bluuebunny/crossref_metadata_2025_split huggingface dataset:
Whole genome and transcriptome sequencing of lung cancer: Options for personalized cancer treatment.
Authors: Chooback Negar , Ho Cheryl , Shen Yaoqing , Tsang Erica S , Zhao Yongjun , Mungall Andrew J. , Moore Richard , Lim Howard John , Renouf Daniel John , Gelmon Karen A. , Yip Stephen , Jones Steven , Laskin Janessa J. , Marra Marco 
Published: September 2018

e20567 Background: Targeted therapy against driver mutations has revolutionized lung cancer management. The Personalized OncoGenomics (POG) program uses whole genome and transcriptome derived information to build pathways and identify potential therapeutic targets. We examined the lung adenocarcinoma (LUAD) patients enrolled in POG in order to identify novel cancer drivers and correlate the findings with clinical characteristics. Methods: Patients with advanced LUAD and survival > 6 months were eligible. Blood, archival and fresh tumour specimens were subjected to comprehensive DNA and RNA sequencing. SNV data were compared to the TCGA-LUAD cohort using the cBioPortal platform. Whole tumor transcriptome data were compared to matched normal blood specimens. Clinical characteristics were collected by chart review. Results: 30 POG LUAD cases were analyzed. Baseline characteristics; 47% female, median age 60, 57% never/light smokers, biopsy site - 50% lung, 50% metastatic lesion. High mutations rates in TP53, KRAS, NF1 were comparable to the TCGA-LUAD cohort. Four genes ( GOLGA6L2, FAM186A, ARMCX4 and RBMXL3), were mutated 17-27% of the time in POG patients, while the rate in TCGA-LUAD was < 1%. Driver mutations ( KRAS and EGFR) and known fusions (ROS1 and RET) were present in 63%.Other potential drivers included ERBB3, ERBB2, SDC:NRG1 fusion were identified. Copy number alterations and expression data revealed variations in cell cycle, mTOR, androgen receptor,HSP90, MET and Wee1 proteins, all potential targets for therapy. PD-L1 over-expression and a strong smoking signature were not mutually exclusive to EGFR copy gain and FGFR3 overexpression. Conclusions: The molecular signature of NSCLC is complex and involves multiple key oncogenic drivers. Whole genome sequencing and transcriptome data should be used together to map out the pathways of carcinogenesis and reliably identify targets for therapy.
Circulating biomarkers and outcomes in advanced non-small cell lung cancer patients treated with anti-PD1 (program death 1 receptor) monoclonal antibodies.
Authors: Fidler Mary J. , Batus Marta , Tarhoni Imad , Sayidine Selina , Fhied Cristina L. , Basu Sanjib , Bonomi Philip , Borgia Jeffrey Allen 
Published: September 2018

e20592 Background: Current evaluation of immunohistochemical expression of PDL-1 (program death receptor 1 ligand) can select some non-small cell lung cancer (NSCLC) patients who may benefit from anti-PD1 directed therapy. It is an imperfect marker and there is little information about systemic modulation of the immune system on therapy. In this study we explored the prognostic value of baseline circulating immune checkpoint and inflammatory molecules in advanced non-small cell lung cancer (NSCLC) patients receiving anti-PD1 therapy. Methods: Prospectively collected serum from advanced NSCLC patients receiving nivolumab or pembrolizumab were evaluated with the MILLIPLEX Human High Sensitivity T-cell (17-plex) and ProcartaPlex Human Immuno-Oncology Checkpoint (14-plex) panels on our Luminex FlexMAP 3D. Biomarker level cutoffs were optimized and evaluated against progression-free survival (PFS) and overall survival (OS) using log-rank analysis. Results: 21 cases were enrolled in this pilot study: 72% Caucasian, 61% female, 24% never-smokers. IL-10 was found to have a significant association with both PFS (p = 0.0055) and OS (p = 0.024), with levels below 3.32 pg/mL being associated with a superior clinical outcome. We also found IL-2 and IL-6 to have significant associations with PFS (p = 0.033 and 0.040, respectively), again, with low levels being associated with a superior outcome. Neither of these had significant associations with OS. Low circulating levels of the T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) protein were associated with superior PFS (p = 0.036), and a weak trend (p = 0.19) for OS. Conclusions: In this small exploratory pilot study we identified several circulating molecules associated with inflammation and immune system regulation that may have prognostic value for anti-PD-1 therapy. Notably, TIM-3 is a Th1-specific protein associated with macrophage activation and is also a component of T-cell exhaustion along with LAG3 and PD-1. Additional studies to follow up on these findings in larger cohorts are underway.
