tbuckley/cabot-search huggingface dataset:
Thank you, next: The impact of next-generation sequencing in clinical decision making.
Authors: William Davis, Gabriel Makar, Greg J. Kubicek
Journal: Journal of Clinical Oncology (2019)

e13136 Background: Next Generation Sequencing (NGS) is increasingly used to identify actionable mutations for oncology treatment. We examined the results of NGS at our institution. Methods: We retrospectively reviewed the medical charts of 305 consecutive patients who had genomic testing performed on tumor samples from March 2014 to April 2017. Next Generation Sequencing was performed by Foundation One testing. Results: Of the 305 tissue samples sent to Foundation One, 189 reports were potentially usable. Reports were unusable due to an insufficient quantity of tissue (43), inadequate follow-up (32), cessation of oncologic care due to transferring to hospice or expiring (32), or a report not being generated due to the order being cancelled (4) or undocumented reasons (5). Of the 189 usable reports, 76 (40.21%) demonstrated an aberration targetable by on-label therapies, 126 (66.67%) via off-label therapies (66 of these had no available on-label treatment), and 170 (89.94%) revealed actionable aberrations via all potential avenues, including clinical trials. 19 (6.2%) yielded a change in management, 6 of these changes were utilizing on-label therapies, 6 were via off-label therapies, 3 were via enrollment in a clinical trial, and 4 involved discontinuing a medication with a predicted poor response. For the 6 patients with off-label use, median duration of treatment was 46 days and discontinued secondary to death (3 patients) or progression (3 patients). Conclusions: Only a minority of NGS assay results (6.2% percent of all tests ordered and 10% of useable tests) resulted in a management change. A small minority (6 patients, 1.9%) were started on off-label therapy based on NSG results and overall had poor responses to off-label treatment. While in theory NGS may improve oncology outcome, the results of our initial 305 patients who had NGS was poor.
Whole-genome cell-free DNA (cfDNA) changes as a dynamic blood-based biomarker for early response assessment of advanced tumors.
Authors: Andrew A. Davis, Wade Thomas Iams, David Chan, Michael S Oh, Robert William Lentz, Neil Peterman, Alex Robertson, Abhik Shah, Rohith Srivas, Nicole Lambert, Timothy Wilson, Peter George, Becky Wong, Ayse Tezcan, Ram Yalamanchili, Ken Nesmith, John C Spinosa, Haluk Tezcan, Young Kwang Chae
Journal: Journal of Clinical Oncology (2019)

3041 Background: Liquid biopsies have potential clinical utility as dynamic biomarkers for treatment response. We analyzed serial changes in whole-genome (WG) cfDNA to identify patients with disease progression prior to routine imaging. Methods: We prospectively collected clinical data and blood from 69 advanced cancer patients (28 lung, 25 breast, 16 other). Blood was collected at baseline prior to initiation of a new treatment and at one or two additional timepoints (median 21 and 42 days). We isolated plasma cfDNA and prepared sequencing libraries for WG sequencing or WG bisulfite sequencing (median depth 20X). We quantified changes in the fraction of tumor-derived cfDNA over the initial course of treatment to predict progression vs. no progression. Treatment response at first post-treatment imaging was determined by RECIST 1.1 and clinical assessment. Study endpoints were agreement with first post-treatment imaging and progression-free survival (PFS) by cfDNA prediction. Results: Median age of patients was 70 and 59% were female. Patients were treated with the following therapies: chemotherapy (37), immunotherapy (17), endocrine (9), or targeted therapy (6). Patients with predicted progression by cfDNA (14), indicated by an increase in tumor fraction at either post-treatment blood collection, had shorter PFS (median 63 days) compared to patients without an increase (N = 55; median 255 days), with hazard ratio of 10.3 (95% confidence interval 4.6-23.4, log-rank P = 1x10 -11 ). Positive predictive value was 100% for disease progression and negative predictive value was 78%. These findings were consistent in subset analyses of patients with lung (log-rank P = 2x10 -5 ), breast (log-rank P = 3x10 -4 ), and those treated with immunotherapy (log-rank P = 5x10 -6 ). Conclusions: Our results show the ability to detect early disease progression with high fidelity using WG cfDNA prior to first imaging. These findings were consistent across multiple tumor types and treatments, including immunotherapy patients. Once validated, this dynamic, predictive, blood-based biomarker could aid in clinical decision making for early treatment change as a novel and cost-effective approach.
Phase I study of CC-90010 in patients with advanced solid tumors and relapsed/refractory non-Hodgkin lymphoma (R/R NHL).
Authors: Victor Moreno, Irene Braña, Juan Manuel Manuel Sepulveda Sanchez, Maria Vieito Villar, Tatiana Hernandez-Guerrero, Bernard Doger, Omar Saavedra, Olga Ferrero, Rafael Sarmiento, Marina Arias, Juan De Alvaro, Jorge F. DiMartino, Marlene Zuraek, Tania Sánchez Pérez, Ellen Filvaroff, Ida Aronchik, Manisha Lamba, Bishoy Hanna, Zariana G. Nikolova
Journal: Journal of Clinical Oncology (2019)

