Pub Date : 2017-12-05
    Katsuyuki Hotta, Keisuke Aoe, Toshiyuki Kozuki, Kadoaki Ohashi, Kiichiro Ninomiya, Eiki Ichihara, Toshio Kubo, Takashi Ninomiya, Kenichi Chikamori, Daijiro Harada, Naoyuki Nogami, Taizo Hirata, Shiro Hinotsu, Shinichi Toyooka, Katsuyuki Kiura

    Trastuzumab emtansine (T-DM1), an anti-HER2 antibody-drug conjugate, has been shown to significantly improve survival in HER2-positive breast cancer. We report a phase II trial of T-DM1 monotherapy in relapsed non-small-cell lung cancer (NSCLC). with documented HER2-positivity (immunohistochemistry [IHC] 3+, both IHC 2+ and fluorescence in situ hybridization [FISH] +, or exon 20 mutation). This study was terminated early due to limited efficacy. The demographic characteristics in the 15 assessable patients were as follows: age (median: 67 years), sex (male: 47%), performance status (0–1: 80%), and HER2 status (IHC 3+: 33%; IHC 2+/FISH: 20%; mutation: 47%). The median number of delivered cycles was 3 (range: 1–11). One patient achieved a partial response with an ORR of 6.7% (90% confidence interval: 0.2-32.0). With a median follow-up time of 9.2 months, the median progression-free survival time and median survival time were 2.0 and 10.9 months, respectively. Grade 3/4 adverse events included thrombocytopenia (40%) and hepatotoxicity (20%) without any treatment-related deaths. T-DM1 had a limited efficacy for HER2-positive NSCLC in our cohort. It appears challenging to apply the concept of precision medicine to tumors; thus, additional molecular approaches are warranted.

    更新日期:2017-12-14
  • Biomarker-Integrated Neoadjuvant Dasatinib Trial in Resectable Malignant Pleural Mesothelioma
    J. Thorac. Oncol. (IF 6.595) Pub Date : 2017-12-05
    Anne S. Tsao, Heather Lin, Brett W. Carter, J. Jack Lee, David Rice, Ara Vaporcyan, Steven Swisher, Reza Mehran, John Heymach, Monique Nilsson, Youhong Fan, Maria Nunez, Lixia Diao, Jing Wang, Junya Fujimoto, Ignacio I. Wistuba, Waun Ki Hong

    Introduction Window of opportunity trials in malignant pleural mesothelioma (MPM) are challenging but can yield important translational information about a novel agent. Methods We treated patients with MPM (N = 24) with 4 weeks of oral dasatinib followed by surgery with or without radiotherapy and then an optional 2 years of maintenance dasatinib. The primary end point was biomarker modulation of phosphorylated (p) SrcTyr419. Results For all patients, the median progression-free survival (PFS) was 7.5 months and the median overall survival was 19.1 months. No significant responses were seen after 4 weeks of dasatinib therapy; however, modulation of median p-SrcTyr419 immunohistochemistry (IHC) scores was seen: the median pretreatment score was 70 (interquartile range 37.5–110), and the median posttreatment score was 41.9 (interquartile range 4.2–60) (p = 0.004). A decrease in p-SrcTyr419 levels after dasatinib correlated with improved median PFS (6.9 months versus 0.94 months [p = 0.03]), suggesting that p-SrcTyr419 is a viable pharmacodynamic biomarker for dasatinib in MPM. Platelet-derived growth factor receptor (PDGFR) pathway analysis correlated high PDGFR beta [PDGFRB) level (in the cytoplasm [hazard ratio] (HR) = 2.54, p = 0.05], stroma [HR = 2.79, p = 0.03], and nucleus [HR = 6.79, p = 0.023]) with a shorter PFS. Low (less than the median) cytoplasmic p-PDGFR alpha IHC levels were predictive of a decrease in positron emission tomography/computed tomography standard uptake values levels after dasatinib therapy (p = 0.04), whereas higher-than-median IHC scores of PDGFRB (cytoplasmic [HR = 2.8, p = 0.03] and nuclear [HR = 6.795, p = 0.02]) were correlated with rising standard uptake values levels. Conclusions In conclusion, there was no significant efficacy signal, and dasatinib monotherapy will not continue to be studied in MPM. However, our study demonstrated that PDGFR subtypes (platelet-derived growth factor receptor alpha and PDGFRB) may have differential roles in prognosis and resistance to antiangiogenic tyrosine kinase inhibitors and are important potential therapeutic targets that require further investigation.

