bluuebunny/crossref_metadata_2025_split huggingface dataset:
EGFR-mutation detection in VTX-1-enriched CTCs, ctDNA, and comparison to tumor in patients with non-small cell lung cancer (NSCLC).
Authors: Goldman Jonathan Wade , Liu Haiyan , Vuppalapaty Meghah , Wilkerson Charles , Lemaire Clementine , Crouse Steve , Sollier-Christen Elodie 
Published: September 2018

e20525 Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI's) have shown dramatic clinical benefits when EGFR mutations are detected. These assays are mainly performed on tumor biopsies, which carry risks, are expensive and are not always successful. Moreover, secondary mutations, causing resistance to 1st & 2nd generation TKI’s develop during treatment and therefore mutations require ongoing monitoring. Circulating tumor cells (CTCs) or circulating tumor DNA (ctDNA) are promising for monitoring the patient over time and show enhanced sensitivity when combined1. The VTX-1 Liquid Biopsy System enables label-free capture of CTCs from blood and genomic assays downstream2. In this study, we demonstrate the sensitivity of a combined EGFR assay on VTX-1-enriched CTCs and ctDNA, using blood spiked with cancer cells & DNA and then with NSCLC patients. Methods: NSCLC cells (A549: wt, H1975: L858R+ & T790M+, HCC827: 19del+) were used to validate the assay. H1975 cells and HCC827 DNA were spiked in blood. Plasma was extracted and the plasma depleted blood was processed through VTX-1. The collected plasma and enriched cells were subjected to the detection of 19del, L858R and T790M EGFR mutations using the EntroGen ctEGFR kit. Later, blood and tumor were collected from NSCLC patients and analyzed for EGFR mutations on biopsies, ctDNA and CTCs. Results: Mutant DNA was detected for an input as low as 0.5 ng (~83 cells), with a sensitivity from 0.1% to 2% for a total DNA of 25ng (~4 cancer cells & 4000 WBCs) to 1ng (~4 cancer cells & 200 WBCs). Processing of plasma-depleted-blood with Vortex showed the same efficiency compared to whole blood. Mutations were detected from enriched cells and plasma respectively for 100 H1975 cells and 0.5ng of HCC827 DNA spiked in 2mL blood. NSCLC patients are being enrolled and results will be presented at the conference. Conclusions: The ctEGFR assay performed well on VTX-1 enriched cells and ctDNA, enabling a low cost approach to analyze EGFR mutations from a single blood tube with high sensitivity, potentially being a useful tool for guiding treatment of NSCLC patients. 1.Sundaresan, et al. Clin Cancer Res 2016. 2. Kidess-Sigal, et al. Oncotarget 2016.
Local ablative therapy (LAT) for oligoprogressive, EGFR-mutant, non-small cell lung cancer (NSCLC) after treatment with osimertinib.
Authors: Kim Chul , Roper Nitin , Hoang Chuong D. , Szabo Eva , Connolly Maureen , Padiernos Emerson , Kesarwala Aparna Hemant , Cultraro Constance , Waris Maryam , Gao Shaojian , Steinberg Seth M. , Wong David T. , Khan Javed , Rajan Arun , Guha Udayan 
Published: September 2018

e20545 Background: EGFR tyrosine kinase inhibitors (EGFR-TKIs) improve progression-free survival (PFS) in patients with EGFR-mutant NSCLC, but disease progression limits efficacy. Retrospective studies show a survival benefit to LAT in patients with oligoprogressive disease (progression at a limited number of anatomic sites). Methods: This is a prospective study of LAT in patients with oligoprogressive EGFR-mutant NSCLC. Patients with no prior EGFR-TKI therapy (cohort 1) or progression after 1st/2ndgeneration EGFR-TKIs with acquired T790M mutation (cohort 2) receive osimertinib. Upon progression, eligible patients with < = 5 progressing sites undergo LAT and resume