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  • Neighborhood Context and Non-Small Cell Lung Cancer Outcomes in Florida non-Elderly Patients by Race/Ethnicity
    Lung Cancer (IF 4.599) Pub Date : 2020-01-16
    Asal Johnson; Allen Johnson; Robert Hines; Raheleh Mohammadi

    Objective The purpose of this study was to investigate the relationship between neighborhood environment and lung cancer outcomes among Florida residents younger than 65 years of age. Methods and materials This was a retrospective cohort study that included patients diagnosed with non-small cell lung cancer (NSCLC) in Florida from January 2005 to December 2014 (n = 22,750). Multi-level, mixed-effect logistic regression models were used for two outcomes: receipt of treatment and receipt of surgery. Survival analyses, using proportional subdistribution hazard models, were conducted to examine the impact of neighborhood characteristics on risk of death due to lung cancer with adjustment for individual-level variables. Neighborhood exposures of interest were census tract level black and Hispanic segregation combined with economic deprivation. Results White patients who lived in low black segregation/high deprivation areas had 15% lower odds of receiving surgery (95% CI: 0.76-0.93). However, the likelihood of receiving surgery for black patients who lived in high black segregation/low deprivation and high black segregation/high deprivation was lower than for black patients who lived in low black segregation/low deprivation neighborhoods (level 3 AOR = 0.56 [0.38-0.85]; level 4 AOR = 0.69 [0.54-0.88]). Living in suburban and rural areas increased the risk of lung cancer death for white patients by 14% (95% CI: 1.05-1.24) and 26% (95% CI: 1.08-1.46), respectively. Living in rural areas increased the risk of death for black patients by 54% r (SHR = 1.54 [1.19-2.0]). Black patients who live in high Hispanic segregation/high deprivation had 36 % increased risk of death compared to black patients who lived in low Hispanic segregation/low deprivation areas. Conclusion This study suggests that when investigating cancer disparities, merely adjusting for race/ethnicity does not provide sufficient explanation to understand survival and treatment variations. Lung cancer outcomes are impacted by neighborhood environments that are formed based on the distribution of race, ethnicity and class.

  • Cost-effectiveness of Stereotactic Body Radiation Therapy versus Video Assisted Thoracic Surgery in medically operable stage I Non-Small Cell Lung Cancer: A modeling study
    Lung Cancer (IF 4.599) Pub Date : 2020-01-16
    Henri B. Wolff; Leonie Alberts; Naomi van der Linden; Mathilda L. Bongers; Naomi E. Verstegen; Frank J. Lagerwaard; Frederik N. Hofman; Carin A. Uyl-de Groot; Suresh Senan; Sherif Y. El Sharouni; Elisabeth A. Kastelijn; Franz M.N.H. Schramel; Veerle M.H. Coupé

    Objectives Stage I non-small cell lung cancer (NSCLC) can be treated with either Stereotactic Body Radiotherapy (SBRT) or Video Assisted Thoracic Surgery (VATS) resection. To support decision making, not only the impact on survival needs to be taken into account, but also on quality of life, costs and cost-effectiveness. Therefore, we performed a cost-effectiveness analysis comparing SBRT to VATS resection with respect to quality adjusted life years (QALY) lived and costs in operable stage I NSCLC. Materials and Methods Patient level and aggregate data from eight Dutch databases were used to estimate costs, health utilities, recurrence free and overall survival. Propensity score matching was used to minimize selection bias in these studies. A microsimulation model predicting lifetime outcomes after treatment in stage I NSCLC patients was used for the cost-effectiveness analysis. Model outcomes for the two treatments were overall survival, QALYs, and total costs. We used a Dutch health care perspective with 1.5% discounting for health effects, and 4% discounting for costs, using 2018 cost data. The impact of model parameter uncertainty was assessed with deterministic and probabilistic sensitivity analyses. Results Patients receiving either VATS resection or SBRT were estimated to live 5.81 and 5.86 discounted QALYs, respectively. Average discounted lifetime costs in the VATS group were €29,269 versus €21,175 for SBRT. Difference in 90-day excess mortality between SBRT and VATS resection was the main driver for the difference in QALYs. SBRT was dominant in at least 74% of the probabilistic simulations. Conclusion Using a microsimulation model to combine available evidence on survival, costs, and health utilities in a cost-effectiveness analysis for stage I NSCLC led to the conclusion that SBRT dominates VATS resection in the majority of simulations.

  • Is it necessary to sample the contralateral nodal stations by EBUS-TBNA in patients with lung cancer and clinical N0 / N1 on PET-CT?
    Lung Cancer (IF 4.599) Pub Date : 2020-01-13
    Pere Serra; Carmen Centeno; José Sanz-Santos; Mohamed Torky; Sonia Baeza; Leire Mendiluce; Carlos Martínez-Barenys; Pedro López de Castro; Jorge Abad; Antoni Rosell; Felipe Andreo

    Objectives Systematic mediastinal staging (sampling all visible nodes measuring ≥ 5 mm from N3 station to N1, regardless of PET/CT (positron emission tomography/computed tomography) by endobronchial ultrasound transbronchial needle aspiration (EBUS-TBNA) is a decisive step in patients with non-small cell lung cancer (NSCLC). We analyzed the prevalence of N3 disease and the utility of systematic staging in the subgroup of patients who underwent EBUS-TBNA staging without showing mediastinal lesions on the PET/CT (N0/N1) Material and methods We conducted a retrospective analysis of a prospectively collected database that included 174 patients with a final diagnosis of NSCLC, with N0/N1 disease on PET/CT who underwent a systematic EBUS-TBNA staging. Results 174 consecutive patients were included. Systematic EBUS-TBNA detected N2 mediastinal involvement in 21 (12%) cases, and no cases of N3 disease were detected (neither hilar nor mediastinal). Of the remaining 153 patients N0/N1 EBUS-TBNA, 122 underwent lung resection that revealed 4 cases of N2 disease while 117 were confirmed to be N0/N1. Thirty-three patients with N0/1 disease after EBUS-TBNA did not undergo surgery and were excluded for the NPV calculation. Sensitivity, specificity, negative predictive value (NPV), positive predictive value (PPV) and overall accuracy of systematic EBUS was 84%, 100%, 96.7%, 100% and 97% respectively. Conclusion Systematic EBUS-TBNA is a very accurate method for lymph node staging in patients with NSCLC without mediastinal involvement on PET/CT. Pending more studies, the absence of contralateral hilar nodal involvement in our series, questions the need for a contralateral hilar sampling in this subgroup of patients.

  • Mutations in genes connected with the TCF7L2 transcription factor are associated with a poor prognosis in Non-Small Cell Lung Cancer
    Lung Cancer (IF 4.599) Pub Date : 2020-01-13
    Shawn J. Rice; Xin Liu; Victoria Hyland; Zhenqiu Liu; Chandra P. Belani

    Objectives Precision medicine with molecular profiling has revolutionized the management of lung cancer leading to improved outcomes. Patients with actionable mutations receive targeted therapy. As next-generation sequencing (NGS) becomes standard in lung cancer clinics, we sought to use molecular information to identify novel pathways to target in order to improve survival for non-small cell lung cancer (NSCLC) patients. Materials and Methods This retrospective analysis included 183 lung cancer patients who received commercial NGS sequencing as part of their clinical care, as well as the lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC) dataset from the Cancer Genome Atlas (TCGA). We grouped mutations using a transcription factor enrichment analysis (TFEA), and the resulting TFEA groups were used to sort patients for survival analyses. Results Mutations connected to transcription factor 7 like 2/ Transcription Factor 4 (TCF7L2/TCF4) were associated with poor survival in NSCLC patients. Furthermore, Mutations in CCND1, IDH1, SMARC4, and TP53 are the primary contributors to a poor prognosis in these patients. This four gene panel was also found to be associated with a poor prognosis in the LUAD data of TCGA dataset. Conclusions We determined that the TCF7L2 pathway is associated with a poor prognosis in patients with lung adenocarcinoma. Therefore, targeting the TCF7L2 pathway may improve outcomes for this group of patients.

  • Patterns of care for patients with non-operable T1-4 N+ M0 non-small cell lung cancer in the US and outcomes with radiation or chemotherapy monotherapies
    Lung Cancer (IF 4.599) Pub Date : 2020-01-13
    Ellen Kim; Megan E. Daly; Kenneth Westover; Timur Mitin

    Background Standard management of non-operable N+ M0 non-small cell lung cancer (NSCLC) is concurrent chemoradiation (CRT). However, some patients receive radiation therapy (RTmono) or chemotherapy (CTmono) as monotherapies. This study investigated the patterns of care in the US and analyzed outcomes with monotherapies. Materials and Methods Patients in the National Cancer Database (NCDB) diagnosed in 2004-2013 with N+ M0 NSCLC who did not undergo surgery and received monotherapy with either high dose radiation alone (RTmono) or chemotherapy alone (CTmono) were studied. Patient characteristics and overall survival were compared with descriptive statistics (chi-square, Kruskal-Wallis, logistic regression), Kaplan-Meier and stratified Cox models, and restricted mean survival times (RMST); all used alpha of 0.05. Results 74,867 patients received CRT (10,915, 15%), CTmono (34,978, 47%), RTmono (2,396, 3%), or no aggressive treatment (26,578, 36%). In multivariable analysis, RTmono was associated with non-Medicare insurance, academic or research facility, Western geography, lower T and N stages, and older age. CTmono had better RMST compared to RTmono: at 3 years, average survival was 17.9 vs 16.1 months (difference 1.8, 95% CI 1.3-2.3); at 5 years, average survival was 21.6 vs 18.7 months (difference 2.9, 95% CI 2.2-3.6). In stratified Cox models, female gender, White race, private insurance, metropolitan location, lower Charlson comorbidity score, lower T/N stage, younger age, and later year of diagnosis had better survival. Conclusions Only 15% of non-operable N+ M0 NSCLC patients received definitive CRT. Future studies should focus on patients not receiving concurrent CRT, as outcomes with monotherapies (RTmono or CTmono) are suboptimal.

  • Investigation of Efficacy and Acquired Resistance for EGFR-TKI plus Bevacizumab as First-Line Treatment in Patients with EGFR Sensitive Mutant Non-Small Cell Lung Cancer in a Real World Population
    Lung Cancer (IF 4.599) Pub Date : 2020-01-13
    Liang Zeng; Lili Xiao; Wenjuan Jiang; Haiyan Yang; Dandan Hu; Chen Xia; Yizhi Li; Chunhua Zhou; Yi Xiong; Li Liu; Dehua Liao; Rui Guan; Kunyan Li; Jing Wang; Yongchang Zhang; Nong Yang; Aaron S. Mansfield

    Objectives We aimed to investigate the clinical efficacy of EGFR tyrosine kinase inhibitor (TKI, T) plus bevacizumab (an antiangiogenic therapy, A) in a real-world population and to provide insights into their mechanism of resistance. Methods This study included 256 NSCLC patients harboring EGFR sensitizing mutations (EGFR 19del and L858R) who underwent nextgeneration sequencing (NGS) with 168-gene panel prior to treatment between Jan 2015 to Aug 2018. Cohort A included 60 patients treated with A + T; while cohort B consisted of 120 patients treated with EGFR-TKI monotherapy with the patients identified using Propensity Score Matching (Ratio of 1:2). Clinical outcomes and potential resistance mechanism were evaluated. Results Baseline clinical characteristics were not significantly different between Cohort A and B. Compared with cohort B, cohort A had significantly better overall response rate (95% vs 74.2%, p = 0.001) and longer median progression-free survival (PFS, 16.5m vs.12.0 m, HR = 0.7, p = 0.001). Until Jan 2019, 31 and 103 patients in cohort A and B, respectively, were evaluated with progressive disease and underwent tissue re-biopsy and NGS profiling with 168-gene panel. In cohort B, T790M was the predominant acquired resistance mechanism, detected in 51.5% (53/103) of progressive tumors, followed by amplifications in EGFR (15.5%, 16/103) and MET (6.8%, 7/103). Contrastingly, cohort A had a significantly lower rate of T790 M mutation (35.5%, 11/31, p = 0.0003), followed by mutations in TP53 (29.0%, 9/31), RB1 (9.7%, 3/31), SMAD4 (3.2%, 1/31) and EGFR V834 L (3.2%, 1/31) and amplifications in EGFR (9.7%, 3/31), and MET(6.5%, 2/31). Conclusion Treatment with first-line A + T significantly extends the time to progression and increases the response rate with acceptable safety profile. T790 M was the most common acquired resistance mechanism but it was less common in patients who received A + T.

  • Cytology for PD-L1 testing: a systematic review
    Lung Cancer (IF 4.599) Pub Date : 2020-01-13
    John R. Gosney; Anne-Marie Boothman; Marianne Ratcliffe; Keith M. Kerr

    Evaluation of tumoral programmed cell death ligand-1 (PD-L1) expression is standard practice for patients with advanced non-small-cell lung cancer (NSCLC) who may be candidates for treatment targeting the programmed cell death-1 (PD-1)/PD-L1 pathway. Currently, all of the commercially available immunohistochemistry (IHC) assays have been validated for use with histology specimens although, in routine clinical practice, approximately 30–40% of patients with advanced NSCLC have only cytology specimens available for diagnosis, staging, and biomarker analysis. This systematic review evaluated the success rate, concordance, and clinical utility of using cytology specimens to assess tumor PD-L1 expression levels compared with histology specimens from patients with advanced NSCLC. EMBASE and PubMed database searches identified 142 unique, relevant publications, of which 15 met the inclusion criteria for at least one analysis. In 709 specimens, across seven publications, the proportion of cytology specimens evaluable for PD-L1 testing was 92.0%. Among nine studies eligible for concordance analysis between cytology and histology specimens at a PD-L1 tumor cell expression cutoff of ≥50%, overall percentage agreement was 89.7% (n = 428), 72.0% for positive percentage agreement (n = 218), and 95.0% for negative percentage agreement (n = 258); results using a tumor PD-L1 expression cutoff of ≥1% were similar. Our analyses suggest that using cytology specimens to assess PD-L1 expression is feasible, with good levels of concordance between cytology and histology specimens using PD-L1 tumor cell expression cutoffs of ≥1% and ≥50%. In conclusion, there is no convincing evidence that cytology specimens are inadequate or inferior to histology specimens for assessing PD-L1 expression in patients with NSCLC.