Prognostic significance of neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR) in untreated and treated stage IV non-small cell lung cancer (NSCLC): An Australian cancer centre experience.
Authors: Mandaliya Hiren A. , Jones Mark , Oldmeadow Christopher , Nordman Ina 
Published: September 2018

e20630 Background: Baseline high NLR predicts poorer outcome in stage IV NSCLC; post-treatment variation in NLR and potential impact on overall survival (OS) is not clear in this group. Prognostic implications of PLR and LMR are not well studied for stage IV NSCLC. We aimed to assess the prognostic role of NLR, LMR and PLR in stage IV NSCLC at diagnosis and post-treatment. Methods: A retrospective descriptive study of 279 patients with Stage IV NSCLC treated at our centre over five year period (2010 to 2015). NLR, PLR and LMR calculated at diagnosis and post first cycle chemotherapy/targeted treatment. Demographic variables summarized. Estimates of Kaplan-Meier survival distributions for OS were generated. Cox regression used to derive OS hazard ratios of predictive variables. Approval from ethics committee obtained. Results: Baseline NLR, PLR and LMR showed strong association with OS. A five-unit increase at baseline (treatment start date) in NLR was associated with an 11% increase in the hazard of death (HR = 1.115, 95% CI: 1.077-1.148) while the same increase in PLR was associated with 0.5% increase in the hazard of death (HR = 1.005, 95% CI:1-1.005). A five-unit increase in LMR at baseline was associated with a 50% reduction in the hazard of death (HR = 0.50, 95% CI:0.260-0.956). Post-treatment NLR, PLR and LMR were examined in 221 patients. Fitted models incorporating adjustment for baseline values demonstrated that increasing NLR correlated with a shorter OS (HR = 1.574, 95% CI:1.295-1.917) but no statistically significant relationship could be demonstrated for PLR nor LMR. Conclusions: While NLR, PLR and LMR showed significant associations with OS prior to treatment, only NLR showed an association with OS after treatment. OS was shorter for high NLR and high PLR at baseline compared to low NLR and low PLR at baseline. OS was longer for high LMR at baseline compared to low at baseline. An increase in NLR post-treatment correlated with a shorter OS. This is the first study examining the prognostic significance of all three ratios in patients with untreated and treated stage IV NSCLC.
Coexistence of MET exon 14 mutations with EGFR mutations in non-small cell lung cancer.
