bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparative genomic profiling of paired tissue and blood samples from advanced non-small cell lung cancer patients.
Authors: Wang Xiaoyun , Gao Chan , Wang Guoqiang , Cai Shangli , Fang Zheng 
Published: May 2019

e20521 Background: While tissue-based next generation sequencing (NGS) ushered in a new era of precision medicine, profiling of circulating tumor DNA (ctDNA) has also emerged as a minimally invasive alternative to inform clinical decisions. In non-small cell lung cancer (NSCLC), data describing comparison between mutational profiles of paired tissue and blood samples remained scarce. Methods: Matched formalin-fixed paraffin-embedded tissue and peripheral blood samples (≤14 days apart) were collected from treatment naïve advanced NSCLC patients. Genomic profiling was performed using whole exome sequencing (WES) for tissues and a 150-gene panel for ctDNA, with a mean sequencing depth of 239× and 3417× respectively. Tumor- and blood-based tumor mutational burdens (tTMB and bTMB) were defined as the sum of missense, stop-loss, in-frame and frameshift mutations in protein coding regions and the number of somatic single nucleotide variations and indels in targeted coding regions respectively. Maximum somatic allele frequency (MSAF) was also determined for each case as a measure of ctDNA quantity. Results: Matched tissue and blood samples from 48 patients were included for sequencing. A total of 410 mutations were identified, where 84 (20.5%) were covered in both sample types. Sixty-three (15.4%) alterations were only detected in tissues while 263 (64.1%) were exclusively seen in ctDNA. The most frequently altered genes were SMARCA2 (62.5%), TP53 (54.2%), and AR (47.9%) in ctDNA and were TP53 (37.5%) and EGFR (22.9%) in tissues. Aberrations in all genes, except for FAT1 and KRAS, occurred at a higher frequency in ctDNA. The median tTMB and bTMB were 75 and 7, respectively. bTMB displayed a moderate linear relationship with tTMB as indicated by a Spearman correlation of 0.62 (P < 0.01). Patients with bTMB ≥ 7 had significantly higher MSAF (Mann-Whitney P < 0.001), suggesting a positive correlation between bTMB and ctDNA fraction in blood. Conclusions: Mutational profiles as well as TMB levels were in general consistent between blood and tissue samples, further corroborating a role for ctDNA testing as a complementary approach to tissue testing in advanced NSCLC.
Phase II multicenter study of antroquinonol in patients with stage IV non-small cell lung cancer who have failed at least two lines of anti-cancer therapy.
Authors: Ho Ching-Liang , Ettinger David S. , Chen Pei-Ni , Cheng Howard , Wen Wu-Che , Wu Shang-Yin , Jahan Thierry Marie , Fidler Mary J. , Lash Bradley Walter , Rybkin Igor I. , Stanton Natalie 
Published: May 2019

e20522 Background: The aim of this study was to assess the efficacy of Antroquinonol in patients with stage IV NSCLC after failure in two-lines of anti-cancer therapy. Methods: Patients with stage IV non-squamous NSCLC who have failed at 2-4 lines of anti-cancer therapy were eligible, though early stage or naïve patients may voluntarily participate. A maximum of 30 evaluable patients were to receive Antroquinonol 600mg per day, of which 15 patients were to be KRAS-positive and 15 patients KRAS negative. The primary endpoint of the study was progression-free survival from the start of treatment to week 12 with disease control rate and overall survival as key secondary endpoints. Results: There were 31 patients enrolled with evaluable population 30 patients, of which 15 patients were KRAS positive and 15 patients KRAS negative. 73% were with at least two prior chemotherapy. The median PFS of 7 patients with 2 prior chemotherapy was 22.9 weeks (95% confidence interval [CI]: 5.0, 31.1); and 11 patients with more than 2 prior chemotherapy was 11.9 weeks (95% confidence interval [CI]: 6.0, 14.1), with a 1-year PFS of 11.4%. Of 11 patients who had had more than 2 prior chemotherapy, the median OS was 47.3 weeks (95% CI: 14.1,-), with a 1-year OS of 39.3%, and the overall disease control rate was 72.7%, with 100% in KRAS negative and 50% in KRAS positive. No systemic toxicities were observed. Conclusions: The monotherapy of Antroquinonol brought up higher disease control rates and longer progression-free survival and overall survival, compared with historical data. Although KRAS negative shows much better than KRAS positive group, Antroquinonol still work well with KRAS positive patients. Clinical trial information: NCT02047344.
Platinum based chemotherapy in elderly patients with non-small cell lung carcinoma (NSCLC): Experience from an Indian tertiary cancer center.
Authors: Sharma Aparna , Khurana Sachin , Pramanik Raja , Kumar Sunil , Pathy Sushmita , Malik Prabhat Singh 
Published: May 2019

