bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prospective study for usefulness of circulating-free DNA on prediction of third generation EGFR tyrosine kinase inhibitors.
Authors: Yoshida Hironori , Nakashima Chiho , Matsumoto Naohisa , Iwanaga Kentaro , Ebi Noriyuki , Nishiyama Akihiro , Yatera Kazuhiro , Fukuda Minoru , Ushijima Sunao , Umeguchi Hitomi , Harada Daijiro , Kuyama Shoichi , Kashiwabara Kosuke , Suetsugu Takayuki , Fujimoto Nobukazu , Nakatomi Katsumi , Tanaka Fumihiro , Uramoto Hidetaka , Yoshii Chiharu , Sueoka-Aragane Naoko 
Published: May 2020

e21510 Background: Most non-small lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations develop resistance when exposed to EGFR-tyrosine kinase inhibitors (TKIs). T790M develops in about half of patients treated with TKI and can be detected by tumor tissue and cfDNA hotspot tests. However, co-occurring mutations at other loci may impact efficacy. We conducted a prospective, multi-center, observational study to assess the detection rates and predictive values of plasma-based EGFR T790M detection methods for Japanese NSCLC patients treated with osimertinib. Methods: NSCLC patients with tumor EGFR mutations and disease progression after treatment with 1st- or 2nd-generation EGFR-TKI were enrolled. Plasma was collected at the time of clinical disease progression, before osimertinib treatment. The collected plasma was tested for EGFR T90M by in-house plasma MBP-QP and ddPCR assays and compared to clinically tested cobas (Roche) results (including tissue, plasma). The primary endpoint was to demonstrate comparability of our MBP-QP system to cobas using plasma-based EGFR T790M detection to predict the therapeuitic effect of osimertinib via objective response rate (ORR) and disease control rate (DCR). As an exploratory analysis, we used Guardant360 to retrospectively test available banked plasma samples collected describe time points. Results: From Feb 2017 to Jan 2019, 145 patients enrolled. T790M was detected by cobas in 57 cases (44 tissue, 16 plasma, 3 both). ORR and DCR in plasma cobas-positive cases were 62.5% and 81.3%, respectively. MBP-QP found T790M in 9 patients with ORR and DCR 66.7% and 77.8%. ddPCR found 17 cases with ORR and DCR 70.6% and 82.4%. ORR was not correlated to AF. In plasma samples from 54 patients, Guardant360 detected T790M in 57%. Co-occurring alterations such as amplification or minor mutations in EGFR or other genes such as TP53 did not impact ORR, but in the group with poor response to osimertinib, the number of detected gene alterations tended to be large. Two patients with small cell carcinoma transformation had RB1 mutations and MYC amplification. Conclusions: Regardless of the test system, the detection of T790M could predict a good therapeutic effect of osimertinib, but there was no difference in response to osimertinib depending on EGFR T790M AF. Compared to single-gene assessment of EGFR, NGS of cfDNA may be useful for guiding treatment decisions for patients with TKI-resistant NSCLC. Clinical trial information: UMIN000025930.
Molecular characterization of patients with advanced lung adenocarcinoma at diagnosis with next generation sequencing by liquid biopsy in the Mexican population.
Authors: Martínez-Herrera José Fabián , Martinez-Barrera Luis , Rodriguez Cid Jeronimo Rafael Rafael , Sánchez-Ríos Carla Paola , Sanchez-Prieto Mario Alberto , Flores-Mariñelarena Rodrigo Rodrigo , Andrade Moreno Raul Alejandro , Saenz-Frias Julia Angelina , Alatorre-Alexander Jorge 
Published: May 2020