osimertinib until disease progression. Patients previously treated with osimertinib qualifying for LAT upon disease progression are also eligible for treatment (cohort 3). Primary endpoint: evaluation of safety and efficacy of reinitiation of osimertinib after LAT (assessed by PFS). Additional goals are assessment of mechanisms of resistance to osimertinib by multi-omics analyses of tumor, blood, and saliva. Results: Between 04/2016 and 01/2017, 15 patients were enrolled (cohort 1: 9, cohort 2: 3, cohort 3: 3). Median age was 57 (range 36-71). Treatment was well tolerated. The most common adverse events (AEs) were rash, diarrhea, thrombocytopenia, and alanine transaminase elevation. Grade 3/4 AEs were observed in 4 (27%) patients. Among evaluable patients, objective response rates prior to LAT in cohorts 1 and 2 were 71% (5/7) and 100% (2/2), respectively, with 6.8 months median PFS (95% CI: 3.4 months-undefined) in cohort 1 and no progressions in cohort 2. To date, 5 patients (33%; cohort 1: 2; cohort 3: 3) had LAT. Two patients with 3 progressing sites underwent a combination of surgery and radiation. Three patients with 1 progressing site underwent surgery alone. Post-LAT PFS and results of molecular analyses will be presented. Conclusions: Patients with EGFR-mutant NSCLC and oligoprogression after EGFR-TKI therapy can be safely treated with LAT. In selected patients, this approach could potentially maximize duration of EGFR-TKI treatment and prevent premature switching to other systemic therapies. Clinical trial information: NCT02759835.
How sensitive are epidermal growth factor receptor-tyrosine kinase inhibitor for lung adenosquamous cell carcinoma harboring EGFR mutation? A bicenter research and pooled analysis of published reports.
Authors: Liu Yong-Mei , Xia Xueming , Du Wei , Zhang Yan , Xu Jianlin , Gong You-Ling , Xu Yong , Zhu Jiang , Ding Zhen-Yu , Peng Feng , Huang Meijuan , Wang Jin , Ren Li , Lu You , Han Baohui , Wang Yongsheng 
Published: September 2018

e20571 Background: Lung adenosquamous cell carcinoma (ASC) is a rare subtype of lung cancer. Little is known about the efficacy of epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) for lung ASC with EGFR mutation. Methods: We retrospectively analyzed 44 patients with advanced or recurrent lung ASC harboring EGFR mutation who were treated with EGFR-TKI from two cancer centers to investigate the efficacy. Then a pooled analysis on the efficacy of EGFR-TKI was performed in 74 patients including 30 patients selected from 11 published reports. Results: In our bicenter research, for the ASC patients treated with EGFR-TKI, the objective response rate (ORR), the disease control rate (DCR), the median progression free survival (mPFS) and the median overall survival (mOS) were 54.5%, 79.5%, 8.8 months and 19.43 months, respectively. In pooled analysis, the ORR, DCR, mPFS and mOS of ASC patients were 63.4%, 85.9%, 10.00 months and 21.37 months, respectively. Similar PFS (11.0 vs. 10.0 months; P= 0.771) and OS (23.67 vs. 20.33 months; P= 0.973) were found in patients with deletion in exon 19 and exon 21 L858R mutation. The patients treated with erlotinib or gefitinib had a trend of better OS than those treated with icotinib. Conclusions: EGFR-TKI is an effective treatment for ASC harboring EGFR mutation, comparing with historical data, similar to EGFR-mutated adenocarcinoma (ADC). Further study is needed to identify the different role of the two components of ASC in EGFR treatment.
Novel resistance mechanisms to first-generation EGFR tyrosine kinase inhibitors: A perspective study in NSCLC patients using targeted next generation sequencing.
