Disparities in the diagnosis and treatment of lung cancer among people with disabilities J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-11-16 Dong Wook Shin, Jongho Cho, Jae Myoung Noh, Hyesook Han, Kyungdo Han, Sang Hyun Park, So Young Kim, Jong Heon Park, Jong Hyock Park, Ichiro Kawachi
IntroductionPotential disparities in the diagnosis, treatment, and survival of lung cancer patients with and without disabilities were rarely investigated.MethodsWe conducted a retrospective cohort study with a dataset linking the KNHS database, disability registration data, and Korean Central Cancer Registry data. A total of 13,591 people with disabilities who were diagnosed with lung cancer and 43,809 age- and sex-matched control subjects with diagnosed lung cancer were included.ResultsUnknown stage was more common in people with severe disabilities (13.1% vs. 10.3%), especially those with communication (14.2%) or mental/cognitive disability (15.7%). People with disabilities were less likely to undergo surgery (adjusted odds ratio [aOR] 0.82, 95% confidence interval [95% CI] 0.77-0.86), chemotherapy (aOR=0.80, 95% CI 0.77-0.84), or radiotherapy (aOR=0.92, 95% CI 0.88-0.96). This was more evident for people with severe communication impairment (aORs 0.46 for surgery; 0.64 for chemotherapy) and severe brain/mental impairment (aORs 0.39 for surgery; 0.47 for chemotherapy; 0.49 for radiotherapy). Patients with disabilities had a slightly higher overall mortality compared to people with no disability (adjusted hazard ratio [aHR] 1.08; 95% CI, 1.06-1.11), especially in the severe disability group (aHR, 1.20; 95% CI 1.16-1.24).ConclusionsLung cancer patients with disabilities, especially severe ones, underwent less staging work-up and treatment even though their treatment outcomes were only slightly worse than those of people without a disability. While some degree of disparity might be attributed to reasonable clinical judgement, unequal clinical care for people with communication and brain/mental disabilities suggests unjustifiable disability-related barriers which need to be addressed.
Role of low-dose computerized tomography in lung cancer screening among never-smokers J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-11-13 Hye-Rin Kang, Jun Yeun Cho, Sang Hoon Lee, Yeon Joo Lee, Jong Sun Park, Young-Jae Cho, Ho Il Yoon, Kyung Won Lee, Jae Ho Lee, Choon-Taek Lee
IntroductionThe incidence of lung cancer among never-smokers has been increasing rapidly. The United States National Lung Screening Trial (NLST) study and NELSON trial showed that screening using low-dose computerized tomography effectively reduced lung cancer mortality among heavy smokers. However, its effectiveness in never-smokers has not been well investigated.This study investigated the role of low-dose computerized tomography (LDCT) in lung cancer screening among never-smokers.MethodsThe study was designed as a single-center, retrospective cohort study. We analyzed data of patients who received low-dose computerized tomography screening between May 2003 and June 2016. Nodules detected by computerized tomography were classified according to the Lung Imaging Reporting and Data System criteria. The detection rate and lung cancer outcomes (pathology, staging of lung cancer, and mortality) according to smoking history were determined.ResultsAmong 28,807 enrolled patients, 12,176 patients were never-smokers; of these, 7,744 (63.6%) were women and lung nodules were found in 1,218 (10.0%) patients. Overall, lung cancer was diagnosed in 55 (0.45%) never-smokers. In contrast, lung cancer was diagnosed in 143 (0.86%) patients among 16,631 ever-smokers. Among never-smokers with lung cancer, 51 (92.7%) presented with stage I, and all patients had adenocarcinomas.ConclusionsIn the never-smoker population, low-dose computerized tomography screening helped to detect a significant number of lung cancers. Most of these lung cancers were detected at a very early stage. The positive results of NLST in the US and the NELSON trial may have established the value of LDCT screening for heavy smokers, but future research should consider the value of using LDCT screening in the never-smoker population.
Evaluation of the Prognostic Significance of TNM Staging Guidelines in Lung Carcinoid Tumors J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-11-08 J.Y. Yoon, K. Sigel, J. Martin, R. Jordan, M.B. Beasley, C. Smith, A. Kaufman, J. Wisnivesky, M. Kang Kim
Background The Tumor Lymph Node and Metastasis (TNM) classification for lung cancer, originally designed for non-small cell lung carcinoma, is applied to staging of bronchopulmonary carcinoid tumors. The validity of the 8th Edition staging system for carcinoid tumors has not been assessed. In this study, we evaluated its prognostic accuracy using data from a large national population-based cancer registry. Patients and Methods Patients with typical and atypical bronchopulmonary carcinoids, diagnosed between 2000 and 2013, were identified from the National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) registry. We used competing risks analysis to compare 10-year disease-specific survival (DSS) across stages. Results Overall, 4,645 patients with bronchopulmonary carcinoid tumors were identified. Worsening DSS with increasing TNM status and stage was demonstrated across both typical and atypical carcinoids, with overlaps between adjacent subcategories. The combined stages (I vs II, II vs III, III vs IV) showed greater separation in DSS despite persistent overlaps between groups. For typical carcinoids, we found decreased DSS for stage II, stage III, and stage IV with HR 3.8 (95% CI: 2.6-5.6), HR 4.3 (95% CI: 3.0-6.1), and HR 9.0 (95% CI: 6.1-13.1), respectively, compared to stage I. Conclusion The combined stage categories of the 8th Edition TNM staging system provide useful information on outcomes for typical and atypical carcinoids. However, persistent overlaps in combined stage and subcategories of the staging system limit the usefulness of the TNM staging system, particularly in intermediate stages. These limitations suggest the need for further future study and refinement.
Neoadjuvant Crizotinib in Resectable Locally Advanced Non-Small-Cell Lung Cancer with ALK-rearrangement: A Brief Report J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-11-05 Chao Zhang, Shao-lei Li, Qiang Nie, Song Dong, Yang Shao, Xue-ning Yang, Yi-long Wu, Yue Yang, Wen-zhao Zhong
Background Locally advanced non-small-cell lung cancer (NSCLC) is one of the most heterogeneous condition with multidimensional treatments involved. Neoadjuvant therapy was commonly considered as an optimal management for operable locally advanced patients. However, as targeted therapy has been widely applied in advanced NSCLC, neoadjuvant targeted therapy remains poorly explored in locally advanced disease. Methods We described 11 ALK (anaplastic lymphoma kinase)-positive patients with pathologically confirmed N2 NSCLC who were treated with neoadjuvant crizotinib. All patients were treatment naïve and received crizotinib at a starting dose of 250mg twice daily. Case 3 was provided dynamic monitoring before and after neo-adjuvant therapy through next generation sequencing (NGS) of plasma and tissue. Case 4 was performed NGS for preoperative tissue. Results 10 patients were partial response and one was stable disease after neoadjuvant crizotinib with one suffered from grade 4 hepatic damage. 10/11 (91.0%) patients received R0 resection and 2 patients achieved pathological complete response (pCR) to neoadjuvant crizotinib. 6 patients had disease recurrence and 5 of them receiving crizotinib as first line treatment achieved long duration of response. Dynamic monitoring with both plasma and tissue indicated simultaneously decrease of sensitive ALK-signaling in the patient with partial response (-50%) and no ALK-dependent resistant variants were captured. Conclusion Neoadjuvant crizotinib may be feasible and well-tolerated in locally advanced disease for complete resection. crizotinib prior to surgery may provide thorough elimination of circulating molecular residual disease and not influence the reusing of first-line crizotinib, but ongoing prospective trials are warranted to prove its efficacy in neoadjuvant setting.
Peripheral blood DNA methylation as potential biomarker of Malignant Pleural Mesothelioma in asbestos-exposed subjects J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-11-05 Simonetta Guarrera, Clara Viberti, Giovanni Cugliari, Alessandra Allione, Elisabetta Casalone, Marta Betti, Daniela Ferrante, Anna Aspesi, Caterina Casadio, Federica Grosso, Roberta Libener, Ezio Piccolini, Dario Mirabelli, Irma Dianzani, Corrado Magnani, Giuseppe Matullo
Introduction Malignant pleural mesothelioma (MPM) is an aggressive tumour strongly associated with asbestos exposure. Patients are usually diagnosed when current treatments have limited benefits, highlighting the need for non-invasive early diagnosis tests to monitor asbestos-exposed people. Methods We used a genome-wide methylation array to identify, in asbestos-exposed subjects, novel blood DNA methylation markers of MPM in 163 MPM cases and 137 cancer-free controls (82/68 Training Set; replication in 81/69, Test Set) sampled from the same areas. Results Evidence of differential methylation between MPM cases and controls was found (>800 CpG sites, Pfdr<0.05), mainly in immune system related genes. Considering the “top” differentially methylated signals, 7 single-CpGs and 5 genomic regions of coordinated methylation replicated with similar effect size in the Test Set (pfdr<0.05). The top hypomethylated single-CpG (cases vs controls effect size<-0.15, pfdr <0.05 in both Training and Test sets) was detected in FOXK1 (Forkhead-box K1) gene, an interactor of BAP1 which was found mutated in MPM tissue and as germline mutation in familial MPM. In the Test set, comparison of receiver operating characteristic (ROC) curves and the area under the curve (AUC) of two models, including/excluding methylation, showed a significant increase in case/control discrimination when considering DNA methylation together with asbestos exposure (AUC=0.81 vs AUC=0.89, DeLong’s test p=0.0013). Conclusions We identified signatures of differential methylation in DNA from whole blood between asbestos exposed MPM cases and controls. Our results provide the rationale to further investigate, in prospective studies, the potential use of blood DNA methylation profiles for the identification of early changes related to MPM carcinogenic process.
A population-based study of outcomes in surgically resected T3N0 non-small cell lung cancer in the Netherlands, defined using TNM-7 and TNM-8; justification of changes and an argument to incorporate histology in the staging algorithm? J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-11-05 Hans Blaauwgeers, Ronald Damhuis, Birgit Lissenberg-Witte, Adrianus J. de Langen, Suresh Senan, Erik Thunnissen
Purpose To study outcomes in patients surgically staged as pT3N0 non-small cell lung cancer (NSCLC) in a population registry, comparing TNM-7 and TNM-8 staging classifications. Materials and Methods Details of patients who underwent surgery for a pT3N0M0 NSCLC from 2010 to 2013, based on the TNM-7 classification, were retrieved from the Netherlands Comprehensive Cancer Organization (IKNL). These were next matched with corresponding pathology data from a nationwide registry. Patients were categorized into 4 major pT3 subgroups: ‘> 7cm’ tumor diameter, ‘separate tumor nodules in the same lobe’ (2nd+ nodule), ‘parietal pleural invasion’ and a ‘mixed group’ (mainly ‘> 7 cm’ combined with ‘parietal pleural invasion’). Results 683 patients were eligible for analysis. The 3- and 5-years overall survival (OS) for the subtype ‘> 7 cm’ were 59.9% and 47.2%, respectively, and comparable to the subtype with pleural invasion were 50.4% and 45.3%, respectively. The ‘mixed group’ had a worse 3- and 5-year OS probability of 37.5% and 28.7%, which were comparable to outcomes for TNM-8 staged IIIB and pT4 cases in the IASLC database. For the subtype 2nd+ nodule, 3- and 5-year OS were 70.6% and 62.8%, respectively, with patients with adenocarcinoma showing a significantly better OS compared to squamous cell carcinoma: 5-years OS of 65.1% versus 47.2%, respectively (p<0.001), suggesting that prognosis for the adenocarcinoma subgroup may be comparable to the pT2 category, whereas squamous cell carcinoma nodules can remain pT3. Conclusion This population analysis of overall survivals in pT3N0 subcategories for NSCLC suggests that histology is a relevant descriptor in the 2nd+ nodule category. The findings do not support migration of the ‘>7 cm’ group to the pT4 category in TNM-8, and suggest that a combination of two pT3 descriptors (‘mixed group’) merits migration to pT4.
Co-expression analysis reveals mechanisms underlying the varied roles of NOTCH1 in non-small cell lung cancer J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-11-05 Sara L. Sinicropi-Yao, Joseph M. Amann, David Lopez Y. Lopez, Ferdinando Cerciello, Kevin R. Coombes, David P. Carbone
Introduction Notch receptor family dysregulation can be tumor promoting or suppressing depending on cellular context. Our studies shed light on the mechanistic differences that are responsible for NOTCH1’s opposing roles in lung adenocarcinoma and lung squamous cell carcinoma. Methods We integrated transcriptional patient-derived datasets with gene co-expression analyses to elucidate mechanisms behind NOTCH1 function in subsets of non-small cell lung cancer. Differential co-expression was examined using hierarchical clustering and principal component analysis. Enrichment analyses was used to examine pathways associated with the underlying transcriptional networks. These pathways were validated in vitro and in vivo. Endogenously epitope-tagged NOTCH1 was used to identify novel interacting proteins. Results NOTCH1 co-expressed genes in lung adenocarcinoma and squamous carcinoma were distinct, and associated with either angiogenesis and immune system pathways or cell cycle control and mitosis pathways, respectively. Tissue culture and xenograft studies of lung adenocarcinoma and lung squamous models with NOTCH1 knockdown demonstrated growth differences and opposing effects on these pathways. Differential NOTCH1 interacting proteins were identified as potential mediators of these differences. Conclusions Recognition of the opposing role of NOTCH1 in lung cancer, downstream pathways, and interacting proteins in each context may help direct the development of rational NOTCH1 pathway-dependent targeted therapies for specific tumor subsets of non-small cell lung cancer.
