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  • Conformational landscapes of HER2 exon 20 insertions explain their sensitivity to kinase inhibitors in lung adenocarcinoma
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2020-02-07
    Shen Zhao; Wenfeng Fang; Hui Pan; Yunpeng Yang; Ying Liang; Lin Yang; Xiaorong Dong; Jianhua Zhan; Kai Wang; Li Zhang

    Background HER2 exon 20 insertion (ex20ins) is one of the most intractable problems in lung cancer. Most ex20ins are resistant to available EGFR/pan-HER tyrosine kinase inhibitors (TKIs), with the exception of a few mutants. However, the mechanism for TKI response and resistance of HER2 ex20ins remains poorly understood. Methods NGS-based genomic profiling data of 4,139 lung cancers were interrogated for HER2 ex20ins. Structural modeling and molecular dynamics simulations of common HER2 ex20ins were conducted to provide insights into the mechanism of activation and response heterogeneity of ex20ins. Molecular docking was performed to predict affinity to TKIs. Therapeutic decisions for patients were made based on results of genomic profiling. Results From 155 HER2-mutant lung cancers, Y772_A775dup and G778_P780dup was identified in 74 (47.7%) and 18 (11.6%) cases, respectively. Molecular dynamics simulations revealed that HER2 ex20ins led to ligand-independent kinase activation by changing the conformational landscape of HER2 kinase and restricting kinase conformation in the active state. Compared with Y772_A775dup, G778_P780dup which had a three-amino acid extension in the αC-β4 loop and retainment of HER2-characteristic G776 and G778 had less restriction on kinase conformational sampling and higher affinity to afatinib, dacomitinib, pyrotinib and poziotinib. Treating lung adenocarcinomas carrying G778_P780dup with these inhibitors led to sustained tumor responses in six out of ten patients. Conclusion Kinase conformational landscape dictated by the length of αC-β4 loop and residues at HER2 776 and 778 position explains TKI sensitivity in ex20ins. This finding could guide therapeutic decisions with currently available therapies and future drug development strategies.

    更新日期:2020-02-07
  • Neoadjuvant PD-1 inhibitor (Sintilimab) in Non-Small Cell Lung Cancer
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2020-02-06
    Shugeng Gao; Ning Li; Shunyu Gao; Qi Xue; Jianming Ying; Shuhang Wang; Xiuli Tao; Jun Zhao; Yousheng Mao; Bing Wang; Kang Shao; Wendong Lei; Dali Wang; Fang Lv; Liang Zhao; Fan Zhang; Ziran Zhao; Kai Su; Jie He

    Background Programmed death receptor-1 (PD-1) inhibitors have shown efficacy in first line treatment of non-small cell lung cancer (NSCLC), however, evidence of PD-1 inhibitor as neoadjuvant treatment is limited. This is a phase 1b study to evaluate the safety and outcome of PD-1 inhibitor in neoadjuvant setting. Methods Treatment-naïve patients with resectable NSCLC (stage IA-IIIB) received two cycles of sintilimab (200 mg, intravenously, day 1/22). Surgery was performed between day 29-43. PET-CT was obtained at baseline and prior to surgery. Primary endpoint was safety. Efficacy endpoints included rate of major pathologic response (MPR) and objective response rate (ORR). PD-L1 expression was also evaluated. (Registration Number: ChiCTR-OIC-17013726). Results Forty patients enrolled, all of whom received 2 doses of sintilimab, and 37 underwent radical resection. Twenty-one (52.5%) patients experienced neoadjuvant treatment-related adverse events (TRAEs). Four (10.0%) patients experienced grade 3-4 neoadjuvant TRAEs, and one patient had grade 5 TRAE. Eight patients achieved radiological partial response, resulting in an ORR of 20.0%. Among 37 patients, 15 (40.5%) achieved MPR, including 6 (16.2%) with a pathologic complete response in primary tumor and 3 (8.1%) in lymph nodes as well. Squamouse cell NSCLC exhibited superior response compared to adenocarcinoma (MPR: 48.4% VS. 0%). Decrease of maximum standardized uptake values (SUVmax) after sintilimab treatment correlated with pathological remission (p<0.00001). Baseline PD-L1 expression of stromal cells instead of tumor cells was correlated with pathological regression (p=0.0471). Conclusion Neoadjuvant sintilimab was tolerable for NSCLC patients and 40.5% MPR rate is encouraging. The decrease of SUVmax after sintilimab might predict pathologic response.

    更新日期:2020-02-07
  • Identification of novel CD74-NRG2α fusion from comprehensive profiling of lung adenocarcinoma in Japanese never or light smokers
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2020-02-06
    Shinji Kohsaka; Takuo Hayashi; Masaaki Nagano; Toshihide Ueno; Shinya Kojima; Masahito Kawazu; Yuichi Shiraishi; Satsuki Kishikawa; Yoshiyuki Suehara; Fumiyuki Takahashi; Kazuhisa Takahashi; Kenji Suzuki; Kazuya Takamochi; Hiroyuki Mano

    Introduction Studies have yet to characterize the differences in molecular profiles of lung adenocarcinoma (LUAD) among divergent ethnic groups. Herein, we conducted comprehensive molecular profiling of LUAD in never or light smokers from Asia in order to discover novel targetable mutations and prognostic biomarkers of this distinct disease entity. Methods We analyzed 996 cases of Japanese LUAD, and performed whole-exome sequencing and/or RNA-seq in 125 cases of Japanese LUAD negative for the driver oncogenes defined by conventional laboratory testing. We also investigated the clinical and pathological characteristics among the 996 cases. Results Driver oncogenes were identified in 88 cases (70.4%) with specific hotspot mutations differing from those in The Cancer Genome Atlas (TCGA) study. Two actionable novel fusions of FGFR2 and NRG2α were also identified. Clustering based on mRNA expression profiles, but not genetic mutational ones, could predict patient prognosis. The risk score generated by the expression of a three-gene set was a strong prognostic marker for overall survival and progression-free survival in our cohort, and was further validated using TCGA cohort. Among the 996 cases, each driver alteration is distributed across all histological subtypes. Adenocarcinoma in situ was identified to harbor driver mutations, suggesting that these alterations are early events in the pathogenesis of LUAD. ERBB2 mutations were over-represented in young adults. Conclusion This study indicates the value of applying gene expression profiling for predicting the prognosis after a surgical operation, and that the identification of actionable mutations is important for optimizing targeted drugs in Japanese LUAD.

    更新日期:2020-02-07
  • Characterization of patterns of immune cell infiltration in non-small cell lung cancer (NSCLC).
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2020-02-04
    Max Backman; Linnéa La Fleur; Pinja Kurppa; Dijana Djureinovic; Hedvig Elfving; Hans Brunnström; Johanna Sofia Margareta Mattsson; Victor Pontén; Mohamed Eltahir; Sara Mangsbo; Johan Isaksson; Karin Jirström; Klas Kärre; Ennio Carbone; Karin Leandersson; Artur Mezheyeuski; Fredrik Pontén; Cecilia Lindskog; Patrick Micke

    Introduction Tumor infiltrating immune cells are key elements of the tumor microenvironment and mediate the anti-tumor effects of immunotherapy. The aim of the study was to characterize patterns of immune cell infiltration in non-small cell lung cancer (NSCLC) in relation to tumor mutations and clinicopathological parameters. Methods Lymphocytes (CD3+, CD4+, CD8+, CD20+, FOXP3+, CD45RO+), macrophages (CD163+), plasma cells (CD138+), NK cells (NKp46+) and PD-L1+ were annotated on a tissue microarray including 357 operated NSCLC cases. Somatic mutations and tumor mutational burden were analyzed by targeted sequencing for 82 genes, and transcriptomic immune patterns were established in 197 patients based on RNAseq data. Results We identified somatic mutations (TP53, NF1, KEAP1, CSMD3, LRP1B) that correlated with specific immune cell infiltrates. Hierarchical clustering revealed four immune classes: with (1) high immune cell infiltration (“inflamed”), (2) low immune cell infiltration (“desert”), (3) a mixed phenotype, and (4) a new phenotype with an overall muted inflammatory cell pattern but with an imprint of NK and plasma cells. This latter class exhibited low expression of immune response-related genes (e.g. CXCL9, GZMB, INFG, TGFB1), but was linked to better survival and therefore designated “oasis”. Otherwise, the four immune classes were not related to the presence of specific mutations (EGFR, KRAS, TP53) or histologic subtypes. Importantly, the identified immune classes based on tissue staining could not be translated into RNA expression signatures extracted from crude NSCLC tissue. Conclusion We present a compartment-specific immune cell analysis in the context of the molecular and clinical background of NSCLC and identified the novel immune class “oasis”. The immune classification helps to better define the immunogenic potency of NSCLC in the era of immunotherapy.

    更新日期:2020-02-04
  • AXL targeting abrogates autophagic flux and induces immunogenic cell death in drug resistant cancer cells
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2020-02-01
    Maria L. Lotsberg; Katarzyna Wnuk-Lipinska; Stéphane Terry; Tuan Zea Tan; Ning Lu; Laura Trachsel-Moncho; Gro V. Røsland; Muntequa Ishtiaq Siraji; Monica Hellesøy; Austin Rayford; Kirstine Jacobsen; Henrik J. Ditzel; Olav K. Vintermyr; Trever G. Bivona; John Minna; Rolf A. Brekken; Bruce Baguley; David Micklem; Agnete S.T. Engelsen

    Acquired cancer therapy resistance evolves under selection pressure of immune surveillance and favor mechanisms that promote drug resistance through cell survival and immune evasion. AXL receptor tyrosine kinase is a mediator of cancer cell phenotypic plasticity and suppression of tumor immunity, and AXL expression is associated with drug resistance and diminished long-term survival in a wide range of malignancies. Here, we investigated the mechanism underlying AXL-mediated acquired resistance to first and third generation small molecule EGFR tyrosine kinase inhibitors in non-small cell lung cancer (NSCLC). We found that EGFRi resistance was mediated by upregulation of AXL, and targeting AXL reduced reactivation of the MAPK pathway and blocked onset of acquired resistance to long-term EGFR inhibitor treatment in vivo. High dimensional mass cytometry based analysis of AXL expressing EGFR inhibitor resistant NSCLC cells revealed phenotypic and cell signaling heterogeneity that was incompatible with a simple bypass signaling mechanism. Instead, AXL expressing EGFRi resistant cells were characterized by an increased autophagic flux, and AXL kinase inhibition by the small molecule inhibitor bemcentinib was shown to abrogate transcription of autophagy associated genes in vivo, inhibit the autophagic flux in vitro, and block clonogenicity and induce immunogenic cell death in drug resistant NSCLC. Furthermore, we found a positive correlation between AXL expression and autophagy associated gene signatures in a large cohort of human NSCLC (n = 1018). Our results show that AXL signaling supports a drug resistant persister cell phenotype through a novel autophagy dependent mechanism and reveals a unique immunogenic effect of AXL inhibition on drug resistant NSCLC cells.

    更新日期:2020-02-03
  • New approaches to small cell lung cancer therapy : from the laboratory to the clinic
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2020-02-01
    John T. Poirier; Julie George; Taofeek K. Owonikoko; Anton Berns; Elisabeth Brambilla; Lauren Averett Byers; David Carbone; Huanhuan Joyce Chen; Camilla L. Christensen; Caroline Dive; Anna F. Farago; Ramaswamy Govindan; Christine Hann; Matthew D. Hellmann; Leora Horn; Jane E. Johnson; Young Seok Ju; Sumin Kang; Trudy G. Oliver

    Small cell lung cancer patient outcomes have not yet been significantly impacted by the revolution in precision oncology, primarily due to a paucity of genetic alterations in actionable driver oncogenes. Nevertheless, systemic therapies that include immunotherapy are beginning to show promise in the clinic. While these results are encouraging, many patients do not respond to or rapidly recur after current regimens, necessitating alternative or complementary therapeutic strategies. In this review, we discuss ongoing investigations into the pathobiology of this recalcitrant cancer and the therapeutic vulnerabilities that are exposed by the disease state. Included within this discussion is a snapshot of the current biomarker and clinical trial landscapes for small cell lung cancer. Finally, we identify key knowledge gaps that should be addressed in order to advance the field in pursuit of reduced small cell lung cancer mortality. This review largely summarizes work presented at the Third Biennial IASLC Small Cell Lung Cancer Meeting.

    更新日期:2020-02-03
  • Optimizing mutation and fusion detection in Non-Small Cell Lung Cancer by sequential DNA and RNA sequencing
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2020-01-31
    Danielle Cohen; Liesbeth M. Hondelink; Nienke Solleveld-Westerink; Sandra M. Uljee; Dina Ruano; Anne-Marie Cleton-Jansen; Jan von der Thüsen; Soerindra Ramai; Pieter Postmus; Jacob Frans Graadt van Roggen; Bart Hoppe; Pieter Clahsen; Klaartje Maas; Elisanbeth Ahsmann; Alexandra ten Heuvel; Frank Smedts; Ronald Nanno van Rossem; Tom van Wezel

    Background Frequently, patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) are screened for mutations and fusions. In most labs, molecular work-up includes a multitude of tests: immunohistochemistry (IHC; ALK, ROS1 and PD-L1 testing), DNA sequencing and in situ hybridization for fusion and amplification detection. Especially with fast emergence of new drugs targeting specific fusions and exon-skipping events, this procedure harbors a growing risk of tissue exhaustion. Materials and methods In this study we evaluated the benefit of anchored multiplexed PCR-based targeted RNA sequencing (RNA NGS) in the identification of gene fusions and exon skipping events in patients in which no pathogenic driver mutation was found by DNA-based targeted cancer hotspot NGS (DNA NGS). We analyzed a cohort of stage IV NSCLC cases from both in house and referral hospitals, consisting of 38.5% cytology samples and 61.5% micro-dissected histology samples, mostly core needle biopsies. We compared molecular findings in a parallel work-up (DNA NGS and RNA NGS, cohort 1, n = 198) with a sequential work-up (DNA NGS followed by RNA NGS in selected cases, cohort 2, n = 192). We hypothesized a sequential work-up to be the most efficient procedure. Results In both cohorts, a maximum of one oncogenic driver mutation was found per case. This is in concordance with large whole genome-databases, and suggests that it is safe to omit RNA NGS when a clear oncogenic driver is identified in DNA NGS. Additionally, this reduces the amount of necessary RNA NGS to only 53% of all cases. The tumors of never-smokers, however, are enriched for fusions and exon skipping events (32% versus 4% in former and current smokers, p = 0.00), and therefore benefit more often from the shorter turnaround time in the parallel approach (median 15 days versus only 9 days in the parallel workup). Conclusion We conclude that sequentially combining DNA NGS and RNA NGS is the most efficient strategy for mutation and fusion detection in smoking-associated NSCLC, whereas for never-smokers we recommend a parallel approach. This approach has shown to be feasible on small tissue samples, including cytology, and can drastically reduce the complexity and costs of the molecular work up while providing flexibility in the constantly evolving landscape of actionable targets in NSCLC.