Authors: Jin Ying , Zhang Jianjun , Chen Ming , Shao Yang , Shi Xun , Zhao Jun , Wu Xue , Yu Xinmin 
Published: September 2018

e20576 Background:Patients with non-small-cell lung cancer (NSCLC) harboring sensitive epithelial growth factor receptor (EGFR) mutations invariably develop acquired resistance to EGFR tyrosine kinase inhibitors (TKIs). Identification of actionable mutations conferring drug-resistance can be helpful for guiding the subsequent treatment decision. Currently, the known mechanisms of acquired resistance includes: the secondary gatekeeper EGFR-T790M mutation, activation of members of downstream signaling pathways such as PI3K/AKT/mTOR pathway, activation of bypass signaling such as MET, and changes in tumor histology. However, the mechanisms in the remaining patients are still unknown. Methods:In this prospective study, thirty-one advanced NSCLC patients initially carrying sensitive EGFR mutations and subsequently developing acquired resistance to the first-generation EGFR-TKIs were enrolled. Pre-treatment tumor samples as well as re-biopsies of tumor and plasma when the patients were diagnosed with EGFR-TKI resistance were acquired, followed by mutation profiling using targeted next generation sequencing (NGS) on 416 cancer-related genes. Results: In total, 55% of patients were identified to carry acquired secondary EGFR-T790M mutation. Three patients (~10%) harbor EGFR-T854A mutation, which has been reported as another TKI resistant mutation. 26% and 19% of cases accumulated TP53 and RB1 mutations, respectively. In T790M/T854A-negative cases, 30% of patients acquired MET amplification. Other potential acquired resistance mechanisms includes single nucleotide variants (SNVs) in genes such as SMAD4, DNMT3A, GNAS, ATM, KRAS, PIK3CA and TET2, and copy number variations (CNVs) in genes such as CDK4, MDM2, MYC, RICTOR and ERBB2. Conclusions:The study depicted the genetic landscapes comprehensively in matched pre- and post-EGFR-TKIs samples of NSCLC population resistant to first generation TKI treatments. Our analysis demonstrates new perspectives for further study of resistance and putting forward corresponding relevant tactics against the challenge of disease progression. Clinical trial information: NCT02804217.
Targeted DNA- and RNA-based next-generation sequencing for identifying MET exon 14 alterations in pulmonary sarcomatoid carcinoma.
Authors: Ying Jianming , Gao Lianju , Li Yan , Liu Bing , Deng Lamei , Li Lei , Ma Di , Li Junling , Jiang Zhi 
Published: September 2018

e20591 Background:Highly diverse somatic splice site alteration at MET exon 14 ( METex14) result in exon skipping, which is supposed to be a therapeutic target in NSCLC. Here we report detection of METex14 alterations using targeted DNA- and RNA-based Next-Generation Sequencing (NGS) in pulmonary sarcomatoid carcinoma (PSC) with a high frequency of METex14 skipping. Methods: Tumor specimens were collected from 100 Chinese PSC patients. DNA and RNA were subject to targeted NGS, allowing the detection of somatic splice site alterations and intragenic METex14 skipping respectively. Then, somatic mutations that lead to METex14 skipping were recognized. Meanwhile, cross-platform performance comparison for detecting MET exon 14 skipping was achieved. Moreover, Sanger sequencing was also performed on the METex14-positive specimens. Results: So far, we have detected genetic aberrations in 34 FFPE samples. For RNA-based NGS, METex14 skipping was identified in 8 (23.5%) of 34 patient cases. The population frequency was accordant to the reported percent of 22% (PMID: 26215952). And 5 (62.5%) of 8 METex14-positive patients were detected somatic splice site mutations by DNA-based NGS, including 4 cases with known point mutations at the 3’ splice region and one case with a novel deletion (chr7: 116412027- 116412042) at MET exon14 region, which is newly discovered. No somatic mutation was found at the splice junctions of METex14 in the remaining 3 samples using DNA-based NGS. Conclusions: Mutational events of MET leading to exon 14 skipping are frequent occurred in Chinese PSC patients. Our study also suggests that RNA-based NGS could identify more METex14 skipping, and thus provide more accurate results than DNA-based NGS.
Baseline peripheral blood biomarkers associated with clinical outcome of advanced lung cancer in patients treated with anti-PD-1 antibody.
