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  • 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
  • Brief Report: Novel Germline Mutations in DNA Damage Repair in Patients with Malignant Pleural Mesotheliomas
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2019-12-28
    Robin Guo; Mariel DuBoff; Gowtham Jayakumaran; Mark G. Kris; Marc Ladanyi; Mark E. Robson; Diana Mandelker; Marjorie G. Zauderer

    Introduction Although next-generation sequencing (NGS) has brought insight into critical mutations or pathways (e.g. DNA damage sensing and repair) involved in the etiology of many cancers and directed new screening, prevention, and therapeutic approaches for patients and families, NGS has only recently been utilized in malignant pleural mesotheliomas (MPMs). Methods We analyzed blood samples from patients with MPM using the NGS platform MSK-IMPACT™ to explore cancer-predisposing genes. Loss of function variants or pathogenic entries were identified and clinicopathologic information was collected. Results Of 84 patients with MPM, 12% (10/84) had pathogenic variants. Clinical characteristics were similar between cohorts, although patients with germline pathogenic variants were more likely to have more than 2 first-degree family members with cancer than those without germline mutations (40% vs 12%; Fisher’s exact test, p < 0.05). Novel deleterious variants in mesotheliomas included MSH3 (1% [1/84]; 95% CI: 0-7%), BARD1 (1% [1/84]; 95% CI: 0-7%), and RECQL4 (2% [2/84]; 95% CI: 0-9%). Pathogenic variants previously reported on germline testing in patients with mesotheliomas were BAP1 (4% [3/84]; 95% CI: 1-10%), BRCA2 (1% [1/84]; 95% CI: 0-7%), and MRE11A (1% [1/84]; 95% CI: 0-7%). One patient (1% [1/84]; 95% CI: 0-7%) had a likely pathogenic alteration in SHQ1 that has not been associated with a heritable susceptibility to cancer. Conclusions Our study lends further support for the role of aberrations in DNA damage repair genes in the pathogenesis of malignant pleural mesotheliomas and suggests that targeting members of these pathways for screening and treatment warrants further studying.

    更新日期:2019-12-29
  • Osimertinib for patients with leptomeningeal metastases associated with epidermal growth factor receptor T790M positive advanced NSCLC: the AURA LM analysis
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2019-12-27
    Myung-Ju Ahn; Chao-Hua Chiu; Ying Cheng; Ji-Youn Han; Sarah B. Goldberg; Alastair Greystoke; Jeffrey Crawford; Yanqiu Zhao; Xiangning Huang; Martin Johnson; Karthick Vishwanathan; James W.T. Yates; Andrew P. Brown; Ariadna Mendoza-Naranjo; Tony Mok

    Background Osimertinib has shown promising activity in patients with leptomeningeal metastases (LM) from epidermal growth factor receptor (EGFR) positive NSCLC at 160 mg once daily (qd) (BLOOM; NCT02228369). We report LM activity with osimertinib 80 mg qd in a retrospective analysis of studies across the AURA program (AURA extension, AURA2, AURA17 and AURA3). Methods Patients with EGFR T790M-positive advanced NSCLC and progression on prior EGFR-TKI received osimertinib 80 mg qd. Patients with central nervous system (CNS) metastases (including LM) were eligible if lesions were neurologically asymptomatic and stable. Patients with evidence of LM at study entry were retrospectively included for analysis; brain scans were assessed for radiologic LM response by neuroradiological blinded independent central review as per modified Response Assessment in Neuro-Oncology LM criteria. LM objective response rate (ORR), duration of response (DoR), progression-free survival (PFS) and overall survival (OS) were assessed. A longitudinal analysis was performed to investigate the relationship between baseline non-CNS tumor size changes and LM responses at each visit for AURA LM and BLOOM patients. Results In 22 patients included for analysis, LM ORR was 55% (95% confidence interval [CI]: 32–76). Median LM DoR was not reached (95% CI: 2.8–not calculable [NC]). Median LM PFS and OS were 11.1 months (95% CI: 4.6–NC) and 18.8 months (95% CI: 6.3–NC), respectively. The longitudinal analysis showed similar non-CNS and LM responses between AURA LM and BLOOM patients. Conclusion Patients with EGFR T790M-positive NSCLC and radiologically-detected LM derived clinical benefit from osimertinib 80 mg qd.

    更新日期:2019-12-29
  • THREE-DIMENSIONAL HISTOLOGIC, IMMUNOHISTOCHEMICAL AND MULTIPLEX IMMUNOFLUORESCENCE ANALYSIS OF DYNAMIC VESSEL CO-OPTION OF SPREAD THROUGH AIR SPACES (STAS) IN LUNG ADENOCARCINOMA
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2019-12-27
    Yukako Yagi; Rania G. Aly; Kazuhiro Tabata; Afsar Barlas; Natasha Rekhtman; Takashi Eguchi; Joeseph Montecalvo; Meera Hameed; Katia Manova-Todorova; Prasad S. Adusumilli; William D. Travis

    Background Spread through air spaces (STAS) is a method of invasion in lung adenocarcinoma, associated with tumor recurrence and poor survival. The spatial orientation of STAS cells/clusters to the lung alveolar parenchyma is not known. The aim of this study was to utilize high resolution and high-quality three-dimensional (3D) reconstruction of images from immunohistochemistry (IHC) and multiplex immunofluorescence (IF) experiments to understand the spatial architecture of tumor cell clusters by STAS in the lung parenchyma. Methods Four lung adenocarcinomas: 3 micropapillary (MIP) predominant and 1 solid (SN) predominant adenocarcinoma subtypes, were investigated. A 3D reconstruction image was created from the formalin fixed paraffin-embedded (FFPE) blocks. 350 serial sections were obtained and stained with hematoxylin and eosin (H&E) (100 slides), IHC (200 slides), and multiplex IF (50 slides) with the following antibodies: CD31, collagen type 4, TTF-1 and E-Cadherin. Whole slide images (WSIs) were reconstructed into 3D images for evaluation. Results Serial 3D image analysis by H&E as well as IHC and IF showed the MIP clusters and SN nests of STAS focally attached to alveolar walls away from the main tumor. Conclusion Our 3-D reconstructions demonstrated STAS tumor cells can attach to alveolar walls rather than appearing free floating as seen on 2D sections. This suggests that tumor cells detach from the main tumor, migrate through air spaces and reattach to alveolar walls through vessel co-option allowing them to survive and grow. This may explain the higher recurrence rate and worse survival for STAS positive tumors undergoing limited resection compared to lobectomy.

    更新日期:2019-12-29
  • Validation of the eighth edition clinical T categorization system for clinical stage IA resected lung adenocarcinomas: Prognostic implications of the ground-glass opacity component
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2019-12-24
    Hyungjin Kim; Jin Mo Goo; Young Tae Kim; Chang Min Park

    Introduction There is controversy regarding the clinical T category of lung adenocarcinomas that manifest as part-solid nodules (PSNs). We aimed to validate the clinical T category and to evaluate the independent prognostic role of the nodule type (i.e., part-solid vs. solid). Methods We retrospectively evaluated the prognostic value of clinico-radiological factors on the overall survival of patients with clinical stage IA lung adenocarcinomas that were resected between 2008 and 2014. Clinical T category, nodule type, and their interaction term were included in the multivariable Cox regression analysis with other variables. In addition, a mixture cure model analysis was performed to investigate the association between the covariates and long-term survival. Results A total of 744 patients (420 women; 362 PSNs; median age, 63 years) were included. The multivariable-adjusted HR of the nodule type was not significant (1.30; 95% CI: 0.80, 2.10; P=0.291). However, the clinical T categories were significantly associated with overall survival (HR of cT1b, 2.33 [95% CI: 1.07, 5.06; P=0.033]; HR of cT1c, 5.74 [95% CI: 2.51, 13.12; P<0.001]). There were no interactions between the nodule type and the clinical T categories (all P>0.05). The multivariable mixture cure model revealed that solid nodules were associated with a decreased probability of long-term survival (OR, 0.40; 95% CI: 0.18, 0.92; P=0.030). Clinical T1c was also a negative predictor of long-term survival (OR, 0.26; 95% CI: 0.07, 0.94; P=0.040). Conclusions The clinical T categorization system is valid for PSNs and solid nodules. Nevertheless, PSNs are a prognostic factor associated with long-term survival.

    更新日期:2019-12-25
  • PD-L1 Testing for Lung Cancer in 2019: Perspective from the IASLC Pathology Committee
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2019-12-20
    Sylvie Lantuejoul; Ming Sound- Tsao; Wendy A. Cooper; Nicolas Girard; Fred R. Hirsch; Anja C. Roden; Fernando Lopez-Rios; Deepali Jain; Teh-Ying Chou; Noriko Motoi; Keith M. Kerr; Yasushi Yatabe; Elisabeth Brambilla; John Longshore; Mauro Papotti; Lynette M. Sholl; Erik Thunnissen; Natasha Rekhtman; Mari Mino-Kenudson

    The recent development of immune checkpoint inhibitors (ICI) has led to promising advances in the treatment of non-small cell and small cell lung cancer patients with advanced or metastatic disease. Most of ICI target the PD-1/PD-L1 axis with the aim of restoring anti-tumor immunity. Multiple clinical trials for ICI have examined a predictive value of PD-L1 protein expression in tumor cells and/or tumor-infiltrating immune cells by immunohistochemistry (IHC), for which different assays with specific IHC platforms were applied. Of those, some PD-L1 IHC assays have been validated for the prescription of the corresponding agent for first- or second-line treatment. However, not all laboratories are equipped with the dedicated platforms and many laboratories have set up in-house or laboratory developed tests, which are more affordable than generally expensive clinical trial-validated assays. Although PD-L1 IHC test is now deployed in the most pathology laboratories, its appropriate implementation and interpretation are critical as a predictive biomarker and can be challenging due to the multiple antibody clones and platforms or assays available and given the typically small size of samples provided. As many articles have been published since the issue of the IASLC Atlas of PD-L1 immunohistochemistry testing in lung cancer, this review by the IASLC pathology committee provides updates on the indications of ICI for lung cancer in 2019, and discusses important considerations on pre-analytical, analytical and post-analytical aspects of PD-L1 IHC testing, including specimen type, validation of assays, external quality assurance and training.

    更新日期:2019-12-20
  • The Distribution of Mediastinal Lesions across Multi-Institutional, International, Radiology Databases
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2019-12-20
    Anja C. Roden; Wentao Fang; Shen Yan; Brett W. Carter; Darin B. White; Sarah M. Jenkins; Grant M. Spears; Julian R. Molina; Eyal Klang; Mattia Di Segni; Jeanne B. Ackman; Edward Z. Sanchez; Nicolas Girard; Engjellush Shumeri; Marie-Pierre Revel; Guillaume Chassagnon; Ami Rubinowitz; Demetrius Dicks; Edith M. Marom

    Background Mediastinal lesions are uncommon; studies on their distribution are in general small and from a single institution. Furthermore, these studies are usually based on pathology or surgical databases and therefore miss many lesions that are not biopsied and/or resected. Our aim was to identify the distribution of lesions in the mediastinum in a large international, multi-institutional cohort. Material and Methods At each participating institution, a standardized retrospective radiology database search for interpretations of CT, PET-CT and MRI scans including any of the following terms: “mediastinal nodule”, “mediastinal lesion”, “mediastinal mass” or “mediastinal abnormality” was performed (2011-2014). Standardized data were collected. Statistical analysis was performed. Results Amongst 3,308 cases, thymomas (27.8%), benign mediastinal cysts (20.0%) and lymphomas (16.1%) were most common. The distribution of lesions varied amongst mediastinal compartments; thymomas (38.3%), benign cysts (16.8%) and neurogenic tumors (53.9%) were the most common lesions in the prevascular, visceral and paravertebral mediastinum, respectively (p<0.001). Mediastinal compartment was associated with age; patients with paravertebral lesions were the youngest (p<0.0001). Mediastinal lesions differed by continent/country with benign cysts being the most common mediastinal lesions in China, thymomas in Europe and lymphomas in North America and Israel (p<0.001). Benign cysts, thymic carcinomas, and metastases were more commonly seen in larger hospitals, while lymphomas and thymic hyperplasia occurred more often in smaller hospitals (p<0.01). Conclusions Our study confirmed that spectrum and frequency of mediastinal lesions depends on mediastinal compartment and age. This information provides helpful demographic data and is important when considering the differential diagnosis of a mediastinal lesion.

    更新日期:2019-12-20
  • Pembrolizumab After Two or More Lines of Previous Therapy in Patients With Recurrent or Metastatic Small-Cell Lung Cancer: Results From the KEYNOTE-028 and KEYNOTE-158 Studies
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2019-12-20
    Hyun Cheol Chung; Sarina A. Piha-Paul; Jose Lopez-Martin; Jan H.M. Schellens; Steven Kao; Wilson H. Miller; Jean-Pierre Delord; Bo Gao; David Planchard; Maya Gottfried; Alona Zer; Shadia I. Jalal; Nicolas Penel; Janice M. Mehnert; Ignacio Matos; Jaafar Bennouna; Dong-Wan Kim; Lei Xu; Patrick A. Ott

    Introduction Pembrolizumab has shown clinical benefit in patients with previously treated recurrent/metastatic small-cell lung cancer (SCLC) in the phase 1b multicohort study KEYNOTE-028 (NCT02054806) and the phase 2 multicohort study KEYNOTE-158 (NCT02628067). We present a pooled analysis of patients from KEYNOTE-028 and KEYNOTE-158 who had received ≥2 lines of previous therapy for SCLC. Methods Eligible patients were ≥18 years, had histologically/cytologically confirmed incurable recurrent/metastatic SCLC, an Eastern Cooperative Oncology Group performance status of ≤1, and had received ≥2 lines of previous therapy. Patients in KEYNOTE-028 were required to have a programmed death ligand 1 (PD-L1)–positive tumor. Patients received pembrolizumab 10 mg/kg every 2 weeks (KEYNOTE-028) or 200 mg every 3 weeks (KEYNOTE-158) for up to 2 years. The primary endpoint was objective response rate (ORR) per RECIST version 1.1; presented here per independent review. Results Eighty-three patients who had received ≥2 lines of previous therapy (KEYNOTE-028, n=19; KEYNOTE-158, n=64) were included. Median follow-up duration was 7.7 months (range, 0.5‒48.7). ORR was 19.3% (95% CI, 11.4‒29.4); 2 patients had a complete response (1 with a PD-L1–positive tumor) and 14 had a partial response (13 with PD-L1–positive tumors). Median duration of response was not reached (range, 4.1‒35.8+ months); 61% of responders had responses lasting ≥18 months. Fifty-one patients (61.4%) experienced any-grade treatment-related adverse events; 8 (9.6%) patients had grade ≥3 events. Conclusion Pembrolizumab demonstrated durable antitumor activity in subset of patients with recurrent/metastatic SCLC who had ≥2 previous lines of therapy, regardless of PD-L1 expression. Pembrolizumab was well tolerated.