    更新日期:2020-01-31
  • Safety, Clinical Activity and Pharmacokinetics of Alflutinib (AST2818) in Advanced NSCLC Patients with EGFR T790M Mutation
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2020-01-30
    Yuankai Shi; Shucai Zhang; Xingsheng Hu; Jifeng Feng; Zhiyong Ma; Jianying Zhou; Nong Yang; Lin Wu; Wangjun Liao; Dafang Zhong; Xiaohong Han; Ziping Wang; Xiaodong Zhang; Shukui Qin; Kejing Ying; Jian Feng; Jian Fang; Li Liu; Yong Jiang

    Introduction Alflutinib (AST2818) is a newly developed third-generation EGFR tyrosine kinase inhibitor (TKI) selective for EGFR sensitizing and T790M resistant mutations. We assessed the safety, efficacy and pharmacokinetics (PK) of alflutinib in advanced NSCLC patients with confirmed T790M mutation, who progressed after the first- or second-generation EGFR-TKI therapy. Methods In the dose-escalation (NCT02973763) and dose-expansion (NCT03127449) studies, patients received alflutinib orally until disease progression, unacceptable toxicity, or subject withdrawal. Primary endpoints were the safety, tolerability, and PK for the dose-escalation study, and the objective response rate (ORR, assessed by an independent radiological review committee) for the dose-expansion study. Results Between Nov 30, 2016, and Jul 24, 2018, 130 patients (14 in dose-escalation, 116 in dose-expansion) received alflutinib treatment (20, 40, 80, 160, or 240 mg once daily). By Oct 30, 2018, 79 (61%) patients remained on treatment. No dose limiting toxicities were observed in the dose-escalation study. In the dose-expansion study (40 - 240 mg), the overall ORR was 76.7% (89/116), and it was 70.6% (12/17) in patients with CNS metastases. 79% (103/130) of all patients had possibly treatment-related adverse events (AEs); 8% (11/130) had treatment-related grade ≥3 AEs. Serious adverse events (SAEs) were reported in 15% (20/130) of patients, and two SAEs were treatment related. No clear dose-response (antitumor activity and AEs) relationships were observed. Exposures to alflutinib and its active metabolite (AST5902) were comparable at steady state. Conclusions Alflutinib was clinically effective with an acceptable toxicity profile in advanced NSCLC patients (including those with CNS metastases) with EGFR T790M mutation. Further investigation is ongoing.

    更新日期:2020-01-31
  • Tumor spread through air spaces (STAS) is a predictor of occult lymph node metastasis in clinical stage IA lung adenocarcinoma
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2020-01-30
    Raj G. Vaghjiani; Yusuke Takahashi; Takashi Eguchi; Shaohua Lu; Koji Kameda; Zachary Tano; Jordan Dozier; Kay See Tan; David R. Jones; William D. Travis; Prasad S. Adusumilli

    Introduction In patients with stage IA lung adenocarcinoma (ADC), sublobar resection and tumor spread through air spaces (STAS) are associated with high rates of locoregional recurrence, half of which occur within the regional lymph nodes (LNs). Our objective was to investigate the association between occult LN metastasis (ONM) and STAS and to assess their prognostic value in patients with clinical stage IA lung ADC. Methods The association between STAS and ONM was analyzed in patients who underwent lobectomy and LN dissection for clinical stage IA lung ADC (n=809). Multivariable logistic regression analysis was conducted to identify predictors of ONM. Site-specific recurrence by surgical procedure was investigated in patients with pathologic N0 disease (n=1055) using a competing-risks approach. Results ONM was identified in 129 patients (16%)—one-third of ONMs were located only in intrapulmonary nodes. STAS was more common in patients with ONM (67% vs. 39%; P<0.001) and in patients with multiple ONMs (86%-89% vs. 60%-67%). STAS was a significant predictor of ONM on multivariable analysis, independent of tumor size, maximum standardized uptake value, and lymphovascular invasion. In STAS-positive (high ONM risk) patients, the risk of recurrence in the treated lobe and regional lymph nodes increased as the extent of resection decreased (recurrence risk: lobectomy < segmentectomy < wedge resection). In STAS-negative patients, the risk of locoregional recurrence did not differ by procedure type. Conclusion Presence of STAS predicts ONM in patients with clinical stage IA lung ADC and can help stratify risk of recurrence by extent and type of resection.

    更新日期:2020-01-31
  • Sensitivity of mesothelioma cells to PARP inhibitors is not dependent on BAP1 but is enhanced by temozolomide in cells with high-Schlafen 11and low-MGMT expression
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2020-01-28
    Daniel Rathkey; Manakamana Khanal; Junko Murai; Jingli Zhang; Manjistha Sengupta; Qun Jiang; Betsy Morrow; Christine N. Evans; Raj Chari; Patricia Fetsch; Hye-Jung Chung; Liqiang Xi; Mark Roth; Armando Filie; Mark Raffeld; Anish Thomas; Yves Pommier; Raffit Hassan

    Purpose BRCA1 associated protein-1 (BAP1), a nuclear deubiquitinase thought to be involved in DNA double-strand break repair is frequently mutated in mesothelioma. Because poly-(ADP-ribose) polymerase inhibitors (PARPIs) induce synthetic lethality in BRCA1/2 mutant cancers, we evaluated whether BAP1 inactivating mutations confer sensitivity to PARPIs in mesothelioma and if combination therapy with temozolomide (TMZ) is beneficial. Methods Ten patient-derived mesothelioma cell-lines were generated and characterized for BAP1 mutation status, protein expression, nuclear localization and sensitivity to the PARPIs olaparib and talazoparib alone or in combination with TMZ. BAP1 deubiquitinase (DUB) activity was evaluated by ubiquitin-AMC assay. BAP1-knockout (KO) mesothelioma cell-lines were generated by CRISPR/Cas9. Because Schlafen 11 (SLFN11) and O6-methylguanine-DNA methyltransferase (MGMT) also drive response to TMZ and PARPIs, we tested their expression and relationship with drug response. Results BAP1 mutations and/or copy-number alterations were present in all ten cell lines. However, four cell lines exhibited intact DUB activity and two had nuclear BAP1 localization. Half-maximal inhibitory concentrations of olaparib and talazoparib ranged from 4.8 μM to >50 μM and 0.039 μM to >5 μM, respectively, classifying them into sensitive (two) or resistant (seven) cells, independent of their BAP1 status. Cell lines with BAP1-KO resulted in loss of BAP1 DUB activity but did not increase sensitivity to talazoparib. Response to PARPI tended to be associated with high SLFN11 expression, and combination with temozolomide increased sensitivity of cells with low or no MGMT expression. Conclusions BAP1 status does not determine sensitivity to PARPIs in patient-derived mesothelioma cell-lines. Combination of PARPI with TMZ may be beneficial for patients whose tumors have high SLFN11 and low or no MGMT expression.

    更新日期:2020-01-30
  • IASLC MULTIDISCIPLINARY RECOMMENDATIONS FOR PATHOLOGIC ASSESSMENT OF LUNG CANCER RESECTION SPECIMENS FOLLOWING NEOADJUVANT THERAPY
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2020-01-28
    William D. Travis; Sanja Dacic; Ignacio Wistuba; Lynette Sholl; Prasad Adusumilli; Lukas Bubendorf; Paul Bunn; Tina Cascone; Jamie Chaft; Gang Chen; Teh-Ying Chou; Wendy Cooper; Jeremy J. Erasmus; Carlos Gil Ferreira; Jin-Mo Goo; John Heymach; Fred R. Hirsch; Hidehito Horinouchi; Yasushi Yatabe

    Currently there is no established guidance on how to process and evaluate resected lung cancer specimens following neoadjuvant therapy in the setting of clinical trials and clinical practice. There is also a lack of precise definitions on the degree of pathologic response, including major pathologic response (MPR) or complete pathologic response (CPR). In other cancers such as osteosarcoma, colorectal, breast and esophageal carcinomas, there have been multiple studies investigating pathologic assessment of the effects of neoadjuvant therapy including some detailed recommendations on how to handle these specimens. A comprehensive mapping approach to gross and histologic processing of osteosarcomas following induction therapy has been used for over 40 years. The purpose of this article is to outline detailed recommendations on how to process lung cancer resection specimens and to define pathologic response including MPR and CPR following neoadjuvant therapy. A standardized approach is recommended to assess the percentages of: 1) viable tumor, 2) necrosis and 3) stroma (including inflammation and fibrosis) with a total adding up to 100%. This is recommended for all systemic therapies including chemotherapy, chemoradiation, molecular targeted therapy, immunotherapy or any future novel therapies yet to be discovered whether administered alone or in combination. Specific issues may differ for certain therapies such as immunotherapy, but the grossing process should be similar and the histologic evaluation should contain these basic elements. Standard pathologic response assessment should allow for comparisons between different therapies and correlations with disease free survival and overall survival in ongoing and future trials. The International Association for the Study of Lung Cancer (IASLC) has an effort to collect such data from existing and future clinical trials. These recommendations are intended as guidance for clinical trials, although it is hoped they can be viewed as suggestion for good clinical practice outside of clinical trials, to improve consistency of pathologic assessment of treatment response.

    更新日期:2020-01-30
  • Efficacy of Immune Checkpoint Inhibitors in Lung Sarcomatoid Carcinoma
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2020-01-25
    Charlotte Domblides; Karen Leroy; Isabelle Monnet; Julien Mazières; Fabrice Barlesi; Valérie Gounant; Simon Baldacci; Bertrand Mennecier; Anne-Claire Toffart; Clarisse Audigier-Valette; Ludovic Doucet; Etienne Giroux-Leprieur; Florian Guisier; Charles Ricordel; Olivier Molinier; Maurice Perol; Eric Pichon; Gilles Robinet; Marie Wislez

    Background Immune checkpoint inhibitors (ICI) have improved cancer prognosis, but have not been evaluated specifically in sarcomatoid carcinoma (SC), a rare lung cancer subtype with poor prognosis. As such, our study sought to retrospectively assess the ICI efficacy in SC. Methods All consecutive patients with centrally confirmed SC treated in ≥ second-line between 2011 and 2017 were enrolled. PD-L1 tumor expression was assessed using immunohistochemistry (SP263 clone), and the tumor mutational burden (TMB) with the Foundation One panel. TMB was considered high if ≥10 mutations/megabase (MMb). Results Overall, 37 SC patients were evaluated, predominantly men (73%), median age of 63.2 years (36.8-79.7), current or former smokers (94.6%). Immunotherapy (Nivolumab 86.5% of cases) was given in second-line in 54% patients and third-line or beyond in 46%. The ORR was 40.5% and DCR 64.8%, regardless of PD-L1 status. Median OS was 12.7 months [range: 0.3-45.7]. One-third of patients exhibited early progression. The median PD-L1 expression was 70% [0-100]. There was a trend toward higher PD-L1 expression in responsive diseases, with an ORR of 58.8% in PD-L1+ patients and 0% in the single PD-L1- patient (p=0.44). The median TMB was 18 [4-39] MMb, 87.5% of cases displaying a high TMB. There was a trend towards higher TMB in responders versus stable or progressive diseases (p=0.2). Conclusions SC patients exhibited high response rates and prolonged OS under ICI treatment. These data support the prospective investigation of ICI in SC patients in first-line treatment.