Authors: Soyano Aixa Elena , Dholaria Bhagirathbhai R. , Marin-Acevedo Julian A. , Diehl Nancy N. , Hodge David , Lou Yanyan 
Published: September 2018

e20599 Background: The anti-PD-1 antibodies nivolumab and pembrolizumab have demonstrated improved overall survival (OS) and progression free survival (PFS) in a subset of patients with metastatic or locally advanced lung cancer (LC). To date, no blood biomarkers have been identified to predict clinical outcome to anti-PD-1 agents. Methods: A retrospective analysis of 52 patients with advanced LC and treated with anti-PD-1 antibodies in a single institution was performed. White blood cell count (WBC), absolute neutrophil count (ANC), absolute lymphocyte count (ALC), absolute neutrophil to absolute lymphocyte count ratio (ANC/ALC), absolute eosinophil count (AEC), and platelet counts at baseline before start of anti-PD-1 antibody were assessed. Kaplan–Meier and Cox regression analysis were done. Results: 48 patients were treated with nivolumab (92.3%) and 4 patients with pembrolizumab (7.7%). Median follow up was 13.6 months and median OS was 26 months. Higher baseline ANC and ANC/ALC ratio significantly correlated with worse clinical outcomes. Patients with baseline ANC > 6060/mm3 had a significantly increased risk of death [hazard ratio (HR) = 2.46; 95% CI 1.12–5.42, P = 0.025] and of progression on anti-PD-1 antibody [HR = 2.41; 95% CI 1.25–4.64, P = 0.009] compared with patients with ANC ≤6060/mm3. Similarly, patients with baseline ANC/ALC ratio ≥ 4.59 had a significantly increased risk of death [HR = 2.41; 95% CI 1.11–5.24, P = 0.027] and of progression on anti-PD-1 antibody [HR = 2.08; 95% CI 1.10–3.95, P = 0.027] compared with patients with ANC/ALC < 4.59. One year survival rate in patients who had ANC < 3390/mm3, ANC 3390-6060/mm3 and ANC > 6060/mm3 were 86.5%, 76.9% and 48.1% respectively. Conclusions: Increased baseline ANC and ANC/ALC were associated with poor PFS and OS in LC patients treated with anti-PD-1 antibodies. Although these findings need to be validated in a large sample size, our data suggested that baseline ANC and ANC/ALC ratio might help the risk stratification and assist treatment strategies. The potential predictive value of peripheral blood biomarkers for clinical outcomes to anti-PD-1 antibody should be further investigated in a prospective study.
Predictive impact of different exon 19 deletions in EGFR-mutant NSCLC treated with first-line TKIs.
Authors: Rossi Sabrina , Toschi Luca , 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 
Published: September 2018

e20608 Background: Common Epidermal Growth Factor Receptor (EGFR) mutations in non-small cell lung cancer (NSCLC) predict sensitivity to EGFR tyrosine-kinase inhibitors (TKIs), with exon 19 deletions being associated with better outcome when compared to L858R mutations. We aimed to investigate the impact of different exon 19 deletions on patient outcome in EGFR-mutant NSCLC treated with first-line TKIs. Methods: In this retrospective analysis we included 98 patients with metastatic NSCLC and EGFR exon 19 deletions, treated with first-line EGFR TKIs (gefitinib or afatinib) in 3 Italian centers between 2011 and 2016. The primary endpoint was overall survival (OS), the secondary endpoint progression free survival (PFS). Analyses were performed by grouping exon 19 deletions according to two different models: type of deletion (delE746-A750 vs other) and starting codon of deletion (E746 vs L747). Kaplan-Meier method, the log-rank test and multivariate Cox regression models were used to estimate survival outcomes. Median follow-up time was 40 months. Results: All groups resulted well balanced in terms of patients’ characteristics but the percentage of patients treated with gefitinib was significantly superior in E746 group compared to L747 (p = 0.02). In the whole cohort median OS was 24.6 months [95%CI 21.9 – 33.1] while median PFS was 13.7 months [95%CI 11.6 – 15.9]. When delE746-A750 (n = 60) was compared to the other deletions in exon 19 (n = 38), no differences were evidenced either in terms of OS (24.1 vs 26.0 months; HR 0.80 [95%CI 0.5 – 1.4]; p = 0.42) or PFS (13.9 vs. 12.8 months; HR 0.99 [95%CI 0.6 – 1.6]; p = 0.97). Similarly, no difference in OS or PFS emerged comparing E746 (n = 73) versus L747 group (n = 25) (OS:24.6 and 26.0 months, respectively, HR 0.79 [95%CI 0.4 – 1.4; p = 0.45; PFS 13.9 vs 12.9 months, respectively (HR 0.87 [95%CI 0.5 – 1.4] p = 0.57). On multivariate analysis including age, sex, smoking history, deletions (delE746-A750 vs others or E746 vs L747), presence of brain metastases at diagnosis or during TKI treatment, no variable resulted associated with longer OS or PFS. Conclusions: Different exon 19 deletions are equally sensitive to first-line EGFR TKIs in EGFR-mutant NSCLC.