    更新日期:2017-12-14
  • Paraneoplastic Syndromes and Thymic Malignancies: An Examination of the International Thymic Malignancy Interest Group Retrospective Database
    J. Thorac. Oncol. (IF 6.595) Pub Date : 2017-11-27
    Sukhmani K. Padda, Xiaopan Yao, Alberto Antonicelli, Jonathan W. Riess, Yue Shang, Joseph B. Shrager, Robert Korst, Frank Detterbeck, James Huang, Bryan M. Burt, Heather A. Wakelee, Sunil S. Badve

    Introduction Thymic epithelial tumors (TETs) are associated with paraneoplastic autoimmune (PN/AI) syndromes. Myasthenia gravis is the most common PN/AI syndrome associated with TETs. Methods The International Thymic Malignancy Interest Group (ITMIG) retrospective database was examined to determine (i) baseline and treatment characteristics associated with PN/AI syndromes and (ii) the prognostic role of PN/AI syndromes for patients with TETs. The competing risks model was used to estimate cumulative incidence of recurrence (CIR) and the Kaplan-Meier method was used to calculate overall survival (OS). A Cox proportional hazards model was used for multivariate analysis. Results 6670 patients with known PN/AI syndrome status were identified from 1951-2012. PN/AI syndromes were associated with younger age, female sex, type B1 thymoma, earlier stage, and an increased rate of total thymectomy and complete resection status. There was a statistically significant lower CIR in the PN/AI (+) group compared to the PN/AI (-) group (10-year 17.3% vs. 21.2%, respectively, p=0.0003). The OS was improved in the PN/AI (+) group compared to the PN/AI (-) group (HR 0.63, 95% CI 0.54-0.74, P<0.0001, median OS 21.6 years versus 17.0 years, respectively). However, in the multivariate model for recurrence-free survival and OS, PN/AI syndrome was not an independent prognostic factor. Discussion Previously, there has been mixed data regarding the prognostic role of PN/AI syndromes for patients with TETs. Here, using the largest dataset in the world for TETs, PN/AI syndromes were associated with favorable features (i.e. earlier stage, complete resection status) but were not an independent prognostic factor for TETs.

    更新日期:2017-12-14
  • Evaluation of NGS and RT-PCR methods for ALK rearrangement in European NSCLC patients: Results from the ETOP Lungscape Project
    J. Thorac. Oncol. (IF 6.595) Pub Date : 2017-11-27
    Igor Letovanec, Stephen Finn, Panagiota Zygoura, Paul Smyth, Alex Soltermann, Lukas Bubendorf, Ernst-Jan Speel, Antonio Marchetti, Daisuke Nonaka, Kim Monkhorst, Henrik Hager, Miguel Martorell, Aleksandra Sejda, Richard Cheney, Javier Hernandez-Losa, Eric Verbeken, Walter Weder, Spasenija Savic, Alessia Di Lorito, Atilio Navarro, Enriqueta Felip, Arne Warth, Paul Baas, Peter Meldgaard, Fiona Blackhall, Anne-Marie Dingemans, Hendrik Dienemann, Rafal Dziadziuszko, Johan Vansteenkiste, Cathal O'Brien, Thomas Geiger, Jon Sherlock, Jeoffrey Schageman, Urania Dafni, Roswitha Kammler, Keith Kerr, Erik Thunnissen, Rolf Stahel, Solange Peters

