bluuebunny/crossref_metadata_2025_split huggingface dataset:
PDX validation of a 3D microtumor platform.
Authors: Sampson Ellen , Nikolov Katya , Henderson Paul T. , Apfel Christian , Pan Chong-xian , Zimmermann Maike , Ma Ai-Hong 
Published: May 2019

3029 Title: Patient-derived xenograft validation of a 3D microtumor platform Background: Patient-derived xenograft (PDX) mouse models are thought to most closely reflect the biology of a patient’s cancer. Unfortunately, growing sufficient tumor in a PDX model takes several months and more often than not, the tumor fails to grows at all. The SAGE Direct Platform, an in-vitro model, can create hundreds of live microtumors from virtually every patient’s viable biopsy and test a panel of clinically relevant drugs within no more than 1 week. Thus, concordance of results from a PDX model with results of the SAGE Direct Platform would support a rational for the platform to be potentially useful to predict tumor response in cancer patients. Methods: A bladder cancer from a 77 year old female was used to establish a PDX model. Mice were divided into three groups receiving either saline (control), cisplatin, or gemcitabine intraperitoneal on the days 1, 8, and 13, and tumor growth was observed. One tumor sample was used to create 3D microtumors and those were tested using the same drugs. Results: Tumor growth (exceeding 1,000 mm3) was similar after cisplatin compared to control (4.8 vs. 3.7 weeks). After gemcitabine tumors initially shrank and only started growing a couple of weeks after the end of treatment so that 1,000 mm3 was only reached after 10.2 weeks (p<0.001 compared to cisplatin and control). In the SAGE Direct Platform the EC50 of cisplatin was 97.3 µM and thus two orders of magnitudes higher than the EC50 of gemcitabine, which was 0.7 µM. Conclusions: Both the PDX model and the SAGE Direct Platform have shown this bladder cancer to be virtually resistant to cisplatin while very sensitive to gemcitabine. The next steps of these preliminary data could be to repeat this experimental design with other tumors and/or to start an observational cohort study in patients correlating the SAGE Direct Platform results to patient outcomes.
Anticancer activity in patients with advanced ovarian and biliary tract cancers treated with NUC-1031 and a platinum agent.
Authors: Blagden Sarah Patricia , Bré Jennifer , Mullen Peter , Gnanaranjan Chathunissa , Ghazaly Essam Ahmed , McNamara Mairead Geraldine , Valle Juan W. 
Published: May 2019

3030 Background: The inhibition of cellular nucleotide metabolism to promote apoptosis is a key principle of cancer therapy. This, in combination with platinum-induced DNA-damage, is key to promoting anti-cancer activity in a variety of tumors, including ovarian, biliary tract, lung, breast and bladder. NUC-1031, a phosphoramidate transformation of gemcitabine is designed to overcome resistance mechanisms that limit the efficacy of this nucleoside analog. NUC-1031 has shown broad clinical activity across multiple solid tumors as both a single agent and in combination with platinum agents. We show potential synergism between NUC-1031 and a platinum agent in advanced ovarian (OC) and biliary tract (BTC) cancers. Methods: PRO-002 was a phase Ib study; 25 patients (pts) with recurrent OC who had exhausted all other therapy options received NUC-1031 + carboplatin. 17 pts were considered platinum resistant (10) or platinum refractory (7). ABC-08 is a phase Ib study, 14 pts with advanced BTC treated in the first-line setting with NUC-1031 + cisplatin. Results: In PRO-002, strong efficacy signals were observed in non-platinum-responsive patients. Of the 17 response-evaluable platinum-resistant or refractory pts, 5 partial responses (PRs) and 11 stable diseases (SDs) were achieved, resulting in an ORR of 29% and a DCR of 94%. NUC-1031 + carboplatin was well-tolerated with no unexpected AEs; DLTs were myelosuppression and fatigue. Encouraging response rates were also observed in ABC-08 compared to historical standard of care (ABC-02). One CR (7%), 6 PRs (43%) and 1 SD (7%) were observed, resulting in an ORR of 50%. NUC-1031 + cisplatin was well-tolerated, with no unexpected AEs or DLTs. Complementary in vitro evidence suggests that the beneficial interaction occurs whereby platinum treatment sensitizes cells to NUC-1031. Conclusions: Increasing evidence suggests that NUC-1031 in combination with a platinum agent may have synergistic properties, leading to enhanced anti-cancer activity. In both OC and BTC, durable tumor shrinkage was observed. This was particularly encouraging in a platinum resistant/refractory OC population. Future studies utilizing both NUC-1031 plus a platinum agent will further elucidate the potential of this therapeutic combination.
Dynamic monitoring of circulating tumor DNA next-generation gene sequencing as a predictive biomarker of response and progression-free survival after pembrolizumab monotherapy in patients with advanced NSCLC.
Authors: Aggarwal Charu , Thompson Jeffrey C. , Chien Austin , Quinn Katie , Lefterova Martina , Nagy Rebecca , Yee Stephanie , Ciunci Christine Agnes , Alley Evan W. , Bauml Joshua , Cohen Roger B. , Langer Corey J. , Carpenter Erica L. 
Published: May 2019