    更新日期:2019-12-20
  • Validation of the eighth edition TNM lung cancer staging system; a brief report
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2019-12-18
    Joseph K. Hwang; Barbara J. Page; David Flynn; Linda Passmore; Elizabeth McCaul; Jaccalyne Brady; Ian A. Yang; Henry Marshall; Morgan Windsor; Rayleen V. Bowman; Rishendran Naidoo; Tracey Guan; Shoni Philpot; Michael E. Blake; Kwun M. Fong

    Introduction We performed a validation study at our institution of the Internatonal Union Against Cancer (UICC latest version of TNM Classification of Malignant Tumours Eighth Edition. Methods Data was collected from Queensland Oncology Online (QOOL) registry of NSCLC or SCLC cases between 2000 and 2015 and validated against Queensland Integrated Lung Cancer Outcomes Project (QILCOP) registry using case identification number, first name, last name, and date of birth. Where data was available, cases were classified according to UICC TNM 7th edition stage groupings and then compared to the 8th edition groupings. Kaplan-Meier curves were plotted and log-rank of survival differences using SPSS version 25. Results Of 3636 cases, 3352 and 1031 had complete clinical and pathological staging respectively. Median survival time was shown to reduce with increasing clinical stage; 7th edition (IA:88, IB:44, IIA:31, IIB:18, IIIA:15, IIIB:8, IV:5 months) vs 8th edition TNM stage (IA1: not reached, IA2:88, IA3:53, IB:56, IIA:36, IIB:22, IIIA:14, IIIB:9, IIIC:8, IVA:6, IVB:3; months). A similar overall pattern was reflected in the pathologic stage; 7th edition (IA:124, IB:110, IIA:48, IIB:42, IIIA:26, IIIB:31, IV:27 months) vs. 8th edition (IA1:not reached, IA2:122, IA3:125, IB:144, IIA:98, IIB:57, IIIA:31, IIIB:24, IVA:7 months). The log-rank test for survival curves was significant at p <0.001. Conclusions Our external validation study confirms the prognostic accuracy of the 8th edition TNM lung cancer classification. Our analyses also demonstrated that IIIB, IIIC and IVA stage groups showed similar survival outcomes, and suggests further research for refinement.

    更新日期:2019-12-19
  • Circulating tumor DNA analysis for oncogene-addicted non-small cell lung cancer patients with isolated central nervous system progression
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2019-12-13
    Mihaela Aldea; Lizza Hendriks; Laura Mezquita; Cécile Jovelet; David Planchard; Edouard Auclin; Jordi Remon; Karen Howarth; Jose Carlos Benitez; Anas Gazzah; Pernelle Lavaud; Charles Naltet; Ludovic Lacroix; Frank de Kievit; Clive Morris; Emma Green; Maud Ngo-Camus; Etienne Rouleau; Benjamin Besse

    Introduction In patients with oncogene-addicted NSCLC and isolated central nervous system progression (iCNS), tissue biopsy is challenging and the clinical utility of plasma liquid biopsy (ctDNA) is unknown. Methods Advanced NSCLC patients with known baseline genomic alteration (GA) (EGFR, ALK, BRAF, KRAS, HER2, ROS1, MET, PIK3CA, STK11, TP53) on tissue were divided in to 3 groups based on their disease progression pattern: iCNS, extra-CNS only (noCNS) or both (cCNS). All patients with available plasma ctDNA were included, analyzed by next-generation sequencing-InVisionFirst®-Lung. ctDNA was considered positive if at least one GA was detected. Cell-free tumor DNA was analyzed in cerebrospinal fluid (CSF) when available. Results Out of 517 patients screened, 247 were included: 54 had iCNS, 99 noCNS and 94 cCNS progressive disease (64, 128 and 110 ctDNA samples respectively). CtDNA was positive in 52% iCNS vs. 84% in noCNS and 92% in cCNS (P<0.00001), with lower detection of driver (37% vs. 77% and 73% respectively) and resistance alterations (6% vs. 45% and 44%). Patients with iCNS and positive ctDNA were more at risk of extra-CNS progression (32% vs. 7%, P=0.026). In 12 iCNS patients, ctDNA was positive in 6 (50%) plasma and in 10 (83%) paired CSF (p=0.193). Conclusion Although tagged amplicon-based NGS has high detection rates of GA in plasma ctDNA in NSCLC patients with extraCNS disease, detection rate of GAs (52%) is lower in the subset of iCNS disease patients. Complementary tests, such as CSF cell-free DNA, may be useful. Further evidence would be beneficial to understand the genomic landscape in iCNS NSCLC patients.

    更新日期:2019-12-13
  • Allele frequency-adjusted blood-based tumor mutational burden as a predictor of overall survival for non-small cell lung cancer patients treated with PD-1/PD-L1 inhibitors
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2019-12-12
    Zhijie Wang; Jianchun Duan; Guoqiang Wang; Jing Zhao; Jiachen Xu; Jiefei Han; Zhengyi Zhao; Jun Zhao; Bo Zhu; Minglei Zhuo; Jianguo Sun; Hua Bai; Rui Wan; Xin Wang; Kailun Fei; Shuhang Wang; Xiaochen Zhao; Yuzi Zhang; Jie Wang

    Introduction Blood-based tumor mutational burden (bTMB) has been studied to differentiate non-small cell lung cancer (NSCLC) patients who would benefit from anti-programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1) therapies. However, it failed to predict overall survival (OS) benefits, which warrants further exploration. Methods Three independent cohorts of NSCLC patients treated with immunotherapy were used in this study. A new bTMB algorithm was first developed in the two independent cohorts (POPLAR, N=211 and OAK, N=462) and further validated in the third National Cancer Center cohort (NCC, N=64). Results bTMB-H (bTMB≥cut-off point) was not associated with favorable OS following immunotherapy regardless of the cut-off points in either the POPLAR and OAK or the NCC cohorts (P>0.05) due to its correlation with the circulating tumor DNA (ctDNA) amount, which was associated with poor OS. In the POPLAR and OAK cohorts, upon allele frequency (AF) adjustment, a high allele frequency bTMB (HAF-bTMB, mutation counts with an AF>5%) was strongly correlated with the ctDNA amount (Pearson’s r=0.65), while a low allele frequency bTMB (LAF-bTMB, mutation counts with an AF≤5%) was not (Pearson’s r=0.09). LAF-bTMB-H was associated with favorable OS (hazard ratio [[HR], 0.70; 95% confidence interval [CI], 0.52-0.95; P=0.02), progression-free survival (PFS) (HR, 0.62; 95% CI, 0.47-0.80; P<0.001), and the objective response rate (ORR) (P<0.001) following immunotherapy but not chemotherapy, with a cut-off point of 12 trained in the POPLAR cohort and validated in the OAK cohort. The LAF-bTMB algorithm was further validated in the NCC cohort in which LAF-bTMB-H was associated with OS (HR, 0.20; 95% CI, 0.05-0.84; P=0.02), PFS (HR, 0.30; 95% CI, 0.13-0.70; P=0.003), and the ORR (P=0.001). Conclusions We developed and validated a new LAF-bTMB algorithm as a feasible predictor of OS, PFS, and the ORR following anti-PD-1/PD-L1 therapies in NSCLC patients, which needs to be prospectively validated.

    更新日期:2019-12-13
  • Evolution and clinical impact of EGFR mutations in circulating free DNA in the BELIEF trial
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2019-12-05
    Miguel-Angel Molina-Vila, Rolf A. Stahel, Urania Dafni, Núria Jordana-Ariza, Ariadna Balada-Bel, Mónica Garzón-Ibáñez, Beatriz García-Peláez, Clara Mayo-de-las-Casas, Enriqueta Felip, Alessandra Curioni Fontecedro, Oliver Gautschi, Solange Peters, Bartomeu Massutí, Ramon Palmero, Santiago Ponce Aix, Enric Carcereny, Martin Früh, Miklos Pless, Rafael Rosell

    Background Longitudinal evaluation of mutations in blood samples was a pre-specified secondary objective in the BELIEF trial of erlotinib/bevacizumab in advanced EGFR-positive NSCLC. Here we report the testing results and explore the correlation of EGFR status in blood with clinical outcomes. Methods Blood samples were prospectively collected from patients at baseline, response evaluation and progression and sent to a central laboratory. Circulating free DNA (cfDNA) was purified and EGFR mutations were analyzed with a validated real-time quantitative PCR assay. Results EGFR exon-19/21 mutations were detected in 55/91 (60.4%) baseline blood samples and correlated with a significantly worse PFS: 11.4m (95%CI:9.0-14.8m) for the positive patients vs. 22.9m (95%CI:9.5-33.9m) for the negatives, (log-rank.p=0.0020). Among the 74 samples at response, exon-19/21 mutations were detected only in three cases (4.1%). In contrast, 29/58 patients (50.0%) were exon 19/21 positive at progression and showed a significantly worse median OS of 21.7m (95%CI:17.0-30.9m), compared to 37.4m (95%CI:22.6-53.1m) for negatives (log-rank.p=0.011). Blood samples at the three timepoints were available for 48 patients. Of those, among 14 exon-19/21 EGFR-negative at presentation, 13 (93%) were persistently negative for the sensitizing mutations after progression and the p.T790M could only be detected in the blood of two. Conclusions Longitudinal testing of EGFR mutations in blood can offer valuable clinical information. In patients of the BELIEF study, detection of EGFR mutations in cfDNA at presentation was associated with shorter PFS, while positivity at progression correlated with shorter OS. Finally, patients negative in blood at presentation were almost invariably negative at relapse.

    更新日期:2019-12-05
  • The IASLC Thymic Tumors Staging Project. The Impact of the 8th Edition of the UICC/AJCC TNM Stage Classification of Thymic Tumors: Results of a Survey
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2019-11-27
    Enrico Ruffini, Wentao Fang, Francesco Guerrera, James Huang, Meinoshin Okumura, Dong Kwan Kim, Nicolas Girard, Andrea Billè, Souheil Boubia, Ayten Kayi Cangir, Frank Detterbeck, Conrad Falkson, Pier Luigi Filosso, Giuseppe Giaccone, Kazuya Kondo, Maurizio Infante, Marco Lucchi, Mirella Marino, Hisao Asamura

    Objective The IASLC Staging and Prognostic Factors Committee - Thymic Domain (SPFC-TD) conducted a web-based cross-sectional survey to assess the acceptance of the TNM thymic staging system in the thoracic community. Methods A 50-question web-based questionnaire was circulated to the members of the major thymic organizations worldwide from September to December 2018. The survey consisted of 6 sections (general information; overall perception of the TNM system; pretreatment staging; T category; N category; perioperative treatments). Results 217 responses were collected from 37 countries in 4 continents. The TNM classification was considered useful by 78% of the responders (N=169); the Masaoka-Koga staging system was still used in 87% (N=189) of the responders. With regards to the T category, the majority of the responders (mostly surgeons) felt that the capsular and mediastinal pleura involvement are to be considered separate T categories. As for the N category, 48% (N=105) of the responders used the ITMIG/IASLC thymic nodal map, and lymph node dissection (N1/N2) was performed in 50%/21% in thymomas and 66%/41% in thymic carcinomas. When analyzing the results by the 3 continents (Europe, Asia and Americas), Asia responders reported the largest use of the TNM system, the greatest attention to the N category and the best participation in international thymic databases. Conclusions The survey indicates that the UICC/AJCC TNM stage classification of thymic tumors is gaining acceptance among the scientific community. The present results will guide the work of the SPFC-TD for the revision of the 9th edition of the TNM stage classification of thymic tumors.

    更新日期:2019-11-27
  • Anaplastic lymphoma kinase (ALK) Gene Rearrangement in Children and Young Adults with Mesothelioma
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2019-11-26
    Idrees Mian, Zied Abdullaev, Betsy Morrow, Rosandra N. Kaplan, Shaojian Gao, Markku Mettienen, David S. Schrump, Valerie Zgonc, Jun S. Wei, Javed Khan, Svetlana Pack, Raffit Hassan

    Introduction Children and young adults diagnosed with malignant mesothelioma may have unique genetic characteristics. In this study, we evaluated for the presence of the anaplastic lymphoma kinase (ALK) translocations in these patients. Methods In a prospective study of mesothelioma natural history (MNH) (ClinicalTrials.gov number NCT01950572) we assessed for the presence of the ALK translocation in patients less than 40 years old, irrespective of site of disease. The presence of this translocation was assessed via fluorescence in-situ hybridization (FISH). If positive, both immunohistochemistry (IHC) and RNA sequencing (RNASeq) were performed on the tumor specimen. Results Between September 2013 and December 2018, 373 patients were enrolled on the MNH study of which 32 patients were <40 years old at the time of their mesothelioma diagnosis. 25 patients had peritoneal, 5 pleural, 1 pericardial and 1 had bi-compartmental mesothelioma. Presence of an ALK translocation by FISH was seen in 2 of the 32 (6%) mesothelioma patients. Both patients, a 14 year old female and a 27 year old male, had peritoneal mesothelioma and neither had history of asbestos exposure, prior radiation or predisposing germline mutations. Neither had detectable ALK expression by IHC. RNAseq revealed the presence of an STRN fusion partner in the female patient but failed to identify any fusion protein in the male patient. Conclusions Young patients with peritoneal mesothelioma should be evaluated for the presence of ALK translocations. Presence of this translocation should be assessed by FISH and these patients could potentially benefit from tyrosine kinase inhibitors targeting ALK.

    更新日期:2019-11-27
  • Beyond Margin Status: Population-Based Validation of the Proposed IASLC Residual Tumor Classification Re-categorization
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2019-11-26
    Raymond U. Osarogiagbon, Nicholas R. Faris, Walter Stevens, Carrie Fehnel, Cheryl Houston-Harris, Philip Ojeabulu, Olawale Akinbobola, Yu-Shen Lee, Meredith A. Ray, Matthew P. Smeltzer

    Introduction The International Association for the Study of Lung Cancer’s (IASLC’s) proposal to re-categorize the residual tumor (R) classification for resected non-small cell lung cancer needs validation. Methods Using a 2009-2019 population-based multi-institutional non-small cell lung cancer resection cohort from the United States, we classified resections by Union for International Cancer Control (UICC) and IASLC R criteria, compared the distribution of R classification variables and their survival associations. Results Of 3361 resections, 95.3% were R0, 4.3% R1 and 0.4% were R2 by UICC criteria; 33.3% were R0, 60.8% R-uncertain, and 5.8% were R1/2 by IASLC criteria; 2044 patients (63.8%) migrated from UICC R0 to IASLC R-uncertain. Median survival was not reached, 69 (CI, 64-77), and 25 (CI, 18-36) months respectively for patients with IASLC R0, R-uncertain and R1 or R2 resections. Failure to achieve nodal dissection criteria caused 98% of migration to R-uncertainty, metastasis to the highest mediastinal node station, 5.8%. Compared to R0, R-uncertain resections with mediastinal nodes, no mediastinal nodes and no nodes had adjusted hazard ratios of 1.28 (CI, 1.10-1.48), 1.47 (CI, 1.24-1.74) and 1.74 (CI, 1.37-2.21), respectively, suggesting a dose-response relationship between nodal R-uncertainty and survival. Accounting for mediastinal nodal involvement, the highest mediastinal station involvement was not independently prognostic. The incomplete resection variables were uniformly prognostic. Conclusions The proposed R classification recategorization variables were mostly prognostic, excepting highest mediastinal nodal station involvement. Further categorization of R-uncertainty by severity of nodal quality deficit should be considered.

    更新日期:2019-11-27
  • Inter-observer Reliability of Programmed Cell Death Ligand-1 Scoring Using the VENTANA PD-L1 (SP263) Assay in Non-Small Cell Lung Cancer
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2019-11-25
    Gareth H. Williams, Andrew G. Nicholson, David R.J. Snead, Erik Thunnissen, Sylvie Lantuejoul, Paul Cane, Keith M. Kerr, Marco Loddo, Marietta L.J. Scott, Paul W. Scorer, Craig Barker

    Introduction The VENTANA PD-L1 (SP263) Assay is approved for use with anti-programmed cell death-1/programmed cell death ligand-1 (PD-1/PD-L1) therapies in non-small cell lung cancer (NSCLC) and urothelial carcinoma. Here, we investigate inter-observer reliability of the SP263 assay, applied to PD-L1 scoring of tumor cells (TCs) in NSCLC. Methods Six practicing European pulmonary pathologists independently scored the proportion of TCs expressing PD-L1 (TC score) from 200 archival, commercially sourced, formalin-fixed paraffin-embedded NSCLC resections stained using the SP263 assay. Agreement in scores was analyzed using the intra-class correlation coefficient (ICC) and concordance in patient classification using Fleiss’ kappa. Results Results from 172 samples showed strong pair-wise correlations between pathologists (R2 >0.89) for TC scoring with an ICC of 0.96. Overall agreement was >90% for TC ≥1% and >94% for TC ≥25% and ≥50%. Fleiss’ kappa showed substantial agreement for TC ≥1% and almost perfect agreement for TC ≥25% and ≥50%. Conclusions Assessment of TC score in NSCLC was highly reproducible using the SP263 assay, building confidence in the accuracy of this assay in patient selection for anti-PD-1/PD-L1 therapy.