  • A systematic review of survival following anti-cancer treatment for small cell lung cancer
    Lung Cancer (IF 4.599) Pub Date : 2020-01-11
    Gavin S Jones; Kelly Elimian; David R Baldwin; Richard Hubbard; Tricia M McKeever

    Objectives We conducted a systematic review and meta-analysis of survival following treatment recommended by the European Society of Medical Oncology for SCLC in order to determine a benchmark for novel therapies to be compared with. Materials and Methods Randomized controlled trials and observational studies reporting overall survival following chemotherapy for SCLC were included. We calculated survival at 30 and 90-days along with 1-year, 2-year and median. Results We identified 160 for inclusion. There were minimal 30-day deaths. Survival was 99% (95%CI 98.0-99.0%, I233.9%, n = 77) and 90% (95%CI 89.0-92.0%, I279.5%, n = 73) at 90 days for limited (LD-SCLC) and extensive stage (ED-SCLC) respectively. The median survival for LD-SCLC was 18.1 months (95%CI 17.0-19.1%, I277.3%, n = 110) and early thoracic radiotherapy (thoracic radiotherapy 18.4 months (95%CI 17.3-19.5, I278.4%, n = 100)) vs no radiotherapy 11.7 months (95%CI 9.1-14.3, n = 10), prophylactic cranial irradiation (PCI 19.7 months vs No PCI 13.0 months (95%CI 18.5-21.0, I275.7%, n = 78 and 95%CI 10.5-16.6, I281.1%, n = 15 respectively)) and better performance status (PS0-1 22.5 months vs PS0-4 15.3 months (95%CI 18.7-26.1, I272.4%, n = 11 and 95%CI 11.5-19.1 I277.9%, n = 13)) augmented this. For ED-SCLC the median survival was 9.6 months (95%CI 8.9-10.3%, I295.2%, n = 103) and this improved when irinotecan + cisplatin was used, however studies that used this combination were mostly conducted in Asian populations where survival was better. Survival was not improved with the addition of thoracic radiotherapy or PCI. Survival for both stages of cancer was better in modern studies and Asian cohorts. It was poorer for studies administering carboplatin + etoposide but this regimen was used in studies that had fewer patient selection criteria. Conclusion Early thoracic radiotherapy and PCI should be offered to people with LD-SCLC in accordance with guideline recommendations. The benefit of the aforementioned therapies to treat ED-SCLC and the use of chemotherapy in people with poor PS is less clear.

  • Micropapillary pattern is associated with the development of brain metastases and the reduction of survival time in EGFR-mutation lung adenocarcinoma patients with surgery
    Lung Cancer (IF 4.599) Pub Date : 2020-01-10
    Changhui Li; Yinchen Shen; Fang Hu; Tianqing Chu; Xiaohua Yang; Jinchen Shao; Xiaoxuan Zheng; Jianlin Xu; Hai Zhang; Baohui Han; Hua Zhong; Xueyan Zhang

    Objective The role of micropapillary pattern (MIP) in EGFR-mutated NSCLC patients with brain metastases (BM) after complete surgical resection still remains unclear. Therefore, a retrospective study was conducted to evaluate the role of MIP in those patients. Methods This study included 332 stage I-III patients with EGFR-mutant lung adenocarcinoma and complete resection. Patients were classified in four groups: the MIP-positive patients without BM development, the MIP-negative patients without BM development, the MIP-positive patients with BM development and the MIP-negative patients with BM development. Intracranial disease-free survival (iDFS), systemic disease-free survival (DFS) and overall survival (OS) were evaluated. Results The median OS in the whole group was 70 months. The patients with MIP show inferior DFS (13 months vs. 22 months; P < 0.001) and OS (56 months vs. 74 months; P < 0.001). Furthermore, BM development was more likely to be found in patients with MIP (P = 0.001). In addition, the MIP-positive patients showed a significantly shorter iDFS compared with MIP-negative patients (14.5 months vs. 26 months; P < 0.001). Furthermore, the MIP-positive patients had significantly inferior iDFS in both BM as first line development groups (13 months vs. 19 months; P < 0.001) and BM as non-first line development groups (18 months vs. 33 months; P = 0.007). Conclusions MIP was related to the earlier recurrence and shortened survival time. In addition, MIP was an independent poor prognostic factor for the increase of BM rate and the shortened time of BM development after surgery.

  • Randomized phase II study of chemoradiotherapy with cisplatin + S-1 versus cisplatin + pemetrexed for locally advanced non-squamous non-small cell lung cancer: SPECTRA study
    Lung Cancer (IF 4.599) Pub Date : 2020-01-10
    Seiji Niho; Tatsuya Yoshida; Tetsuo Akimoto; Kentaro Sakamaki; Akira Ono; Takashi Seto; Makoto Nishio; Noboru Yamamoto; Toyoaki Hida; Hiroaki Okamoto; Takayasu Kurata; Miyako Satouchi; Koichi Goto; Takeharu Yamanaka; Yuichiro Ohe

    Objectives SPECTRA is a multicenter, randomized phase II study of chemotherapy with cisplatin (CDDP) plus S-1 versus CDDP plus pemetrexed (PEM) in combination with thoracic radiotherapy (TRT) for locally advanced non-squamous non-small cell lung cancer, in order to determine which of these two regimens might be preferable for comparison with standard therapies in a future phase III study. Materials and methods Patients were randomly assigned to receive CDDP + S-1 (CDDP 60 mg/m2 on day 1 and S-1 80 mg/m2 on days 1–14, every 4 weeks, up to 4 cycles) or CDDP + PEM (CDDP 75 mg/m2 + PEM 500 mg/m2 on day 1, every 3 weeks, up to 4 cycles) combined with TRT (60 Gy in 30 fractions). The primary endpoint was the 2-year progression-free survival (PFS) rate. The sample size had been set at 100 patients. Results A total of 102 patients were randomized to receive CDDP + S-1 or CDDP + PEM (CDDP + S-1, n = 52; CDDP + PEM, n = 50) between January 2013 and October 2016. The results in the CDDP + S1 group and CDDP + PEM group were as follows: completion rates of TRT (60 Gy)/chemotherapy (4 cycles) was 92 %/73 % and 98 %/86 %, respectively; the response rates were 60 % and 64 %, respectively; median PFS after a median follow-up of 32.1 months, 12.7/13.8 months (hazard ratio [HR] = 1.16; 95 % confidence interval [CI], 0.73–1.84); 2-year PFS rate, 36.5 % (95 % CI, 23.5–49.6)/32.1 % (95 %CI, 18.9–45.4); median OS, 48.3/59.1 months (HR = 1.05; 95 %CI, 0.58–1.90); 2-year OS rate, 69.2 % (95 %CI, 56.7–81.8)/66.4 % (95 %CI, 53.0–79.9); Grade 3 toxicities: febrile neutropenia (12 %/2 %), anorexia (8 %/16 %), diarrhea (8 %/0 %), esophagitis (6 %/8 %), and neutropenia (35 %/50 %); Grade 2 or worse radiation pneumonitis, 15 % (8 patients)/4 % (2 patients). Conclusion The 2-year PFS rate in the CDDP + S-1 arm was higher than that in the CDDP + PEM arm. Both treatments were safe, with manageable toxicities.

  • Cryobiopsy increases the EGFR detection rate in non-small cell lung cancer
    Lung Cancer (IF 4.599) Pub Date : 2020-01-07
    Maik Haentschel; Michael Boeckeler; Ahmed Ehab; Robert Wagner; Werner Spengler; Volker Steger; Hans Boesmueller; Marius Horger; Richard A. Lewis; Falko Fend; Lothar Kanz; Irina Bonzheim; Juergen Hetzel

    Objectives Detection of activating epidermal growth factor receptor (EGFR) mutation is crucial for individualized treatment of advanced non-small-cell lung cancer (NSCLC). However little is known about how biopsy technique affects the detection rate of EGFR mutations. This retrospective, single center study evaluated the detection rate of EGFR mutations in tissue obtained by bronchoscopic cryobiopsy and compared this to other standard tissue sampling techniques. Materials and Methods We retrospectively analyzed 414 patients with histologically confirmed NSCLC and known EGFR mutation status between 3/2008-7/2014. Tumor specimens obtained by tissue preserving bronchoscopic cryobiopsy were compared to those obtained by other techniques. Results and Conclusion Analysis of bronchoscopic cryobiopsy tissue detected 29 activating EGFR mutations in 27 (21.6%) out of 125 patients, while analysis of tissue obtained by non-cryobiopsy techniques (bronchoscopic forceps biopsies, fine needle aspiration, imaging guided transthoracical and surgical procedures) detected 42 EGFR mutations in 40 (13.8%) out of 298 patients (p < 0.05). Cryobiopsy increased detection rate of EGFR mutations in central tumors compared with forceps biopsy (19.6% versus 6.5%, p < 0.05), while an insignificant trend was detected also for peripheral tumors (33.3% versus 26.9%). Bronchosopic cryobiopsy increases the detection rate of activating EGFR mutations in NSCLC in comparison to other tissue sampling techniques. This will help to optimize individualized treatment of patients with advanced tumors. Because of the retrospective nature of this analysis, a prospective trial is mandatory for final assessment.

  • COPD and lung cancer incidence in the Women’s Health Initiative Observational Study: A brief report
    Lung Cancer (IF 4.599) Pub Date : 2020-01-07
    Misako Nagasaka; Amy Lehman; Rowan Chlebowski; Brittany M. Haynes; Gloria Ho; Manali Patel; Lori C. Sakoda; Ann G. Schwartz; Michael S. Simon; Michele L. Cote

    Objectives Lung cancer is the leading cause of cancer mortality in both men and women in the United States. COPD is associated with lung cancer independently of cigarette smoking, but remains understudied in women. Utilizing data from the Women’s Health Initiative Observational Study (WHI-OS), this report investigates the association between COPD and development of lung cancer, with a focus on ethnicity and cancer subtype. Materials and methods The WHI-OS, part of the larger Women’s Health Initiative (WHI), is comprised of postmenopausal women between ages 50 and 79 years old at enrollment. Self-administered questionnaires were utilized to gather baseline demographic, socioeconomic, and behavioral information from participants. For this analysis, COPD status was determined at study entry (baseline) and on annual survey (incident). Information on the primary outcome of interest, diagnosis of lung cancer, was also collected annually. Results and conclusion Of the 92,789 women examined, 1,536 developed lung cancer. Overall, women with COPD were 1.64 times more likely to develop lung cancer than those without COPD, after adjusting for smoking status and intensity, ethnicity, education, body mass index, and income (HR = 1.64, 95% CI: 1.43, 1.89). The relationship between COPD and lung cancer was not found to be significantly different between ethnic groups (p-value = 0.697). The associations between COPD and lung cancer was similar across subtypes (HR range 1.31-2.16), after adjusting for smoking status and intensity. COPD increases risk of lung cancer in women, thus they may benefit from more intensive surveillance compared to similar women without COPD.

  • Elucidation of the relationships of MET protein expression and gene copy number status with PD-L1 expression and the immune microenvironment in non-small cell lung cancer
    Lung Cancer (IF 4.599) Pub Date : 2020-01-07
    Katsuhiro Yoshimura; Yusuke Inoue; Kazuo Tsuchiya; Masato Karayama; Hidetaka Yamada; Yuji Iwashita; Akikazu Kawase; Masayuki Tanahashi; Hiroshi Ogawa; Naoki Inui; Kazuhito Funai; Kazuya Shinmura; Hiroshi Niwa; Takafumi Suda; Haruhiko Sugimura

    Objectives Alterations in the MET gene, such as mutations and high-level amplification, are important drivers of non-small cell lung cancer (NSCLC). The efficacy of immune checkpoint inhibitors (ICIs) in lung cancer with MET abnormalities is unclear. We evaluate the potential relationship between MET alterations and the tumor immune microenvironment and PD-1/PD-L1 axis. Material and Methods MET and phospho-MET protein expression were assessed in 622 resected NSCLC specimens. MET amplification was assessed by fluorescence in-situ hybridization in 272 tumors. PD-L1 expression was evaluated by immunohistochemistry. CD8+, Foxp3+, CD45RO, and PD-1+ tumor-infiltrating lymphocytes (TILs) in the tumor nest and surrounding stroma were profiled. Associations with MET alterations were explored. Results The cohort comprised 425 male patients (68.3%), 184 never-smokers (29.6%), and 408 adenocarcinoma (ADC) patients (65.6%). Median age was 68 years. MET alteration was observed mainly in ADCs (18.9% MET-positive, 3.9% phospho-MET-positive, and 15.1% with MET amplification). PD-L1 expression was significantly increased in MET-altered ADCs (P < 0.001 for MET; P = 0.002 for phospho-MET; P = 0.019 for MET amplification). Most TIL subset numbers in the tumor nest were significantly increased in MET-altered tumors. Only MET amplification was independently associated with tumoral CD8 + TILs. Three of the six patients responded to ICI treatment; two of them showed MET overexpression and an increase in MET copy number. Conclusion MET-altered tumors showed significantly stronger PD-L1 expression and more abundant tumoral TILs than non-MET-altered tumors. Among the MET alterations assessed, MET amplification was particularly implicated in the inflamed microenvironment, suggesting that MET-amplified tumors might respond to ICIs.

  • Predicting Risk of Chemotherapy-induced Severe Neutropenia: A Pooled Analysis in Individual Patients Data with Advanced Lung Cancer
    Lung Cancer (IF 4.599) Pub Date : 2020-01-03
    Xiaowen Cao; Apar Kishor Ganti; Thomas Stinchcombe; Melisa L. Wong; James C. Ho; Chen Shen; Yingzhou Liu; Jeffery Crawford; Herbert Pang; Xiaofei Wang

    Objectives Neutropenia is associated with the risk of life-threatening infections, chemotherapy dose reductions and delays that may compromise outcomes. This analysis was conducted to develop a prediction model for chemotherapy-induced severe neutropenia in lung cancer. Materials and Methods Individual patient data from existing cooperative group phase II/III trials of stages III/IV non-small cell lung cancer or extensive small-cell lung cancer were included. The data were split into training and testing sets. In order to enhance the prediction accuracy and the reliability of the prediction model, lasso method was used for both variable selection and regularization on the training set. The selected variables was fit to a logistic model to obtain regression coefficients. The performance of the final prediction model was evaluated by the area under the ROC curve in both training and testing sets. Results The dataset was randomly separated into training [7606 (67%) patients] and testing [3746 (33%) patients] sets. The final model included: age (>65 years), gender (male), weight (kg), BMI, insurance status (yes/unknown), stage (IIIB/IV/ESSCLC), number of metastatic sites (1, 2 or ≥3), individual drugs (gemcitabine, taxanes), number of chemotherapy agents (2 or ≥3), planned use of growth factors, associated radiation therapy, previous therapy (chemotherapy, radiation, surgery), duration of planned treatment, pleural effusion (yes/unknown), performance status (1, ≥2) and presence of symptoms (yes/unknown). Conclusions We have developed a relatively simple model with routinely available pre-treatment variables, to predict for neutropenia. This model should be independently validated prospectively.