3040 Background: Circulating tumor DNA next generation sequencing (ctDNA NGS) is increasingly being used to detect mutations (MT) in patients (pts) with metastatic (m) NSCLC. Limited data exist on the correlation of baseline ctDNA NGS profile and serial ctDNA NGS monitoring to response to immunotherapy. Methods: We conducted a prospective study in pts with mNSCLC receiving pembrolizumab monotherapy. Plasma was collected at weeks 0 (T0), 9 (T1), and 18 (T2). ctDNA NGS was performed using a 73 gene panel. Number of MTs and variant allelic fraction (VAF) were determined at baseline, and serially; change in mean VAF was calculated between T1-T0, and T2-T0. Response rate (RR) was assessed using RECIST 1.1. Correlations were made for pt characteristics, RR, progression free survival (PFS), and overall survival (OS). Results: We analyzed 95 samples from 33 pts, 21 female, median age 69 (range 51-89 years), smokers (n = 29), adenocarcinoma (n = 23), 25 pts enrolled at initial diagnosis, majority had high PD-L1 ≥50% (n = 29, 88%). At T0, 32 pts had detectable MT, median number of MTs was 4 (range 0-21), (non-synonymous MT = 3), most common MT was TP53 (n = 21). Confirmed PR was 27% (n = 9), clinical benefit rate (SD+PR) was 64% (n = 21), and 2 pts were not evaluable for response. Smokers were more likely to have higher number of MT at T0 (4 vs. 1 p = 0.003); there was no correlation with smoking and overall RR (p = 0.17). RR was not related to number of MT at T0, p = 0.37. A decrease in ctDNA VAF was seen in 6/9 pts with PR (mean VAF change range -0.11 to -0.001); 2/5 pts with PD showed an increase in mean VAF while 3 showed decrease. At median follow up of 9.26 months (mos), median PFS and OS were 7.4 and 10.5 mos, respectively. Median PFS was longer for pts with a decrease in ctDNA VAF at both T1-T0 (8.9 vs. 5 mos, p = 0.02) and T2-T0 (9.1 vs. 5.5 mos, p = 0.006). OS and additional biomarker analyses including correlation of response to a 2mb ctDNA plasma-based NGS panel will be reported at the meeting. Conclusions: Our results demonstrate that it is feasible to serially monitor plasma NGS, decline in mean ctDNA VAF correlates with radiographic response and PFS on immunotherapy with pembrolizumab.
NMR-metabolite-resonance signature to predict HR+ breast cancer patient response to CDK4/6 inhibitors.
Authors: Zhang Bo , Warner Jason , Pinto Christopher , Juric Dejan , ODay Elizabeth 
Published: May 2019

3043 Background: Advanced ER+ breast cancer patients have reported prolongation of stable disease when treated with a CDK4/6 inhibitor as a monotherapy or in combination with endocrine treatment. However ~20% of patients are intrinsically resistant and all patients eventually acquire resistance to these therapies. There is a critical need to identify biomarkers that accurately predict response and resistance to CDK4/6 inhibitors. ER-positivity, luminal patterns of gene expression, Rb function, overexpression of cyclin D1, cyclin E, CDK6 and low levels of p16 are biomarkers that do not accurately match clinical outcomes. Methods: We performed a retrospective study analyzing plasma-based metabolites from a baseline (pre-dose) and ~2 months post treatment of 21 women with estrogen-receptor-positive (ER+) metastatic breast cancer treated with CDK4/6 inhibitors. Results: By correlating the metabolite expression profiles to clinical outcomes we were able to identify a metabolic signature that could differentiate the CDK4/6 responders and resistant patients with a predictive accuracy of > 90%. Further we were able to identify independent signatures predictive of response for individual CDK4/6 inhibitors palbociclib and ribociclib. Conclusions: The results of this study could lead to a paradigm shift in the administration of CDK4/6 inhibitors wherein prior to treatment and during treatment patient plasma is screened to determine whether that individual patient is responsive or resistant to a CDK4/6 inhibitor.
Identification and validation of a serum microRNA panel for detection of early-stage breast cancer.
Authors: Zou Ruiyang , Zhou Lihan , Loke Sau Yeen , Too Heng-Phon , Lee Ann 
Published: May 2019