Authors: Li Wen-Feng , Kang Jin , Zhang Xu-Chao , Jian Su , Chen Huajun , Wang Zhen , Wang Bin-Chao , Zhou Qing , Tu Hai-Yan , Wu Yi-Long , Yang Jin-Ji 
Published: September 2018

e20636 Background: Activation of MET oncogene as the result of amplification or activation MET exon 14 mutations represents an emerging molecular target for non-small cell lung cancer (NSCLC) treatment. MET exon 14 mutations account for 1.0% in Chinese NSCLC patients. However, few data have been reported on the coexisting of MET exon 14 mutations and EGFR mutations in NSCLC. Moreover, the clinicopathological characteristics and targeted therapy of these MET/ EGFR-coexisting patients remain elusive. Methods: Next-generation sequencing was performed on the DNA of 969 patients and Sanger sequencing was conducted on cDNA of 621 patients for MET exon 14 mutations in NSCLCs. EGFR mutations were determined by direct DNA sequencing. Results: Fifteen patients harbored positive MET exon 14 mutations. Frequency of concomitant EGFR and MET exon 14 mutations was 0.2%(3/1590). 3 patients with concomitant MET exon 14 mutation and EGFR activating mutation were all female, never smokers and adenocarcinoma. Their stagings were stageⅠB (n = 1) and stage Ⅳ(n = 2). The stage ⅠB patient harboring concomitant MET exon 14 skipping and EGFR L858R mutation did not relapse 2 years after operation. The other two stage Ⅳ patients received first-line gefitinib. Case one harbored concomitant MET exon 14 point mutations (IVS13-36G > A) and EGFR exon 19 deletion, and showed resistance to gefitinib with progression free survival(PFS) of 2 weeks and overall survival(OS) of 1 month. Case two had concomitant MET exon 14 point mutations (IVS13-36G > A) and EGFR L858R mutation. Meanwhile, she also had both METamplification and c-Met overexpression at the baseline. She showed partial response (PR) to gefitinib with 3.8 months PFS. Then she was enrolled in a clinical trial (NCT02374645) to receive volitinib plus gefitinib on December 20, 2016. Initial response was good PR on January 24, 2017. Only grade 1 rash was observed. Conclusions: Coexisting MET exon 14 /EGFR mutation is an uncommon molecular event in NSCLC patients. Such coexisted patients might show relative resistance to EGFR inhibitor. However, combination of MET and EGFR inhibitors will be potentially a good strategy to overcome such a relative resistance for MET exon 14 /EGFR co-mutant patients.
Phase ib study of safety, tolerability and pharmacokinetics of simotinib in patients with advanced non-small cell lung cancer.
Authors: Hu Xingsheng , Han Xiaohong , Zhang Li , Ding Yanhua , Wang Hanping , Mu Hua , Sun Yan , Shi Yuankai 
Published: September 2018

e20642 Background: Simotinib is a novel small molecule agent specifically inhibits EGFR and its downstream signaling pathway. Phase Ia study in healthy volunteers demonstrated that simotinib was well-tolerated at doses up to 500 mg. Here, we report a phase Ib study in NSCLC patients with EGFR sensitive mutations to investigate the safety, tolerability and pharmacokinetics of simotinib (ClinicalTrials.gov identifier: NCT01772732). Methods: Patients with histologically confirmed advanced or metastatic NSCLC with EGFR sensitive mutations, relapsed after first-line platinum-contained chemotherapies were eligible. Patients were orally administered with simotinib twice daily continuously, with assessment of dose-limiting toxicities (DLTs) during the first cycle (28 days). Dose escalation was carried out to determine maximum tolerated dose (MTD) using a 3+3 design and 100 mg as starting dose. Pharmacokinetics of simotinib was assessed on Days 1 and 15, respectively. Tumor response was assessed on Day 29 and every 8 weeks afterwards. Results: Fourty-one patients were enrolled and 40 patients were evaluable for response. Simotinib was well tolerated without DLTs, and MTD was not reached up to dose 650 mg. Thirty-nine (95.1%) patients experienced at least one adverse event (AE), and most of them were mild or moderate. Rash (41.5%) and diarrhea (56.1%) were the most frequent AEs. Within the doses examined, simotinib was rapidly absorbed (Tmax ranged 1-4 hours), and the elimination T1/2 ranged 6.2-13.0 hours. Exposure to simotinib was approximately proportional with a single dose from 200 mg to 650 mg, but was less than dose proportional after multiple doses. Sixteen (40%) patients achieved partial response (PR). Median progress free survival (PFS) and overall survival (OS) were 9.9 months and 14.6 months, respectively. Notably, 5 of 8 (62.5%) patients with brain metastasis (BM) in dose cohorts of 500 mg and 650 mg achieved PR. Conclusions: Simotinib was well tolerated, with encouraging efficacy observed in NSCLC patients with EGFR sensitive mutations, particularly in those with BM. Further study of simotinib in treatment of NSCLC patients with BM is warranted and on-going. Clinical trial information: NCT01772732.
Prognostic benefit of statin with or without metformin in elderly patients with advanced non-small cell lung cancer: A nationwide population-based outcome study.