    Introduction The reported prevalence of ALK rearrangement in NSCLC ranges from 2%-7%. The primary standard diagnostic method is fluorescence in situ hybridization (FISH). Recently, immunohistochemistry (IHC) has also proven to be a reproducible and sensitive technique. Reverse transcriptase-polymerase chain reaction (RT-PCR) has also been advocated and most recently the advent of targeted Next-Generation Sequencing (NGS) for ALK and other fusions has become possible. This study compares ALK evaluation with all 4 techniques in resected NSCLC from the large ETOP Lungscape cohort. Methods 96 cases from the ETOP Lungscape iBiobank, with any ALK immunoreactivity were examined by FISH, central RT-PCR and NGS. H-score>120 defines IHC-positivity. RNA was extracted from the same formalin-fixed, paraffin-embedded tissues. For RT-PCR, primers covered the most frequent ALK translocations. For NGS, the Oncomine™ Solid Tumour Fusion Transcript Kit was used. The concordance was assessed using the Cohen’s kappa coefficient (two-sided alpha≤5%). Results NGS provided results for 77 out of the 95 cases tested (81.1%), while RT-PCR for 77 out of 96 (80.2%). Concordance occurred in 55 cases out of the 60 cases tested with all 4 methods (43 ALK-negative, 12 ALK-positive). Using ALK co-positivity for IHC and FISH as gold standard, we derive sensitivity for RT-PCR/NGS 70.0%/85.0%, with specificity 87.1%/79.0%. Combining either RT-PCR or NGS with IHC, the sensitivity remains the same, while the specificity increases to 88.7% and 83.9% respectively. Conclusion NGS evaluation with the Oncomine™ Solid Tumour Fusion transcript kit and RT-PCR proves to have high sensitivity and specificity advocating their use in routine practice. For maximal sensitivity and specificity, ALK status should be assessed using two techniques and a third one in discordant cases. We therefore propose a customizable testing algorithm. These findings significantly influence existing testing paradigms and have clear clinical and economic impact.

    更新日期:2017-12-14
  • Comparison of four PD-L1 immunohistochemical assays in lung cancer
    J. Thorac. Oncol. (IF 6.595) Pub Date : 2017-11-23
    Shona Hendry, David J. Byrne, Gavin M. Wright, Richard J. Young, Sue Sturrock, Wendy A. Cooper, Stephen B. Fox

    Introduction Four different PD-L1 immunohistochemical assays are approved or in development as companion or complementary diagnostics to different immunotherapeutic agents in lung carcinoma. We sought to determine whether these assays are technically equivalent and whether one antibody can be used on an alternate staining platform. Methods Serial sections of tissue microarrays constructed from 368 cases of resected lung cancer were stained for 22C3 and 28-8 on the Dako Link 48 platform, and for SP142 and SP263 on the Ventana Benchmark Ultra platform, strictly as per product insert. A protocol was developed to use the 22C3 antibody on the Ventana Benchmark Ultra platform. Results Differences in mean TC and IC staining were observed between the four assays (p<0.001). Differences between 22C3 and 28-8 were not statistically significant. Concordance of TC scores was good (ICC=0.674), particularly when SP142 was excluded as an outlier (ICC=0.755). Highest concordance was seen between 22C3 and 28-8 (ICC=0.812). Concordance was poor for IC staining (ICC=0.212). When dichotomized according to clinically relevant cut-offs, pairwise comparisons showed poor to moderate concordance (κ=0.196–0.578), with positive percent agreement ranging from 15.1% to 90.0%. 22C3 performed comparably on the Dako Link 48 platform and the alternate Ventana Benchmark Ultra platform (ICC=0.921, κ=0.897). Conclusions Concordance between the four PD-L1 immunohistochemical assays when performed and scored as intended show, apart from 28-8 and 22C3, they cannot be used interchangeably in clinical practice. A protocol was successfully developed to use 22C3 on an alternate platform, which may help to overcome some barriers to implementation.

    更新日期:2017-12-14
  • Current and Emergent Therapy Options for Advanced Squamous-Cell Lung Cancer
    J. Thorac. Oncol. (IF 6.595) Pub Date : 2017-11-23
    Mark A. Socinski, Coleman Obasaju, David Gandara, Fred R. Hirsch, Philip Bonomi, Paul A. Bunn, Edward S. Kim, Corey J. Langer, Ronald B. Natale, Silvia Novello, Luis Paz-Ares, Maurice Pérol, Martin Reck, Suresh S. Ramalingam, Craig H. Reynolds, David R. Spigel, Heather Wakelee, Nick Thatcher

    Squamous-cell lung cancer (SqCLC) is a distinct histologic subtype of non-small-cell lung cancer (NSCLC) that is challenging to treat due to specific clinicopathologic characteristics, which include older age, advanced disease at diagnosis, co-morbid diseases, and the central location of tumors. These characteristics have a bearing on treatment outcomes in advanced SqCLC, resulting in a median survival approximately 30% shorter than for patients with other NSCLC subtypes. In the context of the specific features of SqCLC, we review challenges of treating SqCLC and the current guideline-recommended treatments for advanced (metastatic) SqCLC in different patient subpopulations. We also evaluate recently approved treatment options, including necitumumab, afatinib, nivolumab, pembrolizumab, and atezolizumab, discuss the survival benefits associated with each agent in the advanced SqCLC population, and propose a treatment algorithm incorporating these agents for this challenging-to-treat disease. Lastly, we review the preliminary clinical evidence for immunotherapy agents in development for advanced NSCLC.