Compliance and outcome of elderly patients treated in the Concurrent ONce daily VErsus twice-daily RadioTherapy (CONVERT) trial J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-10-31 Marianna Christodoulou, Fiona Blackhall, Hitesh Mistry, Ahmet Leylek, Joost Knegjens, Vincent Remouchamps, Isabelle Martel-Lafay, Nuria Farré, Matjaz Zwitter, Delphine Lerouge, Nicolas Pourel, Henri Janicot, Arnaud Scherpereel, Caroline Tissing-Tan, Karin Peignaux, Xavier Geets, Krzysztof Konopa, Corinne Faivre-Finn
Introduction There is a lack of data on the efficacy and safety of concurrent chemo-radiotherapy in elderly, limited-stage, patients with small cell lung cancer. Methods We compared outcomes of patients aged ≥70 years vs. younger patients within the Concurrent ONce-daily VErsus twice-daily RadioTherapy (CONVERT) trial. Patients were randomised to receive 45Gy/30 twice-daily fractions/3 weeks or 66Gy/33 once-daily fractions/6.5 weeks concurrently with platinum-based chemotherapy. Overall survival (OS) and progression free survival (PFS) were evaluated using Kaplan-Meier methodology and Cox proportional hazards regression. Results Of 547 patients randomised between April 2008-November 2013, 57 did not receive protocol treatment and were excluded. Of the 490 patients included, 67 (14%) were aged ≥70 years (median age: 73 years; range 70-82). Fewer older patients received the optimal number of radiotherapy fractions (73% vs. 85%; p=0.03); however, chemotherapy compliance was similar in both groups (p=0.24). Neutropenia grade 3/4 occurred more frequently in the elderly (84% vs. 70%; p=0.02) but rates of neutropenic sepsis (4% vs. 7%; p=0.07) and death (3% vs. 1.4%; p=0.67) were similar in both groups. With a median follow-up of 46 months; median survival in the elderly vs. younger groups was 29 (95% confidence interval (CI) 21-39) vs. 30 months (95% CI 26-35) respectively; (hazard ratio (HR) 1.15, 95% CI 0.84-1.59; p=0.38). Median time to progression in the elderly vs. younger groups was 18 (95% CI 13-31) vs. 16 months (95% CI 14-19) respectively; (HR 1.04, 95% CI 0.76-1.41; p=0.81). Conclusions Concurrent chemo-radiotherapy with modern radiotherapy techniques should be a treatment option for fit, older patients.
PET scan-directed chemoradiation for esophageal squamous cell carcinoma: no benefit for a change in chemotherapy in PET non-responders J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-11-01 M. Greally, J. Chou, D. Molena, V.W. Rusch, M.S. Bains, B.J. Park, A.J. Wu, K.A. Goodman, D.P. Kelsen, Y.Y. Janjigian, D.H. Ilson, G.Y. Ku
Introduction Pre-operative or definitive chemoradiation is an accepted treatment for locally advanced esophageal squamous cell carcinoma (ESCC). The MUNICON study demonstrated that PET response following induction chemotherapy was predictive of outcomes in patients with gastroesophageal junction adenocarcinoma. We evaluated the predictive value of PET following induction chemotherapy in ESCC patients and assessed the impact of changing chemotherapy during radiation in PET non-responders. Methods We retrospectively reviewed all patients with locally advanced ESCC who received induction chemotherapy and chemoradiation; all patients had a PET before and after induction chemotherapy. Survival was calculated from date of repeat PET using Kaplan-Meier analysis and compared between groups using the log-rank test. Results Of 111 patients, 70 (63%) were PET responders (defined as ≥35% decrease in maximum standard uptake value) to induction chemotherapy. PET responders received the same chemotherapy during radiation. Of 41 PET non-responders, 16 continued with the same chemotherapy and 25 were changed to alternative chemotherapy with radiation. Median progression-free (PFS; 70.1 vs. 7.1 months, p<0.01) and overall survival (OS; 84.8 vs. 17.2 months, p<0.01) were improved for PET responders vs. non-responders. Median PFS and OS for PET non-responders who changed chemotherapy vs. those who did not were 6.4 vs. 8.3 months (p=0.556) and 14.1 vs. 17.2 months (p=0.81), respectively. Conclusions PET after induction chemotherapy highly predicts for outcomes in ESCC patients who receive chemoradiation. However, our results suggest that PET non-responders do not benefit from changing chemotherapy during radiation. Future trials should utilize PET non-response after induction chemotherapy to identify poor prognosis patients for novel therapies.
Concurrent genetic alterations predict the progression to target therapy in EGFR-mutated advanced non-small cell lung cancer J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-11-01 Youjin Kim, Boram Lee, Joon Ho Shim, Se-Hoon Lee, Woong-Yang Park, Yoon-La Choi, Jong-Mu Sun, Jin Seok Ahn, Myung-Ju Ahn, Keunchil Park
Introduction EGFR-mutant non-small cell lung cancer (NSCLC) displays diverse outcomes to tyrosine kinase inhibitor (TKI) treatment. Since co-occurring genomic alterations might describe different biological subsets of patients with this cancer, exploring co-occurring genomic alterations that impact patient`s outcome using a comprehensive gene panel is potentially important. Methods This retrospective cohort study was conducted with the panel-sequencing data acquired from January 2014 to May 2017, and clinical outcome data collected until February 2018. This study includes all eligible patients who possess panel-sequencing data prior to treatment with 1st/2nd-generation EGFR-TKIs (cohort 1) or 3rd-generation EGFR-TKIs following initial EGFR-TKI failure (cohort 2). Results Seventy-five patients (mean [SD] age, 58.5 [11.0] years; 68.0% women) were included in cohort 1, and 82 patients (mean [SD] age, 57.3 [9.1] years; 67.1% women) were included in cohort 2. In cohort 1, alterations in TP53 were independently associated with worse PFS (hazard ratio [HR], 2.02; [95% CI, 1.04–3.93]; p = 0.038) in multivariate analysis. In cohort 2, TP53 mutation was associated with significantly worse PFS (8.9 versus 12.8 months; p = 0.029). RB1 mutation was significantly associated with worse (median PFS, 1.9 versus 11.7 months; p < 0.001). PTEN mutation was associated with significantly worse PFS (2.6 versus 10.3 months; p = 0.001). MDM2 amplification was associated with worse PFS (6.6 versus 10.4 months; p = 0.025). In cohort 2, multivariate analysis revealed that alterations in TP53 (HR, 2.23; 95% CI, 1.16–4.29; p = 0.017), RB1 (HR, 5.62; 95% CI, 1.96–16.13; p = 0.001), PTEN (HR, 5.84; 95% CI, 1.56–21.85; p = 0.009), and MDM2 (HR, 2.46; 95% CI, 1.02–5.94; p = 0.046) were independently associated with worse PFS. Conclusions Co-occurring genomic alterations detected by panel sequencing are associated with the clinical outcomes of EGFR-TKI treatment in NSCLC.
Hybrid capture-based genomic profiling of circulating tumor DNA from patients with advanced non-small cell lung cancer J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-10-24 Alexa B. Schrock, Allison Welsh, Jon H. Chung, Dean Pavlick, Eric H. Bernicker, Benjamin C. Creelan, Brady Forcier, Jeffrey S. Ross, Philip J. Stephens, Siraj M. Ali, Ibiayi Dagogo-Jack, Alice T. Shaw, Tianhong Li, Sai-Hong Ignatius Ou, Vincent A. Miller
Introduction Genomic profiling informs selection of matched targeted therapies as part of routine clinical care in non-small cell lung cancer (NSCLC). Tissue biopsy is the gold standard; however, genomic profiling of blood-derived circulating tumor DNA (ctDNA) has emerged as a minimally invasive alternative. Methods Hybrid capture-based genomic profiling of 62 genes was performed on blood-based ctDNA from 1,552 patients with NSCLC. Results Evidence of ctDNA was detected in 80% of samples, and of these at least one reportable genomic alteration (GA) was detected in 86% of cases. Frequently altered genes were TP53 (59%), EGFR (25%), and KRAS (17%). Comparative analysis with a tissue genomic database (n = 21,500) showed similar frequencies of GA per gene, although KRAS mutation and EGFR T790M were more frequent in tissue and ctDNA, respectively (both P <0.0001), likely reflecting use of liquid versus tissue biopsy after relapse on targeted therapy. In temporally matched ctDNA and tissue samples from 33 patients with evidence of ctDNA in the blood, 64% of GA detected in tissue were also detected in ctDNA, including 78% (58/74) of short variants and 100% (4/4) of rearrangements, but only 16% (4/25) of amplifications. Conclusions Genomic profiling of ctDNA detected clinically relevant GAs in a significant subset of NSCLC cases. Most alterations detected in matched tissue were also detected in ctDNA. These results suggest utility of ctDNA testing in advanced NSCLC as a complementary approach to tissue testing. Blood-based ctDNA testing may be particularly useful at the time of progression on targeted therapy.
Predicting Malignancy Risk of Screen Detected Lung Nodules – Mean Diameter or Volume J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-10-25 Martin Tammemagi, Alex J. Ritchie, Sukhinder Atkar-Khattra, Brendan Dougherty, Calvin Sanghera, John R. Mayo, Ren Yuan, Daria Manos, Annette M. McWilliams, Heidi Schmidt, Michel Gingras, Sergio Pasian, Lori Stewart, Scott Tsai, Jean M. Seely, Paul Burrowes, Rick Bhatia, Ehsan A. Haider, Stephen Lam
Purpose In lung cancer screening practice using low-dose computed tomography (LDCT), diameter or volumetric measurement have been used in the management of screen detected lung nodules. The aim of this study is to compare the performance of nodule malignancy risk prediction tools using diameter or volume and between computer-aided detection (CAD) and radiologist measurements. Methods Multivariable logistic regression models were prepared using data from two multi-center lung cancer screening trials. For model development and validation, baseline LDCT scans from the PanCan Study and a subset of National Lung Screening Trial (NLST) scans with lung nodule ≥3 mm in mean diameter were analysed using the CIRRUS Lung Screening Workstation (Radboud University Medical Center, Nijmegen, the Netherlands). In the NLST sample, nodules with cancer had been matched on size to nodules without cancer. Results Both CAD-based mean diameter and volume models showed excellent discrimination and calibration, with similar areas under the receiver-operating-characteristic curves of 0.947. The two CAD models had similar predictive performance to the radiologist-based model. In NLST validation data, the CAD Mean Diameter and Volume models also demonstrated excellent discrimination: AUC’s 0.810 and 0.821, respectively. These performance statistics are similar to the PanCan Malignancy Probability Model in these data using radiologist measured maximum diameter. Conclusion Either CAD-based nodule diameter or volume can be used to assist in predicting nodule malignancy risk.
Distinct clinicopathological characteristics and prognosis based on the presence of ground glass opacity component in clinical-stage IA lung adenocarcinoma J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-10-25 Aritoshi Hattori, Shunki Hirayama, Takeshi Matsunaga, Takuo Hayashi, Kazuya Takamochi, Shiaki Oh, Kenji Suzuki
Objectives We evaluated differences in the clinicopathological characteristics and prognosis based on the presence of ground glass opacity (GGO) components in small-sized lung adenocarcinoma. Methods We retrospectively investigated 634 lung adenocarcinomas classed as c-stage IA in the 8th TNM classification. Staging was defined according to the solid component size measured by thin-section computed tomography. All tumors were grouped into either a GGO or Solid group, based on the presence of a GGO component. Results Of the cases, 215 (34%) were classed as c-stage IA1 (T1mi: 88, T1a-GGO: 102, T1a-Solid: 25), 255 (40%) as c-stage IA2 (T1b-GGO: 122, T1b-Solid: 133), and 164 (26%) as c-stage IA3 (T1c-GGO: 44, T1c-Solid: 120). Among the 546 c-stage IA cases excluding the T1mi lesions, cox regression analysis revealed that presence of GGO was an independently significant prognosticator (p=0.024). The result was validated in 494 c-stage IA lung adenocarcinomas with a non-predominant GGO component, showing the presence of GGO as a significant prognosticator (p=0.048). When we evaluated the prognostic impact of GGO presence in each clinical-stage, the 5y overall survival (OS) was significantly different between the GGO and Solid groups (IA1; 97.8% vs. 86.6%, p=0.026, IA2; 89.3% vs. 75.2%, p=0.007, IA3; 88.5% vs. 62.3%, p=0.003). Furthermore, the 5y-OS was distinct in parallel similar pathologic findings when comparing a lepidic versus an invasive component (IA1; 97.9% vs. 85.6%, p=0.031, IA2; 86.1% vs. 69.4%, p=0.007, IA3; 77.5% vs. 55.8%, p<0.001). Conclusions Clinicopathological and oncological outcomes were disparate based on the presence of a GGO component in the 8th edition of c-stage IA lung adenocarcinoma.
Prediction modelling using routine clinical parameters to stratify survival in Malignant Pleural Mesothelioma patients undergoing cytoreductive surgery J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-10-24 Edward JA. Harris, Steven Kao, Brian McCaughan, Takashi Nakano, Nobuyuki Kondo, Rebecca Hyland, Anna K. Nowak, Nicholas H. de Klerk, Fraser JH. Brims
Background Malignant Pleural Mesothelioma (MPM) is an uncommon cancer with a poor prognosis and heterogeneous survival. Surgery for MPM is offered in some specialist centres to highly selected patients. A previously described classification and regression tree (CART) model stratified survival in unselected MPM patients using routinely collected clinical data. This study aimed to examine the performance of this CART model on a highly selected surgical population. Methods Data were collected from subjects undergoing cytoreductive surgery for MPM from specialist centres in Hyõgo, Japan and Sydney, Australia between 1991 and 2016. The CART model was applied using the combination of clinical variables to stratify subjects into risk groups (1-4); survival characteristics were then compared. Results 289 cases were included (205 from Australia, 84 from Japan). Overall median survival was 34.6 (IQR 17.5-56.1) months; median age 63.0 (IQR 57.0-67.8) years, 240/289 (83.0%) were male. There were no clinically meaningful differences between the two cohorts. Survival across the four risk groups was significantly different (p<0.0001); the model stratified survival well with a Harrell's c-statistic of 0.62 (96% CI 0.57-0.66) at 36 months. The group with the longest survival (median 82.5 months) had: no weight loss, Hb >153g/L and serum albumin >43g/L at time of referral to the surgical centre. Conclusion Using routinely available clinical variables the CART model was able to stratify surgical patients into risk groups with statistically different survival characteristics with fair to good performance. Presence of weight loss, anaemia and low albumin should confer caution when considering surgical therapy for MPM.
Cribriform Subtype is an Independent Predictor of Recurrence and Survival after Adjustment for the Eighth Edition of TNM Staging System in Patients with Resected Lung Adenocarcinoma J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-10-15 Kyuichi Kadota, Yoshio Kushida, Seiko Kagawa, Ryou Ishikawa, Emi Ibuki, Kosuke Inoue, Tetsuhiko Go, Hiroyasu Yokomise, Tomoya Ishii, Norimitsu Kadowaki, Reiji Haba
Introduction At present, cribriform arrangements are regarded as a pattern of acinar adenocarcinoma. However, recent studies have indicated that clinical outcome for lung adenocarcinoma patients with cribriform subtype is unfavorable. To validate the prognostic significance of the cribriform pattern, we analyzed a series of 735 Japanese patients with resected lung adenocarcinoma, which was restaged according to the 8th edition of TNM staging system. Methods Tumors were classified in accordance with the 2015 WHO classification of lung carcinomas. The cribriform pattern was defined by invasive back-to-back fused tumor glands with poorly formed glandular spaces or invasive tumor nests of tumors cells that produce glandular lumina. Recurrence-free probability (RFP) and overall survival (OS) was analyzed using the log-rank test and the Cox proportional hazards model. Results After the addition of the cribriform pattern, 54 of 90 acinar predominant tumors were reclassified as cribriform subtype. Five-year RFP for patients with the cribriform subtype (51%) was lower than it was for patients with acinar and papillary subtype (81% and 80%, respectively) but was comparable to that for patients with solid subtype (48%). Five-year OS for patients with the cribriform subtype (49%) was lower than it was for patients with acinar and papillary subtype (90% and 81%, respectively). On multivariate analysis adjusted for the 8th edition of TNM staging system, the cribriform subtype was an independent prognostic factor of a worse RFP and OS. Conclusion We have validated that the cribriform subtype is an independent factor of poor prognosis in patients with resected lung adenocarcinoma.