e20528 Background: Instituting platinum based chemotherapy in elderly population is often associated with poor tolerance and attending toxicities. We present our limited center experience of chemotherapy in the geriatric population group. Methods: This is a retrospective single center experience of all registered patients in lung cancer clinic (LCC) in the department of medical oncology, Dr. B.R.A. IRCH, AIIMS. All histopathologically proven cases of NSCLC with age more than 70 years who received platinum based chemotherapy (single/doublet) with complete patient records were analysed. The study was carried out between November 2016 and August 2018.Data was analysed using STATA v13. Results: The cohort consisted of 25 patients who satisfied the inclusion criteria. Males comprised 84%(n = 21) of the cohort. Median age of study population was 72.7 years years (Range 70-84). 36%(n = 9) of the study population had one comorbidity while 8% (n = 2) had multiple comorbidities. 68% (n = 17) of the cohort were smokers. ECOG(Eastern cooperative oncology group) PS (performance status) 1 was seen in 48% (n = 12) and PS 2 in 32% (n = 8) and PS 3 in 16% (n = 4) respectively of the patients. Histopathologically, 48% (n = 12) of the population constituted squamous cell carcinoma while 40%(n = 10) had adenocarcinoma. 76%(n = 19) patients had Stage 4 NSCLC. Most common chemotherapy regimes used were weekly Paclitaxel carboplatin (n = 11, 44%), three weekly paclitaxel carboplatin (n = 8 , 32%) Pemetrexed carboplatin (n = 5, 20%) and gemcitabine carboplatin (n = 1, 4%). Only 12% (n = 3) could complete more than 4 cycles of chemotherapy and 3 could receive maintenance chemotherapy. Best responses according to RECIST (Response Evaluation Criteria In Solid Tumors) criteria v1.1 achieved were complete response in 12%(n = 3), partial response in 16% (n = 4), stable disease 24%(n = 6) and progressive disease in 48%(n = 12). Most common grade 3 and 4 adverse events according to CTCAE (common terminology criteria for adverse events) v4.03 were mucositis 29.17%(n = 7), diarrhea 12% (n = 3), peripheral neuropathy 12.5 (n = 3) and hematological toxicity 16%(n = 4). Conclusions: The patient number in this study cohort is limited.However, our experience demonstrates that abbreviated therapy in elderly subgroup is fairly well tolerated. Various tools like comprehensive geriatric assessment need to be utilized to provided tailored therapy in the elderly subgroup. A prospective study is required to address the efficacy and toxicity profile of chemotherapy in this select population.
Clinical importance of long noncoding RNA LINC00460 expression in plasma cell-free tumor RNA in EGFR-mutant adenocarcinoma.
Authors: Isobe Kazutoshi , Nakano Yuta , .Kobayashi Hiroshi , Kaburaki Kyohei , Sano Go , Sakamoto Susumu , Takai Yujiro , Tochigi Naobumi , Mikami Tetsuo , Iyoda Akira , Homma Sakae 
Published: May 2019