    更新日期:2019-11-26
  • Final Overall Survival, Other Efficacy and Safety Results from ASCEND-3: Phase II Study of Ceritinib in ALKi-Naïve Patients With ALK-Rearranged Non–Small-Cell Lung Cancer
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2019-11-25
    Makoto Nishio, Enriqueta Felip, Sergey Orlov, Keunchil Park, Chong-Jen Yu, Chun-Ming Tsai, Manuel Cobo, Mark McKeage, Wu-Chou Su, Tony Mok, Giorgio V. Scagliotti, David R. Spigel, Kalyanee Viraswami-Appanna, Zhe Chen, Vanessa Q. Passos, Alice T. Shaw

    Introduction The phase II, single-arm ASCEND-3 study assessed efficacy and safety of ceritinib in anaplastic lymphoma kinase (ALK) inhibitor (ALKi)-naïve patients with ALK-rearranged non–small-cell lung cancer (NSCLC) who had received ≤ 3 prior lines of chemotherapy. Here, we report the final efficacy and safety results. Methods Eligible patients (including those with asymptomatic or neurologically stable brain metastases [BM]) received oral ceritinib 750 mg/day (fasted). Primary endpoint: investigator-assessed overall response rate (ORR). Secondary endpoints: Blinded Independent Review Committee (BIRC)-assessed ORR; investigator- and BIRC-assessed overall intracranial response rate, duration of response (DOR), time to response, disease control rate, and progression-free survival (PFS); overall survival (OS); and safety. Exploratory endpoints: patient-reported outcomes. Results Of the 124 patients enrolled, 122 (98.4%) had received prior antineoplastic medications (31 patients [25.0%], ≥ 3 regimens), and 49 (39.5%) had baseline BM. Median follow-up time (data cutoff: January 22, 2018): 52.1 months (range, 48.4–60.1). Investigator-assessed ORR was 67.7% (95% CI, 58.8 to 75.9) and median PFS was 16.6 months (95% CI, 11.0 to 23.2). Median OS was 51.3 months (95% CI, 42.7 to 55.3). Most common adverse events (AEs [all grades], ≥ 60% of patients, all-causality): diarrhea (85.5%), nausea (78.2%), and vomiting (71.8%). Overall, 18 patients (14.5%) had an AE leading to treatment discontinuation. Health-related quality of life was maintained during ceritinib treatment. Conclusion Ceritinib demonstrated prolonged and clinically meaningful OS, PFS, and DOR in chemotherapy pretreated (≤ 3 lines), ALKi-naïve patients with ALK+ NSCLC. The safety profile is consistent with that of previously reported studies.

    更新日期:2019-11-26
  • Phase II trial of concurrent atezolizumab with chemoradiation in unresectable non-small cell lung cancer
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2019-11-25
    Steven H. Lin, Yan Lin, Luyang Yao, Neda Kalhor, Brett W. Carter, Mehmet Altan, George Blumenschein, Lauren A. Byers, Frank Fossella, Don L. Gibbons, Jonathan M. Kurie, Charles Lu, George Simon, Ferdinandos Skoulidis, Joe Y. Chang, Melenda D. Jeter, Zhongxing Liao, Daniel R. Gomez, Anne S. Tsao

    Introduction Consolidation durvalumab after chemoradiation (CRT) is the current standard of care in locally advanced non-small cell lung cancer. We hypothesized that adding immunotherapy concurrently with CRT (cCRT) increased efficacy without significant additive toxicity. Methods This phase II study was conducted in two parts. Part 1 (N=10) administered conventionally fractionated CRT followed by consolidation chemotherapy-atezolizumab x 2 cycles and maintenance atezolizumab up to 1 year. Part 2 (N=30) administered cCRT with atezolizumab followed by the same consolidation and maintenance therapy as in Part 1. PD-L1 staining cutoffs (1% or 50%) using Dako 22c3 immunohistochemistry were correlated to clinical outcomes. Results The overall toxicities for Parts 1/2 are: overall AE grade ≥ 3: 80%/80%; immune-related AEs ≥ grade 3: 30%/20%; pneumonitis ≥ grade 2: 10%/16%. For preliminary efficacy results, in Part 1, with a median follow up of 22.5 months (mos) the median PFS is 18.6 mos and OS is 22.8 mos . In Part 2, with a median follow up time of 15.1 mos, the median PFS is 13.2 mos and OS is not reached. There was no significant difference in cancer recurrence regardless of PD-L1 status. Conclusion Atezolizumab with cCRT is safe and feasible and has no added toxicities over historical rates.

    更新日期:2019-11-26
  • Brigatinib in Crizotinib-Refractory ALK+ Non–Small Cell Lung Cancer: 2-Year Follow-up on Systemic and Intracranial Outcomes in the Phase 2 ALTA Trial
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2019-11-19
    Rudolf M. Huber, Karin H. Hansen, Luis Paz-Ares Rodríguez, Howard L. West, Karen L. Reckamp, Natasha B. Leighl, Marcello Tiseo, Egbert F. Smit, Dong-Wan Kim, Scott N. Gettinger, Maximilian J. Hochmair, Sang-We Kim, Corey J. Langer, Myung-Ju Ahn, Edward S. Kim, David Kerstein, Harry J.M. Groen, D. Ross Camidge

    Introduction We report updated data from a phase 2 randomized study evaluating brigatinib in crizotinib-refractory anaplastic lymphoma kinase (ALK)-positive non–small cell lung cancer (NSCLC). Methods Patients were randomized 1:1 to oral brigatinib 90 mg qd (arm A) or 180 mg qd with 7-day lead-in at 90 mg (B), stratified by central nervous system (CNS) metastases and best response to crizotinib. Primary endpoint was investigator-assessed confirmed objective response rate (cORR) per Response Evaluation Criteria In Solid Tumors v1.1. Secondary endpoints included independent review committee (IRC)-assessed progression-free survival (PFS), intracranial PFS (iPFS) and overall survival (OS). Exploratory analyses included CNS vs ex-CNS target lesion response and correlation of depth of response with PFS and OS. Results Among 222 randomized patients (A/B: n=112/110), 59 (27%) remained on brigatinib at analysis (median follow-up: 19.6/24.3 months in A/B). At baseline, 71%/67% had brain lesions. Investigator-assessed cORR was 46%/56%. Median IRC-assessed PFS was 9.2 months (95% confidence interval, 7.4–12.8)/16.7 months (11.6–21.4). Median OS was 29.5 months (18.2–not reached [NR])/34.1 months (27.7–NR). IRC-confirmed intracranial ORR (iORR) in patients with measurable baseline brain lesions was 50% (13/26)/67% (12/18); median duration of intracranial response (iDOR) was 9.4/16.6 months. IRC-assessed iPFS was 12.8/18.4 months. Across arms, median IRC-assessed PFS was 1.9, 5.5, 11.1, 16.7, and 15.6 months for patients with no, 1%–25%, 26%–50%, 51%–75%, and 76%–100% target lesion shrinkage, respectively. No new safety findings were observed with longer follow-up. Conclusions Brigatinib (180 mg qd with lead-in) continues to demonstrate robust PFS, long iPFS and iDOR, and high iORR in crizotinib-refractory patients. Depth of response may be an important endpoint to capture in future targeted therapy trials.

    更新日期:2019-11-20
  • Thoracic SMARCA4-deficient sarcomatoid tumors represent primarily smoking-related undifferentiated carcinomas rather than primary thoracic sarcomas
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2019-11-18
    N. Rekhtman, J. Montecalvo, J.C. Chang, D. Alex, R.N. Ptashkin, N. Ai, J.L. Sauter, B. Kezlarian, A. Jungbluth, P. Desmeules, A. Beras, J.A. Bishop, A.J. Plodkowski, M.M. Gounder, A.J. Schoenfeld, A. Namakydoust, B.T. Li, C.M. Rudin, W.D. Travis

    Background Highly aggressive thoracic neoplasms characterized by SMARCA4 (BRG1) deficiency and undifferentiated round cell or rhabdoid morphology have been recently described, and proposed to represent thoracic sarcomas. However, it remains unclear whether such tumors may instead represent sarcomatoid carcinomas, and how their clinicopathologic characteristics compare to those of non-sarcomatoid SMARCA4-deficient non-small cell lung carcinomas (SD-NSCC). Methods We identified 22 thoracic SMARCA4-deficient sarcomatoid tumors (SD-STs) with round cell/rhabdoid morphology and 45 SD-NSCCs, and comprehensively analyzed their clinicopathologic, immunohistochemical and genomic characteristics using 341-468 gene next-generation sequencing and other molecular platforms. Results The relationship of SD-STs with NSCC was supported by 1) the presence of NSCC components juxtaposed with sarcomatoid areas in 5 cases, 2) focal expression of NSCC lineage markers TTF1 or p40 in 4 additional cases, 3) smoking history in all but one patient (mean 51 pack-years), accompanied by genomic smoking signature, and 4) high tumor-mutation burden (mean 14.2 mutations/Mb) and mutations characteristic of NSCC in a subset. Compared with SD-NSCCs, SD-STs exhibited significantly larger primary tumor size (p<0.0001), worse survival (p=0.004), and more frequent presentation at younger age (30-50 years) despite heavier smoking history. Distinctive pathologic features of SD-STs included consistent lack of adhesion molecule claudin-4, SMARCA2 (BRM) co-deficiency, and frequent expression of stem-cell markers. Conclusion SD-STs represent primarily smoking-associated undifferentiated/dedifferentiated carcinomas rather than primary thoracic sarcomas. Despite their histogenetic relationship with NSCC, these tumors have unique clinicopathologic characteristics, supporting their recognition as a distinct entity. Further studies are warranted to determine therapeutic approaches to this novel class of exceptionally aggressive thoracic tumors.

    更新日期:2019-11-19
  • Dynamic Changes of Health Utility in Lung Cancer Patients Receiving Different Treatments: A 7-Year Follow-up
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2019-07-25
    Szu-Chun Yang, Chin-Wei Kuo, Wu-Wei Lai, Chien-Chung Lin, Wu-Chou Su, Sheng-Mao Chang, Jung-Der Wang

    Introduction This study aimed to estimate the utility values of all subtypes of lung cancer. The trajectories after different kinds of treatments and their major determinants were explored on the basis of real-world data and repeated measurements. Methods From 2011 to 2017, all patients with lung cancer who visited a medical center were invited to fill out the EuroQol Five-Dimension and WHO Quality of Life-Brief questionnaires at each visit. Utility values of quality of life (QoL) after diagnosis and treatments were depicted using a kernel smoothing method. We constructed linear mixed models to predict health utility in each time period and cross-validated them with domain scores of the WHO Quality of Life-Brief. Results A total of 1715 patients were enrolled, with 6762 QoL measurements. Utility values were lower in patients with advanced-stage disease and older patients. Patients receiving second-line targeted therapy showed higher utility values at 0 to 3 months, 3 to 6 months, and 6 months and beyond (0.89, 0.90, and 0.88, respectively) than did those undergoing chemotherapy (0.81, 0.85, and 0.80, respectively). After using mixed models to control confounders, including poor performance status and disease progression, patients receiving second-line chemotherapy showed health utility similar to that at quasi-baseline, whereas utility values related to second-line targeted therapy were higher at 3 to 6 months and 6 months and beyond (β = 0.07, p = 0.010 and β = 0.07, p < 0.001, respectively). There was convergent validity between the utility values and scores of the physical and psychological domains. Conclusion Targeted therapy provided treated patients with a higher health utility value than was provided to those treated with chemotherapy. Development of the longitudinal trajectory may help predict changes in QoL and improve the care of lung cancer survivors.

    更新日期:2019-11-18
  • Mutations in the KEAP1-NFE2L2 Pathway Define a Molecular Subset of Rapidly Progressing Lung Adenocarcinoma
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2019-07-16
    Frauke Goeman, Francesca De Nicola, Stefano Scalera, Francesca Sperati, Enzo Gallo, Ludovica Ciuffreda, Matteo Pallocca, Laura Pizzuti, Eriseld Krasniqi, Giacomo Barchiesi, Patrizia Vici, Maddalena Barba, Simonetta Buglioni, Beatrice Casini, Paolo Visca, Edoardo Pescarmona, Marco Mazzotta, Ruggero De Maria, Marcello Maugeri-Saccà

    Introduction Molecular characterization studies revealed recurrent kelch like ECH associated protein 1 gene (KEAP1)/nuclear factor, erythroid 2 like 2 gene (NFE2L2) alterations in NSCLC. These genes encode two interacting proteins (a stress response pathway [SRP]) that mediate a cytoprotective response to oxidative stress and xenobiotics. Nevertheless, whether KEAP1/NFE2L2 mutations have an impact on clinical outcomes is unclear. Methods We performed amplicon-based next-generation sequencing to characterize the SRP in patients with metastatic NSCLC (Regina Elena National Cancer Institute cohort [n = 88]) treated with first-line chemotherapy. Mutations in the DNA damage response (tumor protein p53 gene [TP53], ATM serine/threonine kinase gene [ATM], and ATR serine/threonine kinase gene [ATR]) were concomitantly analyzed. In lung adenocarcinoma (LAC), we also determined the expression of phosphorylated ataxia telangiectasia mutated kinase and ataxia telangiectasia and Rad3-related protein. Two independent cohorts (the Memorial Sloan Kettering Cancer Center cohort and The Cancer Genome Atlas cohort) with data from approximately 1400 patients with advanced LAC were used to assess the reproducibility of the results. Results In the Regina Elena National Cancer Institute cohort, patients whose tumors carried mutations in the KEAP1/NFE2L2 pathway had significantly shorter progression-free survival and overall survival than their wild-type counterparts did (log-rank p = 0.006 and p = 0.018, respectively). This association was driven by LAC in which KEAP1/NFE2L2 mutations were overrepresented in fast progressors and associated with an increased risk of disease progression and death. LACs carrying KEAP1/NFE2L2 mutations were characterized by elevated expression of phosphorylated ataxia telangiectasia mutated (pATM) kinase and ataxia telangiectasia and Rad3-related (pATR) protein in association with a pattern of mutual exclusivity with TP53 alterations. The relationship between KEAP1/NFE2L2 mutations and shorter survival was validated in the Memorial Sloan Kettering Cancer Center cohort (n = 1256) (log-rank p < 0.001) and in The Cancer Genome Atlas cohort (n = 162) (log-rank p = 0.039). Conclusion These findings suggest that a mutant SRP represents a negative prognostic/predictive factor in metastatic LAC and that KEAP1/NFE2L2 mutations may define a molecular subtype of chemotherapy-resistant and rapidly progressing LAC.

