bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mastocheck: Notable plasma protein biomarker for diagnosis of breast cancer in the real clinical practice by using multiple reaction monitoring-based mass spectrometry.
Authors: Kim Yumi , Kang Un-Beom , Kim Sungsoo , Lee Han-Byoel , Jung Jigwang , Kim Hong Kyu , Moon Hyeong-Gon , Han Wonshik , Noh Dong-Young 
Published: May 2019

3044 Background: Breast cancer is the most frequently diagnosed cancer and the most leading cause of cancer-related deaths among women worldwide. Although screening mammography is available, there is an ongoing interest in improved early detection and prognosis. And also, serum tumor marker levels, such as CA 15-3 and others, may reflect disease progression and recurrence, they have not proven to be sensitive for early disease detection. Research investigating biomarkers for early detection, prognosis and the prediction of treatment responses in breast cancer is rapidly expanding. However, no validated biomarker currently exists for use in routine clinical practice, and breast cancer detection and management remains dependent on invasive procedures We aimed to develop biomarker for diagnosis of breast cancer in the real clinical practice by using proteomics technology. Methods: Based on our previous studies, we performed verification and validation of 124 candidate proteins by using proteomics approach. Among these 124 candidate proteins, the three proteins (neural cell adhesion molecule L1-like protein, apolipoprotein C-1, carbonic anhydrase-1) with highest statistical significance were selected. We created the performance algorithm of the 3-protein diagnostic model to predict of the breast cancer. We performed several experiments for establishment and validation of cut-off value. Furthermore we conducted test for acquisition of sample stability and more experiments to achieve the reproducibility and level of evidence, compared with other cancers (colon, thyroid, ovary, pancreas and lung cancer) and established effect of anesthesia. Results: Total 1226 samples (532 patients of breast cancer, 562 healthy women and 100 sample of other cancers) was analyzed. The sensitivity, specificity and accuracy from confirmation experiment was 71.58%, 85.25% and AUC 0.8323, respectively. The result of comparison with other cancers, there are no statistical significant difference and no relevance with effects of anesthesia. With these results, we recently got permission it to use for in vitro diagnostic use from Korea Food and Drug Administration. Conclusions: In this study, we developed a plasma protein biomarker that may help to diagnosis of breast cancer in the real clinical practice. By using MRM approach, the 3-protein biomarker was validated in an independent cohort with acceptable accuracy for early diagnosis of breast cancer.
Comprehensive genomic profiling of circulating cell-free DNA (cfDNA) distinguishes focal amplification (amp) from aneuploidy among MET amps in diverse advanced cancer types.
Authors: Kumaki Yuichi , Ikeda Sadakatsu , Rich Thereasa A. , Zhao Jing , Yoshino Takayuki , Cho Byoung Chul , Peled Nir , Han Ji-Youn , Shiotsu Yukimasa , Franovic Aleksandra , Raymond Victoria M. , Kurzrock Razelle , Lanman Richard B. , Lee Jeeyun , Mok Tony S. K. 
Published: May 2019

3046 Background: MET amps can occur from focal gene copy number gain (e.g. MET-driven) or gain of chromosome 7 (e.g. aneuploidy); however, the contribution of each to MET amp is not well established. MET inhibitor-sensitive lung cancers harboring high-level MET amp have been reported in the absence of other sensitizing MET alterations (alts), e.g. exon 14 skipping, particularly among those with higher MET to chromosome 7 ratios. Methods: 3,114 samples from 2,902 Asian patients with advanced solid tumors were tested with a comprehensive cfDNA NGS panel (Guardant360) between Oct 2015-Dec 2018. This 70-73 gene assay evaluates single nucleotide variants (SNV), selected insertion-deletions (indels), fusions, and copy number gains. Focal amp was determined bioinformatically as having statistically higher copy number relative to other genes, such as BRAF, or CDK6, in the same chromosome arm. Results: MET alts associated with aberrant signaling were found in 223 pts (7.7%) with 18 different cancer types, most commonly lung (128/1,678), colorectal (36/349), and prostate (11/48). Among 223 pts, 189 pts (84.8%) had amps, 38(17.0%) had exon 14 skipping, and 8 (3.6%) had activating SNVs. 39.7% of MET amp was focal but differed by cancer type; highest prevalence was in gastroesophageal (80%) and lowest in prostate cancers (9%). Samples with focal MET amp had higher plasma copy number compared to those with non-focal MET amp (mean 5.8 vs. 2.5; p < 0.0001) and lower total number of alts per sample (8.8 vs. 11; p = 0.0122). Focal MET amp was more common than non-focal MET amp among 419 EGFR mutated samples (6.9% vs. 3.8%, p = 0.05) suggesting focal MET amp may be biologically more relevant as a mechanism of EGFR TKI resistance. Conclusions: This is the first study to use cfDNA to examine focal vs. non-focal MET amp. Focal MET amp accounted for ~40% of all MET amps, was found in 2.6% of pts with diverse cancers, was associated with higher plasma copy number, and found in a higher proportion of EGFR mutated lung cancer samples. The ability to differentiate may be clinically relevant given higher MET to chromosome 7 ratios have been associated with improved therapeutic response.
CTC versus biopsy tissue sequencing: A concordance analysis of genomic copy number profile from mCRPC patients (pts).
Authors: Scher Howard I. , Lee Jerry , Dago Angel E. , Barnett Ethan , Sutton Ramsay , Carbone Emily , Schreiber Nicole A. , Hullings Melanie , Ebrahim Nadia , Landers Mark Andrew , Wang Yipeng , Solit David B. , Berger Michael F. , Schultz Nikolaus , Dittamore Ryan 
Published: May 2019