    更新日期:2020-01-26
  • RET Solvent Front Mutations Mediate Acquired Resistance to Selective RET Inhibition in RET-driven malignancies
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2020-01-24
    Benjamin J. Solomon; Lavinia Tan; Jessica J. Lin; Stephen Q. Wong; Sebastian Hollizeck; Kevin Ebata; Brian B. Tuch; Satoshi Yoda; Justin F. Gainor; Lecia V. Sequist; Geoffrey R. Oxnard; Oliver Gautschi; Alexander Drilon; Vivek Subbiah; Christine Khoo; Edward Y. Zhu; Michele Nguyen; Dahlia Henry; S. Michael Rothenberg

    Introduction Novel RET-specific tyrosine kinase inhibitors (TKIs) such as selpercatinib (LOXO-292) have shown unprecedented efficacy in tumors positive for RET fusions or mutations, notably RET fusion-positive non-small lung cancer (NSCLC) and RET-mutated medullary thyroid cancer (MTC). However, the mechanisms of resistance to these agents have not yet been described. Methods Analysis was performed of circulating tumor DNA and tissue in patients with RET fusion-positive NSCLC and RET-mutation positive MTC who developed disease progression following an initial response to selpercatinib. Acquired resistance was modeled preclinically using a CCDC6-RET fusion positive NSCLC patient derived xenograft (PDX). The inhibitory activity of anti-RET multikinase inhibitors (MKIs) and selective RET TKIs was evaluated in enzyme and cell-based assays. Results Following a dramatic initial response to selpercatinib in a patient with KIF5B-RET NSCLC, analysis of circulating tumor DNA (CtDNA) demonstrated emergence of RET G810R, S and C mutations in the RET solvent front prior to the emergence of clinical resistance. Post-mortem biopsy studies demonstrated intratumor and intertumor heterogeneity with distinct disease subclones containing G810S, G810R and G810C mutations in multiple disease sites indicative of convergent evolution upon the G810 residue resulting in a common mechanism of resistance. Acquired mutations in RET G810 were identified in progressing tissue from a second patient with CCDC6-RET fusion-positive NSCLC and in plasma from additional RET fusion-positive NSCLC and RET-mutant MTC patients progressing on an ongoing phase 1/2 trial of selpercatinib. Preclinical studies demonstrated the presence of RET G810R mutations in a CCDC6-RET PDX model of acquired resistance to selpercatinib. Structural modeling predicted that these mutations sterically hinder binding of selpercatinib, and in vitro assays confirmed loss of activity for both anti-RET MKIs and selective RET TKIs. Conclusion RET G810 solvent front mutations represent the first described recurrent mechanism of resistance to selective RET inhibition with selpercatinib. Development of potent inhibitor of these mutations, while maintaining activity against RET gatekeeper mutations, could be an effective strategy to target resistance to selective RET inhibitors.

    更新日期:2020-01-24
  • Clinicopathologic Characteristics of BRG1-Deficient Non-Small Cell Lung Cancer
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2020-01-24
    Ibiayi Dagogo-Jack; Alexa B. Schrock; Marina Kem; Nicholas Jessop; Jessica Lee; Siraj M. Ali; Jeffrey S. Ross; Jochen K. Lennerz; Alice T. Shaw; Mari Mino-Kenudson

    Background Ten percent of non-small cell lung cancers (NSCLCs) harbor mutations in SMARCA4, the gene encoding the SWI/SNF ATPase BRG1. In preclinical models, BRG1 inactivation increases tumor aggressiveness but enhances sensitivity to drugs that target oxidative phosphorylation and inhibit SMARCA2, EZH2, or CDK4/6. To facilitate translation of preclinical findings into clinical studies exploiting these therapeutic vulnerabilities, we assessed the clinical features of patients with tumors harboring BRG1-inactivating mutations. Methods Datasets from Massachusetts General Hospital and Foundation Medicine were reviewed to determine the prevalence of SMARCA4-mutant NSCLC and describe its clinicopathologic characteristics. BRG1 expression was evaluated by immunohistochemistry and correlated with SMARCA4 mutations. Treatment outcomes were retrospectively assessed. Results We detected SMARCA4 genomic alterations in 9% (n=117/1,422) and 11% (n=3,188/27,281) of NSCLCs in the institutional and Foundation Medicine datasets, respectively. In both cohorts, truncating mutations comprised over one-third of SMARCA4 alterations. Twenty-nine (45%) of 64 SMARCA4-mutant NSCLCs assessed for BRG1 expression demonstrated loss of expression, most (90%) of which had truncating SMARCA4 mutations. Overall, eighty-four percent (n=26/31) of evaluated NSCLCs with truncating SMARCA4 mutations lacked BRG1 expression. Deficient BRG1 expression was predominantly detected in adenocarcinomas with co-occurring mutations in KRAS, TP53, KEAP1, and STK11. Among patients with BRG1-deficient NSCLC who received first-line platinum doublet chemotherapy (n=11) or chemotherapy plus immunotherapy (n=5), median progression-free survival was 38 and 35 days, respectively. Conclusions BRG1 deficiency is enriched in NSCLCs with truncating SMARCA4 mutations. Clinical outcomes are poor in this molecular subgroup, highlighting the importance of developing novel strategies to target unique vulnerabilities associated with the BRG1-deficient state.

    更新日期:2020-01-24
  • Osimertinib overcomes alectinib resistance caused by amphiregulin in a leptomeningeal carcinomatosis model of ALK-rearranged lung cancer
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2020-01-21
    Sachiko Arai; Shinji Takeuchi; Koji Fukuda; Hirokazu Taniguchi; Akihiro Nishiyama; Azusa Tanimoto; Miyako Satouchi; Kaname Yamashita; Koshiro Ohtsubo; Shigeki Nanjo; Toru Kumagai; Ryohei Katayama; Makoto Nishio; Mei-mei Zheng; Yi-Long Wu; Hiroshi Nishihara; Takushi Yamamoto; Mitsutoshi Nakada; Seiji Yano

    Introduction Leptomeningeal carcinomatosis (LMC) occurs frequently in anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer (NSCLC) and develops acquired resistance to ALK tyrosine kinase inhibitors (ALK-TKIs). This study aimed to clarify the resistance mechanism to alectinib, a second generation ALK-TKI, in LMC and test a novel therapeutic strategy. Methods We induced alectinib-resistance in an LMC mouse model with ALK-rearranged NSCLC cell line, A925LPE3, by continuous oral alectinib treatment, established A925L/AR cells. Resistance mechanisms were analyzed using several assays, including western blot and receptor tyrosine kinase array. We also measured amphiregulin concentrations in cerebrospinal fluid (CSF) from ALK-rearranged NSCLC patients with alectinib-refractory LMC by ELISA. Results A925L/AR cells were moderately resistant to various ALK-TKIs, such as alectinib, crizotinib, ceritinib, and lorlatinib, compared with parental cells in vitro. A925L/AR cells acquired the resistance by epidermal growth factor receptor (EGFR) activation due to amphiregulin overexpression caused by decreased expression of microRNA-449a. EGFR-TKIs and anti-EGFR antibody re-sensitized A925L/AR cells to alectinib in vitro. In the LMC model with A925L/AR cells, combined treatment with alectinib and EGFR-TKIs, such as erlotinib and osimertinib, successfully controlled progression of LMC. Imaging mass spectrometry showed accumulation of the EGFR-TKIs in the tumor lesions. Moreover, notably higher amphiregulin levels were detected in CSF from alectinib-resistant ALK-rearranged NSCLC patients with LMC (N=4), compared with those in EGFR-mutated NSCLC patients with EGFR-TKI-resistant LMC (N=30) or patients without LMC (N=24). Conclusions These findings indicate the potential of novel therapies targeting both ALK and EGFR for the treatment of ALK-TKI-resistant LMC in ALK-rearranged NSCLC.

    更新日期:2020-01-21
  • Efficacy and safety of anti-PD-1 immunotherapy in patients with advanced Non Small Cell Lung Cancer with BRAF, HER2 or MET mutation or RET-translocation. GFPC 01-2018.
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2020-01-13
    Florian Guisier; Catherine Dubos-Arvis; Florent Viñas; Helene Doubre; Charles Ricordel; Stanislas Ropert; Henri Janicot; Marie Bernardi; Pierre Fournel; Régine Lamy; Maurice Pérol; Jerome Dauba; Gilles Gonzales; Lionel Falchero; Chantal Decroisette; Pascal Assouline; Christos Chouaid; Olivier Bylicki

    Introduction Immune-checkpoint inhibitor (ICI) efficacy in patients with non-small cell lung cancer (NSCLC) harboring molecular alterations remains poorly elucidated. This study was undertaken to determine ICI efficacy against BRAF/HER2/MET/RET-NSCLC in a real-world setting. Methods In this retrospective, multicenter study in ICI-treated BRAF-, HER2-, MET- or RET-NSCLCs, we analyzed clinical characteristics and outcomes: ICI-treatment duration, progression-free survival (PFS), objective response rate, duration of response (DoR), and overall survival (OS). Results 107 NSCLC patients (mean age, 65.5 years) were included from 21 centers: 37% never-smokers, 54% male and 93% with adenocarcinoma. Among them, 44 had BRAF- mutation (V600: 26), 23 HER2 mutation, 30 MET mutation and 9 RET translocation. PDL1 status was known for 45 patients: ≥1% in 34. Before ICI, patients had received a median of one treatment line. Median DoR, PFS and OS were 15.4 (95%CI, 12.6 – NR) months, 4.7 (95%CI, 2.3–7.4) months and 16.2 (95%CI, 12.0 – 24.0) months for the entire cohort, respectively. Response rate for BRAF-V600, BRAF-nonV600, HER2, MET and RET-altered NSCLC was 26%, 33%, 27%, 38% and 38%, respectively. For PDL1 negative and positive patients, PFS was 3.0 (95%CI, 1.2 – NR) and 4.3 (95%CI, 2.1 – 8.5) months, respectively, and OS was 13.3 (95%CI, 4.1 – NR) and 35.2 (95%CI, 9.0 – 35.2) months, respectively. Toxicities were reported in 28 (26%) patients including 11 (10%) grade ≥3. Conclusion In this real-world setting, ICI efficacy against BRAF-, HER2-, MET- or RET-NSCLC patients appeared close to that observed in unselected NSCLC patients. Large prospective studies on these patient subsets are needed.

    更新日期:2020-01-13
  • FREQUENT HOMOZYGOUS DELETIONS OF TYPE I INTERFERON GENES IN PLEURAL MESOTHELIOMA CONFER SENSITIVITY TO ONCOLYTIC MEASLES VIRUS
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2020-01-13
    Tiphaine Delaunay; Carole Achard; Nicolas Boisgerault; Marion Grard; Tacien Petithomme; Camille Chatelain; Soizic Dutoit; Christophe Blanquart; Pierre-Joseph Royer; Stéphane Minvielle; Lisa Quetel; Clément Meiller; Didier Jean; Delphine Fradin; Jaafar Bennouna; Antoine Magnan; Laurent Cellerin; Frédéric Tangy; Jean-François Fonteneau

    Oncolytic immunotherapy is based on the use of non-pathogenic replicative oncolytic viruses (OV) that infect and kill exclusively tumor cells. Recently, we showed that the spontaneous oncolytic activity of the Schwarz strain of measles virus (MV) against human malignant pleural mesothelioma (MPM) depends on defects in the antiviral type I interferon (IFN I) response in tumor cells. In this study, we identify the most frequent defect as the homozygous deletions (HD) of all fourteen IFN I genes (IFN-α and IFN-β) that we found in more than half of MV-sensitive MPM cell lines. These HD occur together with the HD of the tumor suppressor gene CDKN2A also located in the 9p21.3 chromosome region. Therefore, the IFN I-/- MPM cell lines develop a partial and weak IFN I response when they are exposed to the virus compared to normal cells and MV-resistant MPM cell lines. This response consists in the expression of a restricted number of IFN-stimulated genes that do not depend on the presence of IFN I. In addition, the IFN I-/- MPM cell lines infected by MV also develop a pro-inflammatory response associated with a stress of the endoplasmic reticulum. Our study emphasizes the link between HD of IFN I encoding genes and CDKN2A gene in MPM and sensitivity to MV oncolytic immunotherapy.

    更新日期:2020-01-13
  • Afatinib for the Treatment of Non-Small Cell Lung Cancer Harboring Uncommon EGFR Mutations: A Database of 693 Cases
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2020-01-10
    James Chih-Hsin Yang; Martin Schuler; Sanjay Popat; Satoru Miura; Simon Heeke; Keunchil Park; Angela Märten; Edward S. Kim

    Introduction Limited clinical data are available regarding the efficacy of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) in patients with non-small cell lung cancer (NSCLC) harboring uncommon EGFR mutations. This pooled analysis assessed the activity of afatinib in 693 patients with tumors harboring uncommon EGFR mutations treated in randomized clinical trials, compassionate-use and expanded-access programs, phase IIIb trials, non-interventional trials and case series/studies. Methods Patients had uncommon EGFR mutations categorized as: i) T790M; ii) exon 20 insertions; iii) ‘major’ uncommon mutations (G719X, L861Q and S768I, with or without any other mutation except T790M and/or an exon 20 insertion); iv) compound mutations and v) ‘other’ uncommon mutations. Key endpoints were overall response rate (ORR), duration of response (DoR) and time to treatment failure (TTF). Results In EGFR-TKI naïve patients (n=315), afatinib demonstrated activity against major uncommon mutations (median TTF 10.8 months; 95% CI: 8.1–16.6; ORR 60.0%), compound mutations (14.7 months; 95% CI: 6.8–18.5; 77.1%), other uncommon mutations (4.5 months; 95% CI: 2.9–9.7; 65.2%), and some exon 20 insertions (4.2 months; 95% CI: 2.8–5.3; 24.3%). Median DoR was 17.1, 16.6, 9.0 and 11.9 months, respectively. Activity of afatinib was also observed in EGFR-TKI pretreated patients (n=378). A searchable database of these outcomes by individual genotype was generated. Conclusion Afatinib has clinical activity in NSCLC against major uncommon and compound EGFR mutations. It also has broad activity against other uncommon EGFR mutations and some exon 20 insertions. The data support the use of afatinib in these settings.