e21511 Background: Non-small cell lung cancer (NSCLC) is the leading cause of cancer mortality worldwide. Tumor biopsy represents the standard for molecular diagnosis, nevertheless it is not always feasible to obtain. Liquid Biopsy (LB) may offer an alternative in the first line setting. Methods: Retrospective review of case files and next generation sequencing report (NGS) from LB from patients in a Validation Trial, performed from January 2018 to September 2019. We present the molecular alterations and clinical characteristics of the population. Results: 147 records and LB reports of patients 18 years and older with metastatic lung adenocarcinoma without prior treatment were included. 40% of the population had been selected based on a commercial local PCR test for EGFR (Idylla). 49% of them were female with Mean age of 60.9 ± 12.7. 56% had a history of smoking with an average packs/year of 20.5 (1-156) and 39% had exposure to wood smoke, 92% had an ECOG 0-1. 65 % of the Patients were diagnosed in Clinical Stage (8th Edition) IVA and 22% in IVB. 13% had SNC metastasis. The LB detected genomic alterations in 85.5% of the cases. 78% represent pathogenic mutations and 7.5% variants of uncertain significance (VUS).14.5% of the biopsies could not detect any ctDNA. The most frequent aberrations reported were TP53 in 51.7%, KRAS 16%, EGFR 16%, ALK 9%, PIK3CA 4%, RET 4%, BRAF 3%, BRCA 3, and HER2 3%. In addition, 20% had bTMB ≥10. Only 20% of the patients could receive a targeted therapy or immunotherapy of the potential ≈50%. Most cases had co-mutations (1-6 x case). Looking for factors associated with the presence of bTMB by a logistic regression model, it was possible to identify the presence of CNS metastases and smoking as identified with an OR of 3,688 (p = 0. 0.042) and 3.952 (p = 0. 024) respectively. Conclusions: It is feasible to have tumor molecular analysis through liquid biopsy in most cases, with genetic alterations previously reported in tumor tissue in the first line setting. [Table: see text]
Analysis of canonical and noncanonical splicing site mutation of MET that causes exon 14 skipping.
Authors: Yu Yongfeng , Chen Rongrong , Zhao Jun , Yi Xin , Lu Shun 
Published: May 2020

e21513 Background: The hepatocyte growth factor receptor gene ( MET) exon 14 skipping ( METex14) has been wildly accepted as a driver alteration in lung cancer targetable by tyrosine kinase inhibitors (TKIs) such as crizotinib. While it is easy to interpret canonical splicing site mutations, it is more controversial to interpret noncanonical splicing site mutations. Methods: Hybrid capture–based next generation sequencing of 59-1021 genes including MET was performed at the request of individual treating physicians. The mutation profiling of MET were retrospectively analyzed. Results: Of 3500 lung cancers profiled by comprehensive genomic profiling, 211 harbored MET single nucleotide mutation (SNV), or small insertion/deletion (InDel). Among which 66 cases were predicted to have METex14. Forty-two (62.1%) cases harbored mutations affecting the splicing donor site, while 24 harbored mutations affecting the splicing acceptor site. Thirty-four of the 42 cases affecting the splicing donor site had mutations in the canonical splicing site, including 3 cases harbored MET c.3028G > A/T/C mutation, 14 cases harbored c.3028+1G > A/T/C, 10 cases harbored c.3028+2T > A/C/G, 8 cases harbored deletion of the whole canonical splicing site. Interestingly, all the seven cases affecting the noncanonical splicing donor site were c.3028+3A > G/T mutation. On the contrary, all the 24 mutations affecting the splicing acceptor site were deletion with/without insertion, with 12 affecting the canonical site and 12 the noncanonical site. We speculated that the polypyrimidine tract around the splicing acceptor site making it more susceptible to deletion/insertion, and thus single nucleotide variant less common. Conclusions: At the 5’ end of the exon 14 of MET, most of the genome alterations are deletions with/without insertions affecting the canonical and noncanonical splicing acceptor site. At the 3’ end, they are mostly point mutations affecting the splice donor site. The noncanonical splicing donor site c.3028+3A plays crucial role in the splicing of exon 14 in MET.
Specific organ metastases and survival of advanced non-small cell lung cancer (NSCLC) patients with EGFR mutation.
Authors: Shi Tiantian , Wang Long , Fan Zhisong , Feng Li , Han Jing , Su Yu , Zhou Xinliang , Zuo Jing , Liu Fengling , Jiang Da , Xu Xiaoli , Wang Yudong 
Published: May 2020