3050 Background: MSK-IMPACT (Integrated Mutation Profiling of Actionable Cancer Targets), is a high throughput, targeted-DNA-sequencing panel for somatic mutations created by the Department of Pathology at Memorial Sloan Kettering Cancer Center (MSK). The MSK-IMPACT is FDA approved for tumor tissue profiling to guide treatment selection. Recognizing access to tumor tissue in many cancers is difficult and may harbor inter & intra lesional heterogeneity, we sought to evaluate concordance of sequencing single CTCs vs. paired biopsy analyzed by MSK-IMPACT, to assess CTC vs. tumor clonality, and their relationship to outcomes. Methods: 148 biopsy samples from 138 mCRPC pts were submitted for IMPACT analysis and a blood draw within 30-day prior to initiation of a new line of treatment. Blood samples were sent to Epic Sciences for CTC detection. The detected CTCs underwent single cell low pass whole genome sequencing for copy number variation (CNV). For each set of matched samples, DNA copy number profiles from IMPACT and CTC sequencing were compared for similarity. Results: Of the 114 successfully sequenced samples 58 were from lymph nodes, 23 from bone, 25 from liver or lung, and 8 from other soft tissue. Of the 111 patients with CTCs analyzed, a total of 1073 CTCs were sequenced (range 1-27, median = 4 per pt). Of patients with both IMPACT & CTC, >80% pts had multiple subclones with distinguishable CNV. Concordance of genomics clones was found in 63%, and discordant in 37% cases. The clonal concordance between tissue biopsy and CTC was higher when the biopsy was obtained from bone marrow or a visceral site (71% concordance) than from a lymph node (53% concordance). Conclusions: Single CTC sequencing is often concordant to metastatic tissue, but unique CTC clones and the presence of multi-clonal disease highlight the potential to be underrepresented through tissue biopsy, especially when taken from the lymph node.[Table: see text]
Associations between baseline serum biomarker levels and cachexia/precachexia in pretreated non-small cell lung cancer (NSCLC) patients.
Authors: Lobato Gabriela C. , Fidler Mary J. , Fialkoff Jared D. , Multani Maneet , Fughhi Ibtihaj , Wakefield Connor , Basu Sanjib , Batus Marta , Bonomi Philip D. , Borgia Jeffrey Allen 
Published: May 2019