    更新日期:2020-01-11
  • 更新日期:2020-01-01
  • In vivo study of a novel chemoablative, thermoresponsive hydrogel for intratumoural administration in a murine A549 xenograft model: 68P
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2018
    Seóna M Rossi,Benedict K. Ryan,Helena M Kelly

    tumor mutational burden detected by tissue next generation sequencing (NGS) was found to be correlated with response to immune checkpoint inhibitors. Methods: In this retrospective study, data were collected on NSCLC patients treated in multiple medical centers in Israel between 2014 and 2017. We used NGS on cell-free circulating tumor DNA (ctDNA) to evaluate whether mutational burden influences the response to immunotherapy in these patients. Results: Overall, 336 NSCLC patients underwent NGS on ctDNA. Of these 336 patients, 192 (57%) were females and 144 (43%) were males. The average age (range) was 64 (23–103) years. Clinical treatment information is currently available for 117 patients, of whom 50 (43%) received immune check-point inhibitors. Rates of stable disease, partial and complete responses (RECIST criteria), as well as progression-free survival and overall survival will be reported. In addition, to unravel the genomic determinants of response to immunotherapy we will use the blood-derived ctDNA to understand if hypermutated ctDNA is a predictive biomarker of response to immunotherapy. Conclusions: ctDNA collection was feasible in 336 patients. Prediction model to associate the ctDNA signature with response to immunotherapy will be presented. Legal entity responsible for the study: Soroka Medical Hospital Funding: Has not received any funding Disclosure: L.C. Roisman: Lectures fees from Roche, Astrazenca, MSD, Pfizer. S. Geva: Travel grant from Teva Pharmaceuticals, honorarium from Guardant Health. L. Soussan-Gutman, A. Dvir, R. Yair, T. Twito: Works at Oncotest-Teva, which is a distributor of Guardant Health in Israel. R. Larman: Employee by Guardant Health inc. N. Peled: Advisor & honorarium from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, FoundationMedicine, Gaurdant360, MSD, Novartis, NovellusDx, Pfizer, Roche, Takeda. All other authors have declared no conflicts of interest.

    更新日期:2020-01-01
  • A Novel Method for Detecting Surface PD‐L1 on Circulating Tumor Cells in Peripheral Blood of Patients with SCLC: P028
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2018
    Deping Zhao,Hongxuan Li,Yunqiang Liu,Jing Yu Liu,Yanan Cheng

    Background: Angiogenesis plays an important role in the occurrence, development, invasion and metastasis of tumors. Bevacizumab is a monoclonal antibody targeting VEGF-A and the first approved anti-angiogenic drug, which was approved in July 2015 for the first-line treatment of advanced non-squamous NSCLC in China. However, for the treatment of recurrent NSCLC, the clinical application value of bevacizumab needs further verification and analysis. Method: The data of 43 patients with advanced non-squamous NSCLC in the Tumor Hospital of Jilin province from April 2013 to April 2017 were retrospectively analyzed. All the patients were diagnosed by pathology or cytology and were clinically attribute to stage IV, and were treated with the combination of pemetrexed or gemcitabine or docetaxel or vincristine combined with bevacizumab (carboplatin or cisplatin) regimen. The dosage of bevacizumab was 7.5mg/kg, every 3 weeks. 20 patients were treated with second-line treatment and 23 were treated with second and third-line treatment. There were 17 cases with positive mutation of epidermal growth factor receptor (EGFR) and 26 cases with negative mutation. The efficacy and safety of bevacizumab combined with chemotherapy were evaluated in 17 cases of brain metastases, including 8 cases with related symptoms. Univariate and multivariate analyses were performed on the factors that may affect the prognosis. Results: A total of 43 patients were included with an objective remission rate of 18.6% and a disease control rate of 74.4%. Median progression-free survival was 5.4 months and median overall survival was 11.7 months. In the subgroup analysis, there was no statistically significant difference in median PFS between patients with positive and negative epidermal growth factor receptor (EGFR) mutation and those with negative mutation. The difference in median PFS between patients with brain metastasis and those without brain metastasis was no statistically significant (5.2 months vs. 5.4 months, P1⁄40.052). In the group of patients who use bevacizumab more than 3 cycles, the median progression-free survival was 9.1 months, the median progression-free survival was 14.2 months; but in those who use less, the median progression-free survival was 4.3 months, and the median progression-free survival was 10.2 months. The application period of bevacizumab (more than 4 cycles or not) is an independent factor influencing PFS (P1⁄40.004). The common adverse events during the treatment with bevacizumab include hypertension, proteinuria and hemorrhage, most of which are grade 1-2. Conclusion: Bevacizumab combined with chemotherapy can improve the survival and safety of patients with second-line and above advanced non-squamous NSCLC.

    更新日期:2020-01-01
  • Competing CNS or Systemic Progression Analysis for EGFR Mutation‐Positive NSCLC Patients on Afatinib in LUX‐Lung 3, 6, and 7: P06
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2018
    ‐. J.C. Yang,Yan-liang Wu,Vera Hirsh,K. O’Byrne,Naoyoshi Yamamoto,Shreeya Popat,Akiko Tamiya,Diego Kaen,Angela Märten,Martin Schuler

    CNS metastases are known complications of advanced EGFR mutation-positive NSCLC, thus, LUX-Lung (LL) trials investigating afatinib allowed enrolment of patients with brain metastases (BM). LL3, 6 and 7 previously demonstrated activity of afatinib in patients with BM, with the magnitude of progression-free survival (PFS) improvement with afatinib vs chemotherapy or gefitinib in patients with BM being similar to that observed in patients without BM (HR 0.54, 0.47, and 0.76 in LL3, 6 and 7, respectively). PFS was significantly improved with afatinib vs chemotherapy in a combined analysis of LL3 and 6 in patients with asymptomatic BM (HR 0.50, p=0.0297).1 To investigate whether afatinib can prevent CNS progression or metastasis, competing risk analyses for the progression and metastasis pattern in the CNS or non-CNS region were carried out in patients with and without BM in LL3, 6 and 7.

    更新日期:2020-01-01
  • miR‐338–3p Promotes the Resistance of Non‐Small Cell Lung Cancers To EGFR‐TKI By Targeting PTPN12: P077
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2018
    Qiang Wu,Fen Guo,Yong-xin Li,Wei Li,Guangzhi Ma,Yunfu Deng,Weiren Luo,Yang Zhao,Feng Xu,Qinghua Zhou

    P077 miR-338-3p Promotes the Resistance of Non-Small Cell Lung Cancers To EGFR-TKI By Targeting PTPN12 Q. Wu, F. Guo, Y. Li, W. Li, G. Ma, Y. Deng, W. Luo, Y. Zhao, F. Xu, Q. Zhou Lung Cancer Center & Institute, West China Hospital, Sichuan University, Chengdu/CN, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin/CN, Lung Cancer Center & Institute, West China Hospital, Sichuan University, Chengdu/CN, Department Of Oncology, Chengdu First People’s Hospital, Chengdu/CN, Cancer Center, West China Hospital, Sichuan University, Chengdu/CN

    更新日期:2020-01-01
  • Fast Response to Osimertinib in Patients with EGFR Mutated NSCLC with Brain Metastasis and Carcinomatous Meningitis: P29
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2018
    N. Torressi,Rafael Coveñas,Wainsztein V. Vanina,Valeria Denninghoff,Fernando Galanternik,Alejandra Avagnina,Gonzalo Recondo,Martin Greco

    correlated with the prognosis. Tumor size (P1⁄40.030), skip N2 metastasis (P1⁄40.009), single station N2 metastasis (P1⁄40.01) and lymph node ratio (P<0.001) significantly impacted N2 Nonesmall cell lung cancer prognosis. Cox regression analysis confirmed that tumor size (P1⁄40.017) and lymph node ratio (P1⁄40.010) were the independent prognosis factors. The 5 year over survival was 70.1% for the low risk group with tumor size less than 3cm and lymph node ratio less than 0.19. However, the 5 year over survival of high risk group with tumor size more than 3cm and lymph node ratio more than 0.19 was 24.5%, which was significantly different with the low risk group(P<0.001). Conclusion: Lymph node ratio and tumor size were the independent prognosis factors for N2 Nonesmall cell lung cancer fulfilling NCCN resection criteria, the risking groups based on lymph node ratio and tumor size can be better to predict the prognosis of N2 nonesmall cell lung cancer.

    更新日期:2020-01-01
  • In This Issue/research Watch/news‐in‐brief/news from the Iaslc Tobacco Control Committee
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2018

    To address the inaccuracies and inconsistencies in tumor response assessment using the modified RECIST (Response Evaluation Criteria in Solid Tumors) published in 2004 for mesothelioma trials, the proposed modified RECIST 1.1 for mesothelioma incorporated updated guidelines with recommendations from RECIST 1.1, based on published research since modified RECIST, and approaches to address other practical issues. These issues include (1) definition of minimally measurable disease; (2) definition of measurable lesions; (3) acceptable measurement location; (4) non-pleural disease considerations; (5) characterization of nonmeasurable pleural disease; (6) assessment of pathological lymph nodes; (7) establishing progressive disease; and (8) accommodations for bilateral pleural disease. Adoption of the modified RECIST 1.1 guidelines for mesothelioma would standardize the tumor measurement and response assessment across future clinical trials. (p. 1012)

    更新日期:2020-01-01
  • ctDNA Changes and TCR Diversity Associated with Clinical Outcomes Following Brain Therapy in NSCLC Brain Metastases: P097
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2018
    Chuanyu Wei,Lingjuan Chen,Xiaorong Dong

    Background: Radiotherapy (RT) is a highly effective anti-cancer treatment forming the standard strategies for brain metastasis in non-small cell lung cancer (NSCLC) patients, but local and distal disease recurrence remains a major cause of mortality. RT is known to enhance tumor immunogenicity and T cell receptor (TCR) repertoire diversity. however, the genomic evolution and mechanisms of RT induced immune responses are unknown. Method: Here, we perform targeted deep sequencing of circulating tumor DNA (ctDNA) on peripheral blood samples and cerebrospinal fluid (CSF) samples collected prior to and during brain radiotherapy from 13 NSCLC patients with brain metastasis. We used a panel to identify cancer-associated gene mutations and analyze tumor mutation burden. We applied next-generation sequencing (NGS) to investigate the T-cell receptor (TCR) repertoire. Results: In this study, we showed that patients with high blood TMB (high >10 mutations/Mb) tended to benefit from brain radiotherapy both in the terms of clinical outcomes of brain lesions and lung lesions. High TMB of CSF was correlated with a favorable clinical efficacy of brain. Response to therapy indicated according to the changes of ctDNA level between baseline and 28 days post-treatment was consistent with clinical outcomes of lung lesions measured by thoracic CT. Moreover, we showed that the low overlap of TCR repertoire in paired blood samples (base to T0) was detected in patients with partial relief (PR), and high overlap of TCR repertoire was in patients with disease stable (SD). Within 24h post-therapy, a high degree of TCR overlap in peripheral blood and CSF was observed from patients with PR in lung lesions, and a low degree of TCR overlap was from patients with SD in lung lesions. Conclusion: These data demonstrated the potential of ctDNA analysis to be a sensitive tool for predicting treatment responsivity, and the level of TCR repertoire overlap correlated with clinical outcomes.

    更新日期:2020-01-01
  • Tepotinib in Non‐Small Cell Lung Cancer with MET Exon 14‐Skipping Mutations or MET Amplification: a Phase 2 Trial in Progress: OA06
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2018
    Paul K. Paik,Hiroshi Sakai,R. V. Bruns,Jürgen S. Scheele,Josef Straub,E. Felip

    predictive biomarker for clinical efficacy of immune checkpoint inhibitors (ICIs). There is a lack of standardization for TMB estimation and reporting, which is critical for ensuring consistency for clinical implementation. An international collaboration organized by Friends of Cancer Research (Friends) and Qualitätssicherungs-Initiative Pathologie GmbH (QuIP) is establishing recommendations for achieving consistency in TMB estimation and reporting. Method: Friends and QuIP are using complementary TMB harmonization approaches. Friends will conduct in silico analyses where TCGA data will be compared between TMB estimates derived from whole exome sequencing (WES) and commercial targeted gene panels, followed by the use of patientderived tumor cell lines to establish a universal reference standard for the alignment of panel-derived estimates. QuIP will compare TMB estimates from selected tissue (NSCLC and other solid tumors) using a WES-derived reference standard with commercial next-generation sequencing panels and lab-developed tests at several German academic institutions. These data will inform consistency of TMB estimation, assay comparability, and TMB cutoff values for potential clinical use. Results: Preliminary data indicate several components influence TMB estimation: preanalytical factors (eg, input material quality/quantity), sequencing parameters (eg, enrichment technologies), library preparation, bioinformatics (eg, filtering of germline variants), FFPE-induced deamination artifacts, mutation types, and clonal vs subclonal events. Analyses of panel size and composition suggest that larger panels may yield more reliable TMB estimation and that the panel should include actionable targets, genes associated with mutagenesis (eg, microsatellite instability), and potential negative predictors of response (eg, mutated b2M, JAK1/2, PTEN). Conclusion: The Friends and QuIP collaboration will establish recommendations for reliable and reproducible TMB measurement to ensure consistent identification of patients who are likely to respond to ICIs. Stenzinger A et al., ESMO 2018, Annals of Oncology, Volume 29, 2018 Supplement 6.

    更新日期:2020-01-01
  • DNA Methylation: A More Sensitive Marker for Treatment Monitoring?: P082
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2018
    Silong Xia,Shannon Chuai,Y. Chen,Lucia Huang,Wuguo Deng,Han Han-Zhang,Y. Zhang,F Xu,X-P Ren

    normal tissues. Increased expression of 3 L1 retrotransposons (L1FGGY, L1-ATP8P1 and L1-SVEP1) was significantly associated with poor clinical outcome, large tumor size, central location or smoking history. Among these three, the L1-FGGY occurred frequently in LUSC tumors (38%, 19 out of 50 LUSC cases) and it promoted cell proliferation and invasion, inhibited cell apoptosis, as well as facilitated tumorigenesis in vitro and vivo. Increased L1-FGGY expression in tumors was coupled with decreased expression of FGGY gene, implicating the L1 insertion into FGGY disrupted the expression and function of the tumor-suppressor gene. Lastly, we observed that the reverse transcription inhibitors, nevirapine (NVR) and efavirenz (EFV) dramatically suppressed L1-FGGY expression and elevated FGGY expression, therefore inhibited the proliferation and invasion of L1-FGGY positive LUSC cells both in vitro and vivo. Conclusion: In conclusion, L1-FGGY retrotransposition was a frequent genomic event in LUSC that promoted the development and progression of LUSC and could be a novel prognosis marker and potential therapeutic target for LUSC.