Third-Line Nivolumab Monotherapy in Recurrent Small Cell Lung Cancer: CheckMate 032 J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-10-10 Neal Ready, Anna F. Farago, Filippo de Braud, Akin Atmaca, Matthew D. Hellmann, Jeffrey G. Schneider, David R. Spigel, Victor Moreno, Ian Chau, Christine L. Hann, Joseph Paul Eder, Nicola L. Steele, Anne Pieters, Justin Fairchild, Scott J. Antonia
Introduction For patients with recurrent small cell lung cancer (SCLC), topotecan remains the only FDA-approved or EMA-approved second-line treatment, and outcomes are poor. CheckMate 032 is a phase 1/2, multicenter, open-label study of nivolumab or nivolumab plus ipilimumab in SCLC or other advanced/metastatic solid tumors previously treated with ≥1 platinum-based chemotherapies. We report results of third- or later-line (3L+) nivolumab monotherapy treatment in SCLC. Methods In this analysis, patients with limited-stage or extensive-stage SCLC and disease progression after ≥2 chemotherapy regimens received nivolumab monotherapy 3 mg/kg every 2 weeks until disease progression or unacceptable toxicity. The primary end point was objective response rate (ORR). Secondary end points included duration of response (DOR), progression-free survival, overall survival, and safety. Results Between December 4, 2013 and November 30, 2016, 109 patients initiated 3L+ nivolumab monotherapy. At a median follow-up of 28.3 months (from first dose to database lock), ORR was 11.9% (95% confidence interval: 6.5–19.5) with a median DOR of 17.9 months (range, 3.0 to 42.1). At 6 months, 17.2% of patients were progression-free. The 12-month and 18-month overall survival rates were 28.3% and 20.0%, respectively. Grade 3–4 treatment-related adverse events (TRAEs) occurred in 11.9% of patients. Three patients (2.8%) discontinued due to TRAEs. Conclusions Nivolumab monotherapy provided durable responses and was well tolerated as a 3L+ treatment for recurrent SCLC. These results suggest that nivolumab monotherapy is an effective 3L+ treatment for this patient population.
Neoantigenic potential of complex chromosomal rearrangements in mesothelioma J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-10-10 Aaron S. Mansfield, Tobias Peikert, James B. Smadbeck, Julia B.M. Udell, Enrique Garcia-Rivera, Laura Elsbernd, Courtney L. Erskine, Virginia P. Van Keulen, Farhad Kosari, Stephen J. Murphy, Hongzheng Ren, Vishnu V. Serla, Janet L. Schaefer Klein, Giannoula Karagouga, Faye R. Harris, Carlos Sosa, Sarah H. Johnson, Wendy Nevala, George Vasmatzis
Introduction Malignant pleural mesothelioma is a disease primarily associated with exposure to the carcinogen asbestos. Whereas other carcinogen-related tumors are associated with a high tumor mutation burden, mesothelioma is not. We sought to resolve this discrepancy. Material and Methods We used mate-pair (n=22), RNA (n=28) and T cell receptor sequencing along with in silico predictions and immunologic assays to understand how structural variants of chromosomes affect the transcriptome. Results We observed that inter- or intra-chromosomal rearrangements were present in every specimen and were frequently in a pattern of chromoanagenesis such as chromoplexy or chromothripsis. Transcription of rearrangement-related junctions was predicted to result in many potential neoantigens, some of which were proven to bind patient-specific MHC molecules and to expand intratumoral T cell clones. T cells responsive to these predicted neoantigens were also present in a patient’s circulating T cell repertoire. Analysis of genomic array data from the mesothelioma cohort in The Cancer Genome Atlas suggested that multiple chromothriptic-like events negatively impact survival. Discussion Our findings represent the discovery of potential neoantigen expression driven by structural chromosomal rearrangements. These results may have implications for the development of novel immunotherapeutic strategies and the selection of patients to receive immunotherapies.
Demographics, safety and quality, and prognostic information in both the seventh and eighth editions of the TNM classification in 18,973 surgical cases of the Japanese Joint committee of Lung Cancer Registry database in 2010 J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-10-10 Jiro Okami, Yasushi Shintani, Meinoshin Okumura, Hiroyuki Ito, Takashi Ohtsuka, Shinichi Toyooka, Takeshi Mori, Shun-ichi Watanabe, Hiroshi Date, Kohei Yokoi, Hisao Asamura, Takeshi Nagayasu, Etsuo Miyaoka, Ichiro Yoshino,
Introduction The Japanese Joint Committee of Lung Cancer Registry (JJCLCR) performed the fourth nationwide registry study of surgical cases. Demographics, safety and quality, prognostic information, and correlations between the 7th and the 8th editions of the TNM classification were investigated. The principal results were compared with previous JJCLCR studies. Methods The clinicopathologic profiles, staging, and prognosis of patients who underwent surgery for primary lung cancer in 2010 were retrospectively collected in 2016 and analyzed. Results The cohort consisted of 18,973 cases from 297 hospitals (11,771 males, mean age 68.3 years). Tumor less than 2.0 cm was seen in 39.0%, and limited resection was performed in 22.7%. 30/90-day mortality rates were 0.43/1.26%. Overall/disease-free survival rates at 5 years were 74.7/67.8%. Five-year survival rates by p-stage in the 7th edition in the present study (2010) and in the previous study (2004) were: IA 88.9%/86.8%, IB 76.7%/73.9%, IIA 64.1%/61.6%, IIB 56.1%/49.8%, IIIA 47.9%/40.9%, IIIB 30.2%/27.8%, and IV 36.1%/27.9%, respectively. Five-year survival rates by c-stage in the 8th edition in the present study were: O 97.0%, IA1 91.6%, IA2 81.4%, IA3 74.8%, IB 71.5%, IIA 60.2%, IIB 58.1%, IIIA 50.6%, IIIB 40.5%, IIIC 37.5%, and IVA/B 36.0%. By restaging, the overall survivals of c-stage IA and IB in the 7th edition were stratified into stages O to IA3 and stages IA1 to IIA in the 8th edition, respectively. Conclusions This study demonstrates improved surgical results for lung cancer in Japan. The TNM revision for the 8th edition was supported by the assessment of stage migration from the previous edition and the prognostic stratification.
Survival comparison in patients with Stage IV lung cancer in Academic versus Community Centers in the United States J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-10-09 Sendhilnathan Ramalingam, Michaela A. Dinan, Jeffrey Crawford
Introduction Although metastatic non-small cell lung cancer (NSCLC) is widely treated in both academic and community-based centers, it is unclear whether outcomes are similar across both settings. A growing variety of chemotherapies and targeted agents for an increasingly histology and molecular-based treatment strategy could advantage patients treated in academic centers. Using the National Cancer Database (NCDB), we investigated whether treatment at academic centers was associated with a survival advantage in metastatic NSCLC. Methods We conducted a retrospective analysis of the NCDB following the introduction of novel NSCLC chemotherapy agents from 1998 to 2010. The primary outcome was 2-year survival, analyzed using a multivariable regression model controlling for age, year of diagnosis, gender, primary payer, histology, facility type (academic centers, or ACs, versus community-based centers, or CCs) and an interaction term allowing a time-based comparison of survival between academic and community centers. Alpha was set to 0.001 due to the size of the dataset. Results There were 193,279 patients included in this study. The percentage of patients achieving 2-year survival was higher in ACs versus CCs in 1998, 11.5% versus 9.2% (+2.3%), and by 2010 increased to 17.4% versus 13.1% (+4.3%). Multivariable analysis confirmed a significant relative increase in 2-year survival associated with ACs versus CCs from 1998 to 2010 (p=0.0005). A histology-dependent survival difference was also noted in adenocarcinoma versus squamous cell carcinoma, 10.2% versus 9.9% in 1998 (+0.3%), increasing to 17.3% versus 10.1% in 2010 (+7.2%). Adenocarcinoma survival also varied by treatment facility, where the difference in 2-year survival in ACs versus CCs increased from 12.3% versus 9.1% (+3.2%) in 1998 to 20.5% versus 15.5% (+5%) in 2010, with a trend toward significance in our multivariable model (p=0.005). Conclusion A greater increase in survival was noted in Academic Centers compared to Community centers over this time period, and was particularly pronounced among patients with adenocarcinoma versus squamous cell carcinoma. Given known advances in adenocarcinoma treatment compared with squamous cell lung cancer over this time period, our study suggests potential treatment-related disparities may exist between ACs and CCs. Further study will be needed to validate this disparity in healthcare and address opportunities to improve survival in Stage IV NSCLC patients across treatment setting.
Critical appraisal of PD-L1 reflex diagnostic testing: current standards and future opportunities J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-10-06 Matthew P. Humphries, Stephen McQuaid, Stephanie Craig, Victoria Bingham, Perry Maxwell, Manisha Maurya, Fiona McLean, James Sampson, Patricia Higgins, Christine Greene, Jacqueline James, Manuel Salto-Tellez
Introduction Patient suitability to anti-PD-L1 immune checkpoint inhibition is key to the treatment of non–small cell lung cancer (NSCLC). We present, applied to PD-L1 testing: a comprehensive cross-validation of two immunohistochemistry (IHC) clones; our descriptive experience in diagnostic reflex testing; the concordance of IHC to in-situ RNA (RNA-ISH); and application of digital pathology. Methods 813 NSCLC tumour samples collected from 564 diagnostic samples were analysed prospectively and 249 diagnostic samples analysed retrospectively in TMA format. Validated methods for IHC and RNA-ISH were tested in TMAs and full sections and the QuPath system used for digital pathology analysis. Results Antibody concordance of clones SP263 and 22C3 validation was 97-98% in squamous cell carcinoma and adenocarcinomas, respectively. Clinical NSCLC cases were reported as PD-L1 negative (48%), 1-49% (23%) and >50% (29%), with differences associated to tissue-type and EGFR status. Comparison of IHC and RNA-ISH was highly concordant in both subgroups. Comparison of digital assessment versus manual assessment was highly concordant. Discrepancies were mostly around the 1% clinical threshold. Challenging IHC interpretation included a) calculating the total tumour cell denominator and the nature of PD-L1 expressing cell aggregates in cytology samples; b) peritumoral expression of positive immune cells; c) calculation of positive tumour percentages around clinical thresholds; d) relevance of the 100 malignant cell rule. Conclusions Sample type and EGFR status dictate differences in the expected percentage of PD-L1 expression. Analysis of PD-L1 is challenging, and interpretative guidelines are discussed. PD-L1 evaluation by RNA-ISH and digital pathology appear reliable, particularly in adenocarcinomas.
Detection of minimal residual disease using ctDNA in lung cancer: current evidence and future directions J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-10-06 Young Kwang Chae, Michael S. Oh
Advances in DNA sequencing methods have significantly expanded the potential clinical applications of analyzing circulating tumor DNA (ctDNA). This genetic information can identify the presence of targetable mutations and has been explored for cancer screening purposes. ctDNA can be obtained without the risks inherent to biopsy, allowing for serial assessments over time. Several studies have additionally suggested that ctDNA can be used to detect the presence of minimal residual disease (MRD) after surgical resection in several cancer types, including lung cancer. The ability to detect MRD would allow clinicians to tailor adjuvant therapies, which carry risks of significant toxicities and may benefit only select groups of patients. Here, we review the current state of ctDNA profiling methods and evaluate the evidence supporting the use of ctDNA analysis to assess for MRD. We discuss how MRD detection could help identify patients at increased risk of disease recurrence, and thus guide treatment decisions for resectable lung cancer. Finally, we propose future steps to validate such approaches and expand the utility of these rapidly-progressing technologies.
Minimally invasive approaches do not compromise outcomes for pneumonectomy, a comparison utilizing the National Cancer Database J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-10-05 M.W. Hennon, A. Kumar, H. Devisetty, T. D’Amico, T.L. Demmy, A. Groman, S. Yendamuri
Background Minimally invasive approaches are increasingly being used for the conduct of complex surgical procedures. Whether the benefits of minimally invasive approaches compared to thoracotomy for sublobar and lobar lung resection for nonsmall cell lung carcinoma are realized for patients undergoing pneumonectomy is not clear. Methods The National Cancer Database was queried for patients who underwent pneumonectomy for NSCLC from 2010-2014. Those who underwent resection by a minimally invasive approach (MIS) were compared with those who were done by thoracotomy (Open) in an intention-to-treat analysis. Associations between potential covariates and treatment were analyzed using the Pearson Chi-square test for categorical variables and Wilcoxon Rank Sum test for continuous variables. Univariable and multivariable logistic models and proportional hazards model were used to assess the effect of surgical approach on 30 day and 90 day mortality and overall survival. Relative prognosis was summarized using odds ratios (OR) and hazards ratios (HR) estimates and 95% confidence limits. Results A total of 4,938 patients underwent pneumonectomy during the study period, of which 755 (15.3%) were completed by minimally invasive approaches (MIS). No difference was noted in 30 and 90-day mortality rates for MIS compared to Open approaches (6.8% and 12.3% vs 6.7% and 11.9% respectively, p = 0.9 and 0.86). Tumor histology and stage characteristics were similar between the two groups. Mean lymph nodes examined was higher in the MIS group compared to Open (17.1± 0.4 vs 16.1 ± 0.2, p=0.034). Conversion rate for the minimally invasive cohort was 36.7%. Surgical approach was not associated with any difference in perioperative mortality with univariable or multivariable analysis. MIS was associated with improved overall survival on univariable analysis, but this was not evident with multivariable analysis. Conclusion Pneumonectomy performed by minimally invasive approaches does not compromise perioperative mortality or long term outcomes. Further investigation into the impact of minimally invasive approaches on perioperative outcomes for whole lung resection is warranted.