    更新日期:2017-12-14
  • Peripheral blood biomarkers associated with clinical outcome in non–small cell lung cancer patients treated with nivolumab
    J. Thorac. Oncol. (IF 6.595) Pub Date : 2017-11-21
    Junko Tanizaki, Koji Haratani, Hidetoshi Hayashi, Yasutaka Chiba, Yasushi Nakamura, Kimio Yonesaka, Keita Kudo, Hiroyasu Kaneda, Yoshikazu Hasegawa, Kaoru Tanaka, Masayuki Takeda, Akihiko Ito, Kazuhiko Nakagawa

    Purpose To identify baseline peripheral blood biomarkers associated with clinical outcome in patients with non–small cell lung cancer (NSCLC) treated with nivolumab. Methods Univariable and multivariable analyses were performed retrospectively for 134 patients with advanced or recurrent NSCLC treated with nivolumab to evaluate the relation between survival and peripheral blood parameters measured before treatment initiation, including absolute neutrophil count (ANC), absolute lymphocyte count (ALC), absolute monocyte count, and absolute eosinophil count (AEC) as well as serum C-reactive protein and lactate dehydrogenase levels. Progression-free survival (PFS), overall survival (OS), and response rate were determined. Results Among variables selected by univariable analysis, a low ANC, high ALC, and high AEC were significantly and independently associated with both better PFS (P = 0.001, P = 0.04, and P = 0.02, respectively) and better OS (P = 0.03, P = 0.03, and P = 0.003, respectively) in multivariable analysis. Categorization of patients according to the number of favorable factors revealed that those with only one factor had a significantly worse outcome compared with those with two or three factors. A similar trend was apparent for patients with a PD-L1 tumor proportion score of <50%, whereas all patients with a score of >50% had at least two favorable factors. Conclusions A baseline signature of a low ANC, high ALC, and high AEC was associated with a better outcome of nivolumab treatment, with the number of favorable factors identifying subgroups of patients differing in survival and response rate.

    更新日期:2017-12-14
  • EGFR gene copy number by FISH may predict outcome of necitumumab in squamous lung carcinomas: analysis from the SQUIRE study
    J. Thorac. Oncol. (IF 6.595) Pub Date : 2017-11-20
    Carlo Genova, Mark A. Socinski, Rebecca R. Hozak, Gu Mi, Raffael Kurek, Javad Shahidi, Luis Paz-Ares, Nick Thatcher, Christopher J. Rivard, Marileila Varella-Garcia, Fred R. Hirsch

    Introduction Necitumumab is a monoclonal antibody targeting the epidermal growth factor receptor (EGFR). In the SQUIRE trial, the addition of necitumumab to chemotherapy in squamous cell lung cancer (SCC) significantly improved overall survival (OS) (HR=0.84); in a post-hoc analysis, EGFR copy number gain determined by fluorescence in situ hybridization (FISH) showed a trend towards improved OS (HR=0.70) and progression-free survival (PFS) (HR=0.71) with the addition of necitumumab. We present the analysis of granular EGFR-FISH data from SQUIRE to examine the potential predictive role of high polysomy and gene amplification as both were included in the “FISH-positive” category. Materials and Methods Available specimens from SQUIRE underwent FISH analysis in a central laboratory and each sample was evaluated using the Colorado EGFR scoring criteria. The correlation of granular FISH parameters with clinical outcomes was assessed. Results Samples were available for 557 patients (out of 1093); 208 patients (37.3%) were FISH+, including 167 (30.0%) with high polysomy and 41 (7.4%) with gene amplification. In patients with high polysomy, the addition of necitumumab resulted in a statistically significant increase in PFS (6.08 vs. 5.13 months; p=0.044) and non-statistically significant increase in OS (12.6 vs. 9.5 months; p=0.133); among patients with gene amplification, the addition of necitumumab did not significantly improve PFS (7.4 vs. 5.6 months; p= 0.334), but improved OS (14.8 vs. 7.6 months; p= 0.033). Conclusion EGFR copy number gain by FISH might have a role as predictive biomarker for necitumumab in SCC. In our opinion, these data encourage further studies to prospectively evaluate this potential biomarker.