  • Radiosurgery and Fractionated Stereotactic Radiotherapy in Oligometastatic/Oligoprogressive Non-small Cell Lung Cancer patients: results of a multi-institutional series of 198 patients treated with “curative” intent
    Lung Cancer (IF 4.599) Pub Date : 2020-01-03
    Michela Buglione; Barbara Alicja Jereczek-Fossa; Marco Lorenzo Bonù; Davide Franceschini; Andrei Fodor; Isa Bossi Zanetti; Marianna Alessandra Gerardi; Paolo Borghetti; Davide Tomasini; Nadia Gisella Di Muzio; Olga Oneta; Marta Scorsetti; Ciro Franzese; Paola Romanelli; Giampiero Catalano; Italo Dell'Oca; Giancarlo Beltramo; Giovanni Battista Ivaldi; Paolo Antognoni

    Objectives stereotactic radiosurgery (SRS) and fractionated stereotactic radiotherapy (FSRT) are a therapeutic option for Oligometastatic/Oligoprogressive (OM/OP) NSCLC. This retrospective multicentre analysis aims to analyse clinical outcomes and treatment related toxicity of patients treated to all sites of know disease with SRS and/or FSRT for OM/OP NSCLC in 8 Italian radiation oncology centres. Materials and methods From January 2016 to January 2017 198 OM/OP NSCLC patients (pts) were treated in 8 Centres. Inclusion criteria were as follows: 1- 5 lesions at onset or after previous systemic treatment; Pts must have all metastatic lesions treated. Endpoints analysed were local progression free survival (LPFS); out-of-field recurrence free survival (OFPS); progression free survival (PFS); overall survival (OS). Time to New systemic Therapy free survival (TNT) and toxicity were also analysed. Results At the time of radiotherapy, 119 pts (60%) were treated for a single lesion, 49 (25%) for 2 lesions, 30 (15%) for 3 to 5 metastases. Total number of lesions treated was 333: 204 brain, 68 lung, 24 bone, 16 nodal, 12 adrenal, 8 liver and 1 soft tissue. 83/198 pts (41.8%) had the primary tumour controlled at the time of the SRT. After a median follow-up of 18 months, median OS and PFS were 29.6 months and 10.6 months, respectively. One year LPFS and OPFS were 90% and 47%, respectively. Median TNT was 10 months. At univariate analysis factors associated with better OS were PS 0-1; controlled primary tumour, 1-2 lesions; extracranial metastasis. Multivariate analysis confirmed number of lesions <3 and extracranial metastasis to be related with better survival (Relative Risk 0.4 and 0.41, respectively). Two cases of death possibly related to brain radionecrosis were observed. Conclusion OM/OP NSCLC pts treated with an ablative SRT to all metastatic sites have fair outcomes with acceptable toxicity. Better results might be achieved in case of low disease burden and extracranial possibly when primary tumour is controlled.

  • A phase II trial of single oral FGF inhibitor, AZD4547, as second or third line therapy in malignant pleural mesothelioma
    Lung Cancer (IF 4.599) Pub Date : 2019-12-31
    Wei-Sen Lam; Jenette Creaney; Fred K. Chen; Wee Loong Chin; Sanjeevan Muruganandan; Sukanya Arunachalam; Mary S. Attia; Catherine Read; Kevin Murray; Michael Millward; Jon Spiro; Aron Chakera; Y.C. Gary Lee; Anna K. Nowak

    Objectives Currently, there is no optimal salvage therapy for patients with malignant pleural mesothelioma (MPM) who relapse after treatment with first-line chemotherapy. In line with the strong preclinical rationale for targeting fibroblast growth factor receptor (FGFR) signalling in malignant mesothelioma, we conducted a phase II study assessing the efficacy of AZD4547, an oral tyrosine multi-kinase FGFR 1-3 inhibitor, as a second or third-line treatment. Materials and Methods We conducted a single-center, open-label, single-arm phase II study of AZD4547 in eligible patients with confirmed, measurable MPM and radiological progression after first or second-line systemic chemotherapy. Patients received continuous, twice-daily oral AZD4547 on a 3-weekly cycle. The primary end point was 6-month progression free survival (PFS6). Response was assessed with CT scan every 6 weeks according to the modified RECIST criteria for mesothelioma (mRECIST) and toxicities were also assessed. The study used a Simon’s two-stage design: 26 patients would be recruited to the first stage and more than 7 (27%) of 26 patients were required to achieve PFS6 to continue to stage two, for a potential total cohort of 55 patients. Results 3 of 24 patients (12%) were progression-free at 6 months. Hence, the study fulfilled stopping criteria regardless of further recruitment and warranted discontinuation. The most common toxicities (across all grades) were hyperphosphatemia, xerostomia, mucositis, retinopathy, dysgeusia, and fatigue. Maximum toxicities were grade 2 or below for all patients across all cycles. There was no association between tumour BAP1 protein loss and clinical outcomes. Conclusions The FGFR 1-3 inhibitor AZD4547 did not demonstrate efficacy in patients with MPM who had progressed after first line treatment with platinum-based chemotherapy.

  • Immunotherapy rechallenge after nivolumab treatment in advanced non-small cell lung cancer in the real-world setting: A national data base analysis
    Lung Cancer (IF 4.599) Pub Date : 2019-12-31
    Matteo Giaj Levra; François-Emery Cotte; Romain Corre; Christophe Calvet; Anne-Françoise Gaudin; John R. Penrod; Valentine Grumberg; Baptiste Jouaneton; Ronan Jolivel; Jean-Baptiste Assie; Christos Chouaïd

    Objectives Nivolumab is now a reference treatment for patients with advanced non-small cell lung cancer (NSCLC) after failure of prior platinum-based chemotherapy. Little data are available on treatment approaches following discontinuation of nivolumab and on the interest of a second course of immunotherapy after nivolumab discontinuation. The aims of this study were to describe treatment pathways following nivolumab discontinuation and to describe survival following retreatment with immunotherapy. Materials and methods The analysis includes all patients with NSCLC recorded in a national hospital database, starting nivolumab in 2015-2016. Nivolumab treatment was considered discontinued if ≥3 infusions were missed. Patients starting a second course of PD-1 inhibitor following nivolumab discontinuation were analysed according to the duration of their initial nivolumab treatment course. Results 10,452 patients were included (71% men; mean age: 63.8 ± 9.6 years; squamous histology: 44%). Median nivolumab treatment duration was 2.8 months [IQR :1.4 – 6.9]. Median OS was 11.5 months [95%CI: 11.1-11.9]; 5118 (53.4%) patients received post nivolumab therapy lines: 1517 (29.6%) of these received a second course of PD-1 inhibitor, either after a therapeutic break (resumption: n = 1127) or after intervening chemotherapy (rechallenge: n = 390). Median OS after nivolumab discontinuation was 15.0 months [13.9-16.7] in the resumption group and 18.4 months [14.8-21.9] in the rechallenge group. Median OS was significantly longer in patients with an initial nivolumab treatment duration ≥3 months. Conclusion In this real-world setting, outcome after retreatment with a PD-1 inhibitor following a first course of nivolumab was significantly better in patients with a longer duration of initial nivolumab treatment.

  • Clearing of circulating tumour DNA predicts clinical response to first line tyrosine kinase inhibitors in advanced epidermal growth factor receptor mutated non-small cell lung cancer
    Lung Cancer (IF 4.599) Pub Date : 2019-12-30
    Eva Boysen Fynboe Ebert; Tine McCulloch; Karin Holmskov Hansen; Hanne Linnet; Boe Sorensen; Peter Meldgaard
  • Effects of checkpoint inhibitors in advanced non-small cell lung cancer at population level from the National Immunotherapy Registry
    Lung Cancer (IF 4.599) Pub Date : 2019-12-28
    H.J.M. Smit; J. Aerts; M. van den Heuvel; T.J.N. Hiltermann; I. Bahce; E.F. Smit; A-M.C. Dingemans; L.E. Hendriks; J.A. Stigt; F.M.N.H. Schramel; H. van Tinteren; H.J.M. Groen

    Objective Phase III studies of checkpoint inhibitors changed the therapeutic landscape for lung cancer. In 2015 the Dutch Society of Chest Physicians (NVALT) introduced a national immunotherapy registry for patients with lung cancer; quality standards for hospitals were implemented. At population level we studied clinical benefit in daily practice and in patients who are underrepresented in phase III trials. Materials and Methods From the initial introduction of checkpoint inhibitors in the Netherlands patients were centrally registered. Educational programs and quality control were provided under supervision of NVALT. The largest immunotherapy providing hospitals were compared to hospitals who provided less checkpoint inhibitors as marker of experience. Patients characteristics, treatment and side effects, response rate and survival were studied. Results A total of 2676 patients were registered, 2302 with follow up data were evaluated. Between October 2015 and December 2017 a gradual increase from 12 to 30 qualified hospitals showed no major toxicity differences. Toxicity led to a hospital admission rate of 9.1 with an average duration of 10.4 days. Overall tumor response was 21.8 % and median overall survival 12.6 months. Overall survival was not significantly different for patients aged ≥ 75 years, those having brain metastases or selected auto-immune diseases before start checkpoint inhibitors compared to younger patients or those without, respectively. Survival outcomes were worse in patients with PS 2+, non-smokers, and patients who received any palliative radiotherapy (HR 2.1, 95% CI 1.7-2.7; 1.3, 95% CI 1.0-1.6 and 1.2, 95% CI 1.1-1.4, respectively). Conclusions Changes in the therapeutic landscape did not lead to major differences in quality of care between hospitals. Elderly patients, those with brain metastases or selected auto-immune disease underrepresented in clinical trials did not do worse on checkpoint inhibitors, except for those with PS 2 + .

  • Osimertinib treatment for patients with EGFR exon 20 mutation positive non-small cell lung cancer
    Lung Cancer (IF 4.599) Pub Date : 2019-12-20
    B. van Veggel; J.F. Vilacha Madeira R Santos; S.M.S. Hashemi; M.S. Paats; K. Monkhorst; D.A.M. Heideman; M. Groves; T. Radonic; E.F. Smit; E. Schuuring; A.J. van der Wekken; A.J. de Langen

    Objectives Epidermal growth factor receptor (EGFR) exon 20 insertions comprise 4-10% of EGFR mutations in non-small cell lung cancer (NSCLC) and are associated with primary resistance to first and second generation EGFR tyrosine kinase inhibitors (TKIs). In vitro and preclinical animal studies have shown that osimertinib exerts antitumor activity against EGFR exon 20 mutation positive NSCLC. We report on a cohort of advanced stage NSCLC patients who harbor an EGFR exon 20 mutation and received osimertinib treatment. Material and methods Twenty-one patients were treated with osimertinib 80 or 160 mg once daily from April 2016 to June 2018, in four institutions in the Netherlands. Data were obtained retrospectively. Progression free survival (PFS), disease control rate (DCR), overall survival (OS) and objective response rate (ORR) were assessed using RECIST v1.1. Results Thirteen patients received prior platinum-based chemotherapy, and three patients a first – or second generation EGFR TKI. We observed 1 partial response, 17 patients with stable disease and 3 with progressive disease as best response to osimertinib (ORR 5%). Median PFS was 3.6 (95% CI, 2.6 – 4.5) months. PFS did not differ for patients with co-occurring TP53 mutations (p = 0.937). The DCR at three months was 71%. Median OS was 8.7 (95% CI, 1.1 – 16.4) months. Conclusion Osimertinib has limited antitumor activity in patients with EGFR exon 20 mutated NSCLC, with an ORR of 5%.

  • Immune-related adverse events correlate with clinical outcomes in NSCLC patients treated with Nivolumab: the Italian NSCLC expanded access program
    Lung Cancer (IF 4.599) Pub Date : 2019-12-20
    Editta Baldini; Alice Lunghi; Enrico Cortesi; Daniele Turci; Diego Signorelli; Valeria Stati; Barbara Melotti; Biagio Ricciuti; Antonio Frassoldati; Giampiero Romano; Giovanni Luca Ceresoli; Alfonso Illiano; Francesco Verderame; Gianpiero Fasola; Enrico Ricevuto; Paolo Marchetti; Carmine Pinto; Giacomo Cartenì; Diana Giannarelli

    Objectives The incidence of any and of severe-grade immune-related adverse events (irAEs) with second-line nivolumab monotherapy is 31-65% and 2-5% respectively. While potentially serious and even fatal, in the absence of an appropriate therapy, such events might be indicators of the activation of the immune system and, potentially, of efficacy. Materials and Methods We collected the records of 1,959 non-small-cell lung cancer (NSCLC) patients treated with nivolumab in the Italian expanded access program, and we registered the appearance of any and of severe grade irAEs. We retrospectively searched for correlations between toxicity and efficacy parameters by using Cox's regression analysis. Results Overall, 342 (17.8%) patients developed an irAE of any grade. We observed that patients developing irAE of any grade achieved a significantly higher response rate (RR 27.2% vs 15.2%; p < 0.0001), disease control rate (DCR 60.5% vs 40.2%; p < 0.0001), median progression-free survival (mPFS 6.0 months [95% CI 4.9-7.1] vs 3.0 [95% CI: 2.8-3.2], p < 0.0001) and median overall survival (mOS 16.7 months [95% CI: 13.5-19.9] vs 9.4 [95% CI: 8.4-10.4], p < 0.00001) compared to patients who did not. At multivariate analysis the development of an irAE remained an independent indicator of nivolumab efficacy (HR 1.44 [95% CI: 1.22-1.71] p < 0.0001). Conclusions This report, performed in Caucasian NSCLC patients, showed that the appearance of irAEs correlated with outcome.

  • Percutaneous CT-guided biopsy of lytic bone lesions in patients clinically suspected of lung cancer: diagnostic performances for pathological diagnosis and molecular testing
    Lung Cancer (IF 4.599) Pub Date : 2019-12-19
    Anne-Claire Toffart; Stéphane Asfari; Anne Mc Leer; Emilie Reymond; Adrien Jankowski; Denis Moro-Sibilot; Olivier Stephanov; Julien Ghelfi; Sylvie Lantuejoul; Gilbert R. Ferretti

    Objectives Bone is a common location for lung cancer metastasis. Clinicians are often reluctant to biopsy bone metastases, as they are known to require a decalcification process that damages nucleic acids, which makes it incompatible with molecular testing. We performed this study to assess the diagnostic performance of histopathology and molecular testing of computed tomography (CT)-guided percutaneous bone biopsies of lytic bone lesions during the initial assessment or during the progression of lung cancer. Materials and methods This retrospective study included all patients suspected of having or known to have primary lung cancer and CT-guided percutaneous bone biopsies of lytic bone from January 2010 to June 2017. The main judgment criterion was the diagnostic performance of the pathological analysis. Secondary endpoints were the diagnostic performance of molecular testing and incidence of complications. Results Fifty patients were included. The yield of CT-guided percutaneous bone biopsies for pathological analysis was 100%, allowing for a diagnosis of certainty in all cases. The percentage of tumor cells in samples was higher than the 20% threshold in 83.9% of cases. The yield of molecular analysis was 94.6%. A mutation was found in 60% of cases; most frequently in KRAS (Kirsten rat sarcoma viral oncogene homolog) (28.6%) and EGFR (epidermal growth factor receptor) (14.3%). The complication rate was 2%, i.e. a minor undrained pneumothorax. Conclusion CT-guided percutaneous biopsies of lytic bone is associated with a very low complication rate and high diagnostic performance for histopathology and mutation testing.

  • Timing in Combination with Radiotherapy and Patterns of Disease Progression in Non-small Cell Lung Cancer Treated with EGFR-TKI
    Lung Cancer (IF 4.599) Pub Date : 2019-12-18
    Yi Tang; Bing Xia; Xiao Xu; Minna Zhang; Kan Wu; Bing Wang; Shenglin Ma

    Objectives Tyrosine kinase inhibitor (TKI) has been the standard of care for advanced non-small cell lung cancers (NSCLC) harboring epidermal growth factor receptor (EGFR) mutation, but these tumors invariably develop drug resistance. As progression most frequently advances in sites of original disease, our study sought to explore the time to response for NSCLC to TKI therapy and the patterns of disease progression, to provide evidence for timing and candidates for local therapy intervention. Materials and Methods A cohort of 105 EGFR-mutated IIIB or IV NSCLC patients treated with EGFR-TKI were retrospectively analyzed. The disease progression patterns were divided into 3 categories: progression in sites of original disease, progression in new distant sites, and combined progression. Results Before cut-off date, 80 patients had disease progression. Thirty-three (41.25%) patients had progression in sites of original disease, 34 (42.5%) patients had progression in new sites and 13 (16.25%) patients had combined progression, respectively. The median time to response for responders was 2.00 months (95%CI 1.28-2.92 months), and the median time to maximal tumor shrinkage for SD patients was 2.00 months (95%CI 1.42-2.58 months). Multivariate logistic regression model showed that the 21 exon mutation is related to the incidence of original site failure. Conclusion Over 1/3 of the patients progress at the original sites, which indicated that this subset of patients may benefit from local therapy. Moreover, as the results indicate that considerable shrinkage for TKI therapy occurs in first two months after TKI initiation, local therapy can be adopted after this timepoint, before disease progression. We also propose EGFR gene mutation type as potential inclusion criteria to identify candidates for combined local therapy.