Measurement of multiple solid portions in part-solid nodules for T categorization: Evaluation of prognostic implication J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-10-04 Hyungjin Kim, Jin Mo Goo, Young Joo Suh, Eui Jin Hwang, Chang Min Park, Young Tae Kim
Introduction Our study aimed to analyze the prognostic implication of the multiplicity of solid portion in part-solid nodules (PSNs) on CT and to compare the prognostic performance of various solid portion measures, including the single largest solid portion, solid proportion, and summated multiple solid portion measurements. Methods A total of 345 patients with surgically resected stage IA adenocarcinomas manifesting as PSNs were retrospectively reviewed. A multiplicity of the solid portion in PSNs was determined and the diameter of each solid portion was measured. The prognostic implication of the multiplicity of the solid portion and other clinical variables on disease-free survival (DFS) was analyzed using Cox regression. In addition, risk stratification based on the single largest solid portion, sum of the solid portions, single solid proportion, and sum of the solid proportions was conducted. Then, concordance indices (C-indices) for DFS were obtained for each measure and compared. Intra- and inter-reader measurement variability was assessed. Results Multiplicity of the solid portion did not have a significant effect on DFS, and clinical T category was the only independent risk factor for the tumor recurrence (P<0.05). C-index of the single solid portion (conventional clinical T category) was 0.817 (95% CI: 0.691-0.942). There were no significant differences (P>0.05) between the C-indices of the single solid portion and other solid portion measures. Inter-reader measurement variability was substantial. Conclusions Current clinical T categorization of PSNs based on the single solid portion measurement is appropriate.
Toxicity Related to Radiotherapy Dose and Targeting Strategy: A Pooled Analysis of Cooperative Group Trials of Combined Modality Therapy for Locally Advanced Non-Small Cell Lung Cancer J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-10-04 Steven E. Schild, Wen Fan, Thomas E. Stinchcombe, Everett E. Vokes, Suresh S. Ramalingam, Jeffrey D. Bradley, Karen Kelly, Herbert H. Pang, Xiaofei Wang
Purpose Concurrent chemoradiotherapy(CRT) is the standard treatment for locally-advanced non–small-cell lung cancer(LA-NSCLC). This study was performed to examine thoracic radiotherapy(TRT) parameters and their impact on adverse events(AE’s). Patients and Materials We collected Individual patient data(IPD) from 3600 LA-NSCLC patients participating in 16 cooperative group trials of concurrent CRT. The TRT parameters examined included field design strategy(elective nodal irradiation(ENI) vs. involved field TRT(IF-TRT)) and TRT dose(60Gy vs >60Gy). The primary endpoint of this analysis was the occurrence of AE’s. Odd ratios(ORs) for AE’s were calculated with univariable and multivariable logistic models. Results TRT doses ranged from 60 to 74Gy. ENI wasn’t associated with more grade 3+(>3)AE’s than IF-TRT(multivariable OR:0.77(95%CI:0.543-1.102,p=0.1545). Doses >60Gy(high dose) were associated with significantly more grade 3+AE’s(multivariable OR:1.82(95%CI1.501-2.203,P<0.0001). In contrast, ENI was associated with significantly more grade 4+(>4)AE’s(multivariable OR:1.33(95%CI:1.035-1.709,P=0.0258). Doses>60Gy were also associated with more grade 4+AE’s(multivariate OR1.42(95%CI:1.191-1.700,P=0.0001). Grade 5 AE’s plus treatment related deaths were more frequent with higher dose TRT(p=0.0012) but not ENI(p=0.099). Conclusions For LA-NSCLC patients treated with concurrent CRT, IF-TRT wasn’t associated with the overall risk of grade 3+AE’s but was associated with significantly less grade 4+AE’s than ENI-TRT. This is likely the result of irradiating less adjacent critical normal tissue. Higher TRT doses were associated significantly with grade 3+ and 4+AE’s. Based on these findings and our prior report on survival, CRT employing IF-TRT and 60Gy(conventionally fractionated) were associated with more favorable patient survival and less toxicity than the use of ENI or higher RT doses.
Prophylactic cranial irradiation for limited-stage small-cell lung cancer patients: secondary findings from the prospective randomized phase 3 CONVERT trial J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-10-04 Antonin Levy, Cécile Le Péchoux, Hitesh Mistry, Isabelle Martel-Lafay, Andrea Bezjak, Delphine Lerouge, Laetitia Padovani, Paul Taylor, Corinne Faivre-Finn
Introduction The impact of the dose and fractionation of thoracic radiotherapy on the risk of developing brain metastasis (BM) has not been evaluated prospectively in LS-SCLC patients receiving prophylactic cerebral irradiation (PCI). Methods Data in patients treated with PCI from the CONVERT trial was analysed. Results 449/547 (82%) received PCI after completion of chemoradiotherapy. Baseline brain imaging consisted of CT-scan in 356/449 patients (79%) and MRI in 83/449 (18%) patients. PCI was delivered to 220/273 participants (81%) in the twice-daily (BD) group and 229/270 in the once-daily (OD) group (85%; p=0.49). Total median PCI dose was 25Gy in both BD and OD groups (p=0.74). In patients who received PCI, 75 (17%) developed BM (35 [8%] in OD and 40 [9%] in BD) and 173 (39%) other extracranial progression. In the univariate analysis, GTV was associated with an increased risk of BM (p=0.007) or other radiological progression events (p=0.006), whereas in a multivariate analysis both thoracic GTV (tGTV) and PS were associated with either progression type. The median OS of patients treated with PCI was 29 months. In the univariate analysis of OS, PCI timing from end of chemotherapy, weight loss >10%, and tGTV were prognostic factors associated with OS. In the multivariate analysis, only tGTV was associated with OS. Delay between end of chemotherapy and PCI was not associated with OS. Conclusion Patients receiving OD or BD thoracic RT have the same risk of developing BM. Larger tumours are associated with a higher risk of BM.
Multimodal Treatment in Operable Stage III Non-Small Cell Lung Cancer: A Pooled Analysis on Long Term Results of three SAKK trials (SAKK 16/96, 16/00, 16/01) J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-09-26 Martin Früh M, Daniel C. Betticher, Roger Stupp, Alexandros Xyrafas, Solange Peters, Hans Beat Ris, Rene Olivier Mirimanoff, Adrian Ochsenbein, Ralph Schmid, Oscar Matzinger, Rolf A. Stahel, Walter Weder, Matthias Guckenberger, Sacha Rothschild, Didier Lardinois, Nicholas Mach, Michael Mark, Oliver Gautschi, Miklos Pless
Background Long term data on outcomes of operable stage III non-small cell lung cancer (NSCLC) are scarce. Patients and methods Individual patient data of 368 patients enrolled in one phase III and two phase II trials were pooled and outcomes after applying the 8th (marked with *) vs. the 6th TNM staging edition were compared. Patients were treated with either preoperative radiotherapy following three cycles of induction chemotherapy (tri-modal) or neoadjuvant chemotherapy alone (bi-modal). Results With the 6th version the 5- and 10-year survival rates were 38% and 28% for stage IIIA and 36% and 24% for stage IIIB. Factors associated with improved 5-year overall survival (OS) were younger age, R0 resection and pathologic complete remission (pCR) (P=0.043, P<0.001 and P=0.009). With the 8th TNM staging version 162 patients were moved from stage IIIA to IIIB*. The 5- and 10-year survival rates were 41% and 29% for stage IIIA* and 35% and 27% for stage IIIB* patients. There was no difference in the bi- vs. tri-modal group with regards to median OS (28 months [95% CI: 21–39 months] and 37 months [95% CI: 24-51 months], p=0.9) and event free survival (12 months [95% CI: 9–15 months] vs. 13 months [95% CI: 10-22 months], P=0.71). Conclusions We showed favourable 10-year survival rates of 29% and 27% in stage IIIA* and IIIB*. Younger age, R0 resection and pCR was associated with improved long term survival. Outcomes using the 6th versus 8th edition of the TNM classification were similar in operable stage III NSCLC.
Current and Future Management of Malignant Mesothelioma : A Consensus Report from the National Cancer Institute Thoracic Malignancy Steering Committee, International Association for the Study of Lung Cancer and Mesothelioma Applied Research Foundation J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-09-25 Anne S. Tsao, O. Wolf Lindwasser, Alex A. Adjei, Prasad S. Adusumilli, Matthew Beyers, Gideon M. Blumenthal, Raphael Bueno, Bryan M. Burt, Michele Carbone, Suzanne E. Dahlberg, Marc de Perrot, Dean A. Fennell, Joseph Friedberg, Ritu R. Gill, Daniel R. Gomez, David H. Harpole, Raffit Hassan, Mary Hesdorffer, Shakun M. Malik
On March 28th – 29th 2017, the National Cancer Institute (NCI) Thoracic Malignacy Steering Committee (TMSC), the International Association for the Study of Lung Cancer (IASLC) and the Mesothelioma Applied Research Foundation (MARF), convened the NCI-IASLC-MARF Mesothelioma Clinical Trials Planning Meeting in Bethesda, Maryland. The goal of the meeting was to bring together lead academicians, clinicians, scientists and the FDA to focus on the development of clinical trials for patients diagnosed with malignant pleural mesothelioma (MPM). Based on the discovery of new cancer targets impacting the clinical development of novel agents and immunotherapies in malignant mesothelioma, the objective of this meeting was to assemble a consensus on at least 2-3 practice changing multimodality clinical trials to be conducted via NCI’s National Clinical Trials Network (NCTN).
Immune marker profiling and PD-L1 expression across Non-Small Cell Lung Cancer mutations J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-09-26 Maria I. Toki, Nikita Mani, James W. Smithy, Yuting Liu, Mehmet Altan, Brad Wasserman, Rasikh Tuktamyshov, Kurt Schalper, Konstantinos N. Syrigos, David L. Rimm
Purpose PD-1/PD-L1 axis inhibitors have been proven effective, especially in patients with tumors expressing Programmed Death Ligand 1 (PD-L1). Their clinical efficacy in patients with epidermal growth factor receptor (EGFR) activating mutations is still unclear, while KRAS mutations seem to be associated with good response. Experimental Design We used multiplexed quantitative immunofluorescence (QIF) to investigate PD-L1 expression and to characterize Tumor Infiltrating Lymphocyte (TIL) populations and their activation status in over 150 Non-Small Cell Lung Cancer (NSCLC) patients with known mutation status. Results PD-L1 expression was significantly lower in EGFR mutant compared to KRAS mutant and EGFR/KRAS Wild Type (WT) tumors. KRAS mutant tumors were more inflamed with higher CD4+, CD8+ and CD20+ TILs. Subgroup analysis by TILs activation status revealed that EGFR mutants had a high frequency of inactive TILs even though lymphocytes were present in the tumor microenvironment. In contrast, in KRAS mutants, when TILs were present, they were almost always active. Additionally, we found differences between EGFR mutation sites in CD8+ expression and TILs activation profile. Finally, activated EGFR correlated with increased PD-L1 expression in EGFR mutants but not in EGFR WT, while TIL activation was associated with higher PD-L1 only in EGFR/KRAS WT. Conclusions Our findings demonstrate the unique immune profile of EGFR mutant tumors. The high frequency of inactive TILs could explain the low immunotherapy response rates in these patients, while PD-L1 as a predictive biomarker may reflect the constitutive oncogenic signaling rather than immune signaling, which would be associated with high PD-L1 levels and TILs activation.
Pneumonitis in Non-Small Cell Lung Cancer patients receiving Immune Checkpoint Immunotherapy: incidence and risk factors J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-09-26 Karthik Suresh, Khinh Ranh Voong, Bairavi Shankar, Patrick M. Forde, David S. Ettinger, Kristen A. Marrone, Ronan J. Kelly, Christine L. Hann, Benjamin Levy, Josephine L. Feliciano, Julie R. Brahmer, David Feller-Kopman, Andrew D. Lerner, Hans Lee, Lonny Yarmus, Franco D’Alessio, Russell K. Hales, Tony Lin, Jarushka Naidoo
Checkpoint inhibitor pneumonitis (CIP) is an immune-related adverse event that can occur after initiation of anti-PD-1/PD-L1 immune checkpoint inhibitor (ICI) therapy for the treatment of multiple malignancies, including non-small cell lung cancer (NSCLC). However, the incidence of CIP has not been previously examined in a population that included both trial and non-trial enrolled patients with advanced NSCLC. Furthermore, risk factors and other clinical characteristics associated with CIP severity are not known. In this study, we retrospectively examined clinical characteristics, incidence and risk factors for CIP in a cohort of 205 patients with NSCLC, all of whom received anti-PD-1/PD-L1 ICIs. Our results demonstrate a higher incidence of CIP (19%), than previously reported in clinical trials (3-5%). Our data also suggest that tumor histology may be a risk factor for CIP development. We observed a wide range of time to onset of CIP (median of 82 days), with high morbidity and mortality associated with higher-grade CIP regardless of degree of immunosuppression. Our data provide new insight into the epidemiology and clinical characteristics of CIP. Further studies are needed to increase CIP pharmacovigilance, improve risk stratification, and refine diagnostic algorithms for the diagnosis and management of this potential life-threatening complication of ICI therapy.
Association of mosaic loss of chromosome Y with lung cancer risk and prognosis in a Chinese population J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-09-26 Na Qin, Ni Li, Cheng Wang, Zhening Pu, Zijian Ma, Guangfu Jin, Meng Zhu, Min Dai, Zhibin Hu, Hongxia Ma, Hongbing Shen
Introduction Mosaic loss of chromosome Y (mLOY) is the most commonly detectable mosaic chromosomal event in cancers; however, its underlying relationship with tumorigenesis is still unclear. Methods We conducted a Mendelian randomization study to systematically investigate the effect of mLOY on lung cancer based on a published genome-wide association study and inferred the causal relationship between mLOY and lung cancer. Kaplan-Meier and Cox regression analyses were used to evaluate the effect of mLOY on lung cancer prognosis. Results We identified that genetically defined mLOY was a protective factor for lung cancer in non-smokers, but not in smokers (lifelong non-smokers: OR=0.80, 95% CI=0.69-0.93, P=4.03×10-3; smokers: OR=0.96, 95% CI=0.89-1.04, P=2.90×10-1; PHeterogeneity=3.83×10-2). A U-shaped curve between the copy-number level of chromosome Y and lung cancer risk was fitted (P for Linearity Wald=8.81×10-10) to support that heavy mLOY caused by acquired damaging environmental factors may have different effects on lung cancer from genetically defined mLOY, while genetically predicted mLOY was linearly associated with a decreased lung cancer risk (P for Linearity Wald=0.15). In addition, elevated genetically defined mLOY was also significantly associated with a better outcome of lung cancer (HR=0.86, 95% CI=0.75-0.98, P=2.03×10-2). Conclusions In summary, we propose a two “sides” model: “natural” mLOY reduces the risk and ensures a better prognosis of lung cancer, while the effect can be abolished by an aberrant loss of chromosome Y caused by environmental risk factors. Our results reveal a complex relationship between mLOY and lung cancer and provide important implications for the prevention of lung cancer.