    更新日期:2017-12-14
  • Impact of Nivolumab Versus Docetaxel on Health-Related Quality of Life and Symptoms in Patients With Advanced Squamous Non-Small Cell Lung Cancer: Results From the CheckMate 017 Study
    J. Thorac. Oncol. (IF 6.595) Pub Date : 2017-11-10
    Martin Reck, Fiona Taylor, John R. Penrod, Michael DeRosa, Laura Morrissey, Homa Dastani, Lucinda Orsini, Richard J. Gralla

    Introduction In the phase III CheckMate 017 study, nivolumab prolonged overall survival versus docetaxel in previously treated patients with advanced squamous non-small cell lung cancer (NSCLC). Study objectives included health-related quality of life (HRQoL) and symptom assessments. Methods Patients serially completed Lung Cancer Symptom Scale (LCSS) and European Quality of Life Five Dimensions (EQ-5D) questionnaires. The LCSS average symptom burden index (ASBI; mean score for six lung cancer-specific symptoms; range, 0-100), LCSS 3-item global index, EQ-5D utility index, and EQ-5D visual analog scale scores were analyzed. The proportion of patients exhibiting clinically meaningful improvement (≥10-point decrease) in ASBI scores by week 12 was a secondary end point. Mixed-effect model repeated measures analysis of HRQoL changes from baseline and analyses of time to HRQoL deterioration were conducted. Results Baseline mean (SD) LCSS ASBI scores were similar in nivolumab (29.6 [16.4]) and docetaxel (29.6 [14.7]) groups. By week 12, the proportion of patients (95% CI) with clinically meaningful improvement in ASBI scores was 20.0% (13.6-27.7) with nivolumab and 21.9% (15.3-29.8) with docetaxel. At weeks 16-54, significant improvements in ASBI scores from baseline were seen with nivolumab; clinically meaningful improvements were observed at weeks 42-84. No significant changes in ASBI scores from baseline were observed with docetaxel; at week 36, a clinically meaningful deterioration was seen. Improvements in HRQoL with nivolumab versus docetaxel were supported by other measures, and time to first HRQoL deterioration was longer. Conclusion Nivolumab alleviates symptom burden and improves health status versus docetaxel as second-line squamous NSCLC treatment.

    更新日期:2017-12-12
  • Clinical and translational implications of RET rearrangements in non-small cell lung cancer
    J. Thorac. Oncol. (IF 6.595) Pub Date : 2017-11-08
    Roberto Ferrara, Nathalie Auger, Edouard Auclin, Benjamin Besse

    Since the discovery in 2012 of RET rearrangements in non-small cell lung cancer (NSCLC), at least 12 different fusion variants have been identified, with KIF5B-RET being the most frequent and the best characterized. Unlike ALK and ROS1 rearrangements, RET fusion genes cannot be adequately detected by immunohistochemistry, although fluorescence in situ hybridization and reverse transcriptase PCR are fully complementary diagnostic tools. In large retrospective studies, RET rearrangements correlate with adenocarcinoma histology, never-smoking status, younger age, more advanced stage disease, potentially higher chemo-sensitivity (in particular to pemetrexed-based regimens), and coexistence of other genomic alterations. To date, several preclinical models, clinical trials, and retrospective studies have investigated multi-target inhibitors with anti-RET activity in RET-rearranged lung cancer patients. In the clinical setting, the benefit in terms of response (16% to 47%) and progression-free survival (2 to 7 months) is clearly not comparable to that seen with other targeted agents in oncogene-addicted NSCLC. Furthermore, multi-kinase agents showed high rates of severe toxicities, leading to frequent dose reduction and drug discontinuation. To date, no definitive conclusions about a potentially different impact of anti-RET therapies according to RET fusion variants have been drawn, due to discordant data, coming mostly from small subgroup analyses. Importantly, the absence of a striking clinical benefit in RET-oncogene-addicted NSCLC underscores the clear need for the development of more selective and potent RET inhibitors and for a better characterization of concomitant genomic alterations and mechanisms of resistance to RET inhibition in lung cancer patients.