    更新日期:2019-11-18
  • Expansion of the Concept of Micropapillary Adenocarcinoma to Include a Newly Recognized Filigree Pattern as Well as the Classical Pattern Based on 1468 Stage I Lung Adenocarcinomas
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2019-07-25
    Katsura Emoto, Takashi Eguchi, Kay See Tan, Yusuke Takahashi, Rania G. Aly, Natasha Rekhtman, William D. Travis, Prasad S. Adusumilli

    Introduction The classical micropapillary (MIP) pattern is defined in the 2015 WHO classification as tumor cells growing in papillary tufts forming florets that lack fibrovascular cores, and it is associated with poor prognosis. We observed a novel pattern that we termed a filigree MIP pattern and investigated its relationship with the classical MIP pattern. Methods Filigree pattern was defined as tumor cells growing in delicate, lace-like, narrow stacks of cells without fibrovascular cores. We required at least three piled-up nuclei from the alveolar wall basal layer, with a breadth of up to three cells across. To assess the relationship of the filigree pattern with the classical MIP pattern, we documented their frequencies in the context of the clinical and pathologic characteristics of 1468 stage I invasive adenocarcinomas, including survival analysis using cumulative incidence of recurrence by competing risks. Results We observed the filigree MIP pattern in 35% of cases. By including the filigree pattern as an MIP pattern, we identified 57 more MIP predominant cases in addition to the previously diagnosed 87 MIP predominant adenocarcinomas. These 57 cases were reclassified from papillary (n = 37), acinar (n = 16), and solid (n = 4) predominant adenocarcinoma, respectively. Of the 144 MIP predominant adenocarcinomas, the filigree predominant MIP pattern (n = 78) showed a poor prognosis like the classical predominant MIP pattern (n = 66) (p = 0.464). In addition, like the classical MIP pattern (p = 0.010), even a small amount (≥5%) of filigree MIP pattern was significantly associated with worse cumulative incidence of recurrence (p = 0.001) in multivariable analysis. Conclusion The frequent association with the classical MIP pattern and the similar poor prognosis supports inclusion of the filigree pattern in the MIP pattern subtype.

    更新日期:2019-11-18
  • Spatial and Temporal Heterogeneity of Panel-Based Tumor Mutational Burden in Pulmonary Adenocarcinoma: Separating Biology From Technical Artifacts
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2019-07-23
    Daniel Kazdal, Volker Endris, Michael Allgäuer, Mark Kriegsmann, Jonas Leichsenring, Anna-Lena Volckmar, Alexander Harms, Martina Kirchner, Katharina Kriegsmann, Olaf Neumann, Regine Brandt, Suranand B. Talla, Eugen Rempel, Carolin Ploeger, Moritz von Winterfeld, Petros Christopoulos, Diana M. Merino, Mark Stewart, Albrecht Stenzinger

    Background Tumor mutational burden (TMB) is an emerging biomarker used to identify patients who are more likely to benefit from immuno-oncology therapy. Aside from various unsettled technical aspects, biological variables such as tumor cell content and intratumor heterogeneity may play an important role in determining TMB. Methods TMB estimates were determined applying the TruSight Oncology 500 targeted sequencing panel. Spatial and temporal heterogeneity was analyzed by multiregion sequencing (two to six samples) of 24 pulmonary adenocarcinomas and by sequencing a set of matched primary tumors, locoregional lymph node metastases, and distant metastases in five patients. Results On average, a coding region of 1.28 Mbp was covered with a mean read depth of 609x. Manual validation of the mutation-calls confirmed a good performance, but revealed noticeable misclassification during germline filtering. Different regions within a tumor showed considerable spatial TMB variance in 30% (7 of 24) of the cases (maximum difference, 14.13 mut/Mbp). Lymph node–derived TMB was significantly lower (p = 0.016). In 13 cases, distinct mutational profiles were exclusive to different regions of a tumor, leading to higher values for simulated aggregated TMB. Combined, intratumor heterogeneity and the aggregated TMB could result in divergent TMB designation in 17% of the analyzed patients. TMB variation between primary tumor and distant metastases existed but was not profound. Conclusions Our data show that, in addition to technical aspects such as germline filtering, the tumor content and spatially divergent mutational profiles within a tumor are relevant factors influencing TMB estimation, revealing limitations of single-sample–based TMB estimations in a clinical context.

    更新日期:2019-11-18
  • Improved Prognosis and Increased Tumor-Infiltrating Lymphocytes in Patients Who Have SCLC With Neurologic Paraneoplastic Syndromes
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2019-06-12
    Wade T. Iams, Eileen Shiuan, Catherine B. Meador, Marc Roth, Jennifer Bordeaux, Christine Vaupel, Kelli L. Boyd, IlaSri B. Summitt, Lucy L. Wang, Joseph T. Schneider, Jeremy L. Warner, Zhiguo Zhao, Christine M. Lovly

    Background Approximately 10% of patients with SCLC develop a paraneoplastic syndrome (PNS). Neurologic PNS are thought to improve prognosis, which we hypothesized is related to increased tumor-infiltrating lymphocytes and immune recognition. Methods We queried 2,512,042 medical records from a single institution to identify patients who have SCLC with and without PNS and performed manual, retrospective chart review. We then performed multiplexed fluorescence immunohistochemistry and automated quantitative analysis (AQUA Technology) on tumors to assess CD3, CD4, and CD8 T cell infiltrates and programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) interactions. T cell infiltrates and PD-1/PD-L1 interaction scores were compared among patients with neurologic PNS, endocrinologic PNS, and a control group without PNS. Clinical outcomes were analyzed using the Kaplan-Meier method and Cox proportional hazards models. Results We evaluated 145 SCLC patients: 55 with PNS (25 neurologic and 30 endocrinologic) and 90 controls. Patients with neurologic PNS experienced improved overall survival compared to patients with endocrinologic PNS and controls (median overall survival of 24 months versus 12 months versus 13 months, respectively). Of the 145 patients, we identified tumor tissue from 34 patients that was adequate for AQUA analysis. Among 37 specimens from these 34 patients, patients with neurologic PNS had increased T cell infiltrates (p = 0.033) and PD-1/PD-L1 interaction (p = 0.014) compared to tumors from patients with endocrinologic PNS or controls. Conclusions Tumor tissue from patients with SCLC with neurologic PNS showed increased tumor-infiltrating lymphocytes and PD-1/PD-L1 interaction consistent with an inflamed tumor microenvironment.

    更新日期:2019-11-18
  • Prevalence and Preliminary Validation of Screening Criteria to Identify Carriers of Germline BAP1 Mutations
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2019-07-16
    Marjorie G. Zauderer, Gowtham Jayakumaran, Mariel DuBoff, Liying Zhang, Jasmine H. Francis, David H. Abramson, Andrea Cercek, Garrett M. Nash, Alexander Shoushtari, Paul Chapman, Sandra D’Angelo, Angela G. Arnold, Beth Siegel, Megan Harlan Fleischut, Andy Ni, Andreas Rimner, Valerie W. Rusch, Prasad S. Adusumilli, Mark Robson

    Introduction Inherited mutations are easily detected factors that influence the disease courses and optimal treatment strategies of some cancers. Germline mutations in BRCA1 associated protein 1 (BAP1) are associated with unique disease profiles in mesothelioma, atypical spitz nevi, and uveal melanoma, but the patient characteristics of an unselected population of BAP1 carriers identified by an ascertainment prevalence study are unknown. Methods We collected blood samples, cancer histories, and occupational exposures from 183 unselected patients with BAP1-related diseases. Clinical information for each patient was obtained from medical records. Germline DNA was extracted from blood samples and sequenced using a next-generation sequencing assay. We tested screening criteria developed to identify patients with a possible germline BAP1 mutation. Results Pathogenic or likely pathogenic germline BAP1 mutations were observed in 5 of 180 sequenced specimens and were exclusively found in patients identified by our screening criteria. Several patients with characteristics suspicious for a heritable deleterious mutation did not have a germline BAP1 mutation. The prevalence of pathogenic germline BAP1 mutations in patients with mesothelioma was 4.4% (95% confidence interval 1.1–11.1). Conclusions Results from the first unselected prevalence ascertainment study of germline BAP1 alterations suggest that the frequency of this mutation is low among patients with mesothelioma. The proposed screening criteria successfully identified all patients with germline BAP1-mutant mesothelioma. These screening guidelines may assist physicians in selecting patients who would benefit from genetic testing. Future efforts should validate and refine these criteria and search for other germline mutations associated with mesothelioma and related diseases.

    更新日期:2019-11-18
  • A Novel Acquired Exon 20 EGFR M766Q Mutation in Lung Adenocarcinoma Mediates Osimertinib Resistance but is Sensitive to Neratinib and Poziotinib
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2019-06-27
    Gina M. Castellano, Joseph Aisner, Stephen K. Burley, Brinda Vallat, Helena A. Yu, Sharon R. Pine, Shridar Ganesan

    Introduction Osimertinib is an effective third-generation tyrosine kinase inhibitor (TKI) for EGFR-mutant lung cancers. However, treatment for patients with acquired resistance to osimertinib remains challenging. We characterized a novel EGFR mutation in exon 20 that was acquired while on osimertinib. Methods A 79-year-old woman had disease progression during third-line treatment with osimertinib for an EGFR L858R/T790M–mutant lung cancer. Sequencing of circulating cell-free DNA showed EGFR L858R, an acquired novel EGFR M766Q mutation in exon 20, and no evidence of EGFR T790M. Homology modeling was performed to investigate the effects of M766Q on binding to osimertinib. L858R and L858R/M766Q mutations were retrovirally introduced into Ba/F3 and NIH/3T3 cells and evaluated for sensitivity to first-generation (erlotinib), second-generation (afatinib, neratinib, and poziotinib), and third-generation TKIs (osimertinib) by cell viability and colony-formation assays. EGFR-mediated signaling pathways were interrogated by western blotting. Results Modeling suggested that EGFR M766Q could disrupt osimertinib binding. L858R/M766Q double-mutant cells were 12-fold more resistant to osimertinib, and more than 250-fold more resistant to erlotinib and afatinib, as compared to L858R-mutant cells. In contrast, double-mutant cells remained sensitive to neratinib and poziotinib at clinically relevant doses (concentration that inhibits 50%, 4.3 and 1.3 nM, respectively). This was corroborated by the effects of the TKIs on colony formation and EGFR signaling. Conclusions Acquisition of EGFR M766Q exon 20 mutation is a novel mechanism of acquired resistance to osimertinib. EGFR-mutant lung cancers with an acquired EGFR M766Q mutation in the setting of osimertinib resistance may be sensitive to neratinib and poziotinib.

    更新日期:2019-11-18
  • Rapid Acquisition of Alectinib Resistance in ALK-Positive Lung Cancer With High Tumor Mutation Burden
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2019-07-30
    Go Makimoto, Kadoaki Ohashi, Shuta Tomida, Kazuya Nishii, Takehiro Matsubara, Hiroe Kayatani, Hisao Higo, Kiichiro Ninomiya, Akiko Sato, Hiromi Watanabe, Hirohisa Kano, Takashi Ninomiya, Toshio Kubo, Kammei Rai, Eiki Ichihara, Katsuyuki Hotta, Masahiro Tabata, Shinichi Toyooka, Katsuyuki Kiura

    Introduction The highly selective ALK receptor tyrosine kinase (ALK) inhibitor alectinib is standard therapy for ALK-positive lung cancers; however, some tumors quickly develop resistance. Here, we investigated the mechanism associated with rapid acquisition of resistance using clinical samples. Methods Autopsied samples were obtained from lung, liver, and renal tumors from a 51-year-old male patient with advanced ALK-positive lung cancer who had acquired resistance to alectinib in only 3 months. We established an alectinib-resistant cell line (ABC-14) from pleural effusion and an alectinib/crizotinib-resistant cell line (ABC-17) and patient-derived xenograft (PDX) model from liver tumors. Additionally, we performed next-generation sequencing, direct DNA sequencing, and quantitative real-time reverse transcription polymerase chain reaction. Results ABC-14 cells harbored no ALK mutations and were sensitive to crizotinib while also exhibiting MNNG HOS transforming gene (MET) gene amplification and amphiregulin overexpression. Additionally, combined treatment with crizotinib/erlotinib inhibited cell growth. ABC-17 and PDX tumors harbored ALK G1202R, and PDX tumors metastasized to multiple organs in vivo, whereas the third-generation ALK-inhibitor, lorlatinib, diminished tumor growth in vitro and in vivo. Next-generation sequencing indicated high tumor mutation burden and heterogeneous tumor evolution. The autopsied lung tumors harbored ALK G1202R (c. 3604 G>A) and the right renal metastasis harbored ALK G1202R (c. 3604 G>C); the mutation thus comprised different codon changes. Conclusions High tumor mutation burden and heterogeneous tumor evolution might be responsible for rapid acquisition of alectinib resistance. Timely lorlatinib administration or combined therapy with an ALK inhibitor and other receptor tyrosine-kinase inhibitors might constitute a potent strategy.

    更新日期:2019-11-18
  • Assessment of a New ROS1 Immunohistochemistry Clone (SP384) for the Identification of ROS1 Rearrangements in Non-Small Cell Lung Carcinoma Patients: the ROSING Study
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2019-07-23
    Esther Conde, Susana Hernandez, Rebeca Martinez, Barbara Angulo, Javier De Castro, Ana Collazo-Lorduy, Beatriz Jimenez, Alfonso Muriel, Jose Luis Mate, Teresa Moran, Ignacio Aranda, Bartomeu Massuti, Federico Rojo, Manuel Domine, Irene Sansano, Felip Garcia, Enriqueta Felip, Nuria Mancheño, Fernando Lopez-Rios

    Introduction The ROS1 gene rearrangement has become an important biomarker in non-small cell lung carcinomas (NSCLCs). The CAP/IASLC/AMP testing guidelines support the use of ROS1 immunohistochemistry (IHC) as a screening test, followed by confirmation with fluorescence in situ hybridization (FISH) or a molecular test in all positive results. We have evaluated a novel anti-ROS1 IHC antibody (SP384) in a large multicenter series to obtain real-world data. Methods Forty-three ROS1 FISH-positive and 193 ROS1 FISH-negative NSCLC samples were studied. All specimens were screened by two antibodies (clone D4D6 from Cell Signaling Technology and clone SP384 from Ventana) and the different interpretation criteria were compared with break-apart FISH (Vysis). FISH-positive samples were also analyzed with next-generation sequencing (OncomineTM Dx, Thermo Fisher Scientific). Results An H-score of ≥150 or the presence of ≥70% of ≥2+ stained tumor cells by SP384 clone were the optimal cut-off value (both with 93% sensitivity and 100% specificity). The D4D6 clone showed similar results with an H-score of ≥100 (91% sensitivity and 100% specificity). ROS1 expression in normal lung was more frequent using the SP384 clone (P < 0.0001). EZR-ROS1 variant was associated with membranous staining and an isolated green signal FISH pattern (P = 0.001 and P = 0.017, respectively). Conclusions The new SP384 ROS1 IHC clone showed excellent sensitivity without compromising specificity, so it is another excellent analytical option for the proposed testing algorithm.