3051 Background: The implementation of mammogram-based screening has significantly improved the early detection of breast cancer in the west. However, the use of screening mammography is less prevalent in Asia partly due to social and cultural reasons. The aim of this study was to determine if a serum microRNA (miRNA) panel could be used as biomarkers to assist in the early detection of breast cancer. Methods: We conducted a multi-center, multi-ethnic study to identify and validate miRNA biomarkers for the early detection of breast cancer. A total of 1070 subjects including 550 breast cancer cases (predominantly stage 1 and 2) and 520 matched controls from 6 independent sources were included in this study. Among these, there were 768 American and European subjects recruited by biobanks and 302 Singaporean Asian Subjects recruited at the National Cancer Centre Singapore and the National University Hospital. The study was conducted in 3 phases. First, 119 European Caucasian serum samples (Discovery Cohort) were interrogated to identify differentially expressed miRNAs between early-stage breast cancer cases and matched controls, among 520 circulating miRNA candidates by quantitative RT-PCR using MiRXES assays. The remaining 951 subjects from 5 independent sources were assigned into two groups for biomarker optimization/algorithm development (Optimization Cohort, n = 451) and validation (Validation Cohort, n = 500). Results: Among the 520 circulating miRNAs measured, 241 were quantified in absolute copy numbers for 119 subjects in the Discovery Cohort. Thirty-two candidate miRNAs were identified. These miRNAs consistently showed differential expression between cancer and control subjects in the Optimization Cohort. A multi-variant panel of 8 miRNAs and an algorithm was developed using the combined Discovery and Optimization Cohorts, with an AUC of > 0.90. When validated in the independent Validation Cohort, the panel demonstrated an AUC of > 0.85. Conclusions: We developed and validated a serum miRNA panel that is both sensitive (~70%) and specific (~90%) in detecting early-stage breast cancer.
Changes in DNA hydroxymethylation for the detection of multiple cancers in plasma cell-free DNA.
Authors: Bergamaschi Anna , Collins Francois , Ellison Chris , Ning Yuhong , Guler Gulfem , Phillips Tierney , McCarthy Erin , Wang Wendy , Antoine Michael , Ku Jeremy , Scott Aaron , Lloyd Paul , Ashworth Alan , Levy Samuel 
Published: May 2019

3058 Background: Methylation and hydroxymethylation of cytosines enable the epigenomic regulation of gene suppression and activation. 5-hydroxymethyl-cytosine (5hmC) is globally decreased in tumor tissue. However, genome-wide analysis using precise 5hmC labelling techniques reveals more nuanced changes upon tumorigenesis and raises the possibility that this loss could be exploited for developing a cancer biomarker. This suggests that 5hmC profiles might enable discrete classification of not only tumor tissue but also of tumor cell-free DNA (cfDNA). We sought to identify genome-wide 5hmC changes in plasma based cfDNA from cancer patients representing multiple disease types, stages and clinical characteristics in comparison with non-cancer patients. Methods: cfDNA was isolated from plasma, enriched for the 5hmC fraction using chemical labelling, sequenced, and aligned to the genome to determine 5hmC counts per genomic feature. Regularized regression models were constructed to classify cancer samples (age matched or corrected for smoking status) on non-overlapping training (80% of all samples) and test sample sets (20% of all samples). Results: 226 non-cancer patients and 278 cancers across four cancer types (breast, colorectal, lung-squamous and pancreas) were included in this study, where more than 60% of cancer samples were early stage disease (I or II). Upon comparison with non-cancer samples, 5hmC peaks have reduced enrichment in exons in breast, colorectal and lung cancer but not in pancreatic cancer. Further, 5hmC peaks in pancreas show different patterns of enrichment in 3’UTR, translational termination sites, promoters and LTR. Overall 5hmC signal density was reduced in late stage cancers across all four diseases. The ability to classify non-cancer versus cancer patients was evaluated via cross-validation of out of fold prediction in the training set with AUC > 0.84 for all four cancer types. Further, test set sensitivity across all four cancer types was found to be > 66% with 98% specificity. Conclusions: These findings suggest that 5hmC changes in plasma cfDNA enable classification of early stages of breast, colorectal, lung-squamous and pancreas cancer and are promising biomarkers for disease detection.
Effectiveness of ASCO’s adverse event reporting decision aid: Results from an interventional study.
Authors: Mileham Kathryn Finch , Buchmeier Andrea D. , Chuk Meredith Kathleen , Davis Courtney , Forest Anne Marie , Garrett-Mayer Elizabeth , Hurley Patricia A. , Levit Laura , Perez Raymond P. , Schenkel Caroline , Vose Julie 
Published: May 2019