Detection of known and novel FGFR fusions in non-small cell lung cancer by comprehensive genomic profiling J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-09-26 Angel Qin, Adrienne Johnson, Jeffrey S. Ross, Vincent A. Miller, Siraj M. Ali, Alexa B. Schrock, Shirish Gadgeel
Introduction Activation of the fibroblast growth factor receptor (FGFR) family through fusion with various partners has been described in multiple cancer types including non-small cell lung cancer (NSCLC). FGFR inhibitors are currently being evaluated clinically for patients whose tumors harbor these fusions. Methods Hybrid-capture based comprehensive genomic profiling (CGP) was performed on 26,054 consecutive FFPE NSCLC specimens. Results FGFR fusions retaining the kinase domain were identified in 0.2% of NSCLC cases, including 37 FGFR3-TACC3, two FGFR2-KIAA1598, one BAG4-FGFR1, and 12 novel FGFR1-4 fusion-positive cases. Co-occurring EGFR or MET alterations were observed in 8% (4/52) of cases, KRAS mutation in three additional cases, and FGFR1 or FGFR3 amplification in 10% of cases. The two patients with co-occurring EGFR mutations were previously treated with EGFR inhibitors. One patient with a novel FGFR2-LZTFL1 fusion had a partial response to the pan-FGFR inhibitor JNJ-42756493 and remained progression free for 11 months. Conclusion FGFR fusions were detected using CGP in 0.2% of NSCLCs, and occurred primarily in the absence of other known driver alterations, or in a subset of cases, as likely mechanisms of acquired resistance. One patient with a novel FGFR2 fusion had clinical benefit from an investigational FGFR inhibitor, suggesting that these alterations may predict response to targeted therapies.
Procedure-Specific Risk Prediction for Recurrence in Patients Undergoing Lobectomy or Sublobar Resection for Small (≤2 cm) Lung Adenocarcinoma: An International Cohort Analysis J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-09-22 Sarina Bains, Takashi Eguchi, Arne Warth, Yi-Chen Yeh, Jun-ichi Nitadori, Kaitlin M. Woo, Teh-Ying Chou, Hendrik Dienemann, Thomas Muley, Jun Nakajima, Aya Shinozaki-Ushiku, Yu-Chung Wu, Shaohua Lu, Kyuichi Kadota, David R. Jones, William D. Travis, Kay See Tan, Prasad S. Adusumilli
Purpose To develop and validate procedure-specific risk prediction for recurrence following resection for early-stage lung adenocarcinoma (ADC) and investigate risk prediction utility in identifying patients who may benefit from adjuvant chemotherapy (ACT). Basic Procedures In patients who underwent resection for small (≤2 cm) lung ADC (lobectomy, 557; sublobar resection, 352), an association between clinicopathological variables and risk of recurrence was assessed by a competing risks approach. Procedure-specific risk prediction was developed based on multivariable regression for recurrence. External validation was conducted using cohorts (N=708) from Japan, Taiwan, and Germany. The accuracy of risk prediction was measured using a concordance index (C-index). We applied the lobectomy risk prediction approach to a propensity score–matched cohort of patients with stage II-III disease (n=316, after matching) with or without ACT and compared lung cancer-specific survival between groups among low or high-risk scores. Main Findings Micropapillary pattern, solid pattern, lymphovascular invasion, and necrosis were involved in the risk prediction following lobectomy, and micropapillary pattern, spread through air spaces, lymphovascular invasion, and necrosis following sublobar-resection. Both internal and external validation showed good discrimination (C-index in lobectomy and sublobar resection: internal, 0.77 and 0.75; and external, 0.73 and 0.79). In the stage II-III propensity score–matched cohort, among high-risk patients, ACT significantly reduced the risk of lung cancer–specific death (subhazard ratio 0.43, p=0.001), but not among low-risk patients. Principal Conclusions Procedure-specific risk prediction for patients with resected small lung ADC can be used to better prognosticate and stratify patients for further interventions.
Correlation of PD-L1 expression with tumor mutation burden and gene signatures for prognosis in early stage squamous cell lung carcinoma J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-09-22 Hui Yu, Zhengming Chen, Karla Ballman, Mark A. Watson, Ramaswamy Govindan, Irena Lanc, David G. Beer, Raphael Bueno, Lucian Chirieac, M.Herman Chui, Guoan Chen, Wilbur A. Franklin, David R. Gandara, Carlo Genova, Kristine Brovsky, David Harpole, Marybeth Joshi, Daniel T. Merrick, Fred R. Hirsch
Purpose Anti-PD1/PD-L1 immunotherapy has demonstrated success in the treatment of advanced non-small cell lung cancer (NSCLC). Recently, PD1/PD-L1 blockade also has demonstrated interesting results in small trials of neo-adjuvant treatment in Stage IB-IIIA NSCLC. In addition, several clinical trials using anti-PD1/PD-L1 as an adjuvant or neo-adjuvant treatment in resectable stage NSCLC patients are ongoing. However, few analyses of anti-PD1/PD-L1 immunotherapy related biomarkers in early stage squamous cell lung carcinoma (SqCLC) have been reported. In this study, we evaluated PD-L1 protein expression, tumor mutation burden, and expression of an immune gene signature in early stage SqCLC, providing data for identifying the potential role for anti-PD1/PD-L1 treatment in early stage SqCLC patients. Experimental Design and Results A total of 255 early stage SqCLC patient specimens were identified within the Strategic Partnering to Evaluate Cancer Signatures (SPECS) program participating centers. PD-L1 protein expression by IHC was evaluated using the Dako PD-L1 22C3 pharmDx kit on the Dako Link 48 auto-stainer. Tumor Mutation Burden (TMB) was calculated based on data from targeted genome sequencing. The T-effector and IFN-γ gene signature was determined from Affymetrix gene chip data from frozen specimens. The prevalence of PD-L1 expression was 9.8% at a tumor proportion score (TPS) cutoff of ≥ 50%. PD-L1 mRNA and PD-L2 mRNA positively correlated with PD-L1 protein expression on tumor cells (TCs) and tumor-infiltrating immune cells (TIICs). PD-L1 protein expression on TIICs was correlated with the T-effector and IFN-γ gene signature (P<0.001), but not with TMB. For tumor cells, all of these biomarkers were independent of each other. And neither PD-L1 protein expression, TMB, or T-effector and IFN-γ gene signatures were independently prognostic for patient outcomes. Conclusions Evaluation of PD-L1 expression, TMB, and T-effector and IFN-γ gene signatures in the early-stage SqCLC cohort were found to be independent of each other and none were associated with overall survival. Results also support the hypothesis that PD-L1 expression is regulated by an intrinsic mechanism on tumor cells and an adaptive mechanism on immune cells.
Progression-Free-Survival and Overall Survival beyond 5 years of non-small cell lung cancer patients with synchronous oligometastases treated in a prospective phase II trial (NCT 01282450) J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-09-22 D. De Ruysscher, R. Wanders, L.E. Hendriks, A. van Baardwijk, B. Reymen, R. Houben, G. Bootsma, C. Pitz, L. van Eijsden, A.-M.C. Dingemans
Background Two randomized studies demonstrated an increased progression-free survival (PFS) by adding a radical local treatment to systemic therapy in responding patients with oligometastatic non-small cell lung cancer (NSCLC), but long-term data are lacking. We updated the results of our previous phase II trial with a minimal follow-up exceeding 7 years. Methods Prospective single-arm phase II trial. The main inclusion criteria were pathologically proven NSCLC stage IV with less than five metastases at primary diagnosis, amendable for radical local treatment (surgery or radiotherapy). No previous response to systemic treatment was needed. Results Forty patients were enrolled, 39 of whom were evaluable (18 men, 21 women); mean age was 62.1 ± 9.2 years (range, 44-81). Twenty-nine (74%) had N2 or N3 disease; 17 (44%) brain, seven (18%) bone, and four (10%) adrenal gland metastases. Thirty-five (87%) had a single metastatic lesion. Thirty-seven (95%) of the patients received chemotherapy as part of their primary treatment. Median overall survival (OS) was 13.5 months (95% CI 7.6-19.4); 1-, 2-, 3-, 5-, 6- year OS was 56.4%, 23.3%,12.8%, 10.3%, 7.7 % and 5.1%, respectively. Median progression-free survival (PFS) was 12.1 months (95% CI 9.6-14.3); 1-, 2-, 3-, 5-, 6- year OS was 51.3%, 13.6%, %,12.8%, 7.7%, 7.7 % and 2.5%, respectively. Only three patients (7.7%) had a local recurrence. Conclusions In patients who were not selected according to response to systemic treatment, the PFS at 5 years was 8 %. Entering patients in trials combining local therapy with novel systemic agents (e.g. immunotherapy) remains mandatory.
Lobectomy Is Associated with Better Outcomes than Sublobar Resection in Spread Through Air Spaces (STAS)–Positive T1 Lung Adenocarcinoma: A Propensity Score–Matched Analysis1 J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-09-19 Takashi Eguchi, Koji Kameda, Shaohua Lu, Matthew Bott, Kay See Tan, Joseph Montecalvo, Jason C. Chang, Natasha Rekhtman, David R. Jones, William D. Travis, Prasad S. Adusumilli
Introduction Spread through air spaces (STAS) is a form of invasion wherein tumor cells extend beyond the tumor edge within the lung parenchyma. In lung adenocarcinoma (ADC), we investigated the (a) association between STAS and procedure-specific outcomes (sublobar resection and lobectomy), (b) effect of surgical margin/tumor diameter ratio in STAS-positive patients, and (c) potential utility of frozen section (FS) for detecting STAS intraoperatively. Methods We investigated 1497 patients who underwent lobectomy (n=970) or sublobar resection (n=527) for T1N0M0 lung ADC, following propensity-score matching. Outcomes were analyzed using a competing-risks approach. The effect of margin/tumor ratio on recurrence pattern (locoregional and distant) was investigated in sublobar patients. Five pathologists evaluated the feasibility of intraoperatively identifying STAS using FS (sensitivity, specificity, interrater reliability). Results On multivariable analysis following propensity-score matching (349 pairs/procedure), sublobar resection was significantly associated with recurrence (subhazard ratio, 2.84; P<0.001) and lung cancer–specific death (subhazard ratio, 2.63; P=0.021) in patients with STAS but not in those without STAS. Patients with STAS who underwent sublobar resection had a higher risk of locoregional recurrence regardless of margin/tumor ratio (margin/tumor ratio ≥1 vs. <1: 5-year cumulative incidence of recurrence [CIR], 16% and 25%); among patients without STAS, locoregional recurrences occurred in patients with margin/tumor ratio <1 (5-year CIR, 7%). Sensitivity and specificity for detecting STAS by FS were 71% and 92%, with substantial interrater reliability (Gwet’s AC1, 0.67). Conclusions In T1 lung ADC patients with STAS, lobectomy was associated with better outcomes than sublobar resection. Pathologists can recognize STAS on FS.
Computer-based intensity measurement assists pathologists in scoring PTEN immunohistochemistry - Clinical associations in NSCLC patients of the ETOP Lungscape cohort J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-09-18 Undine Rulle, Zoi Tsourti, Ruben Casanova, Karl-Friedrich Deml, Eric Verbeken, Erik Thunnissen, Arne Warth, Richard Cheney, Aleksandra Sejda, Ernst Jan Speel, Line Bille Madsen, Daisuke Nonaka, Atilio Navarro, Irene Sansano, Antonio Marchetti, Stephen P. Finn, Kim Monkhorst, Keith M. Kerr, Alex Soltermann
Introduction PTEN loss is frequently observed in NSCLC and associated with both PI3K activation and tumoral immunosuppression. PTEN immunohistochemistry is a valuable read-out, but lacks standardized staining protocol and cut-off value. Methods Following an external quality assessment (EQA) using SP218, 138G6 and 6H2.1 anti-PTEN antibodies, scored on webbook and tissue microarray, the ETOP cohort samples (n=2245 NSCLC patients, 8980 TMA cores) were stained with SP218. All cores were H-scored by pathologists and by computerized pixel-based intensity measurements calibrated by pathologists. Results All 3 antibodies differentiated 6 PTEN+ versus 6 PTEN- cases on EQA. For 138G6 and SP218, high sensitivity and specificity was found for all H-score threshold values including prospectively defined 0, calculated 8 (pathologists) and calculated 5 (computer). High concordance among pathologists in setting computer-based intensities and between pathologists and computer in H-scoring was observed. Due to over-integration of the human eye, pixel-based computer H-scores were overall 54% lower. For all cut-off values, PTEN- was associated with smoking history, squamous cell histology and higher tumor stage (p<0.001). In adenocarcinomas, PTEN- was associated with poor survival. Conclusion Calibration of immunoreactivity intensities by pathologists, following computerized H-score measurements has the potential to improve reproducibility and homogeneity of biomarker detection regarding epitope validation in multi-centre studies.
Osimertinib versus standard-of-care EGFR-TKI as first-line treatment in patients with EGFRm advanced NSCLC: FLAURA Asian subset J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-09-18 Byoung Chul Cho, Busayamas Chewaskulyong, Ki Hyeong Lee, Arunee Dechaphunkul, Virote Sriuranpong, Fumio Imamura, Naoyuki Nogami, Takayasu Kurata, Isamu Okamoto, Caicun Zhou, Ying Cheng, Eun Kyung Cho, Pei Jye Voon, Jong-Seok Lee, Helen Mann, Matilde Saggese, Thanyanan Reungwetwattana, Suresh S. Ramalingam, Yuichiro Ohe
Introduction Here we report efficacy and safety data of an Asian subset of the Phase III FLAURA trial (NCT02296125), which compares osimertinib with standard-of-care (SoC) epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) in patients with previously untreated advanced non-small cell lung cancer (NSCLC) with tumors harboring exon 19 deletion (Ex19del)/L858R EGFR-TKI sensitizing mutations (EGFRm). Methods Eligible Asian patients (enrolled at Asian sites) ≥18 years (≥20 years in Japan), with untreated EGFRm advanced NSCLC were randomized 1:1 to receive osimertinib (80 mg orally, once daily [qd]) or SoC EGFR-TKI (gefitinib [250 mg] or erlotinib [150 mg] orally, qd). Primary endpoint: investigator assessed progression-free survival (PFS). Key secondary endpoints: overall survival (OS), objective response rate (ORR), central nervous system (CNS) efficacy, and safety. Results Median PFS was 16.5 versus 11.0 months for the osimertinib and SoC EGFR-TKI groups, respectively; HR 0.54 (95% CI 0.41 – 0.72), p < 0.0001. OS data were immature (24% maturity). ORR was 80% for osimertinib and 75% for SoC EGFR-TKI. Median CNS PFS was not calculable for the osimertinib group and was 13.8 months for the SoC EGFR-TKI group; HR 0.55 (95% CI 0.25–1.17), p = 0.118. Fewer adverse events of Grade ≥3 (40% vs 48%) and fewer adverse events leading to treatment discontinuation (15% vs 21%) were reported with osimertinib versus SoC EGFR-TKI, respectively. Conclusion In this Asian population, first-line osimertinib demonstrated a clinically meaningful improvement in PFS over SoC EGFR-TKI, with a safety profile consistent with the overall FLAURA study population.