  • Survival disparities following surgery among patients with different histological types of non-small cell lung cancer
    Lung Cancer (IF 4.599) Pub Date : 2019-12-17
    Horiana B. Grosu; Andrea Manzanera; Sudeep Shivakumar; Simon Sun; Nogueras Gonzalez Graciela; David E. Ost

    Objectives Clinical decisions for NSCLC patients are often based on TNM stage, which does not account for different histological subtype. Whether histological subtype affects survival still remains unclear. The main objective of this study was to determine the extent to which the survival outcomes of patients with early-stage NSCLC differ by histological subtype. Material and Methods Retrospective cohort study of SEER data base. Patients with stage IA and IB NSCLC that underwent surgery with lymph node dissection were included. The primary outcome was the time to death. Cox proportional hazards models were used to identify risk factors associated with overall survival (OS). The secondary outcome was the time to death from lung cancer. A Cox model and a Fine-Gray subdistribution hazards model in which death from causes other than lung cancer was considered a competing risk event were used to identify risk factors for death from lung cancer. Results Analysis of the SEER database identified 28,584 NSCLC patients, of whom 19,750 (69%) had adenocarcinoma and 8834 (31%) had squamous cell carcinoma. In the multivariate for OS, older age (p < 0.001), male gender (p < 0.001), pneumonectomy (p < 0.001), larger tumor size (p < 0.001), squamous cell carcinoma (p < 0.001) not being Hispanic or Asian were associated with increased risk of death. In the competing risk model, older age (p < 0.001), male gender (p < 0.001), pneumonectomy (p < 0.001), larger tumor size (p < 0.001), and squamous cell carcinoma (p < 0.001) were was associated with an increased risk of death from lung cancer. Conclusion This study suggests that among patients with stage I NSCLC, those with squamous histology have a higher risk of mortality than those with adenocarcinoma histology taking into account competing risks.

  • Next-generation sequencing informs diagnosis and identifies unexpected therapeutic targets in lung squamous cell carcinomas
    Lung Cancer (IF 4.599) Pub Date : 2019-12-16
    Jacob M. Sands; Tom Nguyen; Priyanka Shivdasani; Adrian G. Sacher; Michael L. Cheng; Ryan S. Alden; Pasi A. Jänne; Frank C. Kuo; Geoffrey R. Oxnard; Lynette M. Sholl

    Objectives Potentially targetable genomic alterations have been identified in lung squamous cell carcinoma (LUSC), but none have yet translated into effective therapy. We examined potential benefits of next generation sequencing (NGS) in a cohort of consecutive LUSC patients with emphasis on distinctions between smokers and light/never smokers and implications for clinical trial enrollment. Methods We retrospectively evaluated results from an internally developed NGS assay (OncoPanel) targeting ∼300 genes with a mean overall target coverage of >200x for consecutive LUSC seen at our institution over 30 months. Results Tissue was obtained from 172 patients for targeted NGS. 42 (24 %) samples were insufficient for testing. Median age of tested patients was 66, including 87 % moderate/heavy versus 13 % light/never smokers; 66 % were stage IIIB or IV. Of 130 patients with evaluable NGS results, 49 (38 %) had at least 1 alteration qualifying for enrollment to a LungMAP treatment arm (PIK3CA, MET, FGFR family, cell cycle, or homologous recombination pathways) or for an approved therapy or other clinical trial (e.g. EGFR sensitizing mutations, MET exon 14 splice mutations, TSC1/2 mutation, or microsatellite instability). Therapeutic targets were enriched in light/never smokers (47 % vs 35 % moderate/heavy smokers). Unexpectedly, genomic features suggested an alternative diagnosis (metastatic cutaneous squamous carcinoma; mesothelioma) in 7 patients, including 35 % of never/light smokers. Conclusion NGS in a real-world LUSC cohort yields potentially targetable genomic alterations informing clinical trial enrollment and approved therapies and critical diagnostic insights. Our findings strongly support current guidelines recommending mutational profiling of LUSC arising in light/never smoking patients; the utility of sequencing in smokers with LUSC appears to be limited to identification of research targets.

  • Be-TeaM: an Italian real-world observational study on second-line therapy for EGFR-mutated NSCLC patients
    Lung Cancer (IF 4.599) Pub Date : 2019-12-16
    Maria Lucia Reale; Rita Chiari; Marcello Tiseo; Fabiana Vitiello; Fausto Barbieri; Diego Cortinovis; Giovanni Luca Ceresoli; Giovanna Finocchiaro; Gianpiero Diego Romano; Pier Luigi Piovano; Alessandro Del Conte; Gloria Borra; Francesco Verderame; Vieri Scotti; Daniela Nonnis; Domenico Galetta; Concetta Sergi; Maria Rita Migliorino; Silvia Novello

    Objectives Molecular diagnostics and care of non-small cell lung cancer (NSCLC) are continuously evolving. Few data document the current strategies to manage advanced NSCLC patients beyond progression in clinical practice. Patients and Methods Be-TeaM is an Italian multi-center observational study conducted on consecutive EGFR-mutated stage IV NSCLC patients, progressed during/after a first-line EGFR-TKI. It consists of a retrospective phase, from first-line EGFR-TKI therapy start until study entry (i.e. beginning of the diagnostic process), and a prospective phase, until treatment choice or for 3 months if no therapy was prescribed. Primary objective was to describe the diagnostic and therapeutic approaches adopted after progression in a real-world setting. Results Of 308 patients enrolled in 63 centers from July 2017 to June 2018, 289 were included in the analysis. In first line, 53.3% received gefitinib, 32.5% afatinib and 14.2% erlotinib. The testing rate (i.e. rate of all patients undergone any biopsy -liquid and/or tissue- for the T790 M detection) was 90.7%, with liquid biopsy being the most frequently executed. Of 262 biopsied patients, 64.5% underwent only 1 liquid biopsy, 10.7% only 1 tissue biopsy and 18.3% >1 biopsy, both liquid and solid in 85.4%. The T790 M positivity rate was 45.3%; of 166 patients undergone only a liquid biopsy and tested for the mutation, 39.8% were T790M + and 60.2% T790M-/undetermined. By the observation end, 87.9% patients had a post-progression treatment chosen, osimertinib being the most frequent among the T790M+. Conclusion Be-TeaM provides the first snapshot of current practices for the management of NSCLC patients beyond progression in Italy; in clinical practice, assessing the T790 M status is not always feasible.

    Lung Cancer (IF 4.599) Pub Date : 2019-12-05
    Joan Gibert, Sergi Clavé, Max Hardy-Werbin, Álvaro Taus, Pedro Rocha, Raquel Longarón, Gabriel Piquer, Imane Chaib, Enric Carcereny, Teresa Morán, Marta Salido, Alba Dalmases, Beatriz Bellosillo, Edurne Arriola

    Objectives KRAS mutations are one of the most prevalent alterations in non-small cell lung cancer. However, patients with this driver alteration present heterogeneous clinical outcomes. In this study, we have explored the potential clinical impact of coexisting alterations in this subset of patients. Materials and Methods Samples from a cohort of 69 lung adenocarcinoma patients homogenously treated with platinum doublet as first-line therapy were evaluated using targeted next generation sequencing (NGS). Mutations and copy number alterations were assessed in 37 advanced KRAS-mutant (KRASm) and in 32 KRAS wild-type (KRASwt). Results TP53 was the most frequent additional alteration found in both cohorts. Interestingly, TP53 mutations were more frequent in KRASwt than in KRASm patients (80% vs. 34%; p < 0.05) as well as STK11 mutations (17% vs 8%, p=NS). FGFR3 mutations were only found concomitantly with KRASm (11%). No genomic co-alteration had an impact on overall survival within the KRASm patients treated with chemotherapy. Conclusions KRAS mutated lung adenocarcinoma is a heterogeneous entity and comprehensive characterization of co-alterations using NGS may lead to more accurate patient stratification.

  • Real-world guideline-based treatment of lung cancer improves short- and long-term outcomes and resection rate: A population-based study
    Lung Cancer (IF 4.599) Pub Date : 2019-12-04
    Olli Helminen, Johanna Valo, Heidi Andersen, Anna Lautamäki, Vilma Vuohelainen, Eero Sihvo

    Objectives Recent guidelines for the treatment of lung cancer include comprehensive lists of recommendations for pre-operative risk evaluation, staging, and surgery. Our aim was to evaluate whether the implementation of these in a population-based real-world setting would improve outcomes. Materials and Methods All patients diagnosed with primary lung cancer in Central Finland and Ostrobothnia between January 1, 2006, and December 31, 2017, were identified from registry data (N = 2116), including patients who underwent surgical resection (n = 303). Data were divided into two periods, old and modern, according to which international guidelines were followed. Results Between surgical patients of the old and modern periods, significant changes occurred in the rate of pre-operative stair climbing tests (3.7% vs. 68.6%, p < 0.001), the use of positron emission computed tomography (18.7% vs. 75.7%, p < 0.001), and invasive staging (3.7% vs. 26.0%, p < 0.001). In surgery, the rate of VATS (2.2% vs. 81.1%, p < 0.001), segmentectomy (1.5% vs. 27.2%, p < 0.001), and extended resections (5.2% vs. 13.6%, p = 0.015) increased. However, between these periods, the rate of pneumonectomy decreased from 7.5% to 1.2% (p = 0.005) and bilobectomy from 9.0% to 1.8% (p = 0.004). The overall resection rate increased from 10.5% to 19.7%, mainly due to a higher number of high-risk patients (12.7% vs. 34.3%, p < 0.001). Patients faced fewer major complications (21.6% vs. 8.9%, p = 0.002) and had shorter hospital stays (9 days, IQR 7-11 vs. 5 days, IQR 3-7; p < 0.001). In the modern period, patients underwent adjuvant therapy less often than in the old period (35.1% vs. 22.5%, p = 0.015). Recurrence-free 5-year survival rate improved, however, from 64.0% to 76.8% (p < 0.001). Conclusions The introduction of guideline-based modern patient evaluation and treatment was associated with improved short- and long-term outcomes of lung cancer surgery.

  • Randomized Phase II Trial of Adjuvant Chemotherapy with Docetaxel plus Cisplatin versus Paclitaxel plus Carboplatin in Patients with Completely Resected Non-Small Cell Lung Cancer: TORG 0503
    Lung Cancer (IF 4.599) Pub Date : 2019-11-29
    Kaoru Kubota, Hideo Kunitoh, Takashi Seto, Naoki Shimada, Masahiro Tsuboi, Tatsuo Ohhira, Hiroaki Okamoto, Noriyuki Masuda, Riichiroh Maruyama, Masahiko Shibuya, Koshiro Watanabe

    Objective Adjuvant chemotherapy is standard of care for patients with completely resected stage IB, II and IIIA NSCLC. However, optimum chemotherapy regimen has not been determined. TORG0503 was undertaken to select a preferred platinum-based 3rd generation regimen in this clinical setting. Materials and Methods Patients with completely resected stage IB, IIA, IIB or stage IIIA NSCLC were stratified by stage (IB/IIA vs. IIB/IIIA) and institutions, and randomized to receive 3 cycles of docetaxel (60 mg/m2) plus cisplatin (80 mg/m2) (arm A) or paclitaxel (200 mg/m2) plus carboplatin (AUC 6) (arm B) on day 1, every 3 weeks. The primary endpoint of the study was 2-year relapse free survival, and the key secondary endpoints included overall survival, feasibility and toxicity. Results 111 patients were randomized, 58 patients to arm A and 53 to arm B. Patient demographics were balanced between the two arms. 93% (54/58) of patients on the arm A and 92% (49/53) patients on the arm B completed the planned 3 cycles of chemotherapy. There was no treatment-related death in both arms. The 2 and 5 year relapse free survival was 74.5% (95%CI: 68.6-80.4) and 61.6% in the arm A, and 72.0% (95%CI: 65.7-78.3) and 46.0% in the arm B. The overall 2, 5-year survival was 89.7%, 73.9% in the arm A and 86.9%, 67.5% in the arm B. Conclusion Both docetaxel plus cisplatin and paclitaxel plus carboplatin are safe and feasible regimens as adjuvant chemotherapy. We choose docetaxel plus cisplatin as the control regimen for the next clinical trial.

  • Trends in lung cancer risk and screening eligibility affect overdiagnosis estimates
    Lung Cancer (IF 4.599) Pub Date : 2019-11-28
    Erik F. Blom, Kevin ten Haaf, Harry J. de Koning

    Objectives The degree of overdiagnosis due to lung cancer screening in the general US population remains unknown. Estimates may be influenced by the method used and by decreasing smoking trends, which reduce lung cancer risk and screening eligibility over time. Therefore, we aimed to estimate the degree of overdiagnosis due to lung cancer screening in the general US population, using three distinct methods. Material and Methods The MISCAN-Lung model was used to project lung cancer incidence and overdiagnosis in the general US population between 2018-2040, assuming perfect adherence to the United States Preventive Task Force recommendations. MISCAN-Lung was calibrated to the NLST and PLCO trials and incorporates birth-cohort-specific smoking trends and life expectancies. We estimated overdiagnosis using the cumulative excess-incidence approach, the annual excess-incidence approach, and the microsimulation approach. Results Using the cumulative excess-incidence approach, 10.5% of screen-detected cases were overdiagnosed in the 1950 birth-cohort compared to 5.9% in the 1990 birth-cohort. Incidence peaks and drops due to screening were larger for older birth-cohorts than younger birth-cohorts. In the general US population, these differing incidence peaks and drops across birth-cohorts overlap. Therefore, annual excess-incidence would be absent between 2029-2040, suggesting no overdiagnosis occurs. Using the microsimulation approach, overdiagnosis among screen-detected cases increased from 7.1%-9.5% between 2018-2040, while overdiagnosis among all lung cancer cases decreased from 3.7%-1.4%. Conclusion Overdiagnosis studies should use appropriate methods to account for trends in background risk and screening eligibility in the general population. Estimates from randomized trials, based on the cumulative excess-incidence approach, are not generalizable to the general population. The annual excess-incidence approach does not account for trends in background risk and screening eligibility, and falsely suggests no overdiagnosis occurs in the general population. Using the microsimulation approach, overdiagnosis was limited but not nil. Overdiagnosis increased among screen-detected cases, while overdiagnosis among all cases decreased.