3065 Background: Investigators often send adverse event (AE) reports to sponsors that are incorrectly categorized as serious or attributed to the investigational drug. Such errors contribute to a high volume of uninformative IND safety reports that sponsors submit to FDA and all participating investigators, straining stakeholder resources and impeding the detection of valid safety signals. To improve the quality of AE reporting, ASCO developed and tested a Decision Aid Tool (DAT). Methods: An interventional study with a cross-over design was conducted. Physician investigators and research staff were randomized to receive case studies. Cases were assessed for seriousness and attribution, first unassisted and then with the DAT. Participants completed a feedback survey. Effectiveness of reporting and attribution were assessed using logistic regression. Results are reported as odds ratios (OR) with 95% confidence intervals (CI). Results: Most of the 29 participants reported that the DAT was helpful (93%), improved their decision-making time (69%) and confidence in reporting (83%), and that they would use it in practice (83%). The DAT did not significantly affect accuracy of determining seriousness (OR, 0.87; 95% CI: 0.31, 2.46) but it did significantly increase accuracy of attributing a serious AE to a drug (OR, 3.60; 95% CI: 1.15, 11.4). Conclusions: The DAT shows promise as a method to reduce errors in attribution of AEs, which may help to ensure the detection of valid safety signals. Many participants were experienced clinical trialists, and the DAT may show greater utility as an educational tool for novice investigators, research staff, and students.
Image-guided surgery for tumor agnostic detection of solid tumors using the pH-activated micellar imaging agent ONM-100.
Authors: Voskuil Floris Jan , Steinkamp Pieter Jan , Koller Marjory , van der Vegt Bert , Doff Jan Johannes , Zhao Tian , Hartung Jeffrey P. , Jayalakshmi Yalia , Sumer Baran D. , Gao Jinming , Witjes Max J.H. , Van Dam Gooitzen Michell 
Published: May 2019

3068 Background: ONM-100, a micelle-based polymer imaging agent conjugated to indocyanine green (ICG) and with an exquisitely pH-sensitive binary activation mechanism, may be used for tumor detection. ONM-100 micelles dissociate in acidic environments resulting in activation of the fluorescent ICG tag. As nearly all solid cancer types are acidotic, ONM-100 has the potential to act as a broadly indicated tumor agnostic imaging agent. This first-in-human study investigates the safety and feasibility of ONM-100 as a tumor agnostic imaging agent for intra-operative fluorescent imaging of various solid tumors. Methods: ONM-100 was IV administered 24±8h prior to surgery in a dose escalation scheme (0.1-1.2mg/kg). Patients with histopathologically confirmed breast cancer (BC), head and neck squamous cell carcinoma (HNSCC), colorectal cancer (CRC) and esophageal cancer (EC) were included. Blood was drawn to assess safety and pharmacokinetic data. Intra-operative fluorescence images were collected before and after tumor excision. Post-excision fluorescence images were obtained from serially sliced specimens and correlated with standard histopathological assessment. Results: 30 patients (11 BC, 13 HNSCC, 3 EC, 3 CRC) were enrolled. No ONM-100 related serious adverse events were observed and the agent was well-tolerated. A strong and sharply demarcated fluorescent signal was observed in all patients with vital tumor tissue (median CNR ranging 1.85-14.05) which correlated with tumor on final histopathology. HNSCC and superficially located BC as well as peritoneal metastasis could be clearly visualized in vivo during surgery. In four patients (BC and HNSCC), perioperatively, tumors otherwise unnoticed by the surgeons were detected on the margin or wound bed using fluorescence imaging. Additionally, two BC tumor lesions were detected that were missed by conventional pre-operative imaging and pathological assessment. Conclusions: ONM-100 appears to be safe and enables fluorescent visualization of tumors both in vivo and ex vivo. The first-in-human data demonstrate the feasibility for potential use of ONM-100 for image guided surgery, margin assessment and detection of occult disease. Clinical trial information: NTR 7085.
A functional measurement of MAPK pathway activation to predict response to MEK inhibitors in RAS-mutated patients.
Authors: Kato Shumei , Porter Robert , Okamura Ryosuke , Zelichov Ori , Tarcic Gabi , Vidne Michael , Kurzrock Razelle 
Published: May 2019