    更新日期:2020-01-01
  • Anti‐PD‐1 Combination Therapy as Second Line Treatment or Beyond in Patients with Advanced Non‐Small Cell Lung Cancer: P013
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2018
    Fan Zhang,Dan-dan Huang,Li Li,Junxun Ma,Junying Wang,Shunchang Jiao,Yi Hu

    Background: Effective treatment options are limited for advanced nonsmall cell lung cancer (NSCLC) patients who progressed after first-line therapy. Pronounced efficacy of anti-programmed cell death protein 1 (anti-PD-1) combination strategy was observed in first-line setting, therefore we assessed whether the addition of chemotherapy and/or bevacizumab to anti-PD-1 could improve clinical outcomes in secondline or later advanced NSCLC. Method: Advanced NSCLC patients treated with anti-PD-1 therapy from March 2015 to July 2017 were retrospectively screened for eligibility. First-line treatment or combined drugs beyond chemotherapy or bevacizumab were excluded. The primary objective was progression-free survival (PFS). Secondary objectives were overall response rate (ORR), disease control rate (DCR) and safety. Results: 55 patients were included in the analysis (monotherapy, n1⁄433; combination therapy, n1⁄422). 90.0% of the patients have progressed after standard platinum-based chemotherapy in previous line therapies. Combination group exhibited longer PFS than monotherapy group (median, 7.5 vs 3.3 months, adjusted HR 0.32[0.160.65], P 1⁄40.001). 31.8% (7/22) patients in combination group achieved an objective response compared with 10.0% (3/30) in monotherapy group (P 1⁄4 0.075). The DCR was 95.5% (21/22) in combination group compared with 46.7% (14/30) in monotherapy group (P<0.001). Adverse events of grade 3 or worse were occurred in 22.7% of the patients in the combination group and in 6.1% of those in monotherapy group. Most of the adverse events were manageable. Conclusion: Combination of anti-PD-1 plus chemotherapy and/or bevacizumab could be an effective and tolerable therapy as second-line or later treatment option for advanced NSCLC patients.

    更新日期:2020-01-01
  • STE029 Overcomes EGFR‐TKI Resistance in Human Lung Adenocarcinoma: P063
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2018
    Lingling Huang,Qinghua Zhou

    Background: STE029 is a novel anticancer drug which consists of 3hydroxy-3-methylglutarylcoenzyme A reductase inhibitor and novel cancer cell membrane targeting molecular. This study aimed to investigate the effect and mechanism of STE029 on overcoming the EGFRTKI resistance in NSCLC. Method: CCK8 test was used to test the cell viability and survival rate of EGFR mutated PC9 cell (Gefitinib sensitive), PC9/BB4 cell (acquired Gefitinib resistant), and EGFR wild type A549 cell after treatment of STE029, Gefitinib or combination of both. Edu test was applied to detect changes in cell cycle and Hoechst 33258 was applied to detect apoptosis rate in treatment groups. We examined the activity of EGFR/PI3K/Akt, cell cycle and apoptosis signal pathways. In vivo, nude mice were exposed to STE029, Gefitinib and STE029+Gefitinib for 5 weeks, tumor volume was measured, tumor weight was obtained on the last day. P value less than 0.05 would be considered statistically significant. Results: PC9 Cells was highly sensitive to Gefitinib , while PC9/BB4 and A549 cell showed significant resistance to Gefitinib treatment, the IC50 of Gefitinib in PC9, PC9/BB4 and A549 cell was 0.12±0.113umol/L, 11.41±0.014 umol/L and 14.39±0.016 umol/L, respectively; The IC50 of STE029 in PC9, PC9/ BB4 and A549 cell was 2.48±0.028umol/L, 7.80±0.058umol/L, 8.27±0.016umol/L, respectively; STE029+Gefitinib treatment could significantly decrease the IC50 of Gefitinib in PC9, PC9/BB4 and A549 cells( p<0.05, respectively). In PC9 and PC9/BB4 cells, STE029+Gefitinib can block cell cycle and inhibit cell proliferation, while there was no significant difference in apoptosis rate among three drug intervention groups; However, Apoptosis rate was increased in STE029+Gefitinib group in A549 cell, while no significance detected in cell proliferation. In PC9 and PC9/BB4 cells, the combination of STE029 and Gefitinib could down regulate p-EGFR, p-Akt, p-Cyclin D1 and Cyclin D1,up-regulate the expression of GSK-3b,and the expression of cleaved caspase-8, caspase-8, cleaved caspase-9, caspase-9 showed no difference among groups; In A549 cells, the combination of STE029 and Gefitinib could down regulate p-Akt, up-regulate cleaved caspase-8 and cleaved caspase-9. In vivo, the combination of STE029 and Gefitinib effectively controlled tumor development and progression compared to STE029 alone or Gefitinib alone with significant difference (P<0.05) in PC9 and PC9/BB4 xenografted tumor. Conclusion: STE029 could sensitizer Gefitinib in inhibiting EGFR/PI3K/Akt pathway, blocking the tumor cell cycle and proliferation and inducing apoptosis through caspase-8 and caspase-9 dependent pathway. STE029 deserves further investigations in overcoming EGFR-TKI resistance in lung cancer.

    更新日期:2020-01-01
  • TNM Staging Inversely Correlates with Age in ALK‐positive Lung Cancer: P087
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2018
    W Tang,Chao Liang Zhang,Yu-ying Lei,Roxanna Fu,Jin Uk Kang,Hong-hong Yan,Xue-ning Yang,Hua Tu,Y-L. Wu,Wen-Zhao Zhong

    更新日期:2020-01-01
  • Neurocognitive Functions Before Radiotherapy for Brain Metastasis from Lung Cancer: An Analysis of 74 Cases: P049
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2018
    Jinghao Zhen,Zhaohui Peng,Shan You Li,M. Lai,Liutengzi Cai

    expressed, PD-L1 was up-regulated in NSCLC compared with the adjacent tissues. CD8+ TILs could be seen in tumor stroma and nest. With univariate analysis, we found that the down-expression of MHC-I had an association with poor relapse-free survival (RFS) and overall survival (OS) in NSCLC patients (P 1⁄4 0.007 and P 1⁄4 0.001). RFS and OS in PD-L1 group tended to be longer than that of PD-L1+ group, but the difference was not significant (P > 0.05). Based on the distribution of CD8+ TILs, patients were divided into three groups: immune-inflamed group, immune-excluded group and immune-desert group. RFS and OS of patients with the immune-inflamed phenotype (CD8) were longer than patients with the immune-excluded and immune-desert phenotype (CD8 ) (P 1⁄4 0.013 and P 1⁄4 0.015). Besides, patients were divided into four subgroups based on the PD-L1 and CD8+ TILs expression: PD-L1+/CD8, PD-L1+/CD8, PD-L1 /CD8, and PD-L1 /CD8. Statistical differences were achieved both in RFS and OS (P 1⁄4 0.012 and P 1⁄4 0.032). RFS and OS in patients with PD-L1+/CD8andPD-L1 /CD8 were longer than patients with PD-L1+/CD8 andPD-L1 / CD8. Patients with PD-L1+/CD8 experienced the worst RFS and OS. With multivariate analysis, we found that MHC-I and CD8+ TILs might be independent prognostic factors in surgically resected NSCLC. Conclusion: MHC-I and CD8+ TILs expression had a close association with patients prognosis in this study. The combination of PD-L1 and CD8+ TILs, instead of PD-L1 alone, suggested impressive prognostic values in NSCLC patients. It worth further study to confirm the clinical value of MHC-I, PD-L1 and CD8 TILs expressions in the patients with surgically resected NSCLC.

    更新日期:2020-01-01
  • Which Is the Optimal Immunotherapy for Advanced Non‐Squamous Non‐Small‐Cell Lung Cancer in Combination with Chemotherapy?: P025
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2018
    H. Zhoum,Yin Yang Zhang,Guodong Chen,Shen Zhao,Jianjun Liu,Shaodong Hong,Linghao Zhang

    更新日期:2020-01-01
  • The Optimal ALK inhibitor in Advanced ALK‐Positive NSCLC Patients: An Indirect Comparison Between Brigatinib and Alectinib: P016
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2018
    Guodong Chen,Yuzhi Zhang,Huaqiang Zhou,Shen Zhao,Jianjun Liu,Shaodong Hong,L Zhang

    Background: Cyber Knife robotic stereotactic radiosurgery is minimally invasive tumor treatment modality that can deliver high precision radiotherapy to any part of the body with minimal exposure to adjacent and surrounding vital organs and is used to treat oligometastasis of the lung from primary breast cancer patients. In the modern high precision treatment delivery, utmost care should be taken for motion management of tumor targets. The Objective of this study was to investigate the accuracy and efficacy of Cyber knife in the treatment of lung metastasis from breast cancer using fuducial free respiratory tracking system using cyberknife stereotactic radiosurgery. Method: We examined toxicity and local control rate with fiducial-free CyberKnife stereotactic body radiation therapy (SBRT) for lung metastases from 20 breast cancer patients. All patients had favorable performance status (ECOG 0e2), oligometastatic disease. Total of 56 Lungs lesions were treated with a prescribed dose of 30e35 Gy delivered in five fractions to the planning target volume (PTV) using the CyberKnife with X-sight lung tracking. A median 30 Gy (IQR, 30e35 Gy) dose was delivered to amedian prescription isodose line of 70% (IQR, 65e77%) to 20 patients with a total median follow up of 34 months. Results: The toxicity and local control rates were favourable and 1and 2-year local control estimates were 87% and 73%, respectively. Two of the five local failures were infield in patients who had received irradiation to the gross tumor volume and remaining 3 were in patients who had received irradiation to clinical target volume. No local failures were identified beyond 21 months of therapy. There was no lung, oesophageal or spinal cord toxicity noted in the above patients. Conclusion: Initial evaluation with fiducial free based respiratory tracking system using five-fraction CyberKnife SBRT is a promising treatment option for lung metastasis from breast cancer patients, demonstrating encouraging local control rates with no toxicity. a dose escalation study for the pheripheral lung metastasis from breast cancers is being planned.

    更新日期:2020-01-01
  • Induction of DNA Double Strand Breaks in Human Primary Lung Cells: P37
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2018
    Md Shuayb

    Background: More than 50% of advanced NSCLC patients are older than 65 years old (y), with a median age at diagnosis of 68 y. This group of patients have been usually underrepresented in clinical trials. The aim of our study is to compare whether clinical characteristics, toxicity, response rate, overall survival (OS), and progression free survival (PFS) are different in p > 70y vs. < 70y, treated with platinum based chemotherapy. Method: We reviewed the database of the Instituto Oncologico Córdoba, Argentina (IONC). Survival curvesweremade up by Kaplan-Maier method and compared using the log-rank test. Results: Out of 198 p; 103 p (52 %) < 70y, and 95 p (48 %) > 70y We found significant differences in OS (9.4 vs. 7.5 months, p1⁄40.003) and PFS (6.4 vs. 5.1 months, p1⁄40.002) Significant differences in OS were also found between the two groups regarding anemia, Performance status (PS) and response rate with no difference on sex and histology. Conclusion: Significant differences in OS and PFS were evident between both groups. We observed increased toxicity in p > 70y, but without greater treatment-related mortality. OS and PFS were superior in patients treated with platinum-based doublets when compared to monotherapy (according to historical records); therefore we should choose the former in elderly patients.

    更新日期:2020-01-01
  • Docosapentaenoic Acid and Lung Cancer Risk: A Mendelian Randomisation Study: P038
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2018
    Jianjun Liu,Huaqiang Zhou,Yinghua Zhang,Yan Huang,Wei-Yu Fang,Yunpeng Yang,Shaodong Hong,Guodong Chen,Shen Zhao,Xindong Chen,Zhou Zhang,Jun Shen,Wei Xian,Jun Zhan,Yuanyuan Zhao,Xue Hou,Yu Xiang Ma,Ting Zhou,Hong Yun Zhao,Lan Zhang

    linked immunosorbent assay (ELISA) and westernblot. The difference expression of QSOX1/2 between tumor and para-cancerous tissues in TCGA-Pancancer database was analyzed by bioinformatics method. The difference gene analysis and pathway analysis of QSOX1/2 high and low expression groups were performed by Bayesian method, and the correlation between QSOX1/2 expression level and survival and clinical stage was further analyzed. In vitro, the ability to synthesize Lp(a) of HepG2 cells after QSOX1/2 deletion was verified by Immunoturbidimetric assay (ITA), and cell proliferation was analyzed by EdU and flow cytometry. Results: We found that serum Lp(a) concentrations in 27.5% of patients in the study cohort were higher than the mean value in the normal medical cohort. Serum Lp(a) concentrations in cancer patients were positively correlated with QSOX1/2 serum concentrations (R1⁄40.34,P<0.005). In the TCGA-Pancancer database, the expression level of QSOX1/2 in tumor tissues were higher than that in para-cancerous tissues, and the over expression of QSOX1/2 may be related to abnormal regulation of tumor cell cycle. In vitro, experiments showed that the expression of QSOX1/2 regulated the extracellular synthesis ability of Lp(a). Silencing QSOX1/2 genes significantly inhibited the proliferation of tumor cells. Conclusion: The abnormal expression of QSOX1/2-Lp(a) can be used as a potential bio-marker for the poor prognosis of cancers. And targeted QSOX1/2 treatment may inhibit tumor growth with this molecular subtype.