  • Final progression-free survival results from the J-ALEX study of alectinib versus crizotinib in ALK-positive non-small-cell lung cancer
    Lung Cancer (IF 4.599) Pub Date : 2019-11-28
    Kazuhiko Nakagawa, Toyoaki Hida, Hiroshi Nokihara, Masahiro Morise, Koichi Azuma, Young Hak Kim, Takashi Seto, Yuichi Takiguchi, Makoto Nishio, Hiroshige Yoshioka, Toru Kumagai, Katsuyuki Hotta, Satoshi Watanabe, Koichi Goto, Miyako Satouchi, Toshiyuki Kozuki, Ryo Koyama, Tetsuya Mitsudomi, Tomohide Tamura

    Objectives The J-ALEX study compared the efficacy and safety of alectinib with crizotinib in Japanese patients with advanced ALK-positive non-small-cell lung cancer (NSCLC). Superiority in independent review facility (IRF)-assessed progression-free survival (PFS) was demonstrated for alectinib at the second pre-planned interim PFS analysis (data cutoff: December 3, 2015; hazard ratio [HR] 0.34, 99.7% confidence interval [CI]: 0.17–0.71, P < 0.0001). We report final PFS data and the second pre-planned interim analysis of overall survival (OS) and safety (data cutoff: June 30, 2018). Methods Patients aged ≥20 years who were ALK inhibitor-naïve and chemotherapy-naïve, or had received one prior chemotherapy regimen, were randomized to receive alectinib 300 mg (n = 103) or crizotinib 250 mg (n = 104) twice daily. The primary end point was IRF-assessed PFS. Secondary end points included OS and safety. All patients entered survival follow-up in July 2018. Results Median follow-up was 42.4 months for alectinib and 42.2 months for crizotinib. Sustained improvement in IRF-assessed PFS with alectinib was shown (HR 0.37, 95% CI 0.26–0.52; median PFS 34.1 months vs 10.2 months crizotinib). At the second interim OS analysis, superiority of alectinib to crizotinib could not be concluded (stratified HR 0.80, 99.8799% CI: 0.35–1.82, stratified log-rank P = 0.3860; median OS not reached alectinib vs 43.7 months crizotinib). Fewer alectinib-treated patients experienced grade ≥3 adverse events (36.9% vs 60.6% crizotinib). Conclusions At the final PFS analysis, alectinib continued to demonstrate superiority in IRF-assessed PFS versus crizotinib in ALK-inhibitor-naïve ALK-positive NSCLC, with a favorable safety profile. OS follow-up continues.

  • Is the English Cancer Patient Experience Survey representative? A comparative analysis with the National Lung Cancer Audit
    Lung Cancer (IF 4.599) Pub Date : 2019-11-27
    Yvonne Nartey, Iain Stewart, Aamir Khakwani, Vanessa Beattie, Andrew Wilcock, Ian Woolhouse, Paul Beckett, Richard B. Hubbard, Laila J. Tata

    Objectives Healthcare systems increasingly recognise the importance of service users’ perspectives for improving care organisation and delivery. The English Cancer Patient Experience Survey (CPES) is carried out annually, however, its representativeness within cancer types is unknown. We have explored if the CPES results are representative of people with lung cancer. Materials and methods We linked cancer registry data across multiple sources to assess how CPES represents sociodemographic and clinical characteristics of the National Lung Cancer Audit population, accounting for post-sampling mortality bias. Multivariable logistic regression was used to compare people included and not included in CPES. Results Of 240,375 people diagnosed (2009-2015), 15,967 (7%) were included in CPES. Gender and ethnicity were reasonably represented, as were sociodemographic and clinical groupings, although more received anti-cancer treatment (96% of CPES respondents vs. 56% of patients nationally; adjusted odds ratio = 10.3, 95% confidence interval 9.4-11.2 for any anti-cancer treatment) with chemotherapy most over-represented, followed by surgery and then radiotherapy. CPES under-represented older, more socioeconomically deprived, and certain clinical groups, including those with worse performance status, multiple comorbidities, and diagnosis via emergency presentation. Conclusion CPES includes patients across the sociodemographic and clinical spectrum indicating its value for research and service planning. Unbalanced representation of incident lung cancer cases is a limitation that must be considered in context of using CPES findings to implement service changes. Although half the national lung cancer population who received no anti-cancer treatment do not have their experiences represented, the strength of this dataset is in providing detailed comparisons of patient experiences across different treatment groups.

  • Clinical Response to Crizotinib and Emergence of Resistance in Lung Adenocarcinoma Harboring a MET c-Cbl Binding Site Mutation
    Lung Cancer (IF 4.599) Pub Date : 2019-11-26
    Marcel Wiesweg, Thomas Herold, Martin Metzenmacher, Wilfried E. Eberhardt, Henning Reis, Kaid Darwiche, Clemens Aigner, Martin Stuschke, Ken Herrmann, Felix Nensa, Hans-Ulrich Schildhaus, Martin Schuler

    Objectives MET c-Cbl binding site mutations constitute about 2% of MET exon 14 alterations in lung cancer. Preclinical data suggests regarding these mutations as functional analogs of MET exon 14 skipping mutations, but clinical validation is lacking. Results We report the case of a patient with metastastic lung adenocarcinoma harboring a c-Cbl binding site alteration and demonstrate clinical, radiological and metabolic response to crizotinib with a PFS of 10.6 months. As escape mechanism, a typical MET resistance mutation could be identified. Conclusion MET c-Cbl binding site mutations should be regarded as a distinct subtype of MET exon 14 alterations. Patients with lung cancer harboring such mutations should be offered targeted therapy.

  • The Utility of Endosonography for Mediastinal Staging of Non-Small Cell Lung Cancer in Patients with Radiological N0 Disease
    Lung Cancer (IF 4.599) Pub Date : 2019-11-26
    Sun Hye Shin, Byeong-Ho Jeong, Byung Woo Jhun, Hongseok Yoo, Kyungjong Lee, Hojoong Kim, O Jung Kwon, Jungho Han, Jhingook Kim, Kyung Soo Lee, Sang-Won Um

    Objectives Recent practice guidelines recommend endosonography for patients with radiological N0 non-small cell lung cancer (NSCLC) when the primary tumors are >3 cm in diameter or centrally located. However, any role for endosonography remains debatable. We evaluated the utility of endosonography in patients with radiological N0 NSCLC based on tumor centrality, diameter and histology. Materials and Methods Patients who underwent staging endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) with or without transesophageal bronchoscopic ultrasound-guided fine needle aspiration (EUS-B-FNA) for radiological N0 NSCLC were retrospectively investigated using prospectively collected endosonography data. The radiological N0 stage was defined by node diameter as evident on computed tomography images and 18F-FDG uptake using integrated positron emission tomography-computed tomography. Results In total of 168 patients, the median size of the primary tumor was 39 mm, and 41% of tumors were centrally located. The prevalence of occult mediastinal metastases was 11.3% (19/168). The sensitivity of endosonography in terms of diagnosing occult mediastinal metastases was only 47% (9/19); 6 of 10 patients with false-negative endosonography data exhibited metastases in accessible nodes. The diagnostic performance of endosonography did not differ by tumor centrality or diameter. Patients with adenocarcinoma histology showed higher prevalence of occult mediastinal metastases and higher false-negative results in endosonography compared with those with non-adenocarcinoma histology. Conclusion Not all patients with radiological N0 NSCLC benefit from endosonography, given the low prevalence of occult mediastinal metastases and the poor sensitivity of endosonography in this population. The strategy of invasive mediastinal staging needs to be tailored considering the histology of the tumor in this population.

  • Utility of incorporating next generation sequencing (NGS) in an Asian non-small cell lung cancer (NSCLC) population: incremental yield of actionable alterations and cost effectiveness analysis
    Lung Cancer (IF 4.599) Pub Date : 2019-11-26
    Aaron C. Tan, Gillianne G.Y. Lai, Gek San Tan, Shou Yu Poon, Brett Doble, Tse Hui Lim, Zaw Win Aung, Angela Takano, Wan Ling Tan, Mei-Kim Ang, Bien Soo Tan, Anantham Devanand, Chow Wei Too, Apoorva Gogna, Boon-Hean Ong, Tina P.T. Koh, Ravindran Kanesvaran, Quan Sing Ng, Daniel S.W. Tan

    Objectives There is an expanding list of therapeutically relevant biomarkers for non-small cell lung cancer (NSCLC), and molecular profiling at diagnosis is paramount. Tissue attrition in scaling traditional single biomarker assays from small biopsies is an increasingly encountered problem. We sought to compare the performance of targeted NGS panels with traditional assays and correlate the mutational landscape with PD-L1 status in Singaporean patients. Materials and methods We identified consecutive patients diagnosed between Jan 2016 to Sep 2017 with residual tissue after standard molecular testing. Tissue samples were tested using a targeted next-generation sequencing (NGS) panel for DNA alterations (29 selected genes including BRAF, EGFR, ERBB2 and TP53) and an RNA fusion panel (ALK, ROS1 and RET). PD-L1 immunohistochemistry was also performed. A cost-effectiveness analysis of NGS compared to standard molecular testing was conducted. Results A total of 174 samples were evaluated: PD-L1 (n = 170), NGS DNA panel (n = 161) and RNA fusion (n = 118) testing. Median age was 68 years, 53% were male, 58% were never smokers, 85% were Chinese, 66% had stage IV disease and 95% had adenocarcinoma histology. In patients profiled with NGS on DNA, EGFR (56%), KRAS (14%), BRAF (2%) and ERBB2 (1%) mutations were found. RNA fusion testing revealed fusions in ALK (6%), RET (3%) and ROS1 (1%). Cost-effectiveness analysis demonstrated that compared to sequential testing in EGFR negative patients, upfront NGS testing would result in an additional 1% of patients with actionable alterations for targeted therapy being identified without significant increases in testing cost or turnaround time. Conclusions This study demonstrates that even in an EGFR mutant predominant population, upfront NGS represents a feasible, cost-effective method of diagnostic molecular profiling compared with sequential testing strategies. Our results support the implementation of diagnostic NGS in non-squamous NSCLC in Asia to allow patients access to the most appropriate personalized therapy.

  • Next-generation sequencing based mutation profiling reveals heterogeneity of clinical response and resistance to osimertinib
    Lung Cancer (IF 4.599) Pub Date : 2019-11-25
    Jun Zhao, Gen Lin, Minglei Zhuo, Zaiwen Fan, Liyun Miao, Likun Chen, Aiping Zeng, Rong Yin, Yangming Ou, Zhihui Shi, Jie Yin, Wen Gao, Jianhua Chen, Xiangdong Zhou, Yong Zeng, Xiang Liu, Huamin Xu, Rongrong Chen, David P. Carbone

    Objectives The 3rd generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR TKI) osimertinib has shown promising efficacy both in EGFR-mutant, T790 M positive non-small cell lung cancer (NSCLC) patients who have become resistant to 1st or 2nd generation EGFR TKIs and patients with sensitizing EGFR mutations as the first line therapy. However, the degree and duration of response to osimertinib are heterogeneous. We hypothesized that the concurrent genomic landscape of these tumors could play a role in clinical outcomes and/or mechanisms of resistance. Materials and Methods We conducted a retrospective multicenter study of lung cancer patients who had developed resistance to osimertinib. Genomic profiling was done for all the patients by using targeted next-generation sequencing encompassing 59-1021 cancer-related genes. Results and Conclusion Known EGFR-dependent resistant mutations and activation of alternative pathways were identified in 44% of all the patients with great heterogeneity. Gain-of-function mutations of CTNNB1 were highly enriched in our cohort. Some other putative resistance mechanisms to osimertinib, such as the recurrent EGFR V834 L mutation, were also identified. Moreover, pathogenic mutations of TP53 were negatively related to the efficacy of osimertinib. To sum up, heterogeneity of resistance to osimertinib was not only manifested by inter-individual differences, but also embodied in its intra-individual diversity.

  • Uncommon EGFR mutations associate with lower incidence of T790M mutation after EGFR-TKI treatment in patients with advanced NSCLC
    Lung Cancer (IF 4.599) Pub Date : 2019-11-24
    Shuo Yang, Shiqi Mao, Xuefei Li, Chao Zhao, Qian Liu, Xiaofei Yu, Yan Wang, Yiwei Liu, Yingying Pan, Chunyan Wang, Guanghui Gao, Wei Li, Anwen Xiong, Bin Chen, Hui Sun, Yayi He, Fengying Wu, Xiaoxia Chen, Caicun Zhou

    Objectives Advanced non-small cell lung cancer (NSCLC) patients harboring non-resistant uncommon epidermal growth factor receptor (EGFR) mutations have stepped into the era of targeted therapy. This study aimed to investigate the incidence of acquired T790 M mutation and their outcome to subsequent osimertinib in patients of advanced NSCLC harboring uncommon EGFR mutations. Patients and Methods Patients with EGFR mutation and performed re-biopsy after progression on prior EGFR-tyrosine kinase inhibitors (TKIs) were reviewed and analyzed. Those with T790 M mutation and received subsequent osimertinib treatment were further collected for survival analysis. Results Finally, 754 patients, including 48 with uncommon mutation, 362 with 19del and 344 with L858R were enrolled. T790 M mutation was identified in 341 patients (341/754, 45.2%). The incidence of T790 M mutation was 27.1% in patients harboring uncommon mutations, significantly lower than 55.2% and 37.2% of 19del and L858R (p < 0.001). Logistic regression analysis further found uncommon mutation associated with significantly lower probability of developing T790 M (odds ratio [OR] = 0.32, 95% confidence interval [CI] 0.16-0.64). Among 236 patients received subsequent osimertinib treatment (including 12 uncommon mutation, 145 19del and 79 L858R), patients harboring uncommon mutations showed significantly shorter progression free survival (PFS) (median: 4.6 vs. 11.6 vs. 12.1 months, p < 0.001) and overall survival (OS) (median: 8.1 vs. 35.4 vs. 24.9 months, p = 0.001) compared with 19del and L858R, also associated with numerically lower objective response rate (ORR) (p = 0.085) and lower disease control rate (DCR) (p = 0.074). Multivariate analysis further found that uncommon mutation was the only one significantly associated with both PFS (hazard ratio [HR] = 3.44, 95%CI 1.79-6.58) and OS (HR = 3.64, 95%CI 1.66-7.99). Conclusions Uncommon EGFR mutation showed a significantly lower incidence of acquired T790 M mutation and benefited significantly less from subsequent osimertinib treatment than common EGFR mutations in patients with advanced NSCLC.

  • Long-term Cancer Risk Associated with Lung Nodules Observed on Low-Dose Screening CT Scans
    Lung Cancer (IF 4.599) Pub Date : 2019-11-23
    Paul Pinsky, David S. Gierada

    Objective Non-calcified nodules (NCNs) associated with false positive low-dose CT (LDCT) lung cancer screens have been attributed to various causes. Some, however, may represent lung cancer precursors. An association of NCNs with long-term lung cancer risk would provide indirect evidence of some NCNs being cancer precursors. Methods LDCT arm participants in the National Lung Screening Trial (NLST) received LDCT screens at baseline and years 1-2. The relationship between NCNs found on LDCT screens and subsequent lung cancer diagnosis over different time periods was examined at the person and lobe level. For the latter, a lobe had a cancer outcome only if the cancer was located in the lobe. Separate analyses were performed on baseline and post-baseline LDCT findings; for the latter, those with baseline NCNs were excluded and only new (non-pre-existing) NCNs examined. Raw and adjusted rate-ratios (RRs) were computed for presence of NCNs and subsequent lung cancer risk; adjusted RRs controlled for demographic and smoking factors. Results 26309 participants received the baseline LDCT screen. Over median 11.3 years follow-up, 1675 lung cancers were diagnosed. Adjusted RRs for time periods 0-4, 4-8 and 8-12 years following the baseline screen were 5.1 (95% CI:4.4-5.9), 1.5 (95% CI:1.3-1.9) and 1.5 (95% CI:1.2-1.8) at the person-level and 14.7 (95% CI:12.6-17.2), 2.6 (95% CI: 2.0-3.4) and 2.2 (95% CI:1.6-2.9) at the lobe-level. 18585 participants were included in the post-baseline analysis. Adjusted RRs for periods 0-4, 4-8 and 8-11 years were 5.6 (95% CI: 4.5-7.0), 1.9 (95% CI: 1.3-2.7) and 1.6 (95% CI: 0.9-2.9) at the person-level and 19.6 (95% CI:14.9-25.3), 2.5 (95% CI:1.3-4.7) and 3.3 (95% CI:1.4-7.6) at the lobe-level. Raw RRs were similar. Conclusion NCNs are associated with excess long-term lung cancer risk, suggesting that some may be lung cancer precursors.