3054 Background: We previously reported associations of pretreatment serum biomarkers with clinical outcomes in a cohort of advanced NSCLC patients that progressed on front-line therapy. This study aims to elucidate mechanisms underlying cancer cachexia/ pre-cachexia by evaluating relationships between baseline serum biomarker values and sequential changes in body weight, body mass index (BMI), and neutrophil/lymphocyte ratio (NLR) in NSCLC patients. Methods: We used Luminex immunobead assays to survey 101 protein biomarkers in sera from advanced NSCLC (n = 138) collected prior to their salvage regimen. Serial parameters associated with cancer cachexia included body weight, BMI, and NLR. Outcome variables (progression-free survival (PFS) and overall survival (OS)) were extracted with full IRB-approval. Biomarkers were evaluated as continuous variables with the cachexia surrogates using Pearson correlations, whereas associations of PFS and OS were accomplished with the Cox PH test. Results: High baseline values of BMI and low baseline NLR were associated with both OS and PFS (each p < 0.05), though weight failed to reach significance. PFS and OS were similarly associated with percent changes (relative to baseline) in weight (p < 0.01), BMI (p < 0.01), and NLR (p < 0.001). Thirteen biomarkers were found to be associated (p < 0.05) with baseline BMI values, including positive correlations with leptin, sol.VEGFR2, and c-peptide and inverse correlations with adiponectin, ferritin, ghrelin, IGFBP-1 and IL-8; fifteen biomarkers were associated with baseline NLR (all p < 0.05), including positive correlations with visfatin, insulin, and serum amyloid A and inverse correlations with IGF-II. Fifteen biomarkers were found to be associated (p < 0.05) in common with percent weight and BMI changes, including positive correlations with IGFBP-3 and inverse correlations with insulin, FGF-2, TNF-alpha, and resistin. Only prolactin and placental growth factor were found to be associated (p < 0.05) with percent change in NLR. Conclusions: A series of circulating protein biomarkers primarily connected with metabolic regulation and systemic inflammation/ acute phase response were found to be associated with cachexia/ pre-cachexia in NSCLC patients. Additional cohorts are currently being tested to verify these findings.
Pooled analysis of phase I dose-escalation and dose cohort expansion studies of IMP4297, a novel PARP inhibitor, in Chinese and Australian patients with advanced solid tumors.
Authors: Cao Junning , Zhang Pin , de Souza Paul L. , Gao Bo , Voskoboynik Mark , Ji Dongmei , Shen Weina , Yang Sheng , Zhou Yinglei , Zhang Rong , Lickliter Jason D. , Hoon Siao-Nge , Palmieri David , Cai Suixiong , Tian Ye Edward , Ma Ning , Xu Cong , Yang Stone , Zhang Shuaishuai , Xu Binghe 
Published: May 2019

3059 Background: Poly (ADP-ribose) polymerase (PARP) enzymes play critical roles in DNA damage detection and repair. IMP4297 is a novel, potent PARP1/2 inhibitor (IC50 6.27nM/1.57nM) and has demonstrated to be 20-fold more potent than Olaparib in anticancer animal models. Two phase I studies were performed to evaluate and characterize the tolerability and safety, pharmacokinetics, and antitumor activity of single agent IMP4297 in Chinese and Australian patients with advanced ovarian, breast, prostate and other solid tumors. Methods: Dose escalation used a 3+3 design with a modified Fibonacci escalation. Dose cohort expansion was planned after efficacy was observed at the lowest dose level. Patients received IMP4297 monotherapy orally once a day until disease progression or unacceptable toxicity. Results: As of Jan 12, 2019, 56 patients, including 23 BRCA mutation carriers (BRCA+), had been enrolled at 2-100 mg dose level. No DLT was observed. In these two studies, the most frequent treatment-related adverse events (TRAEs) were leukopenia (20%), followed by anemia (18%), nausea (18%) and thrombocytopenia (14%). The majority of TRAEs were grade 1 or 2. Grade 3 TRAEs occurred in five patients (anemia, n=2; vomiting, n=1; thrombocytopenia, n=1; elevated AST, n=1). Only one patient had a dose reduction due to grade 3 thrombocytopenia. No serious TRAEs were observed. In 15 BRCA+ patients who had measurable lesions, the ORR was 33% and the DCR was 80%. There were 4 BRCA+, platinum-sensitive ovarian cancer patients with an ORR of 75% and a DCR of 100%. One patient with somatic BRCA mutated urothelial carcinoma showed a 76% decrease in tumor size. Conclusions: IMP4297 has been well-tolerated with significant anti-tumor activity. The 100 mg daily dose was selected as the RP2D based on safety, pharmacokinetics and clinical activity, and will be further characterized in dose expansion and phase II studies. Tumor response to treatment (RECIST 1.1) in patients with measurable lesions. Clinical trial information: NCT03508011 and NCT03507543. [Table: see text]
Is the optimal biological dose of oncologic molecular-targeted therapies also clinically effective?
Authors: Corbaux Pauline , El Madani Mevidette , Tod Michel , Peron Julien , Maillet Denis , Lopez Jonathan , Freyer Gilles , You Benoit 
Published: May 2019