The ability of avitinib to penetrate the blood brain barrier and its control of intra-/extra- cranial disease in patients of non-small cell lung cancer (NSCLC) harboring EGFR T790M mutation.
Authors: Wang Hanping , Zhang Li , Zheng Xin , Zhang Xiaotong , Si Xiaoyan , Wang Mengzhao 
Published: September 2018

e20613 Background: Avitinib is an oral, potent, irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor selective for T790M resistance mutations. We report the safety, the intracranial/extracranial efficacy, and the blood brain barrier (BBB) penetration rate of Avitinib in non-small cell lung cancer(NSCLC) patients with EGFR T790m mutation. The data come from Peking Union Medical College hospital-a single center of the Phase I, open-label, multicenter study (NCT02330367). Methods: NSCLC Patients with acquired EGFR T790m (+) were enrolled. Patients were orally administered with dose escalating from 150 mg to 300 mg twice daily for 28-continuous-day cycles until disease progression. Blood (2mL) and cerebrospinal fluid (CSF) samples (2ml) were collected for concentration analysis on day 29 in available patients with brain metastases (BM). Tumor response was assessed on day 29 and then every 8 weeks. Results: Sixteen patients were included. Nine patients had asymptomatic BM. The most frequent adverse events were the elevated hepatic transaminases (10/16, 62.5%) and diarrhea (5/16, 31.3%), Most were mild and reversible. 9 Patients (56.3%) achieved Partial Response (PR), 6 (37.5%) achieved Stable Disease (SD). Median Progress Free Survival (PFS) was 253 days (95%CI: 154.8-339.2). Of the 8 evaluable BM patients, intracranial PFS were shorter than extracranial in only two patients. The blood and CSF analysis of 6 BM patients showed the BBB penetration rate were 0.046%-0.146% (Table). Conclusions: Avitinib is well tolerated and efficacious in EGFR T790m(+) NSCLC patients. Its concentration in CSF is low, and the penetrability of BBB is weak. But it still showed a good control of BM. Further studies are proceeding. Clinical trial information: NCT02330367. [Table: see text]
Distribution and pathogenicity of nsSNPs in receptor tyrosine kinases (RTKs) in non-small cell lung cancer (NSCLC) patients (pts).
Authors: Vanderwalde Ari M. , Stein Matthew K , Morris Lindsay Kaye , Sareen Srishti , Karri Saradasri , Patel Kruti , Sullivan Jennifer , Schwartzberg Lee Steven , Martin Michael Gary 
Published: September 2018

e20618 Background: Non-synonymous SNPs (nsSNPs) in RTKs can alter kinase activity and are not exclusive to the tyrosine kinase domain (TKD). In NSCLC, EGFR lesions were previously identified using TKD-limited tests; however, next-generation sequencing (NGS) enables the entire protein sequence of many RTKs to be interrogated. Methods: We analyzed all nsSNPs in 28 RTKs in lung cancer pts who received tumor profiling with Caris NGS from 2013-2015. Mutations were classified by location including the TKD, extracellular domain (ECD), transmembrane domain (TM), juxtamembrane domain (JM), and carboxy-terminal (CT) regions. nsSNPs underwent in silico analysis using PolyPhen-2 (Harvard) to predict pathogenicity. Results: 167 pts (156 NSCLC, 11 SC) were identified with a median age 65 (range 26-85); 51% male; 65% white, 31% black; 77% ≥20 pack-years (py), 11% non-smokers; 52% samples tested were metastases. NSCLC pts were 63% adenocarcinoma, 22%, squamous, 8% large-cell; 81% stage IV, 14% III; 17 were EGFR+, 6 BRAF+, 3 HER2+, 3 ROS1 rearranged and 1 MET exon 14. A total 300 nsSNPs (286 NSCLC, 14 SC) were found in 28 RTKs, excluding EGFR. 123/156 NSCLC pts (79%) and 9/11 SC (82%) had ≥1 RTK lesion with median 2 (range 0-8); 143/300 (48%) nsSNPs were predicted-damaging (pnsSNP) by in silico and 89 pts (53%) had ≥1 pnsSNP (median 1; range 0-5). 