  • Newly diagnosed patients with advanced non-small cell lung cancer: A clinical description of those with moderate to severe depressive symptoms
    Lung Cancer (IF 4.599) Pub Date : 2019-11-21
    B.L. Andersen, T.R. Valentine, S.B. Lo, D.P. Carbone, C.J. Presley, P.G. Shields

    Objectives The aims of this observational study were to 1) accrue newly diagnosed patients with advanced-stage non-small cell lung cancer (NSCLC) awaiting the start of first-line treatment and identify those with moderate to severe depressive symptoms and, 2) provide a clinical description of the multiple, co-occurring psychological and behavioral difficulties and physical symptoms that potentially exacerbate and maintain depressive symptoms. Materials and methods Patients with stage IV NSCLC (N = 186) were enrolled in an observational study (ClinicalTrials.gov Identifier: NCT03199651) and completed the American Society of Clinical Oncology-recommended screening measure for depression (Patient Health Questionnaire-9 [PHQ-9]). Individuals with none/mild (n = 119; 64%), moderate (n = 52; 28%), and severe (n = 15; 8%) depressive symptoms were identified. Patients also completed measures of hopelessness, generalized anxiety disorder (GAD) symptoms, stress, illness perceptions, functional status, and symptoms. Results Patients with severe depressive symptoms reported concomitant feelings of hopelessness (elevating risk for suicidal behavior), anxiety symptoms suggestive of GAD, and traumatic, cancer-specific stress. They perceived lung cancer as consequential for their lives and not controllable with treatment. Pain and multiple severe symptoms were present along with substantial functional impairment. Patients with moderate depressive symptoms had generally lower levels of disturbance, though still substantial. The most salient differences were low GAD symptom severity and fewer functional impairments for those with moderate symptoms. Conclusions Depressive symptoms of moderate to severe levels co-occur in a matrix of clinical levels of anxiety symptoms, traumatic stress, impaired functional status, and pain and other physical symptoms. All of the latter factors have been shown, individually and collectively, to contribute to the maintenance or exacerbation of depressive symptoms. As life-extending targeted and immunotherapy use expands, prompt identification of patients with moderate to severe depressive symptoms, referral for evaluation, and psychological/behavioral treatment are key to maximizing treatment outcomes and quality of life for individuals with advanced NSCLC.

  • Real-World Effectiveness and Safety of Nivolumab in Patients with Non-Small Cell Lung Cancer: A Multicenter Retrospective Observational Study in Japan
    Lung Cancer (IF 4.599) Pub Date : 2019-11-20
    Ryo Morita, Kyoichi Okishio, Junichi Shimizu, Haruhiro Saito, Hiroshi Sakai, Young Hak Kim, Osamu Hataji, Makiko Yomota, Makoto Nishio, Keisuke Aoe, Osamu Kanai, Toru Kumagai, Kayoko Kibata, Hiroaki Tsukamoto, Satoshi Oizumi, Daichi Fujimoto, Hiroshi Tanaka, Keiko Mizuno, Yuichiro Ohe

    Objectives To describe the treatment patterns and determine the effectiveness and safety of nivolumab treatment for non-small cell lung cancer (NSCLC) in real-world setting in Japan Materials and Methods Japanese patients with NSCLC who received nivolumab were analyzed retrospectively. Patients who had started nivolumab treatment between April 2016 and December 2016 were enrolled. Information regarding patient demographics and clinical backgrounds, treatment patterns from diagnosis to post-nivolumab treatment, effectiveness and safety of nivolumab treatment and that of treatments just before and after nivolumab treatment, and programmed death-ligand 1 (PD-L1) expression status, if available, were collected. Factors associated with nivolumab effectiveness identified by univariate and multivariate analyses were further investigated for plotting Kaplan-Meier curves of epidermal growth factor receptor (EGFR) gene mutation status, PD-L1 expression status, and Eastern Cooperative Oncology Group Performance Status (ECOG PS). Results In this study, 901 NSCLC patients were enrolled. Nivolumab was used the most as a second line treatment with a median number of nivolumab doses of five. The median overall survival (OS) was 14.6 months, one-year survival rate was 54.3%, and median progression-free survival (PFS) was 2.1 months. The objective response rate was 20.5% and disease control rate was 57.4%. According to multivariate analyses, better OS and PFS were associated with favorable ECOG PS and absence of liver metastasis. Better PFS was observed in patients without EGFR mutation and patients with smoking history. PFS and best overall response in PD-L1 expression subgroups were expression level-dependent. The overall incidence of irAEs was 45.8%, and the incidence of adverse events of grade 3 or higher was 14.0%. Conclusion The real-world effectiveness and safety of nivolumab is consistent with that reported by previous clinical trials and other real-world data. Subgroup analysis showed that ECOG PS, EGFR mutation status, smoking status, and PD-L1 were associated with the effectiveness of nivolumab.

  • Highly accurate DNA-based detection and treatment results of MET exon 14 skipping mutations in lung cancer
    Lung Cancer (IF 4.599) Pub Date : 2019-11-18
    M.A. Pruis, W.R.R. Geurts-Giele, Thüsen J.H. von der, I.C. Meijssen, W.N.M. Dinjens, J.G.J.V. Aerts, A.M.C. Dingemans, M.P. Lolkema, M.S. Paats, H.J. Dubbink

    Objectives The oncogenic MET exon 14 skipping mutation (METex14del) is described to drive 1.3%-5.7% of non-small-cell lung cancer (NSCLC) and multiple studies with cMET inhibitors show promising clinical responses. RNA-based analysis seems most optimal for METex14del detection, however, acquiring sufficient RNA material is often problematic. An alternative is DNA-based analysis, but commercially available DNA-based panels only detect up to 63% of known METex14del alterations. The goal of this study is to describe an optimized DNA-based diagnostic test for METex14del in NSCLC, including clinical features and follow-up of patients treated with cMET-targeted therapy and consequent resistance mechanisms Material and methods Routinely processed diagnostic pathology non-squamous NSCLC specimens were investigated by a custom-made DNA-based targeted amplicon-based next generation sequencing (NGS) panel, which includes 4 amplicons for METex14del detection. Retrospectively, histopathological characteristics and clinical follow up were investigated for advanced non-squamous NSCLC with METex14del. Results In silico analysis showed that our NGS panel is able to detect 96% of reported METex14 alterations. METex14del was found in 2% of patients with non-squamous NSCLC tested for therapeutic purposes. In total, from May 2015 - Sep 2018, METex14del was found in 46 patients. Thirty-six of these patients had advanced non-squamous NSCLC, they were predominantly elderly (76.5 years [53-90]), male (25/36) and (ex)-smokers (23/36). Five patients received treatment with crizotinib (Pfizer Oncology), in a named patient based program, disease control was achieved for 4/5 patients (3 partial responses, 1 stable disease) and one patient had a mixed response. Two patients developed a MET D1228 N mutation during crizotinib treatment, inducing a resistance mechanism to crizotinib. Conclusion This study shows that METex14del can be reliably detected by routine DNA NGS analysis. Although a small cohort, patients responded well to targeted treatment, underlining the need for routine testing of METex14del in advanced non-squamous NSCLC to guarantee optimal personalized treatment.

  • The impact of body mass index on the efficacy of anti-PD-1/PD-L1 antibodies in patients with non-small cell lung cancer
    Lung Cancer (IF 4.599) Pub Date : 2019-11-18
    Eiki Ichihara, Daijiro Harada, Koji Inoue, Ken Sato, Shinobu Hosokawa, Daizo Kishino, Kazuhiko Watanabe, Nobuaki Ochi, Naohiro Oda, Naofumi Hara, Katsuyuki Hotta, Yoshinobu Maeda, Katsuyuki Kiura

    Objectives Body mass index (BMI) is reported to be associated with the efficacy of immune checkpoint inhibitors (ICIs) in solid tumors such as melanomas. However, it remains unclear whether such a relationship exists in non-small cell lung cancer (NSCLC) treated with programmed cell death protein 1 (PD-1)/ programmed death-ligand 1(PD-L1) inhibitors. The purpose of this study was to investigate the relationship between BMI and the efficacy of ICI treatment in patients with advanced NSCLC. Materials and Methods The medical records of NSCLC patients who received PD-1/PD-L1 antibody monotherapy at nine institutions between December 2015 and May 2018 were reviewed retrospectively. The effect of BMI was investigated in two cohorts. Cohort 1 included patients with NSCLCs with high PD-L1 expression (≥ 50%) treated with pembrolizumab as first-line therapy, and cohort 2 included patients with NSCLCs treated with nivolumab/pembrolizumab/atezolizumab as second- or later-line treatment. Results A total of 513 from nine institutions were analyzed (84 in cohort 1, 429 in cohort 2). Using a BMI cut-off value of 22 kg/m2, which is an ideal BMI in our country (high BMI: ≥ 22.0 and low BMI: < 22.0), there was no significant difference in the PFS or OS between the high and low BMI patients in cohort 1. However, in cohort 2, survival was significantly longer in patients with a high versus low BMI (PFS: 3.7 vs. 2.8 months, p = 0.036; OS: 15.4 vs. 13.5 months, p = 0.021). Conclusion BMI was significantly associated with the efficacy of ICIs in patients with NSCLC treated with second- or later-line PD-1/PD-L1 inhibitors in our cohort.

  • Detection of TGF-β in pleural effusions for diagnosis and prognostic stratification of malignant pleural mesothelioma
    Lung Cancer (IF 4.599) Pub Date : 2019-11-18
    Paul Stockhammer, Till Ploenes, Dirk Theegarten, Martin Schuler, Sandra Maier, Clemens Aigner, Balazs Hegedus

    Objectives Malignant pleural mesothelioma (MPM) is an aggressive malignancy with dismal prognosis but variable course of disease. To support diagnosis and to risk stratify patients, more reliable biomarkers are warranted. Emerging evidence underlines a functional role of transforming growth factor-beta (TGF-β) in MPM tumorigenesis though its utility as a clinical biomarker remains unexplored. Materials and Methods Corresponding pleural effusions and serum samples taken at primary diagnosis were analyzed for TGF-β by ELISA, and for mesothelin (SMRP) by chemiluminescence enzyme immunoassay. Tumor load was quantified in MPM patients by volumetric analysis of chest CT scans. All findings were correlated with clinicopathological characteristics. Results In total 48 MPM patients, 24 patients with non-malignant pleural disease (NMPD) and 30 patients with stage IV lung cancer were enrolled in this study. Pleural effusions from MPM patients had significantly higher TGF-β levels than from NMPD or lung cancer patients (p < 0.0001; AUC for MPM vs NMPD: 0.78, p = 0.0001). Both epithelioid and non-epithelioid MPM were associated with higher TGF-β levels (epithelioid: p < 0.05; non-epithelioid: p < 0.0001) and levels of TGF-β correlated with disease stage (p = 0.003) and with tumor volume (p = 0.002). Interestingly, high TGF-β levels in pleural effusion, but not in serum, was significantly associated with inferior overall survival (TGF-beta ≥14.36 ng/mL: HR 3.45, p = 0.0001). This correlation was confirmed by multivariate analysis. In contrast, effusion SMRP levels were exclusively high in epithelioid MPM, negatively correlated with effusion TGF-β levels and did not provide prognostic information. Conclusion TGF-β levels determined in pleural effusion may be a promising biomarker for diagnosis and prognostic stratification of MPM.

  • Independent prognostic value of ultra-sensitive quantification of tumor pre-treatment T790 M subclones in EGFR mutated non-small cell lung cancer (NSCLC) treated by first/second generation TKI, depends on variant allele frequency (VAF): results of the French Cooperative Thoracic Intergroup (IFCT) Biomarkers France project
    Lung Cancer (IF 4.599) Pub Date : 2019-11-15
    Michèle Beau-Faller, Erwan Pencreach, Charlotte Leduc, Hélène Blons, Jean-Philippe Merlio, Pierre-Paul Bringuier, Florence de Fraipont, Fabienne Escande, Antoinette Lemoine, L'Houcine Ouafik, Marc Denis, Paul Hofman, Roger Lacave, Samia Melaabi, Alexandra Langlais, Pascale Missy, Franck Morin, Denis Moro-Sibilot, Jacques Cadranel

    Objectives T790 M mutations inEGFR-mutated non-small cell lung cancer (NSCLC) account for nearly 50% of acquired resistance mechanisms to EGFR-TKIs. Earlier studies suggested that tumor T790 M could also be detected in TKI-naïve EGFR-mutated NSCLC. The aim of the study is to assess the prevalence and clinical significance of quantification of tumor pre-treatment T790 M subclones. Materials and methods We analyzed 366 EGFR-mutated NSCLC patients of the real-life IFCT Biomarkers France study with available pre-treatment formalin-fixed paraffin-embedded (FFPE) tumor DNA before treatment by first/second-generation EGFR-TKI. We used ultra-sensitive Droplet Digital Polymerase Chain Reaction (ddPCR) QX200 (BIO-RAD®, Hercules, CA, USA). All samples were tested in duplicate. Results ddPCR identified T790 M in 19/240 specimens (8%). T790M-positive and T790M-negative populations were not different for clinical baseline characteristics. T790 M Variant Allele Frequency (VAF) was >0.01%<0.1%, >0.1%<1%, >1%<10%, and >10% in five (26.3%), six (31.6%), six (31.6%), and two (10.5%) patients, respectively. T790 M VAF was >0.1% in 11/13 (84%) patients with rapid (<3 months) or usual progression (3-20 months) compared to 0/3 with low progression (>20 months) (p = 0.02). In a Cox model, T790M mutation positivity was correlated with overall survival (OS) and progression-free survival (PFS) for 10% > VAF >1% (hazard ratio [HR] = 2.83, 95% confidence interval [CI] 1.13-7.07, p = 0.03; HR=3.62, 95%CI 1.43-4.92, p = 0.007, respectively) and for VAF >10% (HR = 19.14, 95%CI 4.35-84.26, p < 0.001; HR = 17.89, 95%CI 2.21-144.86, p = 0.007, respectively). Conclusion Ultra-sensitive detection of tumor T790 M mutation concerned 8% of EGFR-mutated TKI-naïve NSCLC patients and has a negative prognostic value only for T790 M VAF over 1%.