3071 Background: MEK inhibitors can be used to treat patients with mutations that affect the MAPK pathway. Several MEK inhibitors are currently FDA-approved and effectively treat BRAF-mutated tumors, but RAS-mutated cancers are considered more resistant. However, it is unclear how the many distinct RAS variants impact the MAPK pathway and are affected by MEK inhibitors. We hypothesized that the level of MAPK pathway activation induced by different RAS mutations may predict response to MEK inhibition. Methods: Thirteen RAS mutations from 34 patients treated with MEK inhibitors at UCSD were synthesized, expressed in a HeLa-derived cell line and analyzed in vitro using a functional mutational analysis assay based on assessing downstream reporters in order to measure the activity of these mutations on the MAPK pathway. Each mutation received an activity score based on known oncogenic RAS mutation. Results: The most common type of cancer was colorectal cancer (N = 13). All patients received the MEK inhibitor, trametinib, based therapy. Patients were stratified into two groups: above an activity score of 1 (14 pts) or below it (20 pts). Median progression-free survival (PFS) after MEK inhibitor treatment correlated with higher MAPK activity score (9 vs 3 months; P = 0.041). Conclusions: Using a novel functional assay methodology for characterization of MAPK activation, we show that various RAS mutations activate the MAPK pathway to different levels. Higher activity is associated with longer PFS after MEK inhibitor treatment, suggesting that the relationship between signal transduction strength and clinical relevance merits additional exploration.
Observational, multicenter, prospective study to assess the impact on patients' outcome of a systematic screening of oncogenic drivers in advanced cancer: The GETHI XX-16 study.
Authors: Beato Carmen , Navarro Paloma , Rodriguez-Moreno JF , Navarro L Miguel , Jimenez Munarriz Beatriz , Bruixola Gema , Balana Carmen , Fenor MD , Fuster Jose , Zambrana Francisco , Sevillano Elena , Vila-Navarro Elena , NoguerÃ³n Esther , Mielgo Rubio Xabier , Viudez Antonio , Mediano Maria Dolores , Virizuela Juan Antonio , Ruiz Sergio , Mata Elena , Garcia-Donas Jesus ,   Spanish Groups for Orphan and Rare Cancer (GETHI)
Published: May 2019

3082 Background: Identification of “agnostic” genetic drivers in cancer is foreseen as a major step forward in precision medicine.Unfortunately, “off label” use of targeted therapies is not widely available and many oncogenic alteration do not present the same behaviour accross all tumor types.We aimed to analyze the real impact on patients management of the implementation of a systematic screening of genetic alterations in centers of the Spanish Group for Rare Cancer (GETHI). Methods: We designed an observational, prospective and multicenter study to molecularly characterize any adult patient with advanced cancer.Formalin fixed paraffin-embedded samples were studied by TrkA-C,ROS1 and ALK immunohistochemistry followed by RT-PCR when positive to confirm gene fusions. Additonally, the Next Generation Sequencing paltform ArcherFusion Plex (able to detect point mutations and rearrangements in 53 cancer related genes) was implemented.Clinical data regarding treatment administered and outcome, were collected from patients identified as harboring drugable alterations. Results: Up to 26 hospitals all over the country got involved in the study. 341 tumoral tissues, representing 41 different histologies were collected. Molecular studies could be performed in 292 samples that led to the identification of 33 patients as harboring somatic oncogenic mutations. 21 were considered druggable and 5 got targeted therapy directed against the alteration identified (three glioblastoma patients with EGFR mutations received erlotinib, one prostate cancer with a BRAF fusion received trametinib and one lung cancer with ALK translocation, previously deemed as negative by standard screening, received crizotinib). One of the glioblastoma patients achieved a long lasting stabilitation and both the prostate and lung tumors presented dramatic partial responses. Conclusions: Though only few cases harboring drugable alteratons got specif treatment, 50% achieved a meanignful benefit. A wide access to molecular screening and targeted drugs could improve the outcome of cancer patients.