e21527 Background: The retrospective study was performed to evaluate the clinicopathological characteristics and survival associated with distant metastasis from advanced NSCLC with EGFR mutation. Methods: The records of metastasis NSCLC patients with EGFR mutation at the time of diagnosis between 2012 and 2018 were reviewed. The Kaplan-Meier method was used to assess survival curves and the log-rank test was used in the univariate analysis. The multivariate survival analysis were performed using the Cox proportional hazards model to investigate the effects of clinicopathological factors on survival. All the statistical analyses were performed using SPSS 23.0 statistical software and a statistically significant difference was determined as P < 0.05. Results: A total of 258 NSCLC patients with EGFR mutation were enrolled in this study, including 146 cases of female (56.6%), 241 cases of adenocarcinoma (93.4%) and 212 cases of non-smokers (82.2%). Among these patients, 65(25.2%), 111(43.0%), 22(8.5%), 107 (41.5%), 11(4.3%), 87 (33.7%), 65 (25.2%) had brain, bone, liver, lung, adrenal gland, pleural metastasis and extrathoracic lymph node metastases, respectively. The median OS of total patients was 32.9 months (95% CI: 29.8-36.0). In the univariate analysis, patients with metastases to the bone (p = 0.001), liver (p = 0.012), extrathoracic lymph node(p = 0.006), and pleural(p = 0.008) exhibited a poorer survival compared to those without metastases to these regions. Abdominal metastases (p = 0.005) and extremity metastases (p = 0.002) were statistically independent prognostic factors. Association between metastatic region and the response to TKI treatment, liver metastases (p = 0.033), extrathoracic lymph node metastases (p = 0.000) and bone metastases (p = 0.009) were correlated with the poor response of TKI treatment, and the abdominal metastasis ( p= 0.029) and extremity metastases ( p= 0.016) were correlated with the poor response of TKI treatment. Conclusions: Bone metastases, liver metastases, extrathoracic lymph node metastases and pleural metastases were independent prognostic factors of NSCLC patients with EGFR mutation. Liver metastases, extrathoracic lymph node metastases, and bone metastases were correlated with the poor response of TKI treatment.
Bevacizumab biosimilar and reference bevacizumab in subjects with stage IIIB/IV no squamous non-small cell lung cancer (NSCLC) (STELLA study): Results for the primary endpoint in a confirmatory, double-blind, randomized, controlled study.
Authors: Millan Susana , Trukhin Dmytro , Kolesnik Oleksii , Poddubskaya Elena , Zoran Andric , Bondarenko Igor , Shevnia Serhii , Bullo Felicitas , Sarnago Cristina 
Published: May 2020

e21542 Background: MB02 is a proposed biosimilar of the reference bevacizumab. A multinational, double-blind, randomized, parallel group clinical study (STELLA) is undergoing to confirm clinical similarity between MB02 and bevacizumab in patients with stage IIIB/IV no squamous NSCLC. Methods: Subjects were randomized 1:1 to MB02 or bevacizumab (15 mg/kg) plus chemotherapy (paclitaxel [P] 200 mg/m2 and carboplatin [C] AUC6) on Day 1 of every 3-week cycle for 6 cycles (Week 18) followed by MB02/bevacizumab in blinded monotherapy until disease progression, treatment intolerance, death, patient withdrawal or end of study (Week 52). As primary study endpoint, the efficacy by means of the objective response rate (ORR) evaluated by an independent radiological committee (IRC) was compared between arms at Week 18. Secondary endpoints were Progression Free Survival (PFS) and Overall Survival (OS), safety and immunogenicity (assessed at 18 and 52 weeks). Results: 627 patients were randomized: MB02 (n = 315) and bevacizumab (n = 312). Demographic and baseline characteristics were well balanced between arms. The ORR results were comparable for subjects receiving MB02 or bevacizumab plus P/C. A Risk Ratio (RR) of 1.013 (90% CI: -0.037% to 0.059) and a Risk Difference (RD) of 0.011 (90% CI: -0.037% to 0.059), were within the similarity margin predefined by FDA (0.73, 1.36) and EMA (-12%, +12%) respectively. This ORR assessed by IRC was consistent with the investigator assessment criteria. There was no significant difference between arms for secondary efficacy endpoints (PFS/OS) at week 18. Up to primary endpoint cut-off point, the safety assessment showed no significant differences between MB02 and bevacizumab arms (including the immunogenicity assessment) in terms of nature, frequency and severity of the adverse events (AE), being anaemia and hypertension the most common IMP-related AEs, with a RD between treatment groups < 5%. New signals or observable trends were no reported for MB02-treated subjects. Additional information on the secondary endpoints will be available at week 52 (end of monotherapy period). Conclusions: The statistical analysis executed for ORRs confirm the equivalence of MB02 and bevacizumab, supporting the clinical activity of MB02 treatment. MB02 was well tolerated with manageable AEs in patients with Stage IIIB/IV NSCLC. Clinical trial information: NCT03296163.
Assessment of quality and clinical similarity (pharmacokinetic and safety) of HD204, a biosimilar of bevacizumab.
Authors: Hii Jocelyn , Demarchi Martin , Coliat Pierre , Kim Michael J , Chan Kuo Wei , Feyaerts Peggy , Ang Felicia , Schott Roland , Barthelemy Philippe , Benabdelghani Meher , Deforce Filip , Derde Marie_Paule , Pivot Xavier , Park Lisa Soyeon 
Published: May 2020