    更新日期:2019-11-18
  • Defining Synchronous Oligometastatic Non–Small Cell Lung Cancer: A Systematic Review
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2019-06-11
    Niccolò Giaj-Levra, Matteo Giaj-Levra, Valerie Durieux, Silvia Novello, Benjamin Besse, Baktiar Hasan, Lizza E. Hendriks, Antonin Levy, Anne-Marie C. Dingemans, Thierry Berghmans

    Introduction Synchronous oligometastatic (sOM) disease is an oncological concept characterized by a limited cancer burden. Patients with oligometastasis could potentially benefit from local radical treatments. Despite the fact that the sOM condition is well recognized, a universal definition, including a specific definition for NSCLC, is not yet available. The aim of this systematic review was to summarize the definitions of and staging requirements for use of the term synchronous oligometastatic in the context of NSCLC. Methods The key issue was formulated in one research question according to the population, intervention, comparator, and outcomes strategy. The question was introduced in MEDLINE (OvidSP). All articles dealing with sOM NSCLC and providing a definition of synchronous oligometastasis in NSCLC were selected and analyzed. Results A total of 21 eligible articles focusing on sOM NSCLC were retrieved and analyzed. In 17 studies (81%), patients had to be staged with magnetic resonance imaging or computed tomography of the brain, thoracic and abdominal computed tomography, and positron emission tomography. The total number of metastases allowed in the definitions ranged from one to eight, but in 38.1% of studies the maximum number was 5. Most of the publications did not define the number of involved organs or the maximum number of metastases per organ. For mediastinal lymph node involvement, only five articles (27.8%) counted this as a metastatic site. Conclusions No uniform definition of sOM NSCLC could be retrieved by this systematic review. However, extended staging was mandated in most of the studies. An accepted oncological definition of synchronous oligometastasis is essential for patient selection to define prospective clinical trials.

    更新日期:2019-11-18
  • Asian Thoracic Oncology Research Group expert consensus statement on optimal management of stage III non-small cell lung cancer
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2019-11-13
    Wan Ling Tan, Kevin L.M. Chua, Chia-Chi Lin, Victor H.F. Lee, Lye Mun Tho, Anthony W. Chan, Gwo Fuang Ho, Thanyanan Reungwetwattana, James C. Yang, Dong-Wan Kim, Ross A. Soo, Yong Chan Ahn, Hiroshi Onishi, Myung-Ju Ahn, Tony S.K. Mok, Daniel S.W. Tan, Fan Yang

    Stage III non-small cell lung cancer (NSCLC) represents a heterogeneous disease for which optimal treatment continues to pose a clinical challenge. Recent changes in the American Joint Commission on Cancer (AJCC) staging to the 8th edition has led to a shift in TNM stage grouping and redefined the subcategories (IIIA–C) in stage III NSCLC for better prognostication. Although concurrent chemoradiotherapy (CCRT) has remained standard of care for Stage III NSCLC for almost 2 decades, contemporary considerations include the impact of different molecular subsets of NSCLC, role of tyrosine kinase inhibitors (TKIs) post-definitive therapy, and of immune checkpoint inhibitors following chemoradiotherapy. With rapid evolution of diagnostic algorithms and expanding treatment options, the need for interdisciplinary input – involving multiple specialists (medical oncologists, pulmonologists, radiologists and thoracic surgeons) has become increasingly important. The unique demographics of Asian NSCLC pose further challenges when applying clinical trial data into clinical practice. This includes differences in smoking rates, prevalence of oncogenic driver mutations, and access to healthcare resources including molecular testing, prompting the need for critical review of existing data and identification of current gaps. In this expert consensus statement by the Asian Thoracic Oncology Research Group (ATORG), an interdisciplinary group of experts representing Hong Kong, Korea, Japan, Taiwan, Singapore, Thailand, Malaysia and Mainland China was convened. Standard clinical practices for stage III NSCLC across different Asian countries were discussed from initial diagnosis, staging through to multi-modality approaches including surgery, chemotherapy, radiation, targeted therapies and immunotherapy.

    更新日期:2019-11-13
  • The IASLC Lung Cancer Staging Project: Analysis of Resection Margin Status and Proposals for Residual Tumor (R) Descriptors for Non-Small Cell Lung Cancer
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2019-11-13
    John G. Edwards, Kari Chansky, Paul van Schil, Andrew G. Nicholson, Souheil Boubia, Elisabeth Brambilla, Jessica Donnington, Françoise Galateau-Sallé, Hans Hoffman, Maurizio Infante, Mirella Marino, Edith Marom, Jun Nakajima, Marcin Ostrowski, William D. Travis, Ming S. Tsao, Yasushi Yatabe, Dorothy J. Giroux, Ramón Rami-Porta

    Introduction To validate the prognostic relevance in NSCLC of potential residual tumor (R) descriptors, including the proposed International Association for the Study of Lung Cancer definition for uncertain resection –R(un). Methods 14,712 patients undergoing resection with full R status and survival were analyzed. The following were also evaluated: <3 N2 stations explored; lobe-specific nodal dissection (LSND); extra-capsular extension (ECE); highest lymph node station status; carcinoma in situ at bronchial resection margin (BRMcis); pleural lavage cytology (PLC). Revised categories of R0, R(un), R1 and R2 were tested for survival impact. Results 14,293 cases were R0, 263 R1 and 156 R2 (median survival: not reached, 33, 29 months, respectively). R status correlated with T and N categories. 9,290 (63%) cases had ≥3 N2 stations explored and 6,641 (45%) had LSND, correlated with increasing pN2. ECE was present in 62 (17%) of 364 cases with available data. The highest station was positive in 942 (6.4%). PLC was positive in 59 (3.5%) of 1,705 cases: 13 had BRMcis. After reassignment, due to inadequate nodal staging in 56%, 6,070 cases were R0, 8,185 R(un), 301 R1 and 156 R2. In node positive cases, median survival was 70, 50, 30 months for R0, R(un), (p<0.0001) and R1 (p<0.001), respectively, with no significant difference between R0 and R(un) in pN0 cases. Conclusions R descriptors have prognostic relevance with R(un) survival stratifying between R0 and R1. Therefore, a detailed evaluation of R factor is of particular importance in the design and analyses of clinical trials of adjuvant therapies.

    更新日期:2019-11-13
  • A Recurrence Predictive Model for Thymic Tumors and Its Implication for Postoperative Management: a Chinese Alliance for Research in Thymomas database study
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2019-11-11
    Hui Liu, ZhiTao Gu, Bo Qiu, Frank C. Detterbeck, Anja C. Roden, Enrico Ruffini, Meinoshin Okumura, Nicolas Girard, YangWei Xiang, Yuan Liu, ZhiCheng Du, YuanTao Hao, JianHua Fu, Peng Zhang, LieWen Pang, KeNeng Chen, Yun Wang, ZhenTao Yu, WenTao Fang

    Introduction To investigate appropriate postoperative management based on the risk of disease recurrences in thymic epithelial tumors after complete resection. Methods The Chinese Alliance for Research in Thymomas (ChART) retrospective database was reviewed. Patients having stage I-IIIa tumors without pretreatment and with complete resection were included. Clinico-pathological variables with statistical significance in the multivariate Cox regression were incorporated into a nomogram for building a recurrence predictive model. Results Nine-hundred-and-seven cases were retrieved, including 802 thymomas, 88 thymic carcinomas, and 17 neuroendocrine tumors between 1994 and 2012. With a median follow-up of 52 months, 10-year overall survival (OS) was 89.5%. Distant and/or loco-regional recurrences were noted in 53 (5.8%) patients. The nomogram model revealed histologic type and T stage as independent predictive factors for recurrence, with a bootstrap-corrected C-index of 0.86. Based on this model, patients with T1 thymomas or T2-3 Type A/AB/B1 thymomas had significantly lower incidence of recurrence (low-risk group) than those with T2-3 Type B2/B3 thymomas and all thymic carcinomas/neuroendocrine tumors (high-risk group, 2.7% vs. 20.1%, p<0.001). In the high-risk group, more than half of the recurrences (55.2%, 16/29) were seen within the first 3 post-operative years, while all but one recurrence were recorded within 6 years after surgery. Recurrence occurred quite evenly over 10 post-operative years in the low-risk group . Conclusions A 6-year active surveillance should be considered in high-risk patients regardless of adjuvant therapy. For low-risk patients, annual follow-up may be sufficient. Studies on post-operative adjuvant therapies would be plausible in high-risk patients.

    更新日期:2019-11-13
  • ALK Mutation Status Before and After Alectinib Treatment in Locally Advanced or Metastatic ALK-positive NSCLC: Pooled Analysis of Two Prospective Trials
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2019-11-09
    Johannes Noé, Alex Lovejoy, Sai-Hong Ignatius Ou, Stephanie J. Yaung, Walter Bordogna, Daniel M. Klass, Craig A. Cummings, Alice T. Shaw

    Background The effectiveness of ALK inhibitors can be limited by the development of ALK resistance mutations. This exploratory analysis assessed the efficacy of alectinib in patients with non-small-cell lung cancer (NSCLC) and ALK point mutations using pooled data from two single-arm phase II studies. Methods Studies NP28673 and NP28761 enrolled adults with locally advanced/metastatic ALK-positive NSCLC who had progressed on crizotinib. ALK mutation analysis was conducted on cell-free DNA (cfDNA) from 187 patients post-crizotinib/pre-alectinib, and from 49 of these patients who subsequently progressed on alectinib. Results Baseline characteristics were generally balanced across patient subgroups. At baseline, 34 distinct ALK mutations were identified in 48/187 patients (25.7%). Median investigator-assessed progression-free survival was longer in patients without ALK single-nucleotide variants (n = 138) versus those with (n = 48): 10.2 months (95% confidence interval [CI], 8.1–14.3) versus 5.6 months (95% CI, 4.5–10.9), respectively. Sixteen out of 32 patients (50%) with ALK resistance mutations to crizotinib achieved an investigator-assessed response to alectinib (all partial responses); most of these ALK mutations were known to be sensitive to alectinib. Analysis of plasma samples taken post-progression on alectinib revealed that 26/49 (53%) samples harbored 16 distinct ALK mutations, with known alectinib-resistance mutations, I1171 T/N/S, G1202R, and V1180L, observed in 15/49 (31%) tumors. Conclusion Alectinib appears clinically active against ALK rearrangements and mutations, as well as several ALK variants that can cause resistance to crizotinib. The use of cfDNA in plasma samples may be an alternative non-invasive method for monitoring resistance mutations during therapy.

    更新日期:2019-11-11
  • Salvage Therapy for Locoregional Recurrence After Stereotactic Ablative Radiotherapy for Early-Stage Non-Small Cell Lung Cancer
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2019-11-09
    Eric D. Brooks, Vivek Verma, Suresh Senan, Thierry De Baere, Shun Lu, Alessandro Brunelli, Joe Y. Chang

    Although isolated local (LRs) and regional recurrences (RRs) constitute a minority of post-stereotactic ablative radiotherapy (SABR) relapses, their management is becoming increasingly important as the use of SABR continues to expand. However, few evidence-based strategies are available to guide treatment of these potentially curable recurrences. On behalf of the Advanced Radiation Technology Committee (ART) of the International Association for the Study of Lung Cancer (IASLC), this article was written to address management of recurrent disease. Topics discussed include diagnosis and workup, including the roles of volumetric and functional imaging as well as histopathologic methods; clinical outcomes after salvage therapy; patterns of recurrence after salvage therapy; and management options. Our main conclusions are that survival for patients with adequately salvaged LRs is similar to that for patients after primary SABR without recurrence, and survival for those with salvaged RRs (regardless of nodal burden or location) is similar to that of patients with de novo stage III disease. Although more than half of patients who undergo salvage do not develop a second relapse, the predominant pattern of second failure is distant, especially for RRs. Management requires rigorous multidisciplinary coordination. Isolated LRs can be managed with resection and nodal dissection, repeat SABR, thermal ablation, or systemic therapies. RRs can be treated with combined chemoradiotherapy, radiation or chemotherapy alone, or supportive services. Finally, regular and structured follow-up is recommended after post-SABR salvage therapy.

    更新日期:2019-11-11
  • Efficacy of platinum/pemetrexed combination chemotherapy in ALK-positive non-small cell lung cancer refractory to second-generation ALK inhibitors
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2019-10-26
    Jessica J. Lin, Adam J. Schoenfeld, Viola W. Zhu, Beow Y. Yeap, Emily Chin, Marguerite Rooney, Andrew J. Plodkowski, Subba R. Digumarthy, Ibiayi Dagogo-Jack, Justin F. Gainor, Sai-Hong Ignatius Ou, Gregory J. Riely, Alice T. Shaw

    Background The current standard initial therapy for advanced ALK-positive non-small cell lung cancer (NSCLC) is a second-generation ALK tyrosine kinase inhibitor (TKI) such as alectinib. The optimal next-line therapy after failure of a second-generation ALK TKI remains to be established; however, standard options include the third generation ALK TKI lorlatinib or platinum/pemetrexed-based chemotherapy. The efficacy of platinum/pemetrexed-based chemotherapy has not been evaluated in patients refractory to second-generation TKIs. Methods This was a retrospective study performed at three institutions. Patients were eligible if they had advanced ALK-positive NSCLC refractory to ≥1 second-generation ALK TKI(s) and had received platinum/pemetrexed-based chemotherapy. Results Among 58 patients eligible for this study, 37 had scans evaluable for response with measurable disease at baseline. The confirmed objective response rate to platinum/pemetrexed-based chemotherapy was 29.7% (11/37; 95% CI, 15.9% to 47.0%), with median duration of response of 6.4 months (95% CI, 1.6 months to not reached). The median progression-free survival (PFS) for the entire cohort was 4.3 months (95% CI, 2.9 to 5.8 months). PFS was longer in patients who received platinum/pemetrexed in combination with an ALK TKI, compared to those who received platinum/pemetrexed alone (6.8 months vs 3.2 months, respectively; HR 0.33, p=0.025). Conclusions Platinum/pemetrexed-based chemotherapy shows modest efficacy in ALK-positive NSCLC after failure of second-generation ALK TKIs. The activity may be higher if administered with an ALK TKI, suggesting a potential role for continued ALK inhibition.

    更新日期:2019-10-27
  • Randomized Phase II Study of Paclitaxel plus Alisertib versus Paclitaxel plus Placebo as Second-Line Therapy for Small-Cell Lung Cancer: Primary and Correlative Biomarker Analyses
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2019-10-23
    Taofeek K. Owonikoko, Huifeng Niu, Kristiaan Nackaerts, Tibor Csoszi, Gyula Ostoros, Zsuzsanna Mark, Christina Baik, Anil Abraham Joy, Christos Chouaid, Jesus Corral Jaime, Vitezslav Kolek, Margarita Majem, Jaromir Roubec, Edgardo S. Santos, Anne C. Chiang, Giovanna Speranza, Chandra P. Belani, Alberto Chiappori, David R. Spigel

    Introduction We assessed the Aurora A kinase inhibitor, alisertib, plus paclitaxel as second-line treatment for small-cell lung cancer (SCLC). Methods In this double-blind study, patients with relapsed/refractory SCLC were stratified by relapse type (sensitive versus resistant/refractory) and brain metastases and randomized 1:1 to alisertib/paclitaxel or placebo/paclitaxel (28-day cycles). Primary endpoint was progression-free survival (PFS). Associations of c-Myc expression in tumor tissue (prespecified) and genetic alterations in circulating tumor DNA (retrospective) with clinical outcome were evaluated. Results 178 patients were enrolled (89 in each arm). Median PFS with alisertib/paclitaxel versus placebo/paclitaxel was 3.32 versus 2.17 months (hazard ratio [HR]: 0.77; 95% CI: 0.557–1.067; p = 0.113 in intent-to-treat population, and HR: 0.71; 95% CI: 0.509–0.985; p = 0.038 applying corrected analysis). Among 140 patients with genetic alternations, patients with cell cycle regulator mutations (CDK6/RBL1/ RBL2/RB1) had significantly improved PFS (3.68 versus 1.80 months, HR: 0.395; 95% CI: 0.239–0.654; p = 0.0003) and overall survival (7.20 versus 4.47 months, HR: 0.427; 95% CI: 0.259–0.704; p = 0.00085) with alisertib/paclitaxel versus placebo/paclitaxel. A subset of patients with c-Myc expression showed significantly improved PFS with alisertib/paclitaxel. Incidence of grade ≥3 drug-related adverse events was 67% (58 patients) with alisertib/paclitaxel versus 22% (25 patients) with placebo/paclitaxel. Twelve (14%) versus 11 (12%) patients died on-study, including 4 versus 0 treatment-related deaths. Conclusions Efficacy signals were seen with alisertib/paclitaxel in relapsed/refractory SCLC. c-Myc expression and mutations in cell cycle regulators may be potential predictive biomarkers of alisertib efficacy; further prospective validations are warranted.