Authors: Lee Yun-Gyoo , Lee Ju Hyun , Jang Joung Soon , Kim Jee Hyun 
Published: September 2018

e20661 Background: Taking statin or metformin potentially decreases chronic inflammation, which may reduce cancer mortality as well as incidence. We aimed to clarify the prognostic impact of either use of metformin or statin in elderly patients with advanced non-small cell lung cancer (NSCLC). Methods: Patients ≥ 70 years with advanced NSCLC incident from 2007 to 2012 were identified using reimbursement claims from Korea’s National Health Insurance Service Database, and exposure to metformin and/or statin documented. Median overall survival (OS) was assessed by using Kaplan-Meier methods. Cox proportional-hazards regression model was used to examine the use of metformin and/or statin on mortality. Propensity score matching method adjusted for confounding. Results: Excluding 976 patients treated by upfront EGFR tyrosine kinase inhibitor, 7298 patients receiving palliative chemotherapy were included: 949 (13.0%) had a history of statin use, 1010 (13.8%) used metformin, 255 (3.5%) used both, and 5594 (76.6%) used neither. Median OS of statin + / metformin +, statin + / metformin –, statin - / metformin +, and statin - / metformin – users was 14.5, 12.9, 11.4 and 9.9 months respectively. By multivariate analyses, metformin use was not statistically significantly associated with improved survival in statin non-user (HR 0.99; 95% CI 0.91-1.08; p= 0.819) and statin user (HR 0.99; 95% CI 0.85-1.16; p= 0.898) group. However, use of statin, regardless of metformin, was associated with improved OS (HR 0.80; 95% CI 0.74-0.86; p< 0.001). In propensity-matched cohort, survival benefit was noted not by the use of metformin (HR 0.97; 95%CI 0.85-1.11; p= 0.661) but by the use of statin (HR 0.83; 95%CI 0.73-0.95; p= 0.007). Conclusions: Our findings did not suggest the survival benefit of metformin use in elderly patients with advanced NSCLC receiving palliative chemotherapy. Use of statin may provide a survival improvement in outcomes of elderly NSCLC.
Clinical outcome of EGFR-mutant NSCLC patients continuing TKIs beyond progression in combination with local ablative radiotherapy.
Authors: Rossi Sabrina , Finocchiaro Giovanna , D'Argento Ettore , Di Noia Vincenzo Pio , Cassano Alessandra , Bonomi Maria , Cerchiaro Eleonora , Ceresoli Giovanni Luca , Beretta Giordano D. , Barone Carlo , Santoro Armando , Toschi Luca 
Published: September 2018

e20662 Background: Continuation of EGFR TKIs with or without local ablative treatments in patients with metastatic EGFR-mutant NSCLC experiencing disease progression under TKIs is feasible and may be associated with improved outcomes. Methods: The retrospective analysis includes 130 patients with advanced EGFR-mutant NSCLC experiencing RECIST disease progression under first-line gefitinib or afatinib, treated in 3 Italian centers between 2011 and 2016. In group 1 (n = 99, 76.2%) patients stopped TKI treatment at first RECIST-confirmed progression while in group 2 (n = 31, 23.8%) TKIs were continued and sites of progression were irradiated. The primary endpoint was overall survival (OS). Progression-free survival (PFS) and time to treatment failure (TTF) were calculated from the start of first-line TKIs. Kaplan-Meier method, the log-rank test and multivariate Cox regression models were used to estimate outcome endpoints. Median follow-up time was 40 months. Results: Median OS, PFS and TTF in the whole cohort were 22.4, 11.1 and 13.0 months, respectively. The two groups resulted well balanced in terms of patients’ characteristics and TKI administered. Median OS was significantly longer in group 2 (37.3 vs 15.6 months; HR 0.33; 95%CI 0.22-0.50; p < 0.0001), as well as median PFS (13.8 vs 8.9 months; HR 0.60; 95%CI 0.42-0.86; p = 0.01) and median TTF (29.3 vs 10.4 months; HR 0.30; 95%CI 0.21-0.44; p < 0.0001). Ten out of 31 (32.3%) patients underwent radiotherapy in ≥2 sites of progressive disease; the most frequently irradiated site was bone (n = 16), followed by brain (n = 9), lung (n = 8) and lymph nodes (n = 6). On multivariate analysis including age, sex, smoking history, mutant exon, presence of brain metastases, TKI administered and treatment strategy at progression, only TKI continuation with radiotherapy was independently associated with all outcome endpoints (OS: p = 0.0007, PFS: p = 0.004; TTF: p < 0.0001). Conclusions: In EGFR-mutant NSCLC progressing under first-line TKIs continuation of TKI in association with local ablative radiotherapy is associated with prolonged OS, PFS and TTF. Whether the improved outcome is a result of treatment strategy or more indolent disease remains unclear.