e21556 Background: Prestige Biopharma Pte Ltd is developing HD204, a biosimilar candidate of Bevacizumab (Avastin). Bevacizumab has been approved in the treatment of a variety of metastatic tumours. Bevacizumab, a recombinant humanized monoclonal antibody block angiogenesis which is required for cancer progression by preventing binding of soluble vascular endothelial growth factor (VEGF) to VEGF receptors. Due to heterogeneity nature of antibody therapeutic, the impact on quality of HD204 on safety and pharmacokinetic (PK) was reaffirmed through clinical study to establish clinical similarity between HD204 and Avastin. Methods: Quality attributes identified to influence PK and safety established through comprehensive analytical characterization was used to correlate any potential differences (structural or biological) between the two compounds if any, could result in any clinical meaningful differences in safety and PK in the clinical settings. The PK and safety equivalence of HD204 relative to Avastin was demonstrated in a randomized, single-blind, single-dose, three-arm and parallel-group study clinical Phase I (SAMSON). A total of 120 healthy male subjects randomized 1:1:1 were to receive 1 mg/kg intravenous infusion of either HD204, EU- or US-Avastin. Various PK parameters, safety assessments not limiting to adverse events (AE) and measurement of antidrug antibodies (ADA) and neutralizing antibodies (NAb) were evaluated. Results: The pairwise comparisons of Exposure (AUC0-inf and AUC0-last), maximal concentration (Cmax) established equivalence between the 3 arms. All other PK parameters including half-life, clearance and volume of distribution were comparable between HD204 and Avastin treatment groups. Treatment related TEAEs reported for each group were 25.0%, 30.0% and 25.6% respectively and comparable. There were no treatment-emergent SAEs. Furthermore, none of the subjects treated with HD204 was ADA positive. Conclusions: HD204 demonstrated equivalent PK and safety profile to both US-Avastin and EU-Avastin at 1mg/kg administered as a 90-minute IV infusion to healthy male subjects. A prospective clinical study aimed to demonstrate equivalence in terms of efficacy, PK and safety is currently ongoing. Clinical trial information: 2017-005174-19.
Real-world mutational profiling of Chinese non-small cell lung cancer patients with epidermal growth factor receptor (EGFR) uncommon mutations acquired resistant to icotinib using next generation sequencing: A multicenter study.
Authors: Wang Wen xian , Xu Chunwei , Lei Lei , Zhu You-cai , Li Jinluan , Chen Huafei , Fang Yong , Wang Hong , Zhuang Wu , Fang Meiyu , Zhang Yinbin , Wang Liping , Zhang Huibao , Zhou Ying , Zheng Yu , Hu Xugang , Jiang Weiping , Chen Gang , Lv Tangfeng , Song Yong 
Published: May 2020

e21557 Background: Just like classical EGFR mutations, EGFR uncommon mutations non-small cell lung cancer (NSCLC) will still have acquired resistant problem to icotinib. The mechanism of icotinib resistance in such uncommon EGFR mutant patients has also risen to be a difficult question in lung cancer research. In order to explore the resistance mechanism in EGFR uncommon mutant NSCLC patients treated by icotinib, it is necessary to first identify the resistant gene profiles and clinic-pathologic characteristics of those patients. As far as we know that there is no large cohort of EGFR uncommon mutant NSCLC study in evaluating the efficacy and resistant genomic profiling of icotinib. Methods: We screened 3279 patients with NSCLC for EGFR uncommon mutations. Among them, 106 patients received icotinib treatment, and a total of 69 patients with stage IIIb-IV EGFR uncommon mutations NSCLC were undergoing tumor biopsies or blood withdrawing by the time of primary or acquiring to icotinib, in including formalin-fixed paraffin-embedded (FFPE) samples, serum samples and serous effusions. We used targeted next-generation sequencing to detect genes status of patients. Results: Among 69 patients treated with icotinib, 69.57% (48/69) developed acquired resistance, and 30.43% (21/69) had primary resistance. Using the specimens at the baseline, there were 39(81.25%) patients with EGFR T790M (including 7 patients with EGFR T790M, 32 patients with EGFR T790M plus EGFR amplification), 3(36.25%) patients with EGFR amplification, 1(2.08%) patient with BRAF mutation, 1(2.08%) patient with PIK3CA mutation, 1(2.08%) patient with CTNNB1 mutation, 1(2.08%) patient with ALK fusion, 1(2.08%) patient with ROS1 fusion, and 1(2.08%) patient with unknown status. Conclusions: EGFR T790M, EGFR amplification, BRAF mutation, PI3K-AKT-mTOR signaling pathway (PIK3CA mutations), CTNNB1 mutation, ALK fusion or ROS1 fusion might contribute to molecular mechanisms of acquired resistance to icotinib in EGFR uncommon mutations NSCLC. Our study uncovered EGFR uncommon mutational profiles of NSCLC patients with icotinib resistance with potential therapeutic implications.
Does CNS metastases reduce systemic therapy lines for NSCLC patients with EGFR mutation?
Authors: Giffoni Danilo , Romero Maria Luisa , Doherty Mark 
Published: May 2020