  • Tumor autoantibodies (TAAs) panel can improve the accuracy of early diagnosis in lung cancer presenting with ground-glass nodules (GGNs) in Chinese population
    Lung Cancer (IF 4.599) Pub Date : 2018-02-09
    Yayi He, Shengxiang Ren, Kenichi Suda, Christopher Rivard, Yan Wang, Xuefei Li, Caicun Zhou, Fred R. Hirsch

    Background Autoantibody is an attractive diagnostic approach for early detection of malignant tumors. We performed this study to validate the performance of a panel of 7 tumor autoantibodies (TAAs) (p53, PGP9.5, SOX2, GAGE7, GBU4-5, MAGE A1, CAGE) to aid early diagnosis of lung adenocarcinoma with ground-glass nodules (GGNs) in Chinese population and to find an effective simple blood test which can be used in further assessing the risk of lung cancer being present GGNs. Methods A prospective audit was conducted on 592 individuals known to have lung GGNs. We detected TAAs quantitation by ELISA method. Results 198 were positive detected by autoantibody panel test (186 pulmonary malignant or borderline lung diseases, 12 lung benign GGNs). The sensitivity and specificity of autoantibody assay were 39.6% and 90.2% respectively. In lung invasive adenocarcinoma, the sensitivity of autoantibody assay was 49.4%. When the TAAs were combined with miRNAs panel in patients with GGNs, the sensitive was increased to 50.0%. In GGNs >8 mm patients, the sensitive of the TAAs combined with miRNAs panel was more than 60%. Conclusion The greatest impact of using the new TAAs was the highly significant improvement in the sensitivity and specificity of the test in the clinical setting. Our study suggested that the TAAs can be combined with CT imaging to aid diagnosis of lung cancer with GGNs.

  • Joint use of the radiomics method and frozen sections should be considered in the prediction of the final classification of peripheral lung adenocarcinoma manifesting as ground-glass nodules
    Lung Cancer (IF 4.599) Pub Date : 2019-11-15
    Bin Wang, Yuhong Tang, Yinan Chen, Preeti Hamal, Yajing Zhu, TingTing Wang, Yangyang Sun, Yang Lu, Maheshkumar Satishkumar Bhuva, Xue Meng, Yang Yang, Zisheng Ai, Chunyan Wu, Xiwen Sun

    Objectives To evaluate the diagnostic accuracy of radiomics method and frozen sections (FS) for the pathological classification of peripheral lung adenocarcinoma manifesting as ground-glass nodules (GGNs) in computer tomography (CT). Materials and methods A dataset of 831 peripheral lung adenocarcinoma manifesting as GGNs in CT were divided into two cohorts: training cohort (n = 581) and validation cohort (n = 250). Combined with clinical features, the radiomics classifier was trained and validated to distinguish the pathological classification of these nodules. FS diagnoses in the validation cohort were collected. Diagnostic performance of the FS and radiomics methods was compared in the validation cohort. The predictive factors for the misdiagnosis of FS were determined via univariate and multivariate analyses. Results The accuracy of radiomics method in the training and validation cohorts was 72.5 % and 68.8 % respectively. The overall accuracy of FS in the validation cohort was 70.0 %. The concordance rate between FS and final pathology when FS had a different diagnosis from radiomics classifier was significantly lower than when FS had the same diagnosis as radiomics classifier (46 vs. 87 %, P < 0.001). Univariate and Multivariate analyses showed that different diagnosis between FS and radiomics classifier was the independent predictive factor for the misdiagnosis of FS (OR: 7.46; 95%CI: 4.00–13.91; P < 0.001). Conclusions Radiomics classifier predictions may be a reliable reference for the classification of peripheral lung adenocarcinoma manifesting as GGNs when FS cannot provide a timely diagnosis. Intraoperative diagnoses of the cases where FS had a different diagnosis from radiomics method should be considered cautiously due to the higher misdiagnosis rate.

  • Educational level, management and outcomes in small-cell lung cancer (SCLC): a population-based cohort study
    Lung Cancer (IF 4.599) Pub Date : 2019-11-14
    Salomon Tendler, Marit Holmqvist, Gunnar Wagenius, Rolf Lewensohn, Mats Lambe, Luigi De Petris

    Objectives To examine if educational status is associated with outcome in patients with Small Cell Lung Cancer (SCLC). The study also investigated differences in patterns of management (lead times and treatment intensity) between educational levels. Material and methods This nationwide cohort study was based on data from Lung Cancer Data Base Sweden (LCBaSe) generated by record linkages between the Swedish National Lung Cancer Register and several other population-based registers. Educational level was categorized by number of years of schooling: low (≤ 9 years), medium (10-12 years) and high (≥ 13 years). Risk of death expressed as hazard ratios (HR) with 95% confidence interval (CI) were estimated in multi-variable analyses adjusted for age, sex, disease stage at diagnosis, household size and performance status (PS). Analyses stratified by sex and stage were also performed. Results and conclusions The study population encompassed 4256 patients with an SCLC diagnosis between 2002 and 2011. Higher education was associated with a significantly lower risk of death in univariable and multivariable models. The univariable HR comparing high to low level of education was 0.84 (95% CI: 0.75-0.93), an estimate that was attenuated following adjustments (HR 0.88; 95% CI: 0.80-0.98). Compared to men with a low level of education, the risk of death was significantly lower in men with a high education; HR 0.84 (95% CI: 0.73-0.98). In Limited Disease (LD), the prognosis was significantly better in both men and women with high compared low education (HR 0.76; 95 % CI: 0.58-0.98). In Swedish men with SCLC, and among patients with LD-SCLC, a low level of education was associated with a poorer prognosis compared to patients with high education.

  • The Role of Surgery for Atypical Bronchopulmonary Carcinoid Tumor: Development and Validation of A Model Based on Surveillance, Epidemiology, and End Results (SEER) Database
    Lung Cancer (IF 4.599) Pub Date : 2019-11-14
    Xiaowei Chen, Zhaofei Pang, Yu Wang, Fenglong Bie, Yukai Zeng, Guanghui Wang, Jiajun Du

    Objectives The rarity of atypical carcinoid (AC) of the lung and the lack of prospective clinical trials lead to limited knowledge of its biology, treatment information and prognosis. The current study analyzed AC patients from the Surveillance, Epidemiology, and End Results (SEER) database to better understand the clinical characteristics of this disease and build a prognostic nomogram for clinical practice. Materials and methods A total of 507 AC patients with pathological confirmation from SEER database were performed with univariate Cox regression analyses for both overall survival (OS) and lung cancer specific survival (LCSS) analyses. Of the 507 observations, 464 were used in the multivariable Cox proportional hazards model as training cohort of new nomogram. A new nomogram was constructed based on the training cohort and validated by an external validation cohort to predict the 3-, 5- and 10-year OS of ACs. The accuracy and clinical practicability were separately tested by Harrell's C-indexes, calibration plots and decision curve analyses (DCA). Results Lobectomy and segmental resection were found to be protective factors for AC patients. Age, primary tumor size, N stage, M stage, surgery and regional lymph nodes examination were shown as significant prognostic factors in Cox regression analyses and included in the nomogram as predictors. The C-index in the training cohort for 3-, 5-, and 10-year OS were 0.722, 0.737 and 0.712, respectively. The internal and external calibration plots for predictions of the 3-, 5-, and 10-year OS were in excellent agreement. An online webserver was built based on the proposed nomogram for convenient clinical use. Conclusion AC patients with lobectomy or segmental resection tended to have better OS and LCSS. A nomogram was constructed and validated to predict the OS for AC patients and to provide accurate and individualized survival predictions.

  • Decreasing use of epidural analgesia with increasing minimally invasive lobectomy: Impact on postoperative morbidity
    Lung Cancer (IF 4.599) Pub Date : 2019-11-11
    Masha Zeltsman, Jordan Dozier, Raj G. Vaghjiani, Alexandra Poch, Takashi Eguchi, Alessia Pedoto, David R. Jones, Prasad S. Adusumilli

    Objective The goal of this study is to investigate the use of EA and its impact on the postoperative short-term outcomes of patients with non-small cell lung cancer (NSCLC) who received a lobectomy by either minimally invasive surgery (MIS) or thoracotomy. Materials and methods We investigated 793 patients who underwent lobectomy for pathological stage I-III NSCLC without induction therapy during two time periods, an early-time period (2009-2010: MIS, n = 204 [53%]; and thoracotomy, n = 182 [47%]) and a late-period (2014-2015: MIS, n = 308 [76%]; and thoracotomy, n = 99 [24%]). Patient characteristics, including pulmonary function tests, comorbidities, and use of EA, as well as short-term outcomes, including length of stay, morbidity, and mortality were assessed and compared between early-and late-time periods. We also compared patients who received EA (n = 150) with patients who did not receive EA (n = 158) following MIS lobectomy in the late-time period. Results The use of MIS lobectomy increased during the late-time period compared to the early-time period (p < 0.001). In patients who underwent MIS lobectomy, the use of EA significantly decreased in the late-time period compared to the early-time period (2009-2010 vs. 2014-2015, 95% vs. 51%; p < 0.001). There was no difference in postoperative morbidity and mortality between the two time periods in both MIS and thoracotomy. In the late-time period MIS group, the length of stay in the no EA group (n = 150) was shorter than that in the EA group (n = 158) (3 vs. 4 days, p = 0.038). There was no difference in morbidity and mortality between the EA and no EA groups. Conclusion In our study cohort, the observed decrease in the use of EA with the increasing rate of MIS lobectomy did not negatively affect postoperative short-term outcomes.

  • Disparity in clinical outcomes between pure and combined pulmonary large-cell neuroendocrine carcinoma: a multi-center retrospective study
    Lung Cancer (IF 4.599) Pub Date : 2019-11-11
    Jia-Tao Zhang, Ye Li, Li-Xu Yan, Zheng-Fei Zhu, Xiao-Rong Dong, Qian Chu, Lin Wu, Hong-Mei Zhang, Chun-Wei Xu, Gen Lin, Zong-Yang Yu, Jie Hu, Bo Zhu, Hui-Juan Wang, Fan Yang, Zheng-Bo Song, Zheng-Bo Han, Meng-Xia Li, Wen-Zhao Zhong

    Objectives : The 2015 World Health Organization classification defines pulmonary large-cell neuroendocrine carcinoma (LCNEC) as a high-grade neuroendocrine carcinoma. However, the clinical characteristics and prognostic factors of pure LCNEC and combined LCNEC remain unclear. Hence, we performed a multi-center retrospective study to compare the clinical outcomes of pure versus combined LCNEC. Materials and methods : Data from 381 patients with pulmonary LCNEC admitted to 17 Chinese institutes between 2009 and 2016 were collected retrospectively. Clinical characteristics and prognosis were analyzed among patients receiving adjuvant (adjuvant group; n = 56) and first-line (first-line group; n = 146) chemotherapy, as well as among patients receiving small cell lung cancer (SCLC) and non-SCLC (NSCLC) chemotherapy regimens. The Kaplan-Meier method and multivariable Cox regression were used to identify clinicopathological variables that might influence patient outcomes. Results : Expression levels of neuroendocrine markers (synaptophysin, chromogranin-A, CD56) were associated with patients’ prognosis in the total study cohort. In the adjuvant group, median disease-free survival was non-significantly longer for SCLC-based regimens than for NSCLC-based regimens (P = 0.112). In the first-line group, median progression-free survival was significantly longer for SCLC-based regimens than for NSCLC-based regimens (11.5 vs. 7.2 months, P = 0.003). Among patients with combined LCNEC, adenocarcinoma was the most common combined component, accounting for 70.0% of cases. Additionally, median overall survival was non-significantly shorter for combined LCNEC than for pure LCNEC (P = 0.083). Conclusion : The SCLC regimen is a more effective choice, as either first-line or adjuvant chemotherapy, when compared to the NSCLC regimen for LCNEC treatment. Further studies are needed to clarify the survival differences between patients with pure-, and combined LCNEC.

  • Development of A Predictive Radiomics Model for Lymph Node Metastases in Pre-surgical CT-based Stage IA Non-Small Cell Lung Cancer
    Lung Cancer (IF 4.599) Pub Date : 2019-11-09
    Mengdi Cong, Hui Feng, Jia-Liang Ren, Qian Xu, Lining Cong, Zhenzhou Hou, Yuan-yuan Wang, Gaofeng Shi

    Objectives To develop and validate predictive models using clinical parameters, radiomic features and a combination of both for lymph node metastasis (LNM) in pre-surgical CT-based stage IA non-small cell lung cancer (NSCLC) patients. Methods This retrospective study included 649 pre-surgical CT-based stage IA NSCLC patients from our hospital. One hundred and thirty-eight (21%) of the 649 patients had LNM after surgery. A total of 396 radiomic features were extracted from the venous phase contrast enhanced computed tomography (CE-CT). The training group included 455 patients (97 with and 358 without LNM) and the testing group included 194 patients (41 with and 153 without LNM). The least absolute shrinkage and selection operator (LASSO) algorithm was used for radiomic feature selection. The random forest (RF) was used for model development. Three models (a clinical model, a radiomics model, and a combined model) were developed to predict LNM in early stage NSCLC patients. The area under the receiver operating characteristic (ROC) curve (AUC) value and decision curve analysis were used to evaluate the performance in LNM status (with or without LNM) using the three models. Results The ROC analysis (also decision curve analysis) showed predictive performance for LNM of the radiomics model (AUC values for training and testing, respectively 0.898 and 0.851) and of the combined model (0.911 and 0.860, respectively). Both performed better than the clinical model (0.739 and 0.614, respectively; delong test p-values both<0.001). Conclusion A radiomics model using the venous phase of CE-CT has potential for predicting LNM in pre-surgical CT-based stage IA NSCLC patients.

  • PLEKHM2-ALK: a novel fusion in small-cell lung cancer and durable response to ALK inhibitors
    Lung Cancer (IF 4.599) Pub Date : 2019-11-06
    Tao Li, Fan Zhang, Zhaozhen Wu, Longgang Cui, Xiaochen Zhao, Jinliang Wang, Yi Hu

    Objectives In non-small cell lung cancer (NSCLC), anaplastic lymphoma kinase (ALK) rearrangement identifies a subgroup of patients who are sensitive to ALK tyrosine kinase inhibitors (TKIs). ALK fusion is extremely rare in small-cell lung cancer (SCLC). To the best of our knowledge, only two cases of SCLC harboring ALK fusion mutation has been reported previously, both of whom carrying EML4-ALK fusion. There are no standard treatment options for SCLC patients with ALK fusion mutations. Herein, we described a rare case of ALK-rearranged SCLC responding to ALK inhibitors. Materials and methods Immunohistochemistry (IHC) assay and next-generation sequencing (NGS) were performed on the biopsied tumor tissue. Results NGS detected a novel pleckstrin homology and RUN domain containing M2 (PLEKHM2)-ALK fusion, while the IHC analysis revealed an ALK-positive tumor. For extensive SCLC patients, median OS was about 8-13 months. The patient in this case had durable clinical benefit upon the treatment with ALK inhibitors, achieving an overall survival (OS) of more than 27 months. Conclusion This case provides a meaningful reference for the treatment of SCLC patients with ALK fusion mutations. This case also provides valuable information on the response to ALK inhibitors of patients with PLEKHM2-ALK fusion and better understanding of ALK-TKI applications in the future. NGS may be used as a routine test to explore more treatment opportunities for tumor SCLC patients.