Sequence of stereotactic ablative radiotherapy and immune checkpoint blockade in the treatment of metastatic lung cancer.
Authors: Pinnamaneni Ramya , Hegde Aparna Madhukeshwar , Cherukuri Sulochana Devi , Arastu Hyder Husain , Bowling Mark , Leinweber Clinton , Stroud Chipman Robert Geoffrey , Cherry Cynthia R. , Walker Paul R. 
Published: September 2018

e20665 Background: Monoclonal antibodies targeting immune checkpoint proteins have recently been shown to elicit robust and durable responses in patients with advanced lung cancer. However, with response rates ranging from 15-20%, immunomodulatory strategies are needed to improve outcomes. Stereotactic ablative radiotherapy (SABR) may be a promising immunomodulatory strategy given its synergistic effects without added toxicity. Several pre-clinical trials combining SABR and immunotherapy have shown improvement in progression free and overall survival. Given this, it has been our multidisciplinary programmatic approach to bring in SABR in patients receiving immunotherapy for a potential immune boost. Methods: This is a retrospective study evaluating the overall survival (OS) of all lung cancer patients who received Nivolumab with SABR at our institution. We included lung cancer patients of all pathologic subtypes who received Nivolumab. We identified patients who received SABR, to sites of symptomatic metastatic disease, within 30 days preceding (Before) or during (Sandwich) Nivolumab treatment. Results: Out of 76 lung cancer patients treated with Nivolumab, 22 received RT- 10 Before and 12 Sandwich. At a median follow up time of 10.6 months (mo), median OS for patients with no RT was 4.8 mo, Before was 5.2 mo and Sandwich was not reached (NR) (p = 0.06). The 1 year OS for the Sandwich arm was 52.1%. When compared to no RT, the Before arm had a statistically insignificant reduction in mortality (HR 0.59, 95% CI 0.25 – 1.41, p = 0.24). The Sandwich arm had a statistically significant reduction in mortality (HR 0.37, 95% CI 0.14 – 0.94, p = 0.04). Conclusions: There is an improvement in OS when SABR is administered as a Sandwich approach during Nivolumab treatment, likely due to SABR-induced neoantigen release, increased PDL1 expression and subsequent abscopal effect. Further prospective studies are needed to evaluate optimal sequencing, dose and site of RT with immunotherapy. [Table: see text]
Treatment outcomes with tyrosine kinase inhibitors in patients with uncommon EGFR mutations in non-small cell lung cancer: A multi-centre retrospective analysis.