Impact of Lymph Node Dissection on Thymic Malignancies: Multi-Institutional Propensity Score Matched Analysis J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-09-11 Yoohwa Hwang, Chang Hyun Kang, Samina Park, Hyun Joo Lee, In Kyu Park, Young Tae Kim, Geun Dong Lee, Hyeong Ryul Kim, Se Hoon Choi, Yong-Hee Kim, Dong Kwan Kim, Seung-Il Park, Sumin Shin, Jong Ho Cho, Hong Kwan Kim, Yong Soo Choi, Jhingook Kim, Jae Il Zo, Kyung Young Chung
Introduction Surgical resection is a standard treatment for thymic malignancies. However, prognostic significance of nodal metastases and lymph node dissection remains unclear. The aim of this study is to determine prognostic significance of nodal metastases and role of lymph node dissection (LND) in thymic malignancies. Methods Between 2000 and 2013, 1,597 patients who underwent thymectomy due to thymic malignancy were included. Predictive factors for nodal metastasis and prognostic significance of LND were evaluated. Patients were divided into two groups: 1) LND+ group, with intentional LND (446 patients, 27.9%); and 2) LND- group, without intentional LND (1,151 patients, 72.1%). Propensity score matching was performed between the two groups. Results Lymph Node metastasis was identified in 20 (6.7%) of 298 patients with thymoma and 47 (31.7%) of 148 patients with thymic carcinoma. In multivariable analysis, thymic carcinoma (HR: 19.2, p < 0.001) and tumor size (HR: 1.09, p = 0.02) were significant predictive factors for lymph node metastasis. Ten-year freedom from recurrence (FFR) rate of pN1 and pN2 was significantly worse than that of pN0 (p < 0.001). LND did not increase operative mortality or complication. There was no significant difference in 10-year FFR rate between LND+ and LND- groups (82.4% vs. 80.9%, p = 0.46 in thymoma; 45.7% vs. 44.0%, p = 0.42 in thymic carcinoma). Conclusions Lymph node metastasis was a significant prognostic factor in thymic malignancies. Although LND did not improve long-term outcomes in thymic malignancies, LND played a role in accurate staging, and improved prediction of prognosis.
A brief report of transformation from Non-small cell to small cell lung cancer: Molecular and therapeutic characteristics J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-09-11 Léonie Ferrer, Matteo Giaj Levra, Marie Brevet, Martine Antoine, Julien Mazieres, Giulio Rossi, Rita Chiari, Virginie Westeel, Michel Poudenx, Jacques Letreut, Radj Gervais, Giorgia Osman, Nicolas Girard, Anne Claire Toffart, Silvia Novello, Denis Moro-Sibilot
Histological transformation from Non-small cell lung cancer (NSCLC) to SCLC is a mechanism of resistance in EGFR-mutant tumors but is also occasionally observed in non-mutated NSCLC. Patients and methods We performed a multicenter retrospective collection of cases presenting between 2005 and 2017. The objectives were to analyse survival data and to define epidemiological, clinical, treatment and histo-molecular characteristics at both the time of diagnosis of NSCLC and of SCLC. Results Forty-eight EGFR-mutant NSCLC and 13 non-EGFR-mutant cases were registered. Most EGFR-mutant tumors retained the same EGFR mutation after transformation. The median time to SCLC transformation was shorter in the EGFR-mutant group than in non-EFGR mutants (16 months versus 26 months (p= 0.01)). Both tumors were responsive to platinum etoposide regimens (45% partial response for the EGFR-mutant group versus 40% for non-EFGR mutants). The median overall survival were respectively 28 months in the EGFR-mutant group versus 37 months in the non-EFGR-mutant group. After transformation the median overall survival was 9 months in the non-EGFR-mutant group versus 10 months. Conclusion Transformation into SCLC seems to occur more quickly in EGFR mutated tumors, however once the tumor is transformed its survival and response to treatment seems comparable to that of classical SCLC.
Atezolizumab Treatment Beyond Progression in Advanced Non-Small Cell Lung Cancer: Results From the Randomized, Phase III OAK Study J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-09-11 David R. Gandara, Joachim von Pawel, Julien Mazieres, Richard Sullivan, Åslaug Helland, Ji-Youn Han, Santiago Ponce Aix, Achim Rittmeyer, Fabrice Barlesi, Toshio Kubo, Keunchil Park, Jerome Goldschmidt, Mayank Gandhi, Cindy Yun, Wei Yu, Christina Matheny, Pei He, Alan Sandler, Louis Fehrenbacher
Introduction Cancer immunotherapy may alter tumor biology such that treatment effects can extend beyond radiographic progression. In the randomized, Phase III OAK study of atezolizumab (anti–PD-L1) versus docetaxel in advanced non-small cell lung cancer, overall survival (OS) benefit with atezolizumab was observed in the overall patient population, without improvement in objective response rate (ORR) or progression-free survival (PFS). We examine the benefit-risk of atezolizumab treatment beyond progression (TBP). Methods 850 patients included in the OAK primary efficacy analysis were evaluated. Atezolizumab was continued until loss of clinical benefit. Docetaxel was administered until RECIST v1.1 disease progression (PD)/unacceptable toxicity; no crossover to atezolizumab was allowed. ORR, PFS, and post-PD OS, target lesion change, and safety were evaluated. Results In atezolizumab-arm patients, ORR was 16% versus 14% and median PFS was 4.2 versus 2.8 months per immune-modified RECIST (imRECIST) versus RECIST v1.1. The median post-PD OS was 12.7 months (95% CI: 9.3, 14.9) in 168 atezolizumab-arm patients continuing TBP, 8.8 months (95% CI: 6.0, 12.1) in 94 patients switching to non-protocol therapy and 2.2 months (95% CI: 1.9, 3.4) in 70 patients receiving no further therapy. Of the atezolizumab TBP patients, 7% achieved a post-progression response in target lesions and 49% had stable target lesions. Atezolizumab TBP was not associated with increased safety risks. Conclusions Within the limitations of this retrospective analysis, the post-PD efficacy and safety data from OAK are consistent with a positive benefit-risk profile of atezolizumab TBP in patients performing well clinically at the time of PD.
Brief Report: Increased Hepatotoxicity Associated with Sequential Immune Checkpoint Inhibitor and Crizotinib Therapy in Patients with Non-Small-Cell Lung Cancer J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-09-08 Jessica J. Lin, Emily Chin, Beow Y. Yeap, Lorin A. Ferris, Vashine Kamesan, Inga T. Lennes, Lecia V. Sequist, Rebecca S. Heist, Mari Mino-Kenudson, Justin F. Gainor, Alice T. Shaw
Introduction Immune checkpoint inhibitors (ICIs) are standard therapies in advanced non-small-cell lung cancer (NSCLC). While genotype-directed tyrosine kinase inhibitors (TKIs) represent the standard of care for subsets of oncogene-driven NSCLC, patients may receive ICIs during their disease course. The impact of sequential ICI/TKI therapy on the risk of hepatotoxicity has not been described. Methods Patients with advanced ALK/ROS1/MET-driven NSCLC treated with crizotinib, with or without preceding ICI, were identified. The cumulative incidences of crizotinib-associated grade 3+ transaminase elevations (per the Common Terminology Criteria for Adverse Events version 4.0) were compared. Results We identified 453 patients with NSCLC harboring an oncogenic alteration in ALK, ROS1, or MET who were treated with crizotinib (11 with, 442 without prior ICI). Among 11 patients treated with ICI followed by crizotinib, five (cumulative incidence, 45.5%; 95% confidence interval [CI], 14.9-72.2) developed grade 3 or 4 ALT elevation, and four (36.4%; 95% CI, 10.0-64.2) developed grade 3 or 4 AST elevation. In comparison, among 442 patients who received crizotinib only, grade 3 or 4 ALT and AST elevations occurred in 34 (8.1%; 95% CI, 5.7-11.0; P <0.0001) and 14 patients (3.4%; 95% CI, 1.9-5.5; P <0.0001), respectively. There were no grade 5 transaminitis events. All cases of hepatotoxicity following sequential ICI and crizotinib use were reversible and nonfatal, and no case met Hy’s law criteria. Conclusions Sequential ICI/crizotinib treatment is associated with a significantly increased risk of hepatotoxicity. Careful consideration and monitoring for hepatotoxicity may be warranted in patients treated with crizotinib following prior ICI.
Implications of the Eighth Edition of the TNM Proposal: Invasive vs. Total Tumor Size for the T Descriptor in Pathologic Stage I-IIA Lung Adenocarcinoma J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-09-07 Koji Kameda, Takashi Eguchi, Shaohua Lu, Yang Qu, Kay See Tan, Kyuichi Kadota, Prasad S. Adusumilli, William D. Travis
Introduction The eighth edition of the tumor, node, and metastasis (TNM) staging system included the proposal that the T descriptor be determined according to the invasive component, excluding lepidic component, for nonmucinous lung adenocarcinomas. We sought to conduct a clinicopathologic comparative analysis of the newly proposed classification using invasive size versus total tumor size. Methods Patients who underwent lung resection for primary lung adenocarcinoma with pathologic stage (p-Stage) I-IIA (based on total size [t]) were reviewed (n=1704). Pathologic invasive size was measured, and tumors were reclassified using invasive size (i). Cumulative incidence of recurrence (CIR) and lung cancer–specific cumulative incidence of death (LC-CID) were analyzed using a competing-risks approach. Prognostic discrimination by p-Stage(t) and p-Stage(i) was evaluated using a concordance index (C-index). Results The use of invasive size resulted in downstaging in 377 of 1704 patients (22%), with twice as many patients with p-Stage IA1 (IA1[i] vs. IA1[t]: 389 [23%] vs. 195 [11%]). However, outcomes were similar between the two groups (IA1[i] vs. IA1[t]: 5-year-CIR, 11% vs. 13%; 5-year LC-CID, 5% vs. 7%). Prognostic discrimination by p-Stage(i) was better than by p-Stage(t) (C-index for p-Stage[i] vs. p-Stage[t]: recurrence, 0.614 vs. 0.593; lung cancer–specific death, 0.634 vs. 0.621). Conclusions When invasive size, rather than total size, was used for the T descriptor, a larger number of patients were classified with a favorable prognosis (p-Stage IA1) and better prognostic discrimination of p-Stage I-IIA nonmucinous lung adenocarcinomas was achieved.
Optimization of routine testing for MET exon 14 splice site mutations in non-small cell lung cancer patients J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-09-07 Clotilde Descarpentries, Frédéric Leprêtre, Fabienne Escande, Zoulika Kherrouche, Martin Figeac, Shéhérazade Sebda, Simon Baldacci, Valérie Grégoire, Philippe Jamme, Marie-Christine Copin, David Tulasne, Alexis B. Cortot
Introduction Genomic alterations affecting splice sites of MET exon 14 were recently identified in non-small cell lung cancer (NSCLC) patients. Objective responses to MET tyrosine kinase inhibitors have been reported in these patients. Thus, detection of MET exon 14 splice site mutations represents a major challenge. So far, most of these alterations were found by full-exome sequencing or large capture-based NGS panels, which are not suitable for routine diagnosis. Methods Aiming to provide a molecular testing method applicable in routine practice, we first developed a fragment-length analysis for detecting deletions in introns flanking MET exon 14. Second, we designed an optimized targeted next generation sequencing (NGS) panel called CLAPv1, covering the MET exon 14 and flanking regions in addition to the main molecular targets usually covered in genomic testing. In patients with MET exon 14 mutations, MET gene amplification, gene copy number and MET receptor expression were also determined. Results Among 1514 formalin-fixed paraffin-embedded NSCLC samples, non optimized NGS allowed detection of MET exon 14 mutations in only 0.3% of the patients, and fragment length analysis detected deletions in 1.1% of the patients. Combined, the optimized CLAPv1 panel and fragment length analysis implemented for routine molecular testing revealed MET exon 14 alterations in 2.2% of 365 additional NSCLC patients. MET gene amplification or high gene copy number were observed in 6 out of 30 patients (20%) harboring MET exon 14 mutations. Conclusions These results demonstrate that optimized targeted NGS and fragment-length analysis improve detection of MET alterations in routine practice.
Biomarker Clinical Trials in Lung Cancer: Design, Logistics, Challenges, and Practical Considerations J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-09-04 Jennifer Le-Rademacher, Suzanne Dahlberg, J. Jack Lee, Alex A. Adjei, Sumithra J. Mandrekar
Treatment for lung cancer has evolved in the past three decades starting with platinum-based chemotherapy as the standard of care, regardless of histology, in the early 1990s to the current age of biomarker-driven therapy. Consequently, clinical trials in lung cancer have evolved in response to this new shift of paradigm, leading to novel approaches that simultaneously shorten the development process and allow evaluation of multiple patient cohorts. Herein, we provide an overview of the landscape of lung cancer clinical trials in the era of targeted therapies, precision medicine, and biomarkers. Specific trials are given as examples to illustrate the design paradigms. The paper is organized by drug development phases starting with early phase biomarker discovery to proof of concept trials to definitive trials. We also present some thoughts on future directions.