e20529 Background: Long noncoding RNA (lncRNA) is longer than 200 nucleotides and does not encode proteins. The IncRNA LINC00460 was reported to be involved in physiological and pathological processes such as proliferation, invasion, metastasis, and epithelial–mesenchymal transition (EMT). However, its role in epidermal growth factor receptor ( EGFR)-mutant lung adenocarcinoma is unclear. Methods: Non–small cell lung cancer (NSCLC) cells with knockout of LINC00460 were generated with a CRISPR-Cas9 system and used to investigate the effect of LINC00460 on gefitinib-induced cell death in an MTT assay. Western blot was used to observe change in EMT-related proteins, and changes in expression of EMT-related proteins were detected with an immunofluorescence assay. In addition, among 38 EGFR mutant lung adenocarcinomas treated by EGFR-TKI, cell-free tumor RNA extracted from blood plasma samples was analyzed for LINC00460 by using a real-time PCR assay. In addition, we assessed the association between LINC00460 expression and progression-free survival (PFS) after EGFR-TKI therapy. Results: LINC00460 was up-regulated by EGFR activation. LINC00460 expressions were significantly greater in NSCLC tumors than in adjacent normal tissues (p < 0.01). H1299 cells with LINC00460 knockout were more sensitive to gefitinib. LINC00460 was induced by transcription factors such as FOS and NF-κB in EGFR-mutant lung adenocarcinoma and gefitinib-resistant cells. LINC00460 overexpression was involved in gefitinib resistance. The MTT assay showed that LINC00460 expression was greater in cells with acquired resistance to EGFR-TKIs (gefitinib, erlotinib, and osimertinib). Western blot and immunofluorescence revealed that LINC00460 expression was associated with changes in the expression of EMT-related proteins. Patients with high LINC00460 expression in plasma cell-free tumor RNA had significantly shorter PFS after EGFR-TKI therapy than did those with low expression (median PFS: 688 vs 1089 days, respectively; p = 0.024). Conclusions: LINC00460 appears to be a novel factor involved in malignant transformation of EGFR mutant–positive lung adenocarcinoma and increased EGFR-TKI resistance. LINC00460 expression in plasma cell-free tumor RNA in EGFR-mutant adenocarcinoma was associated with shorter PFS after EGFR-TKI therapy.
Clinical outcomes of various resistance mechanisms of osimertinib in Chinese advanced non-small cell lung cancer patients.
Authors: Xing Puyuan , Junling Li , Hao Xuezhi , Mu Yuxin , Wang Shouzheng , Ma Di , Lin Jing , Liu Hao , Han-Zhang Han , Lizaso Analyn , Xiang Jianxing , Mao Xinru 
Published: May 2019

e20530 Background: Increasing efforts have been invested in elucidating the resistance mechanisms to osimertinib. Major resistance mechanisms include but not limited to acquired EGFR mutations, predominantly C797, mutations in bypass pathways and small cell lung cancer (SCLC) transformation. However, no study has comprehensively investigated clinical outcomes of various mechanisms of resistance. Methods: 103 T790M positive advanced Chinese non-small cell lung cancer (NSCLC) patients who progressed on 1st generation EGFR-TKI were enrolled. Targeted sequencing, using a panel consisting of 168 lung cancer related genes, was performed on paired plasma samples collected prior to osimertinib and after the development of disease progression (PD) to profile mutation spectrum. 7 patients with no mutation detected at PD were excluded from analyses. Results: Major acquired mutations included 25% EGFR mutations, predominantly C797 and L792, 16% MET amplification, 8% TP53 mutations, 4% KRAS mutations, 4% RET fusions, 4% ERBB2 amplification and 6.25% RB1 mutations. Acquired RB1 mutation may indicate the possibility of SCLC transformation. Approximately, 30% of patients with no known resistance mechanisms at PD. In this cohort, we had 61 patients with 19 deletion and 35 patients with EGFR L858R prior to the initiation of osimertinib. We revealed patients with 19del acquired more mutations ( p= 0.014) and were more likely to acquire mutations in MAP/PI3Kpathway ( p= 0.04) and TP53 at PD ( p= 0.021). On the other hand, acquired ERBB2 amplifications were only detected in L858R-mutant patients ( p= 0.047). Furthermore, 36 patients preserved T790M and 60 patients lost T790M at PD. Our data revealed patients retaining T790M, often associated with activation of bypass signaling pathways or continued EGFR activation through tertiary mutations, had a longer progression-free survival (PFS) ( p= 0.047) and overall survival (OS) ( p= 0.04) comparing to patients with T790M loss, often with diverse and EGFR-independent mechanisms. We also show that patients with acquired C797S had significantly longer PFS ( p= 0.031), while patients with acquired MET amplifications had significantly shorter PFS ( p= 0.033). Conclusions: Collectively, we revealed differential clinical outcomes associated with various resistance mechanisms, representing an important step in advancing the understanding of resistance mechanisms of osimertinib.
Treatment beyond RECIST-defined progression in relapsed EGFR-mutated non-small cell lung cancer (NSCLC) patients treated with 2nd line osimertinib.
Authors: Eide Inger Johanne Zwicky , Helland Aslaug , Ekman Simon , Cicenas Saulius , Koivunen Jussi , Grønberg Bjørn Henning , Brustugun Odd Terje 
Published: May 2019