    更新日期:2019-10-24
  • A novel algorithm to differentiate between multiple primary lung cancers and intrapulmonary metastasis in multiple lung cancers with multiple pulmonary sites of involvement
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2019-10-18
    Young Joo Suh, Hyun-Ju Lee, Pamela Sung, Heera Yoen, Sewoo Kim, Seungchul Han, Sungeun Park, Jung Hee Hong, Heekyung Kim, Jiyeon Lim, Hyungjin Kim, Soon Ho Yoon, Yoon Kyung Jeon, Young Tae Kim

    Introduction Differentiating between multiple primary lung cancer (MPLC) and intrapulmonary metastasis (IPM) is critical for developing a therapeutic strategy to treat multiple lung cancers with multiple pulmonary sites of involvement. Methods We retrospectively included 252 lesions (126 pairs) from 126 patients with surgically resected multiple lung adenocarcinomas. Each pair was classified as MPLC or IPM based on histopathologic findings as the reference standard. A novel algorithm was established with four sequential decision steps based on the combination of computed tomography (CT) lesion types (Step 1), CT lesion morphology (Step 2), difference of maximal standardized uptake values on positron-emission tomography/CT (Step 3), and presence of N2/3 lymph node metastasis or distant metastasis (Step 4). The diagnostic accuracy of the algorithm was analyzed. Performances of eleven observers were assessed without and with knowledge of algorithm. Results Among 126 pairs, 90 (71.4%) were classified as MPLCs and 36 (28.6%) as IPMs. On applying the diagnostic algorithm, the overall accuracy for diagnosis of IPM among conclusive cases up to step 4 was 88.9%, and 65 and 44 pairs were correctly diagnosed based on Step 1 and Step 2, respectively. Specificity and positive predictive value for diagnosis of IPM increased significantly in all observers compared with reading rounds without the algorithm. Conclusions Application of the algorithm based on comprehensive information on clinical and imaging variables can allow differentiation between MPLCs and IPMs. When both of two suspected malignant lesions appear as solid predominant lesions without spiculation nor air-bronchogram on CT, IPM should be considered.

    更新日期:2019-10-19
  • LKB1 deficiency renders non-small-cell lung cancer cells sensitive to ERK inhibitors.
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2019-10-18
    Elisa Caiola, Alice Iezzi, Michele Tomanelli, Elisa Bonaldi, Arianna Scagliotti, Marika Colombo, Federica Guffanti, Edoardo Micotti, Marina Chiara Garassino, Lucia Minoli, Eugenio Scanziani, Massimo Broggini, Mirko Marabese

    Background Liver kinase B1 (LKB1/STK11) is one of the most mutated genes in non-small-cell lung cancer (NSCLC) accounting for about one third of cases and its activity is impaired in about half of KRAS mutated NSCLC. At present, these patients cannot benefit from any specific therapy. Methods Through CRISPR/Cas9 technology, we systematically deleted LKB1 in both wild-type and KRAS-mutated human NSCLC cells. By using these isogenic systems together with genetically engineered mouse models we investigated the cell response to ERK inhibitors both in vitro and in vivo. Results In all the systems used here, the loss of LKB1 creates a vulnerability and renders these cells particularly sensitive to ERK inhibitors both in vitro and in vivo. The same cells expressing a wt LKB1 poorly respond to these drugs. At molecular level, ERK inhibitors induced, in the absence of LKB1, a marked inhibition of p90 ribosomal S6 kinase activation, which in turn abolished S6 protein activation, promoting the cytotoxic effect. Conclusions This work shows that ERK inhibitors are effective in LKB1 and LKB1/KRAS mutated tumors, thus offering a therapeutic strategy for this prognostically unfavorable subgroup of patients. Since ERK inhibitors are already in clinical development, our findings could be easily translatable to the clinic. Importantly, the lack of effect in cells expressing wild-type LKB1, predicts that treatment of LKB1 mutated tumors with ERK inhibitors should have a favorable toxicity profile.

    更新日期:2019-10-19
  • Ceritinib plus nivolumab in patients with advanced ALK-rearranged non-small-cell lung cancer: results of an open-label, multicenter, phase 1B study
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2019-10-18
    Enriqueta Felip, Filippo G. de Braud, Michela Maur, Herbert H. Loong, Alice Tsang Shaw, Johan F. Vansteenkiste, Thomas John, Geoffrey Liu, Martijn P. Lolkema, Giovanni Selvaggi, Vanessa Giannone, Pilar Cazorla, Jason Baum, O. Alejandro Balbin, Luojun (Victor) Wang, Yvonne Y. Lau, Jeffrey W. Scott, Daniel Shao-Weng Tan

    Introduction Induction of PD-L1 expression due to constitutive oncogenic signaling has been reported in NSCLC models harboring EML4–ALK rearrangements. We assessed safety and activity of ceritinib plus nivolumab in these patients. Methods In this open-label, phase 1B, multicenter, dose-escalation and expansion study, previously treated (ALK inhibitor [ALKi]/chemotherapy) or treatment-naïve patients with stage IIIB/IV ALK-rearranged NSCLC received nivolumab 3 mg/kg intravenously every 2 weeks plus ceritinib (450 mg/300 mg) daily with low-fat meal. Results In total, 36 patients were treated (450 mg cohort [n=14]; 300 mg cohort [n=22]). In the 450 mg cohort, four patients experienced DLTs. In the 300 mg cohort, two patients experienced DLTs. Among ALKi-naïve patients, the overall response rate (ORR) was 83% (95% CI 35.9–99.6) in the 450 mg cohort and 60% (95% CI 26.2–87.8) in the 300 mg cohort. Among ALKi-pretreated patients, the ORR was 50% (95% CI 15.7–84.3) in the 450 mg cohort and 25% (5.5–57.2) in the 300 mg cohort. The ORR point estimate was observed to be greater in patients who were positive for PD-L1 as compared to those who were negative for PD-L1 with overlapping CIs (e.g., at a cutoff ≥1% PD-L1, 64% [95% CI 35.1–87.2] patients had confirmed responses as compared to those with negative PD-L1 staining (31% [95% CI 11.0–58.7]). Most frequently reported grade 3/4 adverse events were increased alanine aminotransferase (ALT) (25%), increased gamma-glutamyl transferase (22%), increased amylase (14%), increased lipase (11%), and maculopapular rash (11%). Incidence of all grade rash (grouped term) was 64% in both cohorts; grade 3 rash was reported in 29% and 14% patients in the 450 mg and 300 mg cohorts, respectively; no grade 4 rash was reported. Conclusion Ceritinib plus nivolumab has activity; ORR appears to correlate with PD-L1 at baseline. Toxicity, especially rash, is more common than with either single agent.

    更新日期:2019-10-19
  • Nivolumab Monotherapy and Nivolumab Plus Ipilimumab in Recurrent Small Cell Lung Cancer: Results From the CheckMate 032 Randomized Cohort
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2019-10-17
    Neal E. Ready, Patrick A. Ott, Matthew D. Hellmann, Jon Zugazagoitia, Christine L. Hann, Filippo de Braud, Scott J. Antonia, Paolo A. Ascierto, Victor Moreno, Akin Atmaca, Stefania Salvagni, Matthew Taylor, Asim Amin, D. Ross Camidge, Leora Horn, Emiliano Calvo, Ang Li, Wen Hong Lin, David R. Spigel

    Introduction Nivolumab monotherapy is approved in the US for third-line or later metastatic SCLC based on pooled data from non-randomized and randomized cohorts of the multicenter, open-label, phase 1/2 trial of nivolumab ± ipilimumab (CheckMate 032; NCT01928394). We report updated results, including long-term overall survival (OS), from the randomized cohort. Methods Patients with SCLC and disease progression after 1–2 prior chemotherapy regimens were randomized 3:2 to nivolumab 3 mg/kg Q2W or nivolumab 1 mg/kg plus ipilimumab 3 mg/kg Q3W for four cycles followed by nivolumab 3 mg/kg Q2W. Patients were stratified by number of prior chemotherapy regimens and treated until disease progression or unacceptable toxicity. Primary endpoint was objective response rate (ORR) by blinded independent central review. Results Overall, 147 patients received nivolumab and 96 nivolumab plus ipilimumab. Minimum follow-up for ORR/PFS/safety was 11.9 months (nivolumab) and 11.2 months (nivolumab plus ipilimumab). ORR increased with nivolumab plus ipilimumab (21.9% versus 11.6% with nivolumab; odds ratio: 2.12 [95% CI: 1.06–4.26]; p=0.03). For long-term OS, minimum follow-up was 29.0 months (nivolumab) versus 28.4 months (nivolumab plus ipilimumab); median (95% CI) OS was 5.7 (3.8–7.6) versus 4.7 months (3.1–8.3). 24-month OS rates were 17.9% (nivolumab) and 16.9% (nivolumab plus ipilimumab). Grade 3–4 treatment-related adverse event rates were 12.9% (nivolumab) versus 37.5% (nivolumab plus ipilimumab), and treatment-related deaths 1 versus 3. Conclusion While ORR (primary endpoint) was higher with nivolumab plus ipilimumab versus nivolumab, OS was similar between groups. In each group, OS remained encouraging with long-term follow-up. Toxicities were more common with combination therapy versus nivolumab monotherapy.

    更新日期:2019-10-17
  • A Randomized, Double-Blind, Placebo-Controlled, Phase III Noninferiority Study of the Long-Term Safety and Efficacy of Darbepoetin alfa for Chemotherapy-Induced Anemia in Patients With Advanced Non-Small Cell Lung Cancer
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2019-10-16
    Pere Gascón, Rajnish Nagarkar, Martin Šmakal, Konstantinos N. Syrigos, Carlos H. Barrios, Jesús Cárdenas Sánchez, Li Zhang, David H. Henry, David Gordon, Vera Hirsh, Kaoru Kubota, Sergey Orlov, Gary Thomas, Tilman Steinmetz, Jin-Hyoung Kang, Dianne K. Tomita, Alexander N. Fleishman, Joseph K. Park, Cisio De Oliveira Brandao

    Introduction This study evaluated noninferiority of darbepoetin alfa versus placebo for overall survival (OS) and progression-free survival (PFS) in anemic patients with non-small cell lung cancer (NSCLC) treated to a 12.0-g/dL hemoglobin (Hb) ceiling. Methods Adults with stage IV NSCLC expected to receive ≥2 cycles of myelosuppressive chemotherapy and Hb≤11.0 g/dL were randomized 2:1 to blinded 500 μg darbepoetin alfa or placebo Q3W. The primary endpoint was OS; a stratified Cox proportional hazards model was used to evaluate noninferiority (upper confidence limit for hazard ratio [HR] ˂1.15). Secondary endpoints were PFS and incidence of transfusions or Hb≤8.0 g/dL from week 5 to end of the efficacy treatment period (EOETP). Results The primary analysis set included 2516 patients: 1680 randomized to darbepoetin alfa; 836 to placebo. The study was stopped early per independent Data Monitoring Committee recommendation after the primary endpoint was met with no new safety concerns. Darbepoetin alfa was noninferior to placebo for OS (stratified HR=0.92; 95%CI, 0.83‒1.01) and PFS (stratified HR=0.95; 95%CI, 0.87‒1.04). Darbepoetin alfa was superior to placebo for transfusion or Hb ≤8.0 g/dL from week 5 to EOETP (stratified OR=0.70; 95%CI, 0.57‒0.86; P<.001). Objective tumor response was similar between the arms (darbepoetin alfa, 36.4%; placebo, 32.6%). Incidence of serious adverse events (AEs) was 31.1% in both arms. No unexpected AEs were observed. Conclusions Darbepoetin alfa dosed to a 12.0-g/dL Hb ceiling was noninferior to placebo for OS and PFS and significantly reduced odds of transfusion or Hb≤8.0 g/dL in anemic patients with NSCLC receiving myelosuppressive chemotherapy.

    更新日期:2019-10-17
  • Profiling of circulating free DNA using targeted and genome wide sequencing in patients with Small Cell Lung Cancer
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2019-10-16
    Sumitra Mohan, Victoria Foy, Mahmood Ayub, Hui Sun Leong, Pieta Schofield, Sudhakar Sahoo, Tine Descamps, Bedirhan Kilerci, Nigel K. Smith, Mathew Carter, Lynsey Priest, Cong Zhou, T. Hedley Carr, Crispin Miller, Corinne Faivre-Finn, Fiona Blackhall, Dominic G. Rothwell, Caroline Dive, Ged Brady

    Introduction Small cell lung cancer (SCLC) accounts for ∼250,000 deaths worldwide each year. Acquisition of adequate tumour biopsies is challenging and liquid biopsies present an alternative option for patient stratification and response monitoring. Methods We applied whole genome next-generation sequencing (NGS) to circulating-free DNA (cfDNA) from 39 patients with limited-stage (LS-SCLC) and 30 of patients with extensive-stage (ES-SCLC) to establish genome wide copy number aberrations (CNA) as well as targeted mutation analysis of 110 SCLC associated genes. Quantitative metrics were calculated for CNA including Percent Genome Amplified (PGA; percentage of genomic regions amplified), Z-score (measure of standard deviation) and Moran’s I (measure of spatial autocorrelation). In addition CellSearch®, an epitope dependent enrichment platform was used to enumerate circulating tumour cells (CTCs) from a parallel blood sample. Results Genome-wide and targeted cfDNA sequencing data identified tumour related changes in 94% of patients with LS-SCLC and 100% of patients with ES-SCLC. Parallel analysis of CTCs based on ≥ 1 CTC/7.5ml blood increased tumour detection frequencies to 95% for LS-SCLC. Both CTC counts and cfDNA readouts correlated with disease stage and overall survival (OS). Conclusions We demonstrate that a simple cfDNA genome wide copy number approach provides an effective means of monitoring patients through treatment and show that targeted cfDNA sequencing identifies potential therapeutic targets in >50% of patients. We are now incorporating this approach in additional studies and trials of targeted therapies.

    更新日期:2019-10-17
  • Brief report: Three-year overall survival with durvalumab after chemoradiotherapy in Stage III NSCLC - Update from PACIFIC
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2019-10-14
    Jhanelle E. Gray, Augusto Villegas, Davey Daniel, David Vicente, Shuji Murakami, Rina Hui, Takayasu Kurata, Alberto Chiappori, Ki Hyeong Lee, Byoung Chul Cho, David Planchard, Luis Paz-Ares, Corinne Faivre-Finn, Johan F. Vansteenkiste, David R. Spigel, Catherine Wadsworth, Maria Taboada, Phillip A. Dennis, Scott J. Antonia

    Background In the phase 3 PACIFIC study of patients with unresectable, Stage III NSCLC without progression after chemoradiotherapy (CRT), durvalumab demonstrated significant improvements versus placebo in the primary endpoints of progression-free survival (HR, 0.52; 95% CI, 0.42–65; P<0.0001) and overall survival (OS; HR, 0.68; 95% CI, 0.53–0.87; P=0.00251) with manageable safety and no detrimental effect on patient-reported outcomes. Here, we report 3-year OS rates for all patients randomized in the PACIFIC study. Methods Patients, stratified by age, sex and smoking history, were randomized (2:1) to receive durvalumab 10 mg/kg intravenously every 2 weeks or placebo, up to 12 months. OS was analyzed using a stratified log-rank test in the ITT population. Medians and rates at 12, 24 and 36 months were estimated by Kaplan–Meier method. Results As of January 31, 2019, 48.2% of patients had died (44.1% and 56.5% in the durvalumab and placebo groups, respectively). Median duration of follow-up was 33.3 months. Updated OS remained consistent with that previously reported (stratified HR 0.69, 95% CI, 0.55–0.86); median OS not reached with durvalumab versus 29.1 months with placebo. The 12-, 24- and 36-month OS rates with durvalumab and placebo were 83.1% versus 74.6%, 66.3% versus 55.3%, and 57.0% versus 43.5%, respectively. All secondary outcomes examined showed improvements consistent with previous analyses. Conclusions Updated OS data from PACIFIC, including 3-year survival rates, demonstrate the long-term clinical benefit with durvalumab following CRT and further establish the PACIFIC regimen as the standard of care in this population.