Adenocarcinoma of the Lung in Childhood and Adolescence: a systematic review J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-09-04 Ben WR. Balzer, Christine Loo, Craig R. Lewis, Toby N. Trahair, Antoinette C. Anazodo
Introduction Primary lung cancer is extremely rare in children. It often presents with metastatic disease and carries a poor prognosis. Adenocarcinoma is the most common type of bronchogenic carcinoma in children and adults. Our aim was to systematically review the presenting features, approach to diagnosis and management, as well as the outcomes of primary pediatric adenocarcinoma of the lung. Materials and Methods This systematic review was prospectively registered with PROSPERO. The following databases were searched: Medline, Embase, Web of Science and Scopus for English language cases of primary pediatric adenocarcinoma of the lung. Results Forty-eight studies were included, comprising 62 patients with adenocarcinoma and 21 cases of adenocarcinoma in situ (AIS). Presenting features were non-specific, with cough and dyspnea the main symptoms at diagnosis. The majority of patients with adenocarcinoma had metastatic disease at diagnosis. Surgery was the most common form of management. Over half the patients with adenocarcinoma had died at final follow-up whereas 5 of 21 with AIS died. Medical management did not improve outcomes, except for two ALK-rearranged adenocarcinomas that responded to ALK inhibitor therapy alone. Discussion Primary pediatric adenocarcinoma of the lung is a rare entity which often presents with metastatic disease and portends a poor prognosis. Surgery is associated with disease-free status, though new agents such as ALK-inhibitors are able to prolong life without surgical management.
Survival Patterns for Patients with Resected N2 Non-Small Cell Lung Cancer and Postoperative Radiotherapy: A Prognostic Scoring Model and Heat Map Approach J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-09-05 Weiye Deng, Ting Xu, Yifan Wang, Yujin Xu, Xiangyu Liu, Yu Zhao, Pei Yang, Zhongxing Liao
Introduction The positive/resected lymph node ratio (LNR) predicts survival in many cancers, but little information is available on its value for patients with N2 NSCLC who receive PORT after resection. We tested the applicability of prognostic scoring models and heat mapping to predict overall survival (OS) and cancer-specific survival (CSS) in patients with resected N2 non-small cell lung cancer (NSCLC) and postoperative radiotherapy (PORT). Methods Our test cohort comprised patients identified from the Surveillance, Epidemiology, and End Results (SEER) database with N2 NSCLC who received resection and PORT in 2000–2014. Prognostic scoring models were developed to predict OS and CSS using Cox regression; heat maps were constructed with corresponding survival probabilities. Recursive partitioning analysis was applied to the SEER data to identify optimal LNR cutoff point. Models and cutoff points were further tested in 183 similar patients treated at The University of Texas MD Anderson Cancer Center in 2000–2015. Results Multivariate analyses revealed that low LNR independently predicted better OS and CSS in patients with resected N2 NSCLC who received PORT. Conclusions LNR can be used to predict survival of patients with resected N2 NSCLC followed by PORT. This approach, to our knowledge the first application of heat mapping of positive and negative lymph nodes (LNs), was effective in estimating 3-year, 5-year, and 10-year OS probabilities.
Prognostic Impact of Tumor Mutation Burden in Patients With Completely Resected Non–Small Cell Lung Cancer: Brief Report J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-04-12 Yuki Owada-Ozaki, Satoshi Muto, Hironori Takagi, Takuya Inoue, Yuzuru Watanabe, Mitsuro Fukuhara, Takumi Yamaura, Naoyuki Okabe, Yuki Matsumura, Takeo Hasegawa, Jun Ohsugi, Mika Hoshino, Yutaka Shio, Hideaki Nanamiya, Jun-ichi Imai, Takao Isogai, Shinya Watanabe, Hiroyuki Suzuki
IntroductionTumor mutation burden (TMB) is thought to be associated with the amount of neoantigen in the tumor and to have an important role in predicting the effect of immune checkpoint inhibitors. However, the relevance of TMB to prognosis is not yet fully understood. In this study, we investigated the clinical significance of TMB in patients with NSCLC and examined the relationship between TMB and prognosis.MethodsWe calculated TMB within individual tumors by whole-exome sequencing analysis using next-generation sequencing. We included that there were 90 patients with NSCLC who underwent surgery in the Hospital of Fukushima Medical University from 2013 to 2016. No patients received chemotherapy or immunotherapy before surgery. We assessed the correlation between TMB and prognosis.ResultsTMB greater than 62 was associated with worse overall survival (OS) of patients with NSCLC (hazard ratio [HR] = 6.633, p = 0.0003). Multivariate analysis showed poor prognosis with high TMB (HR = 12.31, p = 0.019). In patients with stage I NSCLC, higher TMB was associated with worse prognosis for both OS (HR = 7.582, p = 0.0018) and disease-free survival (HR = 6.07, p = 0.0072).ConclusionsHigh TMB in NSCLC is a poor prognostic factor. If high TMB is a predictor of the efficacy of immune checkpoint inhibitors, postoperative adjuvant therapy with immune checkpoint inhibitors may contribute to improvement of recurrence and OS.
Anti-Epidermal Growth Factor Vaccine Antibodies Enhance the Efficacy of Tyrosine Kinase Inhibitors and Delay the Emergence of Resistance in EGFR Mutant Lung Cancer Cells J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-05-08 Jordi Codony-Servat, Silvia García-Roman, Miguel Ángel Molina-Vila, Jordi Bertran-Alamillo, Ana Giménez-Capitán, Santiago Viteri, Andrés F. Cardona, Erik d’Hondt, Niki Karachaliou, Rafael Rosell
IntroductionMutations in EGFR correlate with impaired response to immune checkpoint inhibitors and the development of novel immunotherapeutic approaches for EGFR mutant non-small cell lung cancer (NSCLC) is of particular interest. Immunization against EGF has demonstrated efficacy in a phase III trial including unselected NSCLC patients, but little was known about the mechanisms involved in the effects of the anti-EGF antibodies generated by vaccination (anti-EGF VacAbs) or their activity in tumor cells with EGFR mutations.MethodsThe EGFR-mutant, NSCLC cell lines H1975 and PC9, together with several gefitinib and osimertinib-resistant cells derived from PC9, were treated with anti-EGF VacAbs and/or EGFR tyrosine kinase inhibitors (TKIs). Cell viability was analyzed by proliferation assays, cell cycle by fluorescence-activated cell sorting analysis and levels of RNA and proteins by quantitative retro-transcription PCR and Western blotting.ResultsAnti-EGF VacAbs generated in rabbits suppressed EGF-induced cell proliferation and cycle progression and inhibited downstream EGFR signaling in EGFR-mutant cells. Sera from patients immunized with an EGF vaccine were also able to block activation of EGFR effectors. In combination, the anti-EGF VacAbs significantly enhanced the antitumor activity of all TKIs tested, suppressed Erk1/2 phosphorylation, blocked the activation of signal transducer and activator of transcription 3 (STAT3) and downregulated the expression of AXL. Finally, anti-EGF VacAbs significantly delayed the emergence in vitro of EGFR TKI resistant clones.ConclusionsEGFR-mutant patients can derive benefit from immunization against EGF, particularly if combined with EGFR TKIs. A Phase I trial of an EGF vaccine in combination with afatinib has been initiated.
Sarcopenia in resected non-small cell lung cancer: Effect on postoperative outcomes J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-05-08 Ryota Nakamura, Yoshihisa Inage, Rika Tobita, Satoshi Yoneyama, Takeshi Numata, Kyoko Ota, Hidetoshi Yanai, Takeo Endo, Yukinori Inadome, Shingo Sakashita, Hiroaki Satoh, Kenji Yuzawa, Toru Terashima
BackgroundSkeletal muscle depletion, referred to as sarcopenia, has recently been identified as a risk factor for poor outcomes in various malignancies. However, the prognostic significance of sarcopenia in patients with non-small cell lung cancer (NSCLC) following surgery has not been adequately determined. This study investigated the impact of sarcopenia in patients undergoing pulmonary resection for lung cancer.MethodsThis retrospective study consisted of 328 patients with pathologically confirmed NSCLC who underwent curative resection between January 2005 and April 2017. Preoperative computed tomography (CT) imaging at the third lumbar vertebrae level was assessed to measure the psoas muscle mass index (PMI, cm2/m2). Sarcopenia was defined as a cutoff value of PMI less than 6.36 cm2/m2 for males and 3.92 cm2/m2 for females, based on PMI values from “healthy” subjects.ResultsThe median patient age was 71 years and 59% were male. Sarcopenia was present in 183 (55.8%) and was significantly related with increasing age (p<0.001), being male (p<0.001), smoking habit (p<0.001), lower body mass index (p<0.001), and postoperative major complication (Clavien Dindo grade ≥3, p=0.036).The prevalence of sarcopenia was higher in men than in women, and the prevalence increased with age in men, whereas the prevalence did not increase in females above 70 years. The five-year survival rate was 61% in patients with sarcopenia and 91% in those without. Multivariate analysis revealed that sarcopenia was an independent unfavorable prognostic factor (p=0.019).ConclusionSarcopenia as determined using preoperative CT could be used to predict postoperative major complication and prognosis in patients with resected NSCLC. Our results may provide some important information for preoperative management.
Brief report on the detection of the EGFR-T790M mutation in exhaled breath condensate from lung cancer patients J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-05-08 Robert J. Smyth, Sinead M. Toomey, Alexander Sartori, Emer O. Hanrahan, Sinead D. Cuffe, Oscar S. Breathnach, Ross K. Morgan, Bryan T. Hennessy
The EGFR-T790M somatic mutation is the most common mechanism of resistance to Tyrosine Kinase Inhibitors (TKI) in non-small cell lung cancer. Patients with advanced disease are not always amenable to repeat biopsy for further molecular analysis. Developing non-invasive methods to detect T790M in cell-free DNA (cfDNA), in the absence of tissue is being actively investigated. Unfortunately the low sensitivity of plasma for T790M detection has limited its clinical use. Exhaled breath condensate (EBC) is an easily collected sample, known to harbour cfDNA, including lung cancer mutations. This report details the potential utility of EBC in the detection of the EGFR-T790M mutation.
The Impact of Staging by Positron Emission Tomography on Overall Survival and Progression-free Survival in Patients with Locally Advanced Non-Small Cell Lung Cancer J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-05-05 Everett E. Vokes, Ramaswamy Govindan, Neill Iscoe, Anwar M. Hossain, Belen San Antonio, Nadia Chouaki, Marianna Koczywas, Suresh Senan
ObjectiveWe investigated the potential impact of stage migration because of positron emission tomography (PET) scan staging on survival in the locally advanced (Stage IIIA/B) non-small cell lung cancer (NSCLC) setting.MethodsIn PROCLAIM, 598 patients with stage IIIA/B nonsquamous NSCLC (intent-to-treat [ITT] population) were randomized to either pemetrexed plus cisplatin and concurrent thoracic radiotherapy (TRT) for 3 cycles followed by 4 cycles of pemetrexed consolidation or etoposide plus cisplatin and concurrent TRT for 2 cycles followed by a consolidation platinum-based doublet regimen for up to 2 cycles. Baseline PET scan (PET Yes vs. No) was one of the stratification factors. Subgroup analyses (PET Yes vs. No) of overall survival (OS) and progression-free survival (PFS) were conducted on the ITT population regardless of treatment, as the study did not demonstrate superior efficacy for either arm.ResultsMajority (491/598; 82.1%) of patients had baseline PET scan staging performed. A longer median OS (PET Yes vs. No: 27.2 vs. 20.8; hazard ratio=0.81, p=0.130) and an improved median PFS (PET Yes vs. No: 11.3 vs. 9.2; hazard ratio=0.73, p=0.012) were observed for patients with PET scans compared to those with conventional staging in both treatment arms.ConclusionsBoth a significantly improved PFS and a numerically longer OS in the PET Yes subgroup, compared to patients with conventional staging, are consistent with improved survival due to stage migration. The magnitude of differences in OS and PFS based on PET scan is a reminder of the potential for factors other than the therapeutic intervention to affect outcomes.
Radiosensitivity of lung metastases by primary histology and implications for stereotactic body radiation therapy using the genomically adjusted radiation dose J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-05-05 Kamran A. Ahmed, Jacob G. Scott, John A. Arrington, Arash O. Naghavi, G. Daniel Grass, Bradford A. Perez, Jimmy J. Caudell, Anders E. Berglund, Eric A. Welsh, Steven A. Eschrich, Thomas J. Dilling, Javier F. Torres-Roca
IntroductionWe assessed the radiosensitivity of lung metastases based on primary histology using a validated gene signature and model lung metastases for the genomically adjusted radiation dose (GARD).MethodsTissue samples were identified from our prospective observational protocol. The radiosensitivity index (RSI) 10 gene assay was run on samples and calculated alongside GARD using the previously published algorithms. A cohort of 105 patients with 137 lung metastases treated with SBRT at our institution was used for clinical correlation.ResultsA total of 138 unique metastatic lung lesions were identified for inclusion from our institution’s tissue biorepository. There were significant differences in the RSI of lung metastases based on histology. In order of decreasing radioresistance, the median RSIs were endometrial adenocarcinoma (0.49), soft tissue sarcoma (0.47), melanoma (0.44), rectal adenocarcinoma (0.43), renal cell carcinoma (0.33), head and neck squamous cell cancer (0.33), colon adenocarcinoma (0.32), and breast adenocarcinoma (0.29), p=0.002. We modeled GARD for these samples and identified the BED necessary to optimize local control. The 12 and 24 month Kaplan-Meier rates of local control for radioresistant vs radiosensitive histologies from our clinical correlation cohort following lung SBRT were 92%/87% and 100%, respectively (p=0.02).ConclusionsIn this analysis, we note significant differences in radiosensitivity based on primary histology of lung metastases and model the BED necessary to optimize local control. This study suggests primary histology may be an additional factor to consider in lung SBRT dose selection and dose personalization may be feasible.
Italian nivolumab expanded access program in nonsquamous non–small-cell lung cancer patients: results in never-smokers and EGFR-mutant patients J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-05-03 M.C. Garassino, A.J. Gelibter, F. Grossi, R. Chiari, H. Soto Parra, S. Cascinu, F. Cognetti, D. Turci, L. Blasi, C. Bengala, E. Mini, E.E. Baldini, S. Quadrini, G.L. Ceresoli, P. Antonelli, E. Vasile, C. Pinto, G. Fasola, D. Galetta, M. Macerelli, D. Giannarelli, G. Lo Russo, F. de Marinis
BackgroundNivolumab is the first checkpoint inhibitor approved for the treatment of nonsquamous non–small-cell lung cancer (nonsq–NSCLC). We report results from the nivolumab Italian expanded access program (EAP), focusing on never-smokers and EGFR-mutant patients with nonsq–NSCLC.Patients and MethodsNivolumab (3 mg/kg intravenously every 2 weeks) was administered upon physicians’ request for patients who had relapsed after ≥1 prior systemic treatment for stage IIIB/IV nonsq–NSCLC. Efficacy and safety were evaluated in patients who received ≥1 nivolumab dose.ResultsOf 1,588 patients with nonsq–NSCLC, 305 (19.2%) were never-smokers. EGFR status was available for 1,395 patients. Of 102 (6.4%) patients with EGFR-mutation–positive tumors, 51 (50%) were never-smokers. Objective response rate (ORR) was significantly higher in EGFR wild-type than EGFR-mutant patients (19.6% vs 8.8%; P=0.007), in former/current smokers than never-smokers (21.5% vs 9.2%; P=0.0001), and in EGFR wild-type than EGFR-mutant never-smokers (11.0% vs 1.9%; P=0.04). There was no significant difference in ORR between EGFR wild-type and EGFR-mutant smokers (22.0% vs 20.6%). There was no statistically significant difference in median progression-free survival (PFS) and in median overall survival (OS). Specifically median OS was 11.0 vs 8.3 months in patients with EGFR wild-type vs EGFR-mutant tumors, 11.6 vs 10.0 months in smokers vs never-smokers, 11.0 vs 5.6 months in never-smokers with EGFR wild-type vs mutant tumors, and 14.1 vs 11.3 months in smokers with EGFR-mutant vs wild-type tumors.ConclusionsItalian EAP data in nonsq–NSCLC populations suggest that subgroups of patients could benefit differently from nivolumab according to EGFR mutational status and smoking habits. These results warrant further investigation.