e20544 Background: After progression on osimertinib in the 2nd line setting, treatment options are few and include combination chemotherapy. Some patients might benefit from continuing osimertinib despite RECIST-defined progression and thus defer time to more toxic treatments. Methods: The investigator-initiated TREM-study is a multicenter, phase 2, single-arm clinical trial conducted in five Northern European countries. Patients with advanced EGFR-mutated NSCLC who progressed on at least one EGFR-TKI and with measurable disease by RECIST 1.1. were assigned to treatment with osimertinib 80 mg daily until radiological progression or death. Patients showing clinical benefit could continue treatment after radiological progression. Both T790M pos and T790M neg patients were included (assessed in tissue biopsy). The primary endpoint was overall response rate (ORR). Results: 199/200 included pts received at least one dose of osimertinib. T790M status was assessable in biopsies from 167 pts. Of these, 110 pts (66 %) were T790M pos and 57 (34 %) T790M neg. Median age was 66 years (range 33-90), 70 % were women and 53% never-smokers. 24 % had CNS metastases at inclusion. Confirmed ORR was 47.1 % (95% CI 39.9 %, 54.3 %) for 189 evaluable pts. T790M pos pts had an ORR of 58.7 % (49.0 %, 68.3 %) and T790M neg 30.9 % (18.3 %, 43.5 %). Median PFS (all pts) was 9.0 months (7.5, 10.6). Median PFS for T790M pos was 10.8 months (8.1, 13.5) vs 5.5 (4.4, 6.5) for T790M neg, p = 0.014. 126/199 pts (63 %) received treatment beyond RECIST-defined progression (TBP). Median duration of TBP was 0.69 months overall, range 0.03-27.6+ months. Median duration of TBP was 1.8 vs 0.4 months in T790M pos and neg, respectively, p = 0.005. There was no significant difference in the proportion of T790M neg and T790M pos pts receiving TBP (63.2 vs 57.3 %), p = 0.82. At 6 months 23/126 (18.3 %) were still on TBP, including 14/63 (22.2 %) T790M pos and 3/36 (8.3 %) T790M neg. At 12 months 8/126 (6.3 %) were on TBP, including 3 T790M pos and one T790M neg pt. Conclusions: A substantial proportion of the patients received TBP regardless of T790M status and some had durable clinical benefit, suggesting this as a treatment option in selected patients. Clinical trial information: NCT02504346.
Estimating long-term survival of previously untreated patients with EGFR mutation-positive (EGFRm) advanced non-small cell lung cancer (NSCLC) who received osimertinib in the FLAURA study.
Authors: Dyer Matthew , Green Matthew , jones simon , Hodge Rachel 
Published: May 2019

e20560 Background: In the Phase III FLAURA trial (NCT02296125), osimertinib, a third-generation EGFR-TKI, provided clinically and statistically significantly longer progression-free survival versus gefitinib/erlotinib as first-line treatment for patients with EGFRm advanced NSCLC. At the time of analysis, data on overall survival (OS) were immature (25% maturity). To better understand the long-term survival potential of osimertinib beyond the observed trial follow-up period, mathematical parametric survival models were used to estimate clinically plausible survival rates up to 5 years from FLAURA. Methods: Following published best-practice guidelines, candidate parametric survival models were evaluated based on both statistical and visual goodness-of-fit to the observed FLAURA OS data. Two modeling approaches were considered: single models with treatment included as a covariate; and separate models fitted to the osimertinib and gefitinib/erlotinib arms. Point estimates of 5-year survival rates with 95% confidence intervals (CIs) are reported for the best fitting model. Results: The best fitting parametric survival model to the FLAURA OS data was the Weibull model with treatment included as a covariate. Based on this model, estimated median OS was longer with osimertinib than with gefitinib/erlotinib (41.4 months vs 30.6 months). The estimated 3- and 5-year survival rates with osimertinib were 57.3% (95% CI 46.6%, 69.2%) and 31.1% (95% CI 23.7%, 41.8%), respectively. In comparison, the estimated 3- and 5-year survival rates with gefitinib/erlotinib were 41.1% (95% CI 31.9%, 52.9%) and 15.5% (95% CI 11.6%, 22.1%), respectively. Conclusions: Based on the best fitting parametric survival model to FLAURA OS data, the estimated 5-year survival rate with osimertinib was double that with gefitinib/erlotinib (31.1% vs 15.5%) in patients with EGFRm advanced NSCLC. Long-term follow-up data from FLAURA (60% OS maturity) will further validate this finding. Clinical trial information: NCT02296125.
Using single cell genomics to change the treatment of lung cancer.
Authors: Chin Venessa T. , Al Eryani Ghamdan , McCloy Rachael , Stone Emily , Havryk Adrian , Plit Marshall , Field Andrew , Watkins Neil , Swarbrick Alex , Powell Joseph 
Published: May 2019