    更新日期:2019-10-15
  • A Randomized-Controlled Phase 2 Study of the MET Antibody Emibetuzumab in Combination with Erlotinib as First-line Treatment for EGFR-mutation Positive NSCLC Patients
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2019-10-14
    Giorgio Scagliotti, Denis Moro-Sibilot, Jens Kollmeier, Adolfo Favaretto, Eun Kyung Cho, Heidrun Grosch, Martin Kimmich, Nicolas Girard, Chun-Ming Tsai, Te-Chun Hsia, Matteo Brighenti, Christian Schumann, Xuejing Aimee Wang, Sameera R. Wijayawardana, Aaron M. Gruver, Johan Wallin, Kambiz Mansouri, Volker Wacheck, Gee-Chen Chang

    Introduction The hepatocyte growth factor (HGF) receptor MET is reported to be a negative prognostic marker in EGFR-mutant NSCLC and involved in resistance to EGFR inhibitors. Emibetuzumab, a humanized IgG4 monoclonal bivalent MET antibody, blocks ligand dependent and independent HGF/MET signaling. This Phase 2 study compared erlotinib±emibetuzumab in first-line EGFR-mutant metastatic NSCLC. Methods Patients with Stage IV EGFR-mutant NSCLC and disease control following an 8-week lead-in with erlotinib (150 mg QD) were randomized to continue erlotinib with or without emibetuzumab (750 mg Q2W). The primary endpoint was progression-free survival (PFS). Additional endpoints included overall survival (OS), overall response rate, safety, pharmacokinetics, and exploratory analysis of MET expression. Results No difference in median PFS was observed in the intent-to-treat population (emibetuzumab+erlotinib 9.3 vs erlotinib 9.5 months; hazard ratio [HR] = 0.89; 90% confidence interval [CI]: 0.64-1.23). Median OS was 34.3 months for emibetuzumab+erlotinib and 25.4 months for erlotinib (HR = 0.74; 90% CI: 0.49-1.11). Emibetuzumab+erlotinib was well tolerated with peripheral edema and mucositis as the only adverse events occurring ≥10% more frequently relative to erlotinib. Exploratory post-hoc analysis showed an improvement of 15.3 months in median PFS for the 24 patients with highest MET expression (MET 3+ in ≥90% of tumor cells) (emibetuzumab+erlotinib 20.7 vs erlotinib 5.4 months; HR: 0.39; 90% CI: 0.17-0.91). Conclusions No statistically significant difference in PFS was noted in the intent-to-treat population. Exploratory analysis confirmed that high MET expression is a negative prognostic marker for patients treated with erlotinib, indicating that emibetuzumab+erlotinib may provide clinically meaningful benefit.

    更新日期:2019-10-15
  • Inhibiting pathways predicted from a steroid hormone gene signature yields synergistic anti-tumor effects in non-small cell lung cancer
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2019-10-10
    Abdulaziz A. Almotlak, Mariya Farooqui, Jill M. Siegfried

    Introduction Mounting evidence supports a role for estrogen signaling in non-small cell lung cancer (NSCLC) progression. We previously reported a 7-gene signature that predicts prognosis in estrogen receptor β positive (ERβ+) NSCLC. The signature defines a network comprised of ER and human epidermal growth factor receptor-2/3 (HER2/HER3) signaling. Methods We tested the efficacy of combining the pan-HER inhibitor, dacomitinib, with the estrogen antagonist, fulvestrant, in ERβ+ NSCLC models with differing genotypes. We assessed the potency of this combination on xenograft growth and survival of host mice, and the ability to reverse the gene signature associated with poor outcome. Results Synergy was observed between dacomitinib and fulvestrant in three human ERβ+ NSCLC models; 201T (Wild-type EGFR), A549 (KRAS mutant), and HCC827 (EGFR 19 deletion) with combination indices of 0.1-0.6. The combination, but not single agents, completely reversed the gene signature associated with poor prognosis in a mechanism that is largely mediated by AP-1 downregulation. In vivo, the combination also induced tumor regression and reversed the gene signature. In HCC827 xenografts treated with the combination, survival of mice was prolonged after therapy discontinuation, tumors that recurred were less aggressive, and two mechanisms of HER inhibitor resistance involving c-Met activation and PTEN loss were blocked. Conclusions The combination of an ER blocker and a pan-HER inhibitor provides synergistic efficacy in different models of ERβ+ NSCLC. Our data support the use of this combination clinically, considering its ability to induce potent antitumor effects and produce a gene signature that predicts better clinical outcomes.

    更新日期:2019-10-10
  • New Fissure-attached Nodules in Lung Cancer Screening: A Brief Report from The NELSON Study
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2019-10-10
    Daiwei Han, Marjolein A. Heuvelmans, Carlijn M. van der Aalst, Lisa H. van Smoorenburg, Monique D. Dorrius, Mieneke Rook, Kristiaan Nackaerts, Joan E. Walter, Harry J.M. Groen, Rozemarijn Vliegenthart, Harry J. de Koning, Matthijs Oudkerke

    Introduction In incidence lung cancer screening rounds, new pulmonary nodules are regular findings. They have a higher lung cancer probability than baseline nodules. Previous studies showed that baseline perifissural nodules (PFNs) represent benign lesions. Whether this is also the case for incident PFNs is unknown. This study evaluated newly detected nodules in the Dutch-Belgian randomized-controlled NELSON study with respect to incidence of fissure-attached nodules, their classification, and lung cancer probability. Method Within the NELSON trial, 7,557 participants underwent baseline screening between April 2004 and December 2006. Participants with new nodules detected after baseline were included. Nodules were classified based on location and attachment. Fissure-attached nodules were re-evaluated to be classified as typical, atypical or non-PFN by two radiologists without knowledge of participant lung cancer status. Result 1,484 new nodules were detected in 949 participants (77.4% male, median age 59 [interquartile range: 55-63]) in the second, third and final NELSON screening round. Based on 2-year follow-up or pathology, 1,393 nodules (93.8%) were benign. In total, 97 (6.5%) were fissure-attached, including 10 malignant nodules. None of the new fissure-attached malignant nodules was classified as a typical or atypical PFN. Conclusion In the NELSON study, 6.5% of incident lung nodules were fissure-attached. None of the lung cancers that originated from a new fissure-attached nodule in the incidence lung cancer screening rounds was classified as a typical or atypical PFN. Our results suggest that also in the case of a new PFN, it is highly unlikely that these PFNs will be diagnosed as lung cancer.

    更新日期:2019-10-10
  • A randomized double-blind phase II study of the Seneca Valley Virus (NTX-010) vs placebo for patients with extensive stage SCLC (ES-SCLC) who were stable or responding after at least 4 cycles of platinum-based chemotherapy: NCCTG (Alliance) N0923 Study
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2019-10-09
    Erin L. Schenk, Sumithra J. Mandrekar, Grace K. Dy, Marie Christine Aubry, Angelina D. Tan, Shaker R. Dakhil, Bradley A. Sachs, Jorge J. Nieva, Erin Bertino, Christine Lee Hann, Steven E. Schild, Troy W. Wadsworth, Alex A. Adjei, Julian R. Molina

    INTRODUCTION The Seneca Valley Virus (NTX-010) is an oncolytic picornavirus with tropism for small cell lung cancer (SCLC). This phase II double-blind, placebo controlled trial evaluated NTX-010 in patients with extensive stage (ES) SCLC after completion of first line chemotherapy. METHODS ES-SCLC patients who did not progress after ≥4 cycles of platinum-based chemotherapy were randomized 1:1 to a single dose of NTX-010 or placebo within 12 weeks of chemotherapy. Primary end point was progression free survival (PFS). A prespecified interim analysis for futility was performed after 40 events. Viral clearance and the development of neutralizing antibodies were followed. RESULTS From January 15, 2010 to January 10, 2013, 50 patients were randomized and received therapy on study (26 NTX-010, 24 placebo). At the specified interim analysis, median PFS was 1.7 months (95% confidence interval (CI) 1.4-3.1 months) for the NTX-010 group versus 1.7 months (95% CI 1.4-4.3 months) for placebo (hazard ratio (HR): 1.03, p = 0.92), and the trial was terminated due to futility. In the NTX-010 group, PFS was shorter in patients with detectable virus at days 7 and 14 versus not detected after treatment (1.0 month (95% CI 0.4-1.5 months) vs 1.8 months (95% CI 1.3-5.5 months; p=0.008); and 0.9 months (95% CI 0.4-2.6 months) vs 1.3 months (95% CI 1.0-5.3 months), p=0.04) respectively. CONCLUSIONS Patients with ES-SCLC did not benefit from NTX-010 treatment after chemotherapy with a platinum doublet. Persistence of NTX-010 in the blood 1 or 2 weeks after treatment was associated with a shorter PFS.

    更新日期:2019-10-10
  • Brief report : High MET overexpression does not predict the presence of MET exon 14 splice mutations in NSCLC : results from the IFCT Predict.amm study
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2019-10-09
    Simon Baldacci, Martin Figeac, Martine Antoine, Clotilde Descarpentries, Zoulika Kherrouche, Philippe Jamme, Marie-Christine Copin, David Tulasne, Isabelle Nanni, Michèle Beau-Faller, Samia Melaabi, Guénaëlle Levallet, Elisabeth Quoix, Denis Moro-Sibilot, Sylvie Friard, Pascale Missy, Fabrice Barlesi, Jacques Cadranel, Alexis B. Cortot

    Background MET exon 14 splice site (METex14) mutations were recently described in Non Small Cell Lung Cancer (NSCLC) and reported to correlate with efficacy of MET tyrosine kinase inhibitors. High diversity of these alterations make them hard to detect by DNA sequencing in clinical practice. Because METex14 mutations induce increased stabilization of the MET receptor, it is anticipated that these mutations are associated with MET overexpression. We aim to determine whether NSCLC with high MET overexpression could define a subset of patients with a high rate of METex14 mutations. Methods From the IFCT Predict.amm cohort of 843 consecutive patients with a treatment-naïve advanced NSCLC who were eligible for a first-line therapy, 108 NSCLC samples with high MET overexpression defined by an immunochemistry (IHC) score 3+ were tested for METex14 mutations using fragment length analysis combined with optimized targeted next generation sequencing (NGS). MET copy number analysis was also derived from the sequencing data. Results METex14 mutations were detected in two patients (2.2%) who also displayed a TP53 mutation and a PIK3CA mutation, respectively. A MET gene copy number increase was observed in 7 additional patients (7.7%). NGS analysis revealed inactivating mutations in TP53 (52.7%) and PTEN (1.1%) and oncogenic mutations in KRAS (28.6%), EGFR (7.7%), PIK3CA (4.4%), BRAF (4.4%), NRAS (2.2%), GNAS (1.1%) and IDH1 (1.1%). Conclusion The rate of METex14 mutations in NSCLC with high MET overexpression was similar to that found in unselected NSCLC. Moreover, we observed a high frequency of driver alterations in other oncogenes. Consequently these findings do not support the use of MET IHC as a surrogate marker for METex14 mutations.

    更新日期:2019-10-10
  • Brief Report: Programmed Cell Death Ligand 1 Expression in Untreated EGFR Mutated Advanced Non-Small Cell Lung Cancer and Response to Osimertinib versus Comparator in FLAURA
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2019-10-09
    Helen Brown, Johan Vansteenkiste, Kazuhiko Nakagawa, Manuel Cobo, Thomas John, Craig Barker, Alexander Kohlmann, Alexander Todd, Matilde Saggese, Juliann Chmielecki, Aleksandra Markovets, Marietta Scott, Suresh S. Ramalingam

    Introduction Epidermal growth factor receptor mutated (EGFRm) non-small cell lung cancer (NSCLC) tumors occasionally express programmed cell death ligand 1 (PD-L1), though frequency and clinical-relevance are not fully characterized. We report PD-L1 expression in patients with EGFRm advanced NSCLC and association with clinical outcomes following treatment with osimertinib or comparator EGFR tyrosine kinase inhibitors in the FLAURA trial (phase III, NCT02296125). Methods Of 231 tissue blocks available from the screened population (including EGFRm positive and negative samples), 197 had sufficient tissue for PD-L1 testing using the SP263 (Ventana) immunohistochemical assay. Tumor cell (TC) staining thresholds of PD-L1 TC≥1%, TC≥25% and TC≥50% were applied. Progression-free survival (PFS) was investigator-assessed, per RECIST 1.1, according to PD-L1 expressors (TC≥1%) or negatives (TC<1%) in randomized patients. Results PD-L1 staining was successful in 193/197 patient FFPE blocks; of these 128/193 were EGFRm positive and 106/128 patients were randomized to treatment (osimertinib: 54; comparator: 52). At PD-L1 TC≥25% threshold, 8% (10/128) of EGFRm positive tumors expressed PD-L1 versus 35% (23/65) of EGFRm negative tumors. With TC≥1% threshold, 51% (65/128) versus 68% (44/65) were mutation positive and negative respectively, and with the TC≥50% threshold, 5% (7/128) versus 28% (18/65), were mutation positive and negative, respectively. For PD-L1 expressors (TC≥1%), median PFS was 18.4 months with osimertinib and 6.9 months with comparator (HR 0.30 [95% CI: 0.15–0.60]). For PD-L1 negative patients (TC<1%), median PFS was 18.9 months with osimertinib and 10.9 months with comparator (HR 0.37 [95% CI: 0.17–0.74]). Conclusions Clinical benefit with osimertinib was unaffected by PD-L1 expression status.

    更新日期:2019-10-10
  • Quantitative assessment of CMTM6 in the tumor microenvironment and association with response to PD-1 pathway blockade in advanced-stage non-small-cell lung cancer
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2019-10-09
    Jon Zugazagoitia, Yuting Liu, Maria Toki, John McGuire, Fahad Shabbir Ahmed, Brian S. Henick, Richa Gupta, Scott Gettinger, Roy Herbst, Kurt A. Schalper, David L. Rimm

    Introduction CMTM6 has been described as a PD-L1 regulator at the protein level by modulating stability via ubiquitination. In this study, we describe the patterns of CMTM6 expression and assess its association with response to PD-1 pathway blockade in non-small-cell lung cancer (NSCLC). Methods We used multiplexed quantitative immunofluorescence to determine the expression of CMTM6 and PD-L1 in 438 NSCLCs represented in tissue microarrays, including two independent retrospective cohorts of immunotherapy treated (n = 69) and untreated (n = 258) patients, and a third collection of EGFR and KRAS genotyped tumors (n = 111). Results Tumor and stromal CMTM6 expression was detected in approximately 70 % of NSCLCs. CMTM6 expression was not associated with clinical features or EGFR/KRAS mutational status and showed a modest correlation with T-cell infiltration (R2 < 0.40). We found a significant correlation between CMTM6 and PD-L1, higher in the stroma (R2 = 0.51) than tumor cells (R2 = 0.35). In our retrospective NSCLC cohort, neither CMTM6 nor PD-L1 expression alone significantly predicted immunotherapy outcomes. However, high CMTM6 and PD-L1 co-expression in the stroma and CD68 compartments (adjusted HR 0.38, p = 0.03), but not in tumor cells (p = 0.15), was significantly associated with longer OS in treated patients, but not observed in the absence of immunotherapy. Conclusion This study supports the mechanistic role for CMTM6 in stabilization of PD-L1 in patient tumors and suggests that high co-expression of CMTM6 and PD-L1, particularly in stromal immune-cells (macrophages), might identify the greatest benefit from PD-1 axis blockade in NSCLC.