  • Phase 2 Study of the Focal Adhesion Kinase Inhibitor Defactinib (VS-6063) in Previously Treated Advanced KRAS Mutant Non-small Cell Lung Cancer
    Lung Cancer (IF 4.599) Pub Date : 2019-11-04
    David E. Gerber, D. Ross Camidge, Daniel Morgensztern, Jeremey Cetnar, Ronan J. Kelly, Suresh S. Ramalingam, David R. Spigel, Woondong Jeong, Pier P. Scaglioni, Song Zhang, Marilyn Li, David T. Weaver, Louis Vaikus, Mitchell Keegan, Joanna C. Horobin, Timothy F. Burns

    Objectives KRAS mutations, which occur in approximately 25% of lung adenocarcinoma cases, represent a major unmet clinical need in thoracic oncology. Preclinical studies have demonstrated that KRAS mutant NSCLC cell lines and xenografts with additional alterations in either TP53 or CDKN2A (INK4A/ARF) loci are sensitive to focal adhesion kinase (FAK) inhibition. Defactinib (VS-6063) is a selective oral inhibitor of FAK. Materials and methods Patients with previously treated advanced KRAS mutant NSCLC were prospectively assigned to one of four molecularly defined cohorts based on the presence or absence of TP53 or CDKN2A alterations and received treatment with defactinib 400 mg orally BID until disease progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS) at 12 weeks. Results Fifty-five patients were enrolled. Mean age was 62 years; 51% were female. The median number of prior lines of therapy was 4 (range 1-8). Fifteen (28%) patients met the 12-week PFS endpoint, with one patient achieving a partial response. Median PFS was 45 days. Clinical efficacy did not correlate with TP53 or CDKN2A status. The most common adverse events were fatigue, gastrointestinal, and increased bilirubin, and were generally grade 1 or 2 in severity. Conclusion In heavily pretreated patients with KRAS mutant NSCLC, defactinib monotherapy demonstrated modest clinical activity. Efficacy was not associated with TP53 and CDKN2A status. Defactinib was generally well tolerated.

  • Clinical utility of dual-energy CT used as an add-on to 18F FDG PET/CT in the preoperative staging of resectable NSCLC with suspected single osteolytic metastases
    Lung Cancer (IF 4.599) Pub Date : 2019-11-04
    Haijun Wu, Song Dong, Xiuhui Li, Lei Shi, Dan Shao, Qing Zhang, Min Chen, Yan Cao, Minn Thant, Xiaoyu Huang

    Objective To determine the clinical value of 18F-FDG-PET/CT and dual-energy virtual noncalcium CT to detect and identify single osteolytic metastases (SOM) in participants with non-small cell lung cancer (NSCLC). Materials and Methods Forty-two participants (mean age, 63.5 years ± 10.1; range, 41–81 years) with suspected SOM diagnosed by whole-body 18F-FDG-PET/CT underwent non-enhanced dual-energy CT. All images were visually and quantitatively evaluated by two nuclear medicine physicians (R1 and R2) and two radiologists (R3 and R4) independently. The results of visual and quantitative analysis of 18F-FDG-PET/CT and dual-energy CT were compared with pathological results. Results In the visual analysis, the specificity and positive predictive value of dual-energy CT for reader 1 and reader 2 is larger than the corresponding figures of18F-FDG-PET/CT for reader 3 and reader 4 (94.1% each vs 82.4%/76.5%; 95.2%/95.0% vs 88.9%/86.2%). The sensitivity and negative predictive value of dual-energy CT is relatively lower than the number of 18F-FDG-PET/CT for readers (80.0%/76.0% vs 96.0%/100.0%; 76.2%/72.7% vs 93.3%/100.0%, respectively). ROI-based analysis of SUVmax on PET/CT images and CT numbers on VNCa images showed a significant difference between metastases and non-metastases (P < 0.001 each). Conclusions Pre-surgical evaluation by combination of whole-body 18F-FDG-PET/CT and dual-energy CT could improve the classification of SOM and may further guide the surgical decision-making in participants with NSCLC.

  • Detection of rare and novel EGFR mutations in NSCLC patients: Implications for treatment-decision
    Lung Cancer (IF 4.599) Pub Date : 2019-11-04
    AC. Sousa, C. Silveira, A. Janeiro, S. Malveiro, AR. Oliveira, M. Felizardo, F. Nogueira, E. Teixeira, J. Martins, M. Carmo-Fonseca

    Objectives Mutations in the gene that encodes epidermal growth factor receptor (EGFR) are biomarkers that predict how non-small cell lung cancer (NSCLC) patients respond to EGFR-targeted therapies collectively known as tyrosine kinase inhibitors (TKIs). Thus, EGFR genotyping provides crucial information for treatment decision. Both Sanger sequencing and real-time PCR methodologies are used for EGFR genotyping. However, methods based on real-time PCR have limitations, as they may not detect rare or novel mutations. The aim of this study was to determine the prevalence of rare mutations in the tyrosine kinase domain (exons 18 to 21) of the EGFR gene not targeted by the most frequently used real-time PCR approaches, i.e., the cobas® EGFR Mutation Test, and the Idylla™ EGFR Mutation Assay. Methods A total of 1228 NSCLC patients were screened for mutations in exons 18 to 21 of the EGFR gene using Sanger sequencing. Results We observed that 252 patients (∼20%) had at least one mutation in the EGFR gene, and 38 (∼3%) carried uncommon genetic alterations that would not be identified by the cobas® or the Idylla™ tests. We further found six new single mutations and seven previously unreported compound mutations. Clinical information and patient outcome are presented for these cases. Conclusions This study highlights the value of sequencing-based approaches to identify rare mutations. Our results add to the inventory of known EGFR mutations, thus contributing to improved lung cancer precision treatment.

  • Impact of Coexisting Gene Mutations in EGFR-Mutated Non–Small Cell Lung Cancer Before Treatment on EGFR T790M Mutation Status After EGFR-TKIs
    Lung Cancer (IF 4.599) Pub Date : 2019-11-03
    Masayuki Takeda, Kazuko Sakai, Hidetoshi Hayashi, Kaoru Tanaka, Koji Haratani, Takayuki Takahama, Ryoji Kato, Kimio Yonesaka, Kazuto Nishio, Kazuhiko Nakagawa

    Objectives The T790 M secondary mutation of epidermal growth factor receptor gene (EGFR) is the most common mechanism of acquired resistance to first- or second-generation EGFR tyrosine kinase inhibitors (TKIs). We investigated the association between gene mutation profile in EGFR mutation–positive non–small cell lung cancer (NSCLC) before EGFR-TKI treatment and T790 M status after EGFR-TKI treatment. Materials and Methods A total of 57 EGFR mutation–positive NSCLC patients who had undergone a repeat biopsy (tissue or liquid) after failure of treatment with a first- or second-generation EGFR-TKI and who had sufficient tumor tissue available from before treatment for genetic analysis was enrolled. The gene mutation profile of tumor tissue obtained before EGFR-TKI treatment was evaluated by next-generation sequencing with a comprehensive cancer gene panel (409 genes). The number of potentially damaging nonsynonymous mutations was predicted with PolyPhen-2 software. Results Progression-free survival during EGFR-TKI treatment did not differ significantly between patients who developed T790M-mediated resistance and those who developed T790M-independent resistance. The predicted number of damaging nonsynonymous mutations in pretreatment tumor tissue was significantly lower in patients who developed T790M-mediated resistance than in those with T790M-independent resistance (P = 0.049). Conclusions Coexisting mutations in tumor tissue before EGFR-TKI treatment may contribute to the emergence of cell clones responsible for development of T790M-dependent or T790M-independent TKI resistance in patients with EGFR-mutated NSCLC. Multiplex genomic testing of pretreatment tumor tissue may thus provide a means of identifying patients likely to develop T790M-mediated TKI resistance and therefore inform treatment selection.

  • Predictive impact of low-frequency pretreatment T790M mutation in patients with EGFR-mutated non-small cell lung cancer treated with EGFR tyrosine kinase inhibitors
    Lung Cancer (IF 4.599) Pub Date : 2019-11-02
    Yoshiya Matsumoto, Kenji Sawa, Mitsuru Fukui, Jun Oyanagi, Naoki Yoshimoto, Tomohiro Suzumura, Tetsuya Watanabe, Hiroyasu Kaneda, Shigeki Mitsuoka, Kazuhisa Asai, Tatsuo Kimura, Nobuyuki Yamamoto, Kazuto Hirata, Yasuhiro Koh, Tomoya Kawaguchi

    Objectives Low-frequency epidermal growth factor receptor (EGFR) T790 M mutation could be detected by ultrasensitive methods in EGFR tyrosine kinase inhibitor (TKI)-naïve non-small cell lung cancer (NSCLC). However, the impact of pretreatment T790 M (preT790 M) on the efficacy of EGFR-TKIs and on resistance remains unclear. Materials and Methods Two independent cohorts consisting of advanced EGFR-mutated NSCLC patients treated with first-line EGFR-TKIs, a derivation cohort that started treatment between August 2013 and July 2016 (cohort A, n = 44) and a validation cohort between August 2016 and December 2017 (cohort B, n = 22), were examined in this study. Among these, 28 patients underwent re-biopsy at disease progression. DNAs from pretreatment tumor biopsy samples and re-biopsy samples were assessed to detect T790 M by the Cobas EGFR Mutation Test v2 (Cobas) and for quantitating T790 M by droplet digital polymerase chain reaction (ddPCR). Results Detection rates of preT790 M were 40.9% (18/44) in cohort A and 45.5% (10/22) in cohort B by ddPCR, and none by Cobas. A cutoff value of 0.3% for dividing into high- vs. low-preT790 M allele frequency was determined by receiver operating characteristic curve analysis in cohort A. Progression-free survival (PFS) was significantly shorter in the high-preT790 M group (n = 12) than in the low-preT790 M (n = 6) and negative (n = 26) groups (combined low-preT790 M) (median: 6.9 vs. 13.8 months, P = 0.00073). These observations were validated in cohort B [median: 6.2 (n = 5) vs. 15.3 months (n = 17), P = 0.0029]. In 28 paired biopsies, Cobas detected post-progression T790M in 60% (3/5) of the high-preT790M, in 57% (4/7) of the low-preT790M, and in 56% (9/16) of the negative-preT790M groups. Conclusion EGFR-mutated NSCLC with high preT790 M had significantly shorter PFS on EGFR-TKIs. However, preT790 M abundance may not necessarily confer post-TKI T790 M resistance.

  • Targeting ROR1 in combination with pemetrexed in malignant mesothelioma cells
    Lung Cancer (IF 4.599) Pub Date : 2019-11-02
    Noriko Miyake, Nobuaki Ochi, Hiromichi Yamane, Takuya Fukazawa, Tomoko Ikeda, Etsuko Yokota, Masami Takeyama, Nozomu Nakagawa, Hidekazu Nakanishi, Hiroyuki Kohara, Yasunari Nagasaki, Tatsuyuki Kawahara, Naruhiko Ichiyama, Tomoki Yamatsuji, Yoshio Naomoto, Nagio Takigawa

    Objective Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is overexpressed in a subset of malignant cells. However, it remains unknown whether ROR1 is targetable in malignant mesothelioma (MM). Therefore, in this study, we investigated the effects of ROR1 inhibition in mesothelioma cells. Materials and Methods Growth inhibition, colony formation, apoptosis, and mRNA/protein levels using siRNA-transfected MM cells were evaluated. Cluster analysis using Gene Expression Omnibus repository of transcriptomic information was also performed. Results Our results indicated that in three (H2052, H2452, and MESO-1) among four MM cell lines, ROR1 inhibition had anti-proliferative and apoptotic effects and suppressed the activation of AKT and STAT3. Although growth inhibition by siROR1 was minimal in another mesothelioma cell line (H28), colony formation was significantly suppressed. Microarray, quantitative polymerase chain reaction, and Western blot analyses showed that there were differences in the suppression of mRNA and proteins between H2452 and H28 cells transfected with siROR1 compared with those transfected with control siRNA. Cluster analysis further showed that MM tumors had relatively high ROR1 expression, although the cluster in them was different from that in MM cell lines. Thymidylate synthase, a target of pemetrexed, was downregulated in H2452 cells transfected with siROR1. Accordingly, a combination of pemetrexed with siROR1 was found to be effective in the four MM cell lines we studied. Conclusion Our findings may provide novel therapeutic insight into the treatment of advanced MM.

  • Attending community-based lung cancer screening influences smoking behaviour in deprived populations
    Lung Cancer (IF 4.599) Pub Date : 2019-11-01
    Haval Balata, Liam Traverse-Healy, Sean Blandin-Knight, Christopher Armitage, Philip Barber, Denis Colligan, Peter Elton, Marie Kirwan, Judith Lyons, Lorna McWilliams, Juliette Novasio, Anna Sharman, Kathryn Slevin, Sarah Taylor, Janet Tonge, Sara Waplington, Janelle Yorke, Matthew Evison, Philip AJ Crosbie

    Objectives The impact of lung cancer screening on smoking is unclear, especially in deprived populations who are underrepresented in screening trials. The aim of this observational cohort study was to investigate whether a community-based lung cancer screening programme influenced smoking behaviour and smoking attitude in socio-economically deprived populations. Material and Methods Ever-smokers, age 55-74, registered at participating General Practices were invited to a community-based Lung Health Check (LHC). This included an assessment of respiratory symptoms, lung cancer risk (PLCOm2012), spirometry and signposting to stop smoking services. Those at high risk (PLCOM2012≥1.51%) were offered annual low-dose CT screening over two rounds. Self-reported smoking status and behaviour were recorded at the LHC and again 12 months later, when attitudes to smoking were also assessed. Results 919 participants (51% women) were included in the analysis (77% of attendees); median deprivation rank in the lowest decile for England. At baseline 50.3% were current smokers. One-year quit rate was 10.2%, quitting was associated with increased baseline symptoms (adjOR 2.62, 95% CI 1.07-6.41; p = 0.035) but not demographics or screening results. 55% attributed quitting to the LHC. In current smokers, 44% reported the LHC had made them consider stopping, 29% it made them try to stop and 25% made them smoke less whilst only 1.7% and 0.7% said it made them worry less about smoking or think it acceptable to smoke. Conclusions Our data suggest a community-based lung cancer screening programme in deprived areas positively impacts smoking behaviour, with no evidence of a ‘licence to smoke’ in those screened.

  • Hyper-progressive disease in a patient with advanced non-small cell lung cancer on immune checkpoint inhibitor therapy: a case report and literature review
    Lung Cancer (IF 4.599) Pub Date : 2019-10-31
    Dongxiao Zhang, Yan Zhang, Yong Huang, Li Kong, Jinming Yu

    Objectives While immune checkpoint inhibitor (ICI) therapy has excellent efficacy in treating multiple cancers, some patients experience accelerated disease progression, defined as hyper-progressive disease (HPD). However, the characteristics of HPD, especially in patients with non-small-cell lung cancer (NSCLC), remain to be elucidated. Materials and Methods We report about an advanced NSCLC patient with striking disease progression, defined as HPD by existing standards, after the administration of pembrolizumab. We also reviewed related studies to discuss the definition, relative factors, and prognosis of HPD. Results and Conclusion This case of NSCLC with HPD had a series of characteristics not widely described in HPD cases previously reported, suggesting the potential complexity of this phenomenon and the necessity to study its characteristics and to more closely monitor patients who are administered ICIs.

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