e20563 Background: Lung cancer (LC) is common with a dismal prognosis. Although treatment with immunotherapy (IO) has improved survival outcomes, these therapies remain expensive. Even using biomarker selection, response rates still fall short of 50%. The majority of immune cell profiling done previously uses samples taken from early stage patients focusing on a single immune cell subtype. Here we use single cell RNA sequencing (scRNA-seq) and Cellular Indexing of Transcriptome and Epitopes by sequencing (CITE-seq) to characterise the innate and adaptive immune cell activation state and assess the response to exposure to IO in vitro from patients with advanced LC. Methods: Patients with locally advanced or metastatic LC having an Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration (EBUS-TBNA) have biopsies collected for analysis. Cells are grown in culture +/- nivolumab for 48 hours. scRNA-seq and CITE-seq is conducted using established protocols. Transcriptomic and proteomic data on the innate and adaptive immune cell subsets assess markers of immune activation and/or suppression and the changes after nivolumab are quantified. Results are correlated with clinical outcomes. Results: In a locally advanced/metastatic population, EBUS-TBNA biopsies yield highly cellular samples with a heterogeneous population of immune cells able to be cultured +/- IO using novel, inclusive techniques. Transcriptomic clustering reveals distinct sub-populations within the T-cell, B-cell and innate immune cell compartments. Within these clusters, CITE-seq shows protein expression on individual cells can determine states of exhaustion, cytolytic ability, migratory potential and innate immune activation. Conclusions: Single cell genomics is feasible and informative in patients with advanced LC. This work will form the basis of a functional, real-time assay to assess individualised responses to IO therapy that has the potential to predict IO response.
Methylation profiling of EGFR mutant primary and metastatic lung cancer with brain metastasis.
Authors: Mamatjan Yasin , Cabanero Michael , Weiss Jessica , Zuccato Jeffrey , Sorotsky Hadas , Tsao Ming Sound , Aldape Kenneth D. , Zadeh Gelareh , Shepherd Frances A. 
Published: May 2019

e20574 Background: EGFR-mutant lung cancer is a key molecular subtype of lung cancer. In recent years there is clear recognition in the value of using methylation signature of cancer for improving diagnosis and predicting outcome as well as understanding the biology of cancer progression. Methods: In this study we chose to characterize the methylome signature of early stage surgically resected EGFR-mutant lung adenocarcinomas in the primary lung tumor. 90 NSCLC cases and 7 matched metastatic brain samples were profiled using Illumina Infinium MethylationEPIC Beadchip. We compared methylation profiles of 1) smokers versus lifetime non-smokers and 2) matched primary lung versus brain metastasis to identify methylation biomarkers. We performed supervised analysis and unsupervised clustering of the methylation data. Results: Unsupervised clustering of all lung and brain samples based on 10K most variable probes showed a similar methylation signature between metastatic brain samples and lung samples. The 7-matched brain and lung samples formed close cluster groups based on matching pairs for the most variable probes from 2.5K to 10K, reflecting the same cell of origin. Supervised analysis of smokers versus lifetime non-smokers did not show any significant methylation differences between the two groups, while unsupervised analysis did not create clusters of smokers and non-smokers based on various number of probe sets we analyzed. Conclusions: Lung tumors that metastasized to the brain share similar methylation features with primary lung tumors. Comprehensive methylation profiling demonstrated no difference between EGFR mutant tumors in smokers versus non-smokers, suggesting that the EGFR mutation is a stronger determinant of outcome independent of smoking.