3060 Background: The determination of the optimal biological dose (OBD) defined as the lowest safe dose associated with biological efficacy, appears to be a promising endpoint for defining the recommended phase 2 trial dose (RP2D) of novel oncologic targeted therapies in early-phase clinical trials. However, the clinical relevance of OBD is still unknown. We conducted a review to assess if the OBDs of molecular targeted therapies defined during early phase trials were useful during subsequent drug development and for oncologic drug approvals. Methods: A systematic review was conducted to identify all the molecular targeted therapies approved by FDA in solid and hematological malignancies, and for which early phase trials defined OBDs. The publications of efficacy trials leading to the first FDA approvals were reviewed, as were the FDA approved doses and dosing schedules, which were compared to OBDs found in the early phase trials. Results: OBDs were reported in the early phase trial articles of 39.5% (32/81) FDA approved targeted therapies from 1999 to 2017 (19 small molecules and 13 monoclonal antibodies (mAbs)). The maximum tolerated doses (MTD) had not been reached for 59.4% (19/32) of these drugs. When both MTD and OBD had been defined, OBD were lower than MTD in 84.6% of cases, and equal for the others. The OBDs were chosen as the RP2Ds for 56.3% of the molecules. In that case, the final FDA approved doses were consistent with the OBDs for 83.3% of the drugs. These percentages did not differ in between small molecules and mAbs. OBDs mainly relied on indirect effects on the involved signaling pathway elements for small molecules (11/19, 57.9%), and on involved receptor occupancies for mAbs (6/13, 46.2%). In total, 23.5% of all FDA approved molecular targeted therapies were approved at their OBDs. Conclusions: Although still poorly investigated, OBD may represent a relevant complementary endpoint in in early phase trials of novel anti-cancer targeted therapies, as OBDs are selected as the final FDA approved doses in 83.3 % of cases when chosen as the RP2Ds, which is much higher than the previously reported 58.0 % when MTDs are chosen as the RP2Ds (Fontes-Jardim et al. JNCI 2015).
A phase I multiple-dose escalation study to assess the safety, tolerability, and pharmacokinetics of VEGF-receptor inhibitor telatinib (EOC315) in Chinese patients with advanced solid tumors.
Authors: Pan Hongming , Liu Tianshu , Tsai Jason , Zhao Yapeng 
Published: May 2019

3061 Background: Telatinib (EOC315) is a highly selective inhibitor of VEGFR/PDGFR (VEGFR 1-3, PDGFR-β, and c-Kit tyrosine kinases). This phase I study was to assess the safety, tolerability, and pharmacokinetics (PK) of Telatinib in Chinese patients with advanced solid tumors. Methods: Telatinib was administered to Chinese patients with advanced refractory solid tumors as a single agent in 3+3 dose escalation design, starting from 600mg and escalated to 900mg and 1200mg, given orally twice daily. The PK profile, safety, and tolerability were evaluated per protocol. Efficacy was evaluated with RECIST 1.1 criteria every 6 weeks. Results: A total of 15 subjects (6 colorectal cancer, 4 lung cancer, 1 head and neck cancer, 1 melanoma, 1 thymic carcinoma, 1 esophageal carcinoma,1 peritoneal carcinoma) were enrolled per protocol between July 2017 and August 2018, and 13 subjects received at least second line therapies before enrollment. Telatinib was well tolerated in the three dose arms. No dose limiting toxicities (DLTs) occurred during the dose escalation phase. CTC grade 3 AEs observed include hypertension (46.7%, 7/15), fatigue (6.7%, 1/15), transaminase elevation (6.7%, 1/15), hand-foot syndrome (6.7%, 1/15), oral mucositis (6.7%, 1/15), neutropenia (6.7%, 1/15), urobilinogen elevation (6.7%, 1/15), left ventricular systolic dysfunction/decreased ejection fraction (6.7%, 1/15). No CTC grade 4 AE were observed. There were 2 drug related SAEs (hospitalization due to high blood pressure. The PK profile of Telatinib (EOC315) at 600, 900, 1200 mg in Chinese patient cohorts is summarized in Table. For 12 evaluable patients, DCR was 58.3%. For all patients, mPFS was 15 weeks (3.3-34.3w). Conclusions: This study demonstrated the safety and tolerability of Telatinib (EOC315) in a multiple dose escalation design at 600, 900, and 1200 mg PO bid in Chinese patients with advanced refractory solid tumor. Telatinib AUC increased dose-proportionally from 600 mg to 900 mg bid, where 900 mg Telatinib bid is the maximum feasible and recommended dose for future studies in Chinese patients with advanced tumors. Clinical trial information: NCT03175497. [Table: see text]
Modular phase I/II clinical trial evaluating the selective MET-kinase inhibitor OMO-1 in patients with advanced malignancies: Safety and proof of mechanism.
Authors: Lolkema Martijn P. , Plummer Elizabeth Ruth , De Vos Filip Yves Francine Leon , Forster Martin David , Angevin Eric , Libouban Marion , Jansen Ellen , Tjwa Marc , Ciamporcero Eric , Meulemans Ann , Van der Aa Annegret , Perera Timothy Pietro Suren , Clack Glen , Krebs Matthew , Blagden Sarah Patricia 
Published: May 2019