    更新日期:2017-12-12
  • Genetic and immune profiles of solid predominant lung adenocarcinoma reveal potential immunotherapeutic strategies
    J. Thorac. Oncol. (IF 6.595) Pub Date : 2017-11-07
    Zhong-Yi Dong, Chao Zhang, Yu-Fa Li, Jian Su, Zhi Xie, Si-Yang Liu, Li-Xu Yan, Zhi-Hong Chen, Xue-Ning Yang, Jun-Tao Lin, Hai-Yan Tu, Jin-Ji Yang, Qing Zhou, Yue-Li Sun, Wen-Zhao Zhong, Yi-Long Wu

    Background Subtype classification of lung adenocarcinoma (LUAD) divides different survivals and therapeutic vulnerabilities, while the underlying molecular mechanism is little to be known. This study sought to determine the genetic and immune profiles of histologic subtypes and identify the evidence for adjuvant immunotherapy. Patients and methods We performed an integrated analysis on multidimensional data from a discovery set including cohorts of The Cancer Genome Atlas (TCGA) and the Broad set from the LUAD public database, and a validation set from the Guangdong Lung Cancer Institute (GLCI). Immunohistochemical staining was carried out to determine the protein expressions of PD1-ligand (PD-L1) and CD8. Results Solid predominant LUAD patients showed poor disease-free survival and a high frequency of relapse/metastasis compared with those with the nonsolid subtype. The solid subtype tented to occur more frequently in those with a smoking history. Solid predominant LUAD exclusively showed increased expression of PD-L1 and a high proportion of combined PD-L1 and CD8+TIL expression. Meanwhile, a notable increase of the tumor mutation burden and higher frequency of GC>TA transversions were specifically identified in the solid subtype tumors. Furthermore, the solid subtype tumor displayed an active cytotoxic immune signature and increased incidence of genetic mutations related to immunogenicity. Conclusion Solid predominant LUAD was identified as a subtype with adaptive immune resistance, higher cytotoxic activity, and enhanced immunogenicity. These findings suggest that patients with solid predominant LUAD may represent a potential selective group that will benefit from adjuvant PD-1 blockade immunotherapy.

    更新日期:2017-12-12
  • Interobserver Variation Among Pathologists And Refinement Of Criteria In Distinguishing Separate Primary Tumours From Intrapulmonary Metastases In Lung
    J. Thorac. Oncol. (IF 6.595) Pub Date : 2017-11-07
    Andrew G. Nicholson, Kathleen Torkko, Patrizia Viola, Edwina Duhig, Kim Geisinger, Alain C. Borczuk, Kenzo Hiroshima, Ming S. Tsao, Arne Warth, Sylvie Lantuejoul, Prudence A. Russell, Erik Thunnissen, Alberto Marchevsky, Mari Mino-Kenudson, Mary Beth Beasley, Johan Botling, Sanja Dacic, Yasushi Yatabe, Wilbur A. Franklin

    Multiple tumor nodules (MTNs) are seen with increasing frequency in clinical practice. Based on the 2015 WHO classification of lung tumors, we assessed the reproducibility of the comprehensive histologic assessment (CHA) to distinguish second primary lung cancers (SPLC) from intrapulmonary metastases (IPM), looking for the most distinctive histological features. An international panel of lung pathologists reviewed a scanned sequential cohort of 126 tumors from 48 patients, recorded an agreed set of histologic features, including tumor typing and predominant pattern of adenocarcinoma, thereby opining whether the case was SPLC, IPM or a combination. Cohen’s Kappa statistics of 0.60 on overall assessment of SPLC or IPM indicated a good agreement. Likewise, there was good agreement (0.64 Kappa score, p<0.0001) between WHO histological pattern in individual cases and SPLC or IPM status but proportions diversified for histology and SPLC or IPM status (McNemar's test, p<0.0001). The strongest associations for distinguishing between SPLC and IM were observed for nuclear pleomorphism, cell size, acinus formation, nucleolar size, mitotic rate, nuclear inclusions, intra-alveolar clusters and necrosis. Conversely, lymphocytosis, mucin content, lepidic growth, vascular invasion, macrophage response, clear cell change, acute inflammation keratinization and emperipolesis did not reach significance with tumor extent. CHA is recommended for distinguishing SPLC from IPM, with good reproducibility among lung pathologists. In addition to main histologic type and predominant patterns of histologic subtypes, nuclear pleomorphism, cell size, acinus formation, nucleolar size, and mitotic rate strongly correlate with p staging status.

    更新日期:2017-12-12
Some contents have been Reproduced with permission of the American Chemical Society.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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