e21558 Background: The latest generation tyrosine kinase inhibitor (TKI), Osimertinib, targets the epidermal growth factor receptor (EGFR) despite the T790M mutation status in non-small-cell lung cancer (NSCLC). In cases where there is a detected EGFR mutation on the exon 19-deletion and on the exon 21-L858R in the NSCLC population, studies have demonstrated that Osimertinib has a positive benefit in overall survival and delayed progression of central nervous system (CNS) metastases. Methods: From January 2010 to December 2018, 56 patients with the metastatic NSCLC-EGFR mutation, treated with Osimertinib 80 mg once daily, were included in this analysis. Retrospective data was extracted through the internal administrative databases located at Sunnybrook Hospital. All patients had EGFR mutation positivity by cytology, plasma or tissue sampling. The primary endpoint was to evaluate whether NSCLC patients who were exposed to Osimertinib and had brain metastases underwent fewer systemic therapy lines as compared to those who did not have metastases involving the brain. Results: Eligible patients were analyzed and the median age at the initial diagnosis was 65 years old; 50% (n = 28) of the patients had brain metastases. The median of systemic treatment lines for patients without CNS metastasis was two and for those who have metastases to the brain was three. 82,2% of this cohort received Osimertinib in 2nd line, after development of acquired resistance to first or second TKI generation. Conclusions: Results from this study did not demonstrate that EGFR mutated, NSCLC patients with CNS metastases received less systemic therapy lines to those without metastases involving the brain. A larger cohort for further investigation is warranted.
Musashi 2 (MSI2) expression as an independent prognostic biomarker in non-small cell lung cancer (NSCLC).
Authors: Deneka Alexander , Kharin Leonid , Karnaukhov Nikolay S. , Voloshin Mark , Ayrapetova Tamara G. , Ratner Elena , Sabirov Alexey , Topchu Yulia , Mazitova Alexandra , Abramova Zinaida , Yugai Veronika , Frantsiyants Elena M. , Kit Oleg Ivanovich , Boumber Yanis 
Published: May 2020

e21583 Background: Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death in the world, and metastasis is the most common cause of death in lung cancer patients. Musashi-2 (MSI2) is a member of RNA-binding protein family and regulates mRNA translation of numerous intracellular targets, and influences multiple biological processes, including maintenance of stem cell identity. Previously we reported that MSI2 is upregulated in the metastasis-competent NSCLC murine and human cell lines, drives NSCLC metastasis, and is progressively elevated in lung cancer patient samples. This study assessed MSI2 as potential clinical biomarker in NSCLC. Methods: The current study included 40 patients with NSCLC, of whom 15 presented with stage II and III respectively (37,5% each), and 10 patients (25%) had stage IV. All patients received treatment in accordance with the NCCN guidelines, and did not participate in clinical trials. All patient samples were obtained before treatment started. We used immunohistochemical (IHC) approach to measure MSI2 expression on the protein level in matching specimens of normal versus tumor tissues, and primary tumor vs. metastasis, followed by correlative analysis in relation to clinical outcomes. In parallel, clinical correlative analysis of MSI2 mRNA expression was performed in silico using publicly available datasets (TCGA/ICGC) as of January 2020. Results: MSI2 protein expression in patient samples was significantly elevated in NSCLC primary tumors and metastatic sites versus normal tissue (p = 0.03). MSI2 elevated expression positively correlated with a decreased progression free survival (PFS) (p = 0.026) at all stages and overall survival at stage IV (p = 0.013). Elevated MSI2 expression on RNA level was observed in primary tumor versus normal tissue samples in TCGA (p < 0.0001), and positively correlated with decreased OS (p = 0.028). No correlation was observed between MSI2 expression and age, sex, smoking, and treatment type. Conclusions: Elevated MSI2 expression in primary NSCLC tumors is associated with poor prognosis and can be used as a novel potential prognostic biomarker in NSCLC patients. Future studies in an extended patient cohort are strongly warranted.