BRAF mutant lung cancer: PD-L1 expression, tumor mutational burden, microsatellite instability status and response to immune check-point inhibitors J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-04-30 Elizabeth Dudnik, Nir Peled, Hovav Nechushtan, Mira Wollner, Amir Onn, Abed Agbarya, Mor Moskovitz, Shoshana Keren, Noa Popovits-Hadari, Damien Urban, Moshe Mishaeli, Alona Zer, Aaron M. Allen, Natalie Maimon Rabinovich, Ofer Rotem, Teodor Kuznetsov, Tzippy Shochat, Laila C. Roisman, Jair Bar
IntroductionThe efficacy of immune check-point inhibitors (ICPi) in BRAF mutant NSCLC is unknown.MethodsMulti-institutional retrospective chart review identified 39 patients with BRAF mutant NSCLC. The patients were divided into two groups: V600E (Group A, n=21) and non-V600E (Group B, n=18). PD-L1 expression, tumor mutational burden (TMB) and microsatellite instability status (MSI) were assessed in 29 (74%), 11 (28%) and 12 (31%) patients, respectively. ORR, PFS with ICPi and OS were analyzed.ResultsHigh (≥50%), intermediate (1-49%), and no (<1%) PD-L1 expression was observed in 8/19 (42%), 6/19 (32%), 5/19 (26%), and 5/10 (50%), 1/10 (10%), and 4/10 (40%) cases in Groups A and B, respectively. Two tumors in Group A demonstrated high TMB (25%); none were MSI-High. Twenty two patients (Group A, n-12; Group B, n-10) received ICPi. ORR with ICPi was 25% and 33% in Groups A and B, respectively (p-1.0). Median PFS with ICPi was 3.7 months (95% CI, 1.6-6.6), and 4.1 months (95% CI, 0.1-19.6) in Groups A and B, respectively (log-rank test - 0.81, p-0.37). Neither BRAF mutation type nor PD-L1 expression affected the response probability/PFS. Median OS was not reached (95% CI, 13-NR) and comprised 21.1 months (95% CI, 1.8-NR) for patients who were and were not exposed to ICPi, respectively (log-rank test - 5.58, p-0.018).ConclusionsBRAF mutant NSCLC is associated with high level of PD-L1 expression, low/intermediate TMB and MS-Stable status. ICPi have favorable activity both in BRAF V600E and BRAF non-V600E mutant NSCLC.
The Care and Outcomes of Older Persons with Lung Cancer in England and the United States, 2008-2012 J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-05-01 Anita Andreano, Michael D. Peake, Samuel M. Janes, Maria Grazia Valsecchi, Kathy Pritchard-Jones, Jessica R. Hoag, Cary P. Gross
IntroductionAlthough prior research has demonstrated lower lung cancer survival in England compared to the United States, more detailed comparisons are needed. We conducted a population-based analysis to compare diagnostic, treatment, and survival patterns.MethodsData from cancer registries and administrative databases were linked for older patients diagnosed with non-small cell lung cancer (NSCLC) in England and the United States (2008-2012). We compared patient and clinical characteristics, as well as the distribution of age-standardized receipt of treatment by stage. We compared relative survival overall, by stage and treatment. Finally, we assessed the degree to which stage distribution and stage-specific survival contributed to survival differences.ResultsAmong patients aged 66 years or older diagnosed with NSCLC in England (n=86,978) and the United States (n=84,415), the pathological confirmation rate was 63% in England compared to 85% in the United States (difference 22·2%, 99% confidence interval [CI], 22·8-21·7%). Receipt of active treatment was lower in England (46% vs 60%; difference, 14·0%; 99% CI, 13·3-14·7%). In England, we identified 98 excess deaths per 1,000 patients with pathologically confirmed NSCLC; these additional deaths could be partially mitigated by adjusting stage at diagnosis (reduction to 54 excess deaths) or stage-specific survival (reduction to 36 excess deaths).ConclusionsCompared to the United States, patients with NSCLC in England are less likely to present with early stage disease and receive treatment, and more likely to die. Future work should explore whether the intensity of resources directed to diagnostic and therapeutic activity may help mitigate disparities in outcomes.
PD-L1 expression heterogeneity in non-small cell lung cancer: defining criteria for harmonization between biopsies and whole sections J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-04-25 E. Munari, G. Zamboni, G. Lunardi, L. Marchionni, M. Marconi, M. Sommaggio, M. Brunelli, G. Martignoni, G.J. Netto, M.O. Hoque, F. Moretta, M.C. Mingari, M.C. Pegoraro, A. Inno, S. Paiano, A. Terzi, A. Cavazza, G. Rossi, F.R. Mariotti, P. Vacca, L. Moretta, G. Bogina
BackgroundPD-L1 expression determination defines eligibility for treatment with pembrolizumab in patients with advanced non-small cell lung cancer (NSCLC). This study was designed to better define which value across core biopsies from the same case more closely reflects the PD-L1 expression status on whole sections and how many biopsies are needed for confident classification of tumors in terms of PD-L1 expression.Materials and MethodsWe built tissue microarrays as surrogate of biopsies collecting 5 cores per case from 268 cases and compared PD-L1 staining results using validated clone SP263 with tumor whole sections.ResultsWe found an overall positivity in 39% of cases at 1% cutoff and 10% of cases at 50% cutoff. The maximum value across cores was associated with high concordance between cores and whole sections and the lowest number of false negative cases overall. In order to reach high concordance with whole sections, 4 and 3 cores are necessary at 1% and 50% cutoff, respectively. Importantly, with 20% as cutoff on biopsies, less than 3 cores showed high sensitivity and specificity in identifying cases with ≥50% of tumor cells positive for PD-L1 on whole sections.Specifically, for PD-L1 values of 20-49% on cores, the probability of tumor specimen expressing PD-L1 in ≥ 50% of cells on whole section is 46% and 24% with 1 and 2 biopsies, respectively.ConclusionsAn accurate definition of the criteria to determine the PD-L1 status of a given tumor may greatly help to select those patients who could benefit from anti-PD1/PD-L1 treatment.
Efficacy of Crizotinib Among Different Types of ROS1 Fusion Partners in Patients with ROS1-Rearranged Non–small-cell Lung Cancer J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-04-25 Ziming Li, Lan Shen, Ding Ding, Jia Huang, Jie Zhang, Zhiwei Chen, Shun Lu
IntroductionROS1 rearrangement-positive non–small-cell lung cancer (NSCLC) can be treated effectively, with an anaplastic lymphoma kinase (ALK)/ROS1/mesenchymal-epithelial transition factor inhibitor such as crizotinib. However the rate of response remains variable. Although several ROS1 fusion partners have been identified, the efficacy of crizotinib in patients with different types of ROS1 fusion partners is poorly understood.MethodsWe reviewed clinicopathological data of patients with ROS1-rearrangement who received crizotinib therapy at our institution between April 2014 and December 2016. ROS1 fusion partners were evaluated using Sanger sequencing for tumor tissue available.ResultsDuring the study duration, 49 patients were found to have ROS1-rearrangement and were subsequently treated with crizotinib. Tumor was available on 36 patients; 19 were found to have CD74-ROS1 fusion partners. Prior to therapy CD74-ROS1 group was found to have a higher rate of brain metastases (6 vs 0, p=0.020). The objective response rate (ORR) of crizotinib was 83.3% for all patients, whereas it was 94.11% and 73.68% in the non-CD74-ROS1 and CD74-ROS1 group respectively. As compared to the CD74-ROS1 group, the non-CD74-ROS1 group had both a significantly longer PFS (17.63 months vs 12.63 months; p = 0.048) as well as overall survival (OS) (44.50 months vs 24.33 months; p = 0.036). On multivariable analysis the only factor associated with OS was presence of brain metastases prior to therapy (p = 0.010). There were no significant factors associated with PFS in the multivariable analysis.ConclusionsThese findings suggests that patients with CD74-ROS1 fusion partners are more likely to present with brain metastases. While not independently significant, a trend in improved survival was observed in patients in the non-CD74-ROS1 group when treated with crizotinib.
Brief report: Afatinib and cetuximab in four patients with EGFR exon 20 insertion positive advanced non-small-cell lung cancer J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-04-24 Bianca van Veggel, Adrianus J. de Langen, Sayed Hashemi, Kim Monkhorst, Daniëlle A.M. Heideman, Erik Thunnissen, Egbert F. Smit
IntroductionEpidermal growth factor receptor (EGFR) exon 20 insertions comprise 4-9% of EGFR mutated non-small-cell lung cancer (NSCLC). Despite being an oncogenic driver, they are associated with primary resistance to EGFR tyrosine kinase inhibitors (TKIs). We hypothesized that dual EGFR blockade with afatinib, an irreversible EGFR TKI, and cetuximab, a monoclonal antibody against EGFR, could induce tumor responses.MethodsFour patients with EGFR exon 20 insertion positive NSCLC were treated with afatinib 40 mg once daily and cetuximab 250-500 mg/m2 every two weeks.ResultsAll patients had stage IV adenocarcinoma of the lung harboring an EGFR exon 20 insertion mutation. Previous lines of treatment consisted of platinum doublet chemotherapy (n=4) and EGFR TKI (n=2). Three out of four patients showed a partial response according to RECIST 1.1. Median progression-free survival was 5.4 months (95% confidence interval 0.0 – 14.2 months; range 2.7 – 17.6 months). Toxicity was manageable with appropriate skin management and dose reduction being required in two patients.ConclusionsDual EGFR blockade with afatinib and cetuximab may induce tumor responses in patients with EGFR exon 20 insertion positive NSCLC.
Identification of mutation accumulation as resistance mechanism emerging in first-line osimertinib treatment J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-04-24 Ken Uchibori, Naohiko Inase, Makoto Nishio, Naoya Fujita, Ryohei Katayama
IntroductionThe survival of patients with epidermal growth factor receptor (EGFR) mutation-positive lung cancer has dramatically improved since the introduction of EGFR tyrosine kinase inhibitors (EGFR-TKIs). Recently, osimertinib demonstrated significantly prolonged progression-free survival than 1st-generation EGFR-TKI in first-line treatment, suggesting that a paradigm change that would move osimetinib to first-line treatment is indicated. We performed N-ethyl-N-nitrosourea (ENU) mutagenesis screening to uncover the resistant mechanism in first- and second-line osimertinib treatment.Materials and MethodsBa/F3 cells harbouring EGFR activating-mutation with or without secondary resistant mutation were exposed to ENU for 24 h to introduce random mutations and selected with gefitinib, afatinib or osimertinib. Mutations of emerging resistant cells were assessed.ResultsThe resistance of T790M and C797S to gefitinib and osimertinib, respectively, was prevalent in the mutagenesis screening with the Ba/F3 cells harbouring activating-mutation alone. From C797S/activating-mutation expressing Ba/F3, the additional T790M was a major resistant mechanism in gefitinib and afatinib selection and the additional T854A and L792H were minor resistance mechanisms only in afatinib selection. However, the additional T854A or L792H mediated resistance to all classes of EGFR-TKI. Surprisingly, no resistant clone due to secondary mutation emerged from activating-mutation alone in the gefitinib + osimertinib selection.ConclusionsWe demonstrated the resistance mechanism to EGFR-TKI focusing on first- and second-line osimertinib using ENU mutagenesis screening. Additional T854A and L792H on C797S/activating-mutation were found as afatinib resistance and not as gefitinib resistance. Thus, compared to afatinib, the first-generation EGFR-TKI might be preferable as second-line treatment to C797S/activating-mutation emerging after first-line osimertinib treatment.
Expression patterns, prognostic value, and intratumoral heterogeneity of PD-L1 and PD-1 in thymoma and thymic carcinoma J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-04-24 Dwight Owen, Benjamin Chu, Amy M. Lehman, Lakshmanan Annamalai, Jennifer H. Yearley, Konstantin Shilo, Gregory A. Otterson
IntroductionThymic epithelial tumors (TET) including thymoma and thymic carcinoma are rare tumors with little data available to guide treatment. Immunotherapy with checkpoint blockade has shown promising activity, but data regarding the expression patterns and prognostic implications of programmed death 1 (PD-1) and its ligand (PD-L1) in TET have yielded conflicting results. Intratumoral heterogeneity of PD-1/L1 expression has been demonstrated in other cancers but has not been described in the TET literature.MethodsWe performed a retrospective single-center review of 35 patients with resected TET. PD-1/L1 expression was assessed by immunohistochemistry utilizing PD-1 clone: NAT105 and PD-L1 clone: 22C3. Tumor samples from 35 patients were evaluated including 32 patients with thymoma and 3 patients with thymic carcinoma.ResultsPD-L1 expression was detected in 83% (29/35) tumor samples, including 100% (3/3) of thymic carcinoma patients and 81% (26/32) of thymoma patients. PD-1 expression was detected in 77% (27/35), including 33% (1/3) of thymic carcinoma patients and 81% (26/32) thymoma patients. High PD-1 expression was associated with lower grade tumors. Unlike prior studies, PD-L1 expression was not associated with higher grade tumors or higher stage. Neither PD-L1 nor PD-1 expression was significantly associated with survival. Three patients with thymoma had multiple tumor sections evaluated for expression of PD-1/L1, with differing expression patterns of both PD-L1 and PD-1 observed in two patients.ConclusionsThis study confirms high expression of PD-L1 and PD-1 in TET and demonstrates for the first time intra-tumoral heterogeneity of PD-L1 and PD-1 in thymoma patients.
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