    更新日期:2019-10-10
  • Phase I Trial of Pembrolizumab and Radiation Therapy after Induction Chemotherapy for Extensive-Stage Small Cell Lung Cancer
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2019-10-09
    James W. Welsh, John V. Heymach, Dawei Chen, Vivek Verma, Taylor R. Cushman, Kenneth R. Hess, Girish Shroff, Chad Tang, Ferdinandos Skoulidis, Melenda Jeter, Hari Menon, Quynh-Nhu Nguyen, Joe Y. Chang, Mehmet Altan, Vassiliki A. Papadimitrakopoulou, George R. Simon, Uma Raju, Lauren Byers, Bonnie Glisson

    PURPOSE Radiation and immunotherapy have separately been shown to confer survival advantages to patients with extensive-stage small cell lung cancer (ES-SCLC), but failure rates remain high and combination therapy has been understudied. In this single-arm phase I trial (NCT02402920), we assessed the safety of combining pembrolizumab with thoracic radiation therapy (TRT) after induction chemotherapy for SCLC. METHODS ES-SCLC patients who had completed chemotherapy received TRT with pembrolizumab. The maximum tolerated dose of pembrolizumab was assessed by 3+3 dose-escalation; doses began at 100 mg and increased in 50 mg increments to 200 mg. Pembrolizumab was given every 3 weeks for up to 16 cycles; TRT was prescribed as 45 Gy in 15 daily fractions. Toxicity was evaluated with the Common Terminology Criteria for Adverse Events v4.0. The primary endpoint was safety of the combined therapy based on the incidence of dose-limiting toxicity (DLTs) in the 35 days following initiation of treatment. RESULTS Thirty-eight ES-SCLC patients (median age 65 years, range, 37–79) were enrolled from September 2015 through September 2017; 33 received per-protocol treatment, and all tolerated pembrolizumab at 100-200 mg with no DLTs in the 35-day window. There were no grade 4-5 toxicities; two (6%) experienced grade 3 events (n=1 rash, n=1 asthenia/paresthesia/autoimmune disorder) that were unlikely/doubtfully related to protocol therapy. The median follow-up time was 7.3 months (range 1–13); median progression-free and overall survival were 6.1 months (95% confidence interval [CI] 4.1–8.1) and 8.4 months (95% CI 6.7-10.1). CONCLUSIONS Concurrent pembrolizumab-TRT was tolerated well, with few high-grade adverse events in the short-term; progression-free and overall survival rates are difficult to interpret due to heterogeneity in eligibility criteria (e.g. enrolling progressors on induction chemotherapy). Although randomized studies have illustrated benefits to TRT alone and immunotherapy alone, the safety of the combined regimen supports further investigation as a foundational approach for future prospective studies.

    更新日期:2019-10-10
  • Brief Report: Calculating the Tumor Nuclei Content for Comprehensive Cancer Panel Testing
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2019-10-09
    Masashi Mikubo, Katsutoshi Seto, Atsuko Kitamura, Masato Nakaguro, Yukinori Hattori, Maeda Nagako, Tatsuhiko Miyazaki, Kazuko Watanabe, Hideki Murakami, Tetsuya Tsukamoto, Tetsuya Yamada, Shiro Fujita, Katsuhiro Masago, Shakti Ramkissoon, Jeffrey S. Ross, Julia Elvin, Yasushi Yatabe

    Comprehensive genetic panel (CGP) testing generally requires 20% or more percent tumor nuclei (%TN) of the analyzed tissues to achieve assay performance comparable to validated specifications. Pathologists play a crucial role in ensuring that the optimal results are achieved by accurately assigning %TN content of the available specimens and selecting the best material to submit for sequencing. This study addresses the issues in evaluating %TN, such as intra-observer variability, and examines whether focused training and feedback can improve the pathologist performance. Nine referring institution (RI) pathologists (all board-certificated, working at the Core Institute and the alignment hospitals under the National Cancer Genome scheme) evaluated 18 tumors, which had undergone CGP testing with the FoundationOne CDx assay. The %TN estimations by RI pathologists were compared with two standards: %TN assigned by the tumor sequencing institution’s (TSI) pathologist (a board-certified pathologist at Foundation Medicine Inc.), and the computational %TN estimated from the mutant allele frequencies after sequencing was completed. The pathologists generally overestimated %TN in the first pre-training round of the evaluation, and the differences in the averaged %TN from the TSI and computational standards were statistically significant. However, the pos-training second-round results became significantly concordant to the standards. This study suggests that %TN content is empirically overestimated but the evaluation skill can be improved by providing a training and feedback program from the testing facility on subsequent specimens.

    更新日期:2019-10-10
  • Outcomes for Surgery in Large Cell Lung Neuroendocrine Cancer
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2019-09-23
    Vignesh Raman, Oliver K. Jawitz, Chi-Fu J. Yang, Soraya L. Voigt, Betty C. Tong, Thomas A. D’Amico, David H. Harpole

    Background There are limited small, single-institution observational studies examining the role of surgery in large cell lung neuroendocrine cancer (LNEC). We investigated the outcomes of surgery for stage I-IIIA LCNEC using the National Cancer Database (NCDB). Methods Patients with stage I-IIIA LCNEC were identified in the NCDB (2004-2015), and grouped by treatment: definitive chemoradiation vs. surgery. Overall survival, by stage,was the primary outcome. Outcomes of surgery patients were also compared to those of patients with small or other non-small cell histotypes. Results A total of 6092 patients met criteria: 96%, 94%, 75%, and 62% of patients received surgery for stage I, II, IIIA, and cN2 disease, respectively. Complete resection was achieved in ≥ 85% of patients. Five-year survival for patients undergoing surgery for stage I and II LCNEC was 50% and 45%, respectively. Surgery patients with stage IIIA and N2 disease had 36% and 32% five-year survival. Surgery was associated with a survival benefit compared to stereotactic body radiation (SBRT) in stage I and chemoradiation in patients with stage II-IIIA disease. Patients with LCNEC undergoing surgery generally experienced worse survival, by stage, compared to those with adenocarcinoma but improved survival compared to small cell. Perioperative chemotherapy was associated with improved survival for pathologic stage II-IIIA disease. Conclusion Surgery is associated with reasonable outcomes for stage I-IIIA LCNEC, although survival is generally worse compared to adenocarcinoma. Surgery should be offered to medically fit patients with both early and locally advanced LCNEC, with guideline-concordant induction or adjuvant therapy.

    更新日期:2019-09-23
  • Exon-16-skipping HER2 as a novel mechanism of osimertinib-resistance in EGFR L858R/T790M-positive non-small-cell lung cancer
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2019-09-23
    Chia-Chi Hsu, Bin-Chi Liao, Wei-Yu Liao, Aleksandra Markovets, Daniel Stetson, Kenneth Thress, James Chih-Hsin Yang

    Background Osimertinib is the current recommended treatment for EGFR T790M-positive NSCLC following EGFR-TKI therapy. However, resistance to osimertinib therapy is inevitably acquired after a period of effective treatment. We had a patient suffering from EGFR L858R/T790M-positive NSCLC who initially responded to osimertinib therapy but eventually developed resistance. Plasma cell-free DNA analysis revealed the occurrence of exon-16-skipping HER2, which may resulted in the HER2 splice variant, HER2D16. HER2D16 has never been reported in lung cancer, and HER2D16-driven signaling was known to be regulated by Src-kinase in breast cancer. We investigated the role of HER2D16 as an osimertinib-resistant mechanism. Methods We constructed and established H1975 cells stably expressing HER2D16. The dimeric formation of HER2D16 was tested using non-reducing polyacrylamide gel electrophoresis (PAGE). The effects of drug on signaling transduction were examined using Western blot. The synergistic effect was assessed using Chou-Talalay method. Results We found HER2D16 can form homo-dimer in NSCLC cells. HER2D16-expressing H1975 cells were resistant to osimertinib treatment. We also found mutant EGFR and HER2D16 cooperated to activate downstream signaling for osimertinib-resistance. Besides, co-treatment with osimertinib and Src-kinase inhibitor failed to reverse resistance, indicating that HER2D16-driven signaling in NSCLC was not through canonical pathway. Finally, we revealed that the combination of osimertinib with the pan-HER small molecular inhibitor, afatinib, could synergistically repress cell growth and signaling in H1975-HER2D16 cells. Conclusion HER2D16 can contribute to osimertinib resistance through Src independent pathway. HER2D16 should be included in the molecular diagnosis panel for lung cancer.

    更新日期:2019-09-23
  • EURACAN/IASLC proposals for updating the histologic classification of pleural mesothelioma: towards a more multidisciplinary approach.
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2019-09-20
    Andrew G. Nicholson, Jennifer L. Sauter, Anna K. Nowak, Hedy L. Kindler, Ritu R. Gill, Martine Remy-Jardin, Samuel G. Armato, Lynnette Fernandez-Cuesta, Raphael Bueno, Nicolas Alcala, Matthieu Foll, Harvey Pass, Richard Attanoos, Paul Baas, Mary Beth Beasley, Luka Brcic, Kelly J. Butnor, Lucian R. Chirieac, Francoise Galateau-Salle

    Introduction Molecular and immunologic breakthroughs are transforming the management of thoracic cancer, although advances have not been as marked for malignant pleural mesothelioma (MPM) where pathologic diagnosis has been essentially limited to three histologic subtypes. Methods A multidisciplinary group (pathologists, molecular biologists, surgeons, radiologists and oncologists), sponsored by EURACAN/IASLC met in 2018, to critically review the current classification. Results Recommendations include: 1) classification should be updated to include architectural patterns, and stromal and cytologic features that refine prognostication 2) subject to data accrual, malignant mesothelioma in situ could be an additional category, 3) grading of epithelioid MPMs should be routinely undertaken, 4) favorable/unfavorable histologic characteristics should be routinely reported, 5) clinically relevant molecular data (PD-L1, BAP1, CDKN2A) should be incorporated into reports, if undertaken, 6) other molecular data should be accrued as part of future trials 7) resection specimens (i.e. extended pleurectomy/decortication and extrapleural pneumonectomy) should be pathologically staged with smaller specimens being clinically staged, 8) ideally, at least 3 separate areas should be sampled from the pleural cavity, including areas of interest identified on pre-surgical imaging, 9) image-acquisition protocols/imaging terminology should be standardized to aid research/refine clinical staging, 10) multidisciplinary tumor boards should include pathologists to ensure appropriate treatment options are considered, 11) all histologic subtypes should be considered potential candidates for chemotherapy, 12) patients with sarcomatoid or biphasic mesothelioma should not be excluded from first line clinical trials unless there is a compelling reason, 13) tumor subtyping should be further assessed in relation to duration of response to immunotherapy, 14) systematic screening of all patients for germline mutations is not recommended, in the absence of a family history suspicious for BAP1 syndrome. Conclusion These multidisciplinary recommendations for pathology classification and application will allow more informative pathologic reporting and potential risk stratification, to support clinical practice, research investigation and clinical trials.

    更新日期:2019-09-21
  • Impact of Specimen Characteristics on PD-L1 Testing in Non-Small Cell Lung Cancer: Validation of the IASLC PD-L1 Testing Guidelines
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2019-09-05
    Andréanne Gagné, Emily Wang, Nathalie Bastien, Michèle Orain, Patrice Desmeules, Sylvain Pagé, Sylvain Trahan, Christian Couture, David Joubert, Philippe Joubert

    Introduction Molecules targeting the Programmed Death Receptor-1 or its ligand (PD-L1) revolutionized the treatment of patients with non-small cell lung carcinoma (NSCLC). The only approved biomarker for predicting treatment response is the PD-L1 tumor proportion score (TPS) determined by immunohistochemistry. According to IASLC recommendations, specimens with fewer than 100 tumor cells or that are older than three years should not be used for PD-L1 testing and the reliability of cell blocks has yet to be validated. Methods This retrospective study included 1249 consecutive patients with NSCLC that were tested for PD-L1 (22C3) between September 2016 and April 2017. The associations between the presence of suboptimal characteristics (specimens with fewer than 100 tumor cells, older than three years, or cell blocks) and PD-L1 TPS were examined using a multinomial logistic regression. Results Specimens from 35.5% of patients had at least one suboptimal characteristic. For patients with a PD-L1 TPS of higher than 50%, there was a significantly higher probability that they had a specimen with more than 100 tumor cells (OR=1.97, p=0.008) and a more recent block (within 30 days versus more than three years, OR=2.46, p=0.023). There was no statistical difference in PD-L1 TPS between cell blocks and tissue specimens (biopsy OR=0.99, p=0.996, surgery OR=0.73, p=0.302). Conclusion Our results suggest that specimens containing fewer than 100 tumor cells or that are older than three years may lead to an underestimation of the PD-L1 status. Our findings also provide support for the use of cell blocks for PD-L1 testing, although further research is needed.

    更新日期:2019-09-06
  • Biologically Effective Dose in Stereotactic Body Radiotherapy and Survival for Patients with Early-Stage Non-Small Cell Lung Cancer
    J. Thorac. Oncol. (IF 12.460) Pub Date : 2019-08-31
    Amy C. Moreno, Bryan Fellman, Brian P. Hobbs, Zhongxing Liao, Daniel R. Gomez, Aileen Chen, Stephen M. Hahn, Joe Y. Chang, Steven H. Lin

    Purpose Stereotactic body radiotherapy (SBRT) results in excellent local control of stage I non-small cell lung cancer (NSCLC). Radiobiology models predict greater tumor response when higher biologically effective doses (BED10) are given. Prior studies support a BED10 ≥100 Gy with SBRT; however, data is limited comparing outcomes after various SBRT regimens. We therefore sought to evaluate national trends and the effect of using “low” versus “high” BED10 SBRT courses on overall survival (OS). Methods This retrospective study used the National Cancer Data Base to identify patients diagnosed with clinical stage I (cT1-2aN0M0) NSCLC from 2004 to 2014 treated with SBRT. Patients were categorized into LowBED (100-129 Gy) or HighBED (≥130 Gy) groups. A 1:1 matched analysis based on patient and tumor characteristics was used to compare OS by BED10 group. Tumor centrality was not assessed. Results Out of 25,039 patients treated with LowBED (n=14,756; 59%) or HighBED (n=10,283; 41%) SBRT, 20,542 were matched. Shifts in HighBED to LowBED SBRT regimen use correlated with key publications in the literature. In the matched cohort, 5-year OS rates were 26% for LowBED and 34% for HighBED groups (P=0.039). On multivariate analysis, receipt of LowBED was associated with significantly worse survival (hazard ratio 1.046, 95% confidence interval 1.004–1.090, P=0.032). Conclusions LowBED SBRT for treating stage I NSCLC is becoming more common. However, our findings suggest SBRT regimens with BED10 ≥130 Gy may confer an additional survival benefit. Additional studies are required to evaluate the dose-response relationship and toxicities associated with modern highBED SBRT.

    更新日期:2019-09-03
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