3062 Background: MET kinase is a therapeutic target in a range of cancer indications; it is a primary oncogenic driver and a mechanism of therapy resistance. OMO-1 is a highly potent, selective oral inhibitor of MET kinase and Organic Cation Transporter 2 (OCT2). Methods: This study assesses the safety, tolerability, pharmacokinetics (PK) and preliminary activity of OMO-1 in patients (pts) with advanced malignancies (NCT03138083). Module 1 data, evaluating ascending doses of OMO-1 monotherapy, are reported here. Results: As of January 16, 2019, 34 pts were enrolled at 5 twice-daily (BD) dose levels of OMO-1: 100, 200, 250, 350, and 400 mg, including 10 with MET gene amplified or mutated tumours. OMO-1 was generally well tolerated between 100 - 250 mg BD; pts were in the study for an average of 94 days (range: 15-291 days) and 20/34 pts discontinued due to disease progression. Most frequently-reported AEs were nausea (17/34), vomiting (14/34) and fatigue (14/34), mainly G1-2. Notably, no peripheral oedema, cardiovascular events or non-malignancy related LFT abnormalities were observed. A total of 36 SAEs were reported: 17 in 11 subjects were considered related to OMO-1, and included nausea (3/17), vomiting (4/17), chills, diarrhoea, influenza-like illness (2/17), increased blood bilirubin, blood creatinine (3/17) and neutrophil count, and sepsis. A dose of 250 mg BD was determined as the recommended Phase 2 dose (RP2D); doses ≥350mg BD were not in keeping with optimum long-term dosing: at 400 mg BD, 2/3 subjects experienced influenza-like illness (G2 and G3) and at 350 mg BD 2/5 subjects had G2 fatigue and nausea/vomiting. OMO-1 has a half-life of 2.5-3 hrs and plasma exposure is dose-proportional without accumulation. Elevated creatinine was observed across all dose levels, consistent with OCT2 inhibition. IHC analysis on paired tumour biopsies from a MET-mutated NSCLC pt dosed at 200 mg BD showed near-complete inhibition of phosphorylated MET, without affecting total MET. Conclusions: OMO-1 has a favourable safety profile at a RP2D of 250mg BD. Expansion cohorts for MET mutated/amplified tumour types are enrolling. Clinical trial information: NCT03138083.
Rethinking about the dose limiting toxicities (DLTs): They can be equivocal!
Authors: Zhong Wei , Bugarini Roberto , Wang Ling , Basu Cynthia , Beaupre Darrin M. 
Published: May 2019

3064 Background: The primary goal of oncology phase I trials is to determine the maximum tolerated dose (MTD) in a small number of patients. Within the standard design methodology currently employed there remains many challenges and one pertains to the variability around defining dose limiting toxicities (DLTs). The pre-specified DLT criteria may not well reflect the clinician’s practical experience with some adverse events, while others may actually be related to the disease status more than the investigational drug and could be misclassified. DLT misclassification seen in testing a small sample size from each dose group could generate a large bias on dose finding and the MTD estimation. Methods: To mitigate the risk of dichotomizing and misclassifying DLTs, we proposed a strategy that introduced the new concept of “equivocal” DLT or AE. A novel dose escalation approach is applied to increase the variability associated with less interpretable AEs so that the model recommendations are more weighted towards the unequivocal AEs/DLTs. To evaluate this novel approach, we established a framework incorporating two types of systematic measurement errors on DLT misclassification, one for the misclassified DLT that is not related to the drug treatment while the other for the non-DLT AE that should be considered severe and relevant to dose finding. In our simulation studies, the Bayesian logistic regression model (BLRM) was used to guide dose escalation in simulated trials to compare the novel weighting approach with the traditional approach. A few numerical examples were also included for method illustration. Results: For different types of measurement errors, simulation studies showed that the weighting approach could successfully improve the trial performance, with higher chance of finding the correct MTD and treating more patients at the MTD level. Conclusions: The DLT weighting strategy provides a flexible but powerful tool that may incorporate the clinician’s valuable experience on some specific DLTs/AEs and improve MTD estimation in oncology phase I dose-escalation trials.