Authors: Hunter Sarah , Nickless Guillermina , El-Shakankery Karim , Yousaf Nadia , Smith Daniel , Brand Gillian , Nicolson Marianne , Neat Michael , Newsom-Davies Tom , Spicer James F. , Montes Ana , Karapanagiotou Eleni 
Published: September 2018

e20678 Background: The clinical significance of common epidermal growth factor receptor (EGFR) mutations (exon 19 deletions and exon 21 L858 mutations) in non-small cell lung cancer is well known1. However, 2-8% of NSCLC patients harbour an uncommon EGFR mutation2. Prognosis and response to tyrosine kinase inhibitors (TKIs) is unclear in this subgroup. The most frequent uncommon EGFR mutations are exon 18 G719 and exon 21 L861. Although not frequently reported, these appear to have favourable outcomes with TKIs3. Methods: We conducted a retrospective review of all patients with uncommon EGFR mutations identified at laboratories in 4 UK centres, between 2012 and 2016. Patient’s not treated with a TKI were excluded. Techniques including cold PCR were in use at contributing laboratories. The T790M resistance mutation was excluded from our study. For patients with uncommon EGFR mutations, patient characteristics and response to TKIs were analysed. Results: 29 patients with uncommon EGFR mutations, with both rare point mutations (86%) and deletions (14%), were identified. All patients were treated with a TKI. Age ranged from 37 to 85 (median 67). The majority (86%) of patients were performance status 1. TKIs used were afatinib (31%), gefitinib (24%) and erlotinib (45%). 19 patients (66%) benefitted from TKI treatment (38% partial response (PR), 28% stable disease (SD). 10 patients (34%) did not respond, including all four with exon 20 mutations. 15 mutations were exon 18 G719 mutations: 40% had a PR and 40% stable disease with TKI therapy. There were two L861 mutations, both responded with a PR. 13 patients remained on TKI treatment at data cut off. The median progression free survival at this time was 8.1months. Tabulated details of response according to mutation will be presented. Conclusions: The majority (66%) of NSCLC patients with uncommon EGFR mutations benefitted from TKI therapy in this series. These high clinical benefit rates, typified by patients with G719 mutation, are in line with the limited previous reports 1,3. Exon 20 mutations were associated with TKI resistance, in line with the literature4.
Brigatinib (BRG) in patients (pts) with ALK+ non-small cell lung cancer (NSCLC): Updates from a phase 1/2 trial.
Authors: Bazhenova Lyudmila , Gettinger Scott N. , Langer Corey J. , Salgia Ravi , Gold Kathryn A. , Rosell Rafael , Shaw Alice Tsang , Weiss Glen J. , Haney Jeff , Rivera Victor M. , Kerstein David , Camidge D. Ross 
Published: September 2018

e20682 Background: The investigational next-generation ALK inhibitor BRG has shown activity in ALK+ NSCLC pts in a phase 1/2 trial; here, we provide updated data with longer follow-up. Methods: In this ongoing phase 1/2, single-arm, open-label, multicenter trial (NCT01449461), pts with advanced malignancies (including ALK+ NSCLC) received oral BRG (30–300 mg/d). Activity by RECIST v1.1 in ALK+ NSCLC pts and safety in all pts are shown. Results: 58% (79/137) pts had ALK+ NSCLC, with median age 54 y; of these, 90% (71/79) had received crizotinib (CRZ). As of May 31, 2016, 41% (32/79) ALK+ NSCLC pts continued to receive BRG; median treatment duration was 20.0 mo (1 d–47.4 mo). The table shows efficacy in CRZ-treated pts; median overall survival was 47.6 mo (95% CI 21.4–47.6 mo). All 8 CRZ-naive pts had confirmed objective responses; median duration of response and progression-free survival (PFS) were not reached. In a post hoc analysis, 53% (95% CI 27%–79%; 8/15) ALK+ NSCLC pts with measurable baseline brain metastases had confirmed intracranial objective responses (last scan date: October 8, 2015). Median intracranial PFS in 46 evaluable ALK+ NSCLC pts with baseline brain metastases was 14.6 mo (95% CI 12.7–36.8 mo). Treatment-emergent adverse events (AEs) in ≥30% of all pts, mainly grade 1/2, were nausea 53%, fatigue 45%, diarrhea 42%, headache 35%, and cough 33%; serious treatment-emergent AEs in ≥5% of pts were pneumonia 7%, dyspnea 6%, and hypoxia 5%. 10% of pts (14/137) discontinued BRG due to an AE. Conclusions: BRG yielded substantial whole-body and intracranial activity in ALK+ NSCLC pts in this trial, with acceptable safety. These data informed design of the pivotal randomized phase 2 trial of BRG (90 mg qd or 180 mg qd [with lead-in]) in CRZ-refractory ALK+ NSCLC (ALTA). Clinical trial information: NCT01449461. [Table: see text]