    更新日期:2020-01-01
  • In This Issue/Research Watch/News‐in‐Brief/News from the IASLC Tobacco Control Committee
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2017

    The authors aimed to validate the new eighth edition of the tumor-node-metastasis (TNM) classification and to determine the association between radiological solid size and pathological invasive size in the T factor among 1792 patients with complete resection in Japan (2003e2011). Solid size and pathological invasive size of preoperative thin-sliced computed tomography (TSCT) were evaluated based on the third edition of the WHO classification and reclassified based on the new TNM classification. Overall survival curves based on the eighth edition at each clinical and pathological stage were well distinct. Five-year survival rates of 100% were observed among patients with newly defined clinical and pathological stage 0. Higher values of concordance probability estimate (CPE) and Akaike’s information criteria (AIC) were found with the eighth edition versus the seventh edition. A strong positive linear relationship was observed between solid size on TSCT and pathological invasive size (Pearson’s correlation coefficient 1⁄4 0.83). The findings indicate that the new TNM classification is more accurate than the previous version in patient prognosis in this patient cohort at a single institution, and demonstrated significant correlation between radiological solid size and pathological invasive size. (p. 1403)

    更新日期:2020-01-01
  • Apatinib Reverses Paclitaxel Resistance in Lung Cancer: P092
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2018
    Xiang Zhang,Yu-Rim Song,Xiaochun Cheng

    words: “BIM” or “BCL-2-like 11” or “BCL2-like 11” or “BCL-2 like 11” AND “polymorphism” AND “lung cancer”. We collected data from the all full-published English papers, not any meeting or conference abstract. A thorough literature search was undertaken using the following databases: PubMed (http://www.ncbi.nlm.nih. gov), Embase (http://www.embase.com), and Science Direct (http://www.sciencedirect.com) databases. Abstracts were scrutinized, and full articles were analyzed. The literature retrieval was performed by two independent authors. And no language or date restrictions were found in literature collection. Results: Sixteen cohort studies, covering 4393 WT and 916 BIM deletion patients were included. Overall, BIM deletion polymorphism was associated with significantly shorter progression-free survival (PFS) and slightly shorter overall survival (OS), compared to the WT group. Moreover, patients with BIM deletion polymorphism showed significantly inferior response to EGFR TKIs. Conclusion: Our analysis confirmed that lung cancer patients harboring the BIM deletion have inferior survival and TKI responses. Examination of the novel biomarker BIM deletion in lung cancer patients, especially for the EGFR mutant cohort, could provide some prognostic utility.

    更新日期:2020-01-01
  • Significance of Low Expression of Tumor Associated Gene ki67 in Recurrence of Small Cell Lung Cancer: P112
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2018
    Xiang Zhang,Lulu Ma,Yubin Hao,Xinyi Zuo,Yufeng Cheng

    Background: Small cell lung cancer (SCLC) has high malignancy and high metastasis rate. Ki67 as an antigen for cell proliferation, the higher the ratio, the more active the cancer cells proliferate. The aim of this study was to observe the effect of Ki67 expression on recurrence and prognosis of small cell lung cancer. Method: From July 2013 to July 2014, 91 patients with SCLC were selected. All cases were confirmed by histopathology, and Ki67 immunohistochemical staining showed positive expression. The short-term efficacy was evaluated according to RECIST 1.1. All data were processed by SPSS 19.0 statistical software. The data were expressed by mean standard deviation (x ±s), chi-square test, Pearson linear correlation analysis, Kaplan-Meier method. and Log-rank test, P < 0.05 was statistically significant. Results: In the study group, 47 patients (51.6%) were under 61 years, 44 (48.4%) were males, Smoking index (smoking index 1⁄4 annual x daily smoking) was <1⁄4 200 for 37 (40.7%) and > 400 for 35 (38.5%). 62 (68.9%) were localized tumor staging. Before chemotherapy of NSE < 11.13 ng / ml was 10 (11%) and > 25 ng/mL was 40 (44%). Ki67 expression index were 14 (15.4%) with over low expression 50-60%, 12 (13.2%) with low expression > 60-70%, 48 (52.7%) with moderate expression > 70-80%, 17 (18.7%) with high expression > 80%.In the study group, 65 patients received treatment, of which 10 (11.0%) were CR, 41 (45.1%) were PR, 13 (14.3%) were SD. Ki67 was statistically significant correlated with smoking (R1⁄40.265, P1⁄40.011), tumor stage (R1⁄40.419,P<0.001), NSE (R1⁄40.214, P1⁄40.042) and optimal efficacy (R1⁄40.244, P1⁄40.02). The median PFS of low expression, low expression, moderate expression and high expression of Ki67 were 408, 538, 228 and 343 days, respectively (P 1⁄4 0.042). In particular, when the expression of Ki67 was 70% as the dividing line, 1⁄4 < 70% as the low expression, and > 70% as the high expression, the PFS was 434 days and 261 days, respectively (P1⁄40. 027). However, there was no significant correlation between Ki67 and OS (2-year survival rate) (P > 0. 05). Conclusion: The lower expression of Ki67 in SCLC is better for drug efficacy, and longer PFS.Ki67 may be one of the predictors of SCLC recurrence. In particular, 70% Ki67 expression index is an important critical index for the progression of small cell lung cancer. In particular, 70% of Ki67 expression index is an important critical index for the progression of SCLC.

    更新日期:2020-01-01
  • The Impact of TP53 Mutation and Tumor Mutation Number on Outcomes in Patients with Stage I Non Small Cell Lung Cancer: P021
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2018
    Shan Zheng,Jianchuan Xia,Fan-chang Zeng,Li-xi Huang,Fajiu Li,Huijuan Zhu,Ga Liao,Zhong-kun Lin,Haiyu Zhou

    Background: Mesenchymal-to-epithelia transition (MET) exon 14 skipping (METex14) has been recognized as a potential driver alteration in lung cancers, and represents an emerging molecular target for lung cancer treatment. However, most studies about patient characterization and clinical outcomes of METex14-positive lung cancer were conducted in Caucasians, relevant data in Chinese patients were lacking. Here, we retrospectively characterized the clinical and molecular features of patients harboring MET mutations causing exon 14 skipping in a large cohort of Chinese lung cancers, and interrogated relevant clinical parameters associated with clinical outcomes of crizotinib treatment. Method: Genomic profiling data obtained from either plasma or tissue of 7,507 lung cancer patients with various histological types were screened to identify patients harboring METex14. Results: A total of 68 patients (0.91%), different from the frequency of Western population (3%), were identified to carry DNA alterations predicted to cause METex14 with a median age of 67.5, which is statistically significantly older than the whole cohort (p<0.001, t-test). In addition, METex14 has a female predominance (p1⁄40.036, Fisher’s exact test). Mutation rates vary in different histological sub-groups: 0.80% in adenocarcinoma, 1.31% in squamous cell carcinoma, and 10.0% in sarcomatoid carcinoma. Collectively, a total of 68 variants (39 unique variants) predicted to cause METex14 were identified, including 7 point mutations and 10 indels affecting splice donor sites, 1 point mutations and 19 indels affecting splice acceptor sites, one point mutation at Y1003, one in-frame deletion within exon 14. Clinical outcomes of 18 METex14-positive patients treated with crizotinib were investigated. The median PFS and median OS were 7.3 and 8.5 months. Overall response rate in this sub-cohort was 22.2% (4/18) and disease control rate was 38.9% (7/18). Among them, METex14positive patients harboring concurrent TP53 mutations had significant shorter OS than patients with wild type TP53 mutations (p1⁄40.0068). In addition, patients diagnosed as squamous cell lung cancers displayed favorable PFS and OS than adenocarcinomas (PFS, p1⁄40.39; OS, p1⁄40.26). Although statistical significance was not achieved due to limited patient number of squamous cell carcinomas, this result warranted further investigation into this observation. Conclusion: We comprehensively characterized METex14 in Chinese lung cancer patients with various histological types. Our data revealed that METex14 defined a unique clinical and molecular subset of lung cancers in Chinese patients. Our study also improved the knowledge of survival stratification in METex14positive lung cancers and might be helpful for clinical therapeutic strategy design.

    更新日期:2020-01-01
  • To Investigate the Prognostic Factors and the Significance of TKI in Advanced NSCLC with Wild‐Type EGFR: P009
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2018
    Da Jiang,Qihe Yu,Xue Zhang,Fang Huang,Y. C. Li,Hui Jin

    Background: To investigate the correlation between genetic mutation state and cancer-associated thrombosis in advanced cancer patients. Method: 133 cases of advanced cancer patients were divided into mutation group and non-mutation group according to their genetic states. Venous Doppler ultrasound examination was performed to determine the incidence of thrombosis. Incidence of thrombosis was compared between 2 groups. Genetic mutation rate was calculated in thrombosis patients. Risk factors for thrombosis were analyzed in 2 groups. Sensitivity and specificity were compared using Khorana risk assessment model. Low-risk subgroups/middle-risk subgroups/high-risk subgroups were determined by Khorana risk assessment model in mutation/nonmutation group. Incidence of thrombosis were compared between corresponding subgroups (low-risk to low-risk, middle-risk to middle-risk, high-risk to high-risk). Results: 1. Genetic mutation rate was 75.2% in all patients. Thrombosis rate was 13.53% in all patients. Genetic mutation rate in thrombosis patients was 88.89%. 2. Thrombosis rates in mutation/non-mutation group were 16.0% and 6.1%, respectively (P1⁄40.2490). 3. The thrombosis rates in EGFR、ALK、TP53、Her-2、KRAS、PIK3CA、T790M gene mutation were 27.8%、5.6%、33.3%、5.6%、11.1%、0、5.6%, respectively (P1⁄40.248,0.873,0.804,1.000,0.959,0.469,1.000). 4. Sensitivity and specificity in mutation group were 16.8% and 60.0% in Khorana risk assessment model. In non-mutation group those were 6.9% and 100.0%, respectively. AUC for 2 groups ROC were 0.571 and 0419, respectively (P>0.05). 5. Thrombosis rates for each corresponding subgroups were 33.3% vs 0% (mutation low-risk subgroup vs non-mutation low-risk subgroup), 10.7% vs 7.1% (mutation middle-risk subgroup vs non-mutation middle-risk subgroup) and 57.1% vs 0% (mutation high-risk subgroup vs non-mutation high-risk subgroup). P values were 0.497, 0.940, 1, separately. Conclusion: There is no correlation between genetic mutation state and cancer-associated thrombosis in advanced cancer patients.

    更新日期:2020-01-01
  • In This Issue/Research Watch/News‐in‐Brief/News from the IASLC Tobacco Control Committee
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2017

    The study investigated 45 East Asian patients with lung adenocarcinomas negative for EGFR, KRAS, ALK, ROS1, and RET mutations with the aim to refine the clinicopathologic and prognostic implications of mesenchymalepithelial transition gene (MET) exon 14 skipping (METex14), which has been shown to correlate with response to mesenchymal-epithelial transition (MET) inhibitors in NSCLC. Of the 17 patients with METex14 skipping (37.8%), 52.9% had the acinar subtype, followed by 35.3% with the solid subtype. MET immunohistochemistry achieved 100% sensitivity and 70.4% specificity. Compared with patients with ALK fusion, higher recurrence rate was found in patients harboring METex14 skipping (hazard ratio 1⁄4 0.283) with stage I to IIIA disease. No significant difference in overall survival was observed after adjusting for pathologic stage (p 1⁄4 0.669). In vitro studies demonstrated inhibitory effect of small interfering RNA (siRNA) targeting METex14 on MET-mediated signaling, as well as cell proliferation in crizotinib-resistant cells in combination treatment. Taken together, higher prevalence of METex14 was found in East Asian patients with lung adenocarcinoma without EGFR, KRAS, ALK, ROS1, and RET mutations. There is an association between METex14 skipping, old age, the acinar or solid histologic subtype, and high MET expression. Prognosis was comparable between the groups. (p. 1233)

    更新日期:2020-01-01
  • Sleeve Lobectomy for Centrally Located Non‐Small Cell Lung Cancer: Experience of a Single Institute: P024
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2018
    Hon-Man Liu,Yongbin Ma,Zhi-qi Yu,Yingke Ren,Chuantao Zhang,Guo-rong Wang

    between oral leukoplakia and lung cancer in the Linxian General Population Trial cohort. Method: The Linxian General Population Trial cohort, with 29,584 healthy adults enrolled in 1985 and followed through the end of 2012. With collected baseline data, hazard ratios (HR) and 95% confidence intervals (95% CI) for developing lung cancer were estimated using Cox proportional hazard models. Results: Overall, a total of 29449 were included in the final analysis. During 28 years of follow up, we confirmed a total of 277 incident lung cancer cases. Overall, participants with oral leukoplakia had little risk for developing lung cancer (HR1⁄41.01, 95%CI: 0.67, 1.16). No significant associations were observed for lung cancer in either all subjects or subgroups. Conclusion: Our results suggest that oral leukoplakia is not associated with increased risk of lung cancer mortality. Future studies are needed to confirm these findings. Keyword: oral leukoplakia; lung cancer; Linxian General Population Trial

    更新日期:2020-01-01
  • Circulating miR‐31 as a predictive marker of EGFR TKI treatment efficacy in squamous cell lung cancer (SCC): A sub‐analysis of the LUX‐Lung 8 trial: 60P
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2018
    Gaston Y. Mathé,Paul Fogel,Séverine Martin-Lannerée,Charles Marcaillou,E. Lallet,Nicole Krämer,Neil Gibson,Flavio Solca,Eva Ehrnrooth,Jacques Cadranel

    of STAT3 (Y705), paxillin (Y118), a readout of FAK, and Src (Y416). The median PFS of 32 KRAS mutant NSCLC p was 2.5 months and the overall survival was 13.4 months. According to CDCP1 levels, the median PFS was 3.5 months for those with low CDCP1 and 1.4 months for those with high CDCP1 (P = 0.012). The median survival was 16.3 months for p with low CDCP1, and only 3.2 months for those with high CDCP1 (P = 0.023). Conclusions: The combination of trametinib plus TPX0005 shows significant in-vitro activity in the majority of KRAS mutant NSCLC cell lines and the mRNA levels of CDCP1 could be a biomarker in KRAS mutant NSCLC p, indicating the activation of Src-YAP signaling. Clinical trials with the combination of MEK inhibitors with TPX0005 are warranted. Legal entity responsible for the study: IGTP, Germans Trias i Pujol Research Institute, Badalona, Barcelona, Spain Funding: Fundacio ́ Obra Social “La Caixa” Disclosure: All authors have declared no conflicts of interest.