28/28 RTKs had ≥3 mutations, with median 11 (range 3-23), and 26/28 contained ≥1 pnsSNP (median 5; range 0-14). RTKs in NSCLC with the most frequent nsSNPs were EPHA3 (14/23 variants were pnsSNP), EPHA5 (11/17), EPHB1 (10/11), RET (9/11), ERBB4 (8/12), ALK (7/16), NTRK3 (7/15), ROS1 (6/22) and FLT1 (6/15). 6/14 lesions in SC pts were pnsSNPs in ERBB3, ERBB4, FGFR1, FLT1, RET and ROS1. nsSNPs were found along RTKs: 57% were ECD (72/172 pnsSNP), 26% TKD (47/77), 10% CT (14/29), 6% JM (8/18) and 1% TM (2/4). 6/6 SC pnsSNPs were ECD. 67% BRAF+ and ROS1-rearranged, 59% EGFR+, 33% HER2+ and 0/1 MET exon 14 pts had ≥1 pnsSNP. Conclusions: Nearly 80% NSCLC and SC pts had ≥1 nsSNP in 28 RTKs, excluding EGFR, with 48% pnsSNPs by in silico analysis. As > 70% nsSNPs were extra-TKD lesions, further characterization is needed to identify kinase-effecting variants and their potential clinical significance.
Incidence and impact of thromboembolic events in lung cancer patients treated with nivolumab.
Authors: Hegde Aparna Madhukeshwar , Stroud Chipman Robert Geoffrey , Cherry Cynthia R. , Yogarajah Meera , Cherukuri Sulochana Devi , Walker Paul R. 
Published: September 2018

e20624 Background: Lung cancer has one of the highest incidences of thromboembolic events (TEE) ranging from 8.4 to13.2%. Cisplatin-based chemotherapy in lung cancer is a well-established risk factor for TEE (11.8%). The incidence of TEE in lung cancer patients (pts) treated with nivolumab (nivo) is unclear. The objective of this study was to evaluate the incidence of TEE, risk factors and its impact on overall survival in lung cancer pts treated with nivo. Methods: This was a retrospective cohort study that included all lung cancer pts treated with nivo from April 2015 to October 2016 at our institution. Medical records were reviewed for incidence, timing, CTCAE grade, type and site of TEE, risk factors and patient demographics. Cox proportional hazard model was used to identify independent predictive factors for TEE. Risk factors with p <0.15 in univariate analysis were included in multivariate model using a stepwise approach. Kaplan-Meier method was used to estimate overall survival (OS). Results: The cumulative incidence (CI) of TEE over a median follow up of 10.8 months after starting nivo was 18.4% (14/76 pts). Of the 14 pts who had TEE, 8 had deep vein thrombosis (DVT), 7 had pulmonary embolism (PE), 1 had concurrent DVT/PE and 2 had arterial thrombosis (AT). 28.6% (4/14) of pts experienced recurrent TEE resulting in 18 total episodes. Median time to TEE after starting nivo was 2.9 months (95% CI 1.9 - 8.4). Gender was the only covariate included in multivariate analysis that showed a significant association with TEE (Female vs Male HR 3.1, 95% CI 1.02 – 9.5, p= 0.045). At a median follow up of 31.8 months since diagnosis of lung cancer, pts who had TEE before receiving nivo had worse OS. TEE occurring after nivo had no impact on OS. Conclusions: The CI of TEE is significantly high at 18.4% in lung cancer pts treated with nivo. However, it had no impact on OS. Further studies are needed to determine the role of prophylactic anticoagulation in this high-risk population. [Table: see text]