    更新日期:2020-01-01
  • Solitary Pulmonary Nodule: Primary or Metastatic Neoplastic Lesion?: P44
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2018
    Mónica Grafino,Eurico J. Reis,Margarida Felizardo,M. O. Fernandes,Alexandre Miroux Catarino,F. Mascaranhas,Cristina Loewenthal,Marcos Pantarotto,S. Furtado,Fernando Martelo

    Background: A solitary pulmonary nodule (SPN) is a common and increasing clinical problem. Differential diagnosis is broad and often challenging, mainly in patients with previous cancer. Aim: Analyze patientswith SPNandprevious cancer and comparemetastatic andprimary lung cancer (PLC) lesions. Method: Patients with SPN on computerized tomography scan and history of cancer (except basal cell carcinoma)who underwent surgical resections between January 2015 and December 2017 at Hospital da LuzeLisboa were included. All cases were evaluated at a multidisciplinary lung cancer tumor board team meeting. We analyzed histology, demographic and radiological features. p-values 0.05 were considered significant. Results: There were included 29 patients with history of cancer: 12 colorectal, 8 breast, 4 genitourinary, 4 lung and 1 sarcoma. PLC was diagnosed in 15 (51.7%), metastasis in 11(37.9%)8 colorectal, 1 genitorectal, 1 atypical lung carcinoid and 1 sarcoma and benign lesions in 3. Surgery was the diagnosis procedure in 24(82.8%)e17 with frozen section. There were no significant differences between primary and metastatic neoplastic lesions in gender, age and smoking history (p>0.05). All subsolid nodules (n1⁄45) were PLC. In solid neoplastic SPN, 10 PLC and 11 metastasis, there was no difference in diameters. Irregular edge was associated with PLC lesions (p1⁄40.008) and smooth margin with metastasis (p1⁄40.001). Lobulated margins did not seem differentiate neoplastic lesions (p1⁄41.0). Conclusion: PLC is an important diagnosis in the differential diagnosis of NPS, including in patients with a history of cancer. Radiological features can help to discern primary to metastatic SPN in this group.

    更新日期:2020-01-01
  • Preliminary Clinical Activity of Repotrectinib (TPX‐0005) in Advanced ROS1 Fusion‐Positive Non‐Small Cell Lung Cancer: OA09
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2018
    S-H.I. Ou,Byoung Chul Cho,Donghyun Kim,Alexander Drilon,Ju Whei Lee,Jessica J Lin,Viola w. Zhu,M-J Ahn,David Ross Camidge,Shanna Stopatschinskaja,Juliet Liu,Jingrong Jean Cui,David M Hyman,Robert C Doebele,Alice Tsang Shaw

    Conclusion: We interrogated the characteristics of ERBB2 exon 20 insertions in a large cohort from single ethnicity. It demonstrated the response heterogeneity to afatinib among different ERBB2 exon 20 insertion subtypes. It highlighted the importance to correlate drug efficacy with specific ERBB2 exon 20 insertion variants in clinical application.

    更新日期:2020-01-01
  • Concurrent ALK/EGFR Alterations in Chinese Lung Cancers: Frequency, Clinical Features, and Differential Response to Therapy: P011
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2018
    Da Wu,Jie-xiao Liu,Zhimin Mu,Li Liu,Kitsum Li,Renbing Jiang,Peng Chen,Qinghua Zhou,Meiling Jin,Yu Xiang Ma,Yuancai Xie,Jianxing Xiang,Tengfei Zhang,Bingxuan Li,Bo Yu

    mutation rate were found between histological and pathological subtypes (P<0.05). 2 There were significant differences between KRAS mutation and invasive adenocarcinoma types (P<0.05). Moreover, the mutation rate was higher in invasive mucinous adenocarcinoma. 3 The relationship between EGFR mutation abundance and clinical features: taking 20% mutation abundance as cutoff value, the mutation abundance of EGFR showed no significant difference with neither of the following: gender (P1⁄40.0.246), age (P1⁄40.453), smoking history (P1⁄41.00), tumor stage (Z1⁄4-0.500, P1⁄40.617). Conclusion: 1 The rate of EGFR mutation is significantly different among different pathological subtypes of lung adenocarcinoma. The frequency of EGFR mutation is higher in acinar and papillary adenocarcinoma, while lower in invasive mucinous adenocarcinoma. The mutation rate of KRAS was higher in invasive mucinous adenocarcinoma. To sum up, the relationship between the mutation status of the driving gene and the pathological subtype of lung adenocarcinoma is not very clear. This study provides a novel perspective for the following exploration of the correlation between pathological subtypes, stages and other clinical data and the mutation status. 2 In lung adenocarcinoma, the mutation abundance of EGFR gene was not significantly associated with age, gender, tumor stage, and smoking history. 3 Next generation sequencing technology can rapidly, sensitively and accurately detect the mutation status and abundance of EGFR, KRAS and other genes.

    更新日期:2020-01-01
  • 更新日期:2020-01-01
  • Prognostic Factors for Advanced Lung Adenocarcinoma Patients Who Received Tyrosine Kinase Inhibitor and Radiotherapy: P030
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2018
    Hanshuo Yang,Baoqing Chen,Yingcheng Wang,Youling Gong,Yong Xu,Liang Zhou,Youjiang Liu,Yanrong Lu

    Background:We sought to identify the independent prognostic factors for survival of the patients with advanced lung adenocarcinoma who respond to first-line tyrosine kinase inhibitor (TKI) and receive radiotherapy Method: Patients with stage III and IV lung adenocarcinoma who responded to first-line TKI and received radiotherapy in West China Hospital from Dec 1, 2007 to Jan, 1, 2018 were retrospectively enrolled. Univariate and multivariate analysis for prognostic factors including gender, age, stage, brain metastasis status, EGFR mutation type, radiotherapy type, duration between TKI and the staring of radiotherapy, biological equivalent dose (BED) of radiotherapy, and progression status before radiotherapy were analyzed by Cox regression model. Radiation-associated PFS (rPFS) was defined as the date of beginning of radiotherapy to the date of newly disease progression. Results: Forty-five patients were enrolled in this study and 8 of them received radiotherapy combined with TKI before progression. Among the patients with progression disease, 17 of them received radiotherapy with continuation of TKI, 20 patients were treated with radiochemotherapy and ceased the use of TKI after progression. The median follow-up for all patients was 58.3 month. The median rPFS was 5.4 month (95%CI: 4.4-6.4). The results of univariate analysis showed that higher BED (HR1⁄40.460, 95%CI: 0.239-0.886, P 1⁄40.020) and radiotherapy prescribed before disease progression (HR1⁄40.354, 95%CI: 0.135 -0.927, P 1⁄40.034) was relevant to longer rPFS. Multivariate analysis revealed that BED (HR1⁄40.464, 95%CI: 0.240-0.899, P 1⁄40.023) and progression status before radiotherapy (HR1⁄40.357, 95%CI: 0.135-0.940, P 1⁄40.037) were independent predicators for rPFS. No difference of rPFS was found between the patients with conventional radiotherapy or stereotactic body radiation therapy (SBRT) (P1⁄40.450). The median overall survival (OS) was 43.3 month (95%CI: 29.7-56.9). Patients with advanced stage (HR1⁄43.749, 95%CI: 0.883 -15.919, P 1⁄40.073) and shorter duration between TKI and the staring of radiotherapy (HR1⁄41.962, 95%CI: 0.892-4.317, P 1⁄40.094) tend to have a shorter OS but without statistical significance. Conclusion: BED of radiotherapy and progression status were independent prognostic factor for rPFS. These results suggested the potential benefit of aggressive radiotherapy for patients with TKI treatment.

    更新日期:2020-01-01
  • Hippo‐YAP Pathway Mediated Resistance to Crizotinib in ROS1‐Positive Lung Cancer: P075
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2018
    Peiyu Sun,H. Gao

    Background: Studies on the mechanisms of lymphangiogenesis and lymphatic metastasis in lung squamous cell carcinoma (LUSC) are rare. Our previous studies analyzed the data fromTCGA and found that the high expression of VASH2 in LUSC patients was significantly related with their poor prognosis. VASH2 has been reported as a pro-angiogenic factor in many kinds of tumors, however, its effects on the occurrence and progression of LUSC has not been illuminated yet.Method: The expression of VASH2 in LUSC amples was detected by quantitative PCR and immunohistochemistry. We analyzed the correlation between the expression of VASH2and the survival andprognosis of patients in LUSCamples. Thenwe constructed a stable LUSC cell line H520 hi with high expression of VASH2, and investigated its regulation on cell proliferation, apoptosis, migration, invasion and lymph node metastasis in vitro, and its role in promoting tumor genesis and lymph node metastasis in vivo. We also applied VEGF-D and Snail inhibitors in vitro and in vivo to investigate their therapeutic effects on lymph nodemetastasis.Results: We observed that the high expression of vash2 was significantly associated with lymph node metastasis in patients with LUSC. In LUSC cell lines with high expression of VASH2, the ability of proliferation, invasion and metastasis was enhanced and lymphangiogenesis was promoted. At the same time, the expression of lymphangiogenesis factor VEGF-D and Snail were upregulated. When Snail was knockdown, the ability of invasion and metastasis was weakened, the expression of VEGF-D was down-regulated and lymphangiogenesis was decreased in H520 . High expression of VASH2 promotes lymph node metastasis in vivo. Lastly, we observed that VEGF-D and Snail inhibitors significantly inhibited cell proliferation, invasion and lymph node metastasis. Conclusion: This study will uncover the mechanisms of lymphangiogenesis and lymphatic metastasis in LUSC, as well as reveal that VASH2 might serve as a new bio-marker for early diagnosis, prognosis evaluation, clinical transformation and targeted therapy of LUSC. Keyword: lung squamous cell carcinoma; VASH2; lymph node metastasis; Snail

    更新日期:2020-01-01
  • Diagnostic Accuracy and Complication Rate of CT‐Guided Core Biopsies of Lung Lesions in a Thoracic Oncology Unit in Mexico: P36
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2018
    Campos Gómez,Manuel Morales-Ruiz,J. J. Valdés‐Andrade,J. Esquivel‐Gutiérrez,David Eduardo Aguirre-Quezada,Barrera J.L. Franco,Guillermo Pacheco-Cuéllar,K. Campos‐Gomez

    Background: More than 50% of advanced NSCLC patients are older than 65 years old (y), with a median age at diagnosis of 68 y. This group of patients have been usually underrepresented in clinical trials. The aim of our study is to compare whether clinical characteristics, toxicity, response rate, overall survival (OS), and progression free survival (PFS) are different in p > 70y vs. < 70y, treated with platinum based chemotherapy. Method: We reviewed the database of the Instituto Oncologico Córdoba, Argentina (IONC). Survival curvesweremade up by Kaplan-Maier method and compared using the log-rank test. Results: Out of 198 p; 103 p (52 %) < 70y, and 95 p (48 %) > 70y We found significant differences in OS (9.4 vs. 7.5 months, p1⁄40.003) and PFS (6.4 vs. 5.1 months, p1⁄40.002) Significant differences in OS were also found between the two groups regarding anemia, Performance status (PS) and response rate with no difference on sex and histology. Conclusion: Significant differences in OS and PFS were evident between both groups. We observed increased toxicity in p > 70y, but without greater treatment-related mortality. OS and PFS were superior in patients treated with platinum-based doublets when compared to monotherapy (according to historical records); therefore we should choose the former in elderly patients.

    更新日期:2020-01-01
  • ASTRIS a RWT with Osimertinib in NSCLC EGFR T790M Mutated: Disease Characteristics from Patients Included in Argentina: P22
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2018
    Marina Biolchi,Gonzalo Recondo,M. Casalnuovo,Florencia Tsou,Diaz I. Perez,Förster Reinhold,Carmen Martín

    Background: Profiling of targetable oncogenic drivers has significantly improved outcomes in patients with nonesmall cell lung cancer (NSCLC). About 40% of individuals with metastatic lung adenocarcinomas may benefit from personalized treatment with kinase inhibitors. There is limited data of the distribution of oncogenic drivers other than ALK and EGFR in our region. In this study we performed next generation sequence (NGS) to study the distribution of molecular alterations in patients with advanced lung cancer. Herein we present preliminary data of a single center experience. Method: A prospective, single-center, observational study was conducted. We included 125 patients> 18 years old with NSCLC from 06/2015 to 06/2018. NGS was performed with DNA/RNA from formalin-fixed, paraffin-embedded (FFPE) tumor tissue with OncomineTM Focus Assay (Ion 520 Chip), sequenced in Ion S5 Next Generation Sequencing Systems, analyzed with Ion ReporterTM Software 5.2.1 and informed with Ion TorrentTM OncomineTM Knowledgebase Reporter. Results were compared with those from standard pathology and molecular biology techniques, when available, like immunohistochemistry (IHQ) and FISH for ROS1 and ALK and PCR and sequencing for EGFR. We report partial results from the first 51 patients included. Results:Median (IQR) age was 65 years (59-74), n1⁄428 were men (55%), smoker/former-smoker/non-smoker n1⁄411 (21.6%)/ n1⁄431 (60.8%)/ n1⁄49 (17.6%), Stage IIIa n1⁄47 (13.7%), IIIb n1⁄46 (11.8%), IV n1⁄438 (74.5%). Adenocarcinoma histology n1⁄443 (84.3%). Assay performance was 100% for DNA analysis and 60.8% for the study of fusions and CNV from RNA. Distribution of molecular alterations: KRAS n1⁄418 (35%), EGFR n1⁄48 (17.6%) BRAF n1⁄42 (4%), METex14 skipping n1⁄42 (4%), HER2 n1⁄41 (2%), ALK rearrangements n1⁄45 (10%) y ROS1 rearrangements n1⁄42 (4%). Co-mutations: EGFR+BRAF n1⁄41, ALK+KRAS n1⁄41, KRAS+AKT n1⁄41. Conclusion: NGS allows to optimize the molecular profiling of tumors from patients with lung cancer in our population. It can simultaneously identify mutations, rearrangements and alternative splicing events in key oncogenic drivers that can select patients to treatment with kinase inhibitors, currently available in the daily practice and in clinical development.

    更新日期:2020-01-01
  • Genomic Profile and T Cell Receptor Repertoire of Lung Adenosquamous Carcinomas: P004
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2018
    Gen Lin,Chunsun Li,Wenfeng Fang,P. Li,Yan Wang,Yanfang Guan,Xuefeng Xia,Lin Yang,Xiaohong Yi,Cheng-long Huang

    Background: Lung adenosquamous carcinomas (ASC) are morphologically mixed tumors that contain the two cell components adenocarcinomas (AC) and squamous cell carcinomas (SCC). However, to date, the genomic profile, TMB status, evolutionary relationship, and immune microenvironment of the two components still remain unclear. Method: Adenocarcinomas component (ACC) and squamous cell carcinomas component (SCCC) in ASC (n1⁄430) were validated by immunohistochemistry and obtained separately by means of laser capture microdissection. Gene panel and T cell receptor (TCR) repertoire sequencing were performed in both components. Normal tissues adjacent to the cancer were used as controls. The two components were compared from the dimension of somatic mutations, TMB, evolution, and the TCR clones. 626 AC tumors and 83 SCC tumors were also included for comparison with ASC. Results: Comparison of frequency of recurrently altered genes in lung SCCC, ACC, AC, and SCC were performed. EGFR (Fisher Exact test, p1⁄40.0476, OR 2.6) and MAP3K1 (p1⁄40.0020, OR 10.2) were enriched but no KRAS were found in ACC compared to AC. Compared with SCC, EGFR (p<0.0001, OR 14.3) is enriched in SCCC, while TP53 (p1⁄40.0129, OR 0.3) with lower mutation frequency. Different mutational spectra suggest that ACC is different from AC, and SCCC is different from SCC. Despite the heterogeneity, there were shared mutations in lung SCCC and ACC. 79% of ACC and 75% of SCCC samples harbored EGFR mutations. 46% of ACC and 64% of SCCC samples harbored TP53 mutations. In the evolutionary tree analysis, EGFR (in 75% of patients) and TP53 (43%) are the most frequent trunk genes. Above 90% (27/28) of patients had trunk genes, indicating that SCCC and ACC in ASC come from the same origin. In ACC, SCCC, AC, and SCC, 14%, 29%, 23%, and 48% of samples were identified as TMB-H respectively. The TMB index of SCCC was higher than that of ACC (Wilcoxon matched pairs test, p1⁄40.0065). The ACC TMB was equivalent to AC (Mann-Whitney test, p1⁄40.9352). The SCCC TMB is marginally lower than SCC (Mann-Whitney test, p1⁄40.0553). Significant difference is showed in the diversity of TCRs between ACC and SCCC (Wilcoxon matched pairs test, p1⁄40.0383). Although the difference is not significant, 65% (14/20) of SCC samples have a higher clonality index than ACC. Conclusion: Our study promote a better knowledge about ACC and SCCC from ASC, supporting the hypothesis that ACC and SCCC in ASC come from the same origin. However, two components also exhibit diverse genomic profile, TMB status, and TCR repertoire.

    更新日期:2020-01-01
  • Clinical and Pathological Characteristics of NSCLC and the Relationship with the Development of Brain Metastases: P04
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2018
    Sebastián Altuna,Maximino Aldana,George Oblitas

    who harbored EGFR activating mutations and received erlotinib as first line treatment, were examined for EGFR amplification by FISH. We analyzed the relationship between EGFR mutational status and copy number profile with clinical outcomes including response rate, overallsurvival (OS), and PFS. Results: Median age was 62-years (range: 2087 years), 53 patients were females (73%), and 68 (94.5%) had common mutations. Twenty-two (30.6%) samples with EGFR activating mutations were identified as having EGFR amplification. EGFR amplification was more frequent in patients with exon 19 deletion (p1⁄40.05) and in those with better performance status (p1⁄40.01). Patients with EGFR gene amplification had a significantly longer PFS than those without [(28.5 months, 95%CI 22.3-34.6) vs. (11.0 months, 95%CI 8.23-16.7); p1⁄40.002] as well as better OS [(EGFR amplified 37.8 months, 95%CI 30.9-44.7) vs. (EGFR non-amplified 27.1 months, 95%CI 12.8-41.3); p1⁄40.009]. EGFR amplification significantly influenced the response to erlotinib (p1⁄40.0001). Conclusion: In the Hispanic population studied, EGFR amplification was present in one third of the patients with lung ADC harboring EGFR activating mutations. EGFR gene copy number detected by FISH, and sensitizing EGFR mutations are biomarkers associated with better OS, PFS, and response to EGFR-TKI therapy in patients with advanced NSCLC. EGFR copy number could serve as a predictive marker for the identification of patients with NSCLC who will most benefit from EGFR-TKI treatment.

    更新日期:2020-01-01
  • Investigation of Mediastinal Lymph Node Metastasis in Non‐Small Cell Lung Cancer: P017
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2018
    Guo-rong Wang,Chuantao Zhang,Hon-Man Liu,Zhi-qi Yu

    更新日期:2020-01-01
  • Relationship Between EGFR and KRAS Mutation and the Clinicopathologic Features of Early Lung Adenocarcinoma: P010
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2018
    Da Jiang,Shugui Wang,Fang Huang,Xue Zhang,Hui Jin,Y. C. Li

    更新日期:2020-01-01
  • Lung Tumor Histology as a Prognostic Factor for Short‐ and Long‐Term Postoperative Outcomes: P12
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2018
    R. Gerard,Frank O. Velez-Cubian,Crawford Moodie,J. Garrett,J. Fontaine,Eric M. Toloza

    Background: Despite targeted therapies impacted on progression-free survival in EGFR positive metastatic NoneSmall Cell lung carcinoma (NSCLC) these agents are not available in brazilian public health care system (SUS). Polychemotherapy based on platinum still being used in this situation in contrast with international guidelines. This analysis aims to estimate the impact of the lack of access to anti-EGFR therapies on the PFS of these patients. Method: The annual number of patients diagnosed with lung cancer was based on epidemiologic data of Cancer National Institute (INCA). Patients who have access to private health insurances were excluded. Only adenocarcinoma histology was considered. The INCA database, a cohort (Wong, 2016) and four clinical trials: EURTAC, LUX-Lung 3, LUX-Lung 7 and FLAURA were used to estimate stage distribution at diagnosis, recurrence rates and progression free survival in 2 years. The population without mutation in EGFR also was excluded. Results: INCA estimates 28,220 new cases of lung cancer per year in Brazil. Of these, 76.3% are supposed to treated in SUS, totalizing 21,532, upon which 3,790 (40%) have adenocarcinoma histology. Of these, 3,790 (44%) have metastasis at diagnosis, and 3,703 (43%), 603 (7%), 517 (6%) are diagnosed in stages III, II and I, respectively. A recurrences rate of 53.79% in stage III (1,992), 46.49% in II (280) and 26.06% in I (135) in 5 years from diagnosis. Of these, 28% have mutation in EGFR. The outcome of our study was that, if they were treated with polychemotherapy, only 71 would be free of progression after 24 months. In contrast, with the use of inhibitors of tyrosine kinase anti-EGFR, the expectation was 312 patients free from disease for Erlotinib, 377 for Gefitinib, 388 for Afatinib and 720 for Osimertinib. Conclusion: The monthly drug costs, in Brazil, were, approximately, R$ 4,000 for Gefitinib, R$ 5,000 for Afatinib, R$ 8,000 for Erlotinib and R$ 32,000 for Osimertinib. With this, a cost-effectiveness study, presented by Gilberto De Lima Lopes Jr. in ASCO this year, showed that Osimertinib, although its high PFS, was not cost-effective in our country. Larger discounts, pharmaceutics support and more clinical trials are necessary to improve access to Osimertinib. In contrast, the incorporation of Gefitinib, Afatinib and Erlotinib in the public health care system should influence in PFS. Despite this, our study showed that, in two years, should avoid the progression of disease in 378 patients.

    更新日期:2020-01-01
  • Circulating Tumor DNA Improves Genotypification and Detection of Targetable Alterations in Selected Lung Cancer Patients: PD.2.05
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2018
    Z. Zatarain‐Barrón,Feliciano Barrón,Af Cardona,Graciela Cruz-Rico,K. Flores‐Veles,Carin R Espenschied,Victoria M. Raymond,R. Lanman,Carlos Vargas,Óscar Arrieta

    更新日期:2020-01-01
  • EGFR clonality and tumor mutation burden (TMB) analysis based on circulating tumor DNA (ctDNA) sequencing in advanced non‐small cell lung cancer (NSCLC): 52PD
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2018
    Xinghao Ai,Yingwei Lin,Aimin Liu,Congying Xie,X. Hu,Qinli Zhao,Yachen Zang,Chandrasekhar Rao,Xiaohong Yi,Shun Lu

    Background: Preclinical models suggest that MAPK pathway is implicated in the immune-resistance of tumors and MEK-inhibition can increase the CD8+ T-cell infiltration and the efficacy of PD-1/PD-L1 blockade. Methods: First, we evaluated PD-L1 mRNA expression by Real Time qPCR and its protein production, togheter with MAPK proteins in a panel of non-small cell lung cancer (NSCLC) cell lines. Then, we studied the changes in PD-L1 and major histocompatibility complex class-I (MHC-I) expression and cytokines’ production, after inhibition with selumetinib or stimulation of MAPK signalling by phorbol 12-myristate 13-acetate (PMA). In addition, we explored the effect of MEK inhibition on T-cell function by using Peripheral blood mononuclear cells (PBMC) from healthy volunteers. Results: A consistent correlation between PD-L1 mRNA and protein expression across cell lines suggested that expression mainly depends on trascriptional regulation, and it is regulated by MAPK signal, through the bindng of p65 to the PD-L1 promoter. Moreover, MEK inhibition resulted in an increased expression of MHC-I on cancer cells and increased mRNA expression levels of IFN gamma, IL-6, IL-1B, and TNFalpha, all molecules involved in the activation and differentiation of TCD8+ cytotoxic lymphocytes (CTL) subset. In this scenario, we also tested the effect of MEK inhibitor on activated T-lymphocytes from PBMC of healthy volunteers. After five days of treatment, RT-qPCR analysis revealed a significant increase of mRNA expression of some typical CD8+ T cell pro-inflammatory cytokines, like IL-12, TNFalpha and IFNgamma. Conclusions: These results further support the idea that MEK inhibitor reduces PD-L1 expression and this allows the establishment of a pro inflammatory microenvironment. On the other side, pheripheral T cells, treated with selumetinib, produce pro inflammatory cytokines typical of CTL subset, that seems more involved in immune response against cancer. In this context, MEK inhibition may represent a potential mechanism to convert otherwise resistant cancers and suggest new potential treatment combination strategies of MEK-inhibitors with anti-PD-L1 antibodies in NSCLC. Legal entity responsible for the study: University of Campania “L. Vanvitelli” Funding: Has not received any funding Disclosure: All authors have declared no conflicts of interest.

    更新日期:2020-01-01
  • Diagnosis and Treatment Experience of 101 Patients with Advanced NSCLC Complicated with Chronic Obstructive Pulmonary Disease: P014
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2018
    Fang Wang,Xiangcheng Xie,Xianfeng Lin,Zhidong Xie,Yangda Qin,Jiexia Zhang,M. Ouyang,Caicun Zhou

    Background: Effective treatment options are limited for advanced nonsmall cell lung cancer (NSCLC) patients who progressed after first-line therapy. Pronounced efficacy of anti-programmed cell death protein 1 (anti-PD-1) combination strategy was observed in first-line setting, therefore we assessed whether the addition of chemotherapy and/or bevacizumab to anti-PD-1 could improve clinical outcomes in secondline or later advanced NSCLC. Method: Advanced NSCLC patients treated with anti-PD-1 therapy from March 2015 to July 2017 were retrospectively screened for eligibility. First-line treatment or combined drugs beyond chemotherapy or bevacizumab were excluded. The primary objective was progression-free survival (PFS). Secondary objectives were overall response rate (ORR), disease control rate (DCR) and safety. Results: 55 patients were included in the analysis (monotherapy, n1⁄433; combination therapy, n1⁄422). 90.0% of the patients have progressed after standard platinum-based chemotherapy in previous line therapies. Combination group exhibited longer PFS than monotherapy group (median, 7.5 vs 3.3 months, adjusted HR 0.32[0.160.65], P 1⁄40.001). 31.8% (7/22) patients in combination group achieved an objective response compared with 10.0% (3/30) in monotherapy group (P 1⁄4 0.075). The DCR was 95.5% (21/22) in combination group compared with 46.7% (14/30) in monotherapy group (P<0.001). Adverse events of grade 3 or worse were occurred in 22.7% of the patients in the combination group and in 6.1% of those in monotherapy group. Most of the adverse events were manageable. Conclusion: Combination of anti-PD-1 plus chemotherapy and/or bevacizumab could be an effective and tolerable therapy as second-line or later treatment option for advanced NSCLC patients.

    更新日期:2020-01-01
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