3015 Background: Bromodomain and extra-terminal (BET) proteins are epigenetic readers that control expression of genes involved in cell growth and oncogenesis. CC-90010 is an oral, potent and reversible BET inhibitor that showed promising activity in lymphoma and solid tumor cell lines and reduced tumor growth in xenograft models. Methods: CC-90010-ST-001 (NCT03220347; 2015-004371-79) is a phase I, first-in-human study of CC-90010 in patients (pts) with advanced solid tumors and R/R NHL. Three schedules and 11 dose levels were evaluated (Table). Primary objectives were to determine safety, maximum-tolerated dose and/or recommended phase II dose (RP2D). Secondary objectives were the identification of early activity signals, pharmacokinetics and pharmacodynamics (PD). Results: As of 10 Dec 2018, 69 pts were enrolled, 67 with solid tumors and 2 with R/R NHL. Data shown are from all pts (N = 69). The median age was 57 y (range, 21–80), 38 (55%) were male, and the median number of prior systemic anticancer regimens was 3 (range, 1–9). The RP2Ds were dose cohorts 3A and 4B. Dose-limiting toxicities (n = 6) occurred in dose cohorts 3A, 3C, and 4B. Grade 3/4 treatment-related adverse events (TRAEs) occurred in 17 pts (25%), most commonly (≥2 pts) thrombocytopenia (7%), platelet count decreased (4%), fatigue (3%), and increased alanine aminotransferase (3%). No deaths from toxicity occurred. Two pts (endometrial carcinoma and astrocytoma) had a partial response (PR); 1 occurred after the data cutoff. Seven pts had prolonged stable disease (SD) &gt; 9 mo. Exposures and PD marker regulation increased with dose in each dosing schedule; terminal half-life was ~ 73 h. Conclusions: Most of the TRAEs observed were mild or moderate in severity, reversible, and manageable by dose adjustments and/or supportive care. Promising ongoing anticancer activity with prolonged SD and PRs were observed. The preliminary clinical data provide the rationale for dose expansion of CC-90010 in pts with selected advanced malignancies. Clinical trial information: NCT03220347. [Table: see text]
Phase II, prospective single-arm study of adjuvant pembrolizumab in N2 positive non-small cell lung cancer (NSCLC) treated with neoadjuvant concurrent chemoradiotherapy followed by curative resection: Preliminary results.
Authors: Myung-Ju Ahn, Sehhoon Park, Hyun Ae Jung, Jong Ho Cho, Jong-Mu Sun, Se-Hoon Lee, Yong Soo Choi, Jin Seok Ahn, Jhingook Kim, Keunchil Park, Jae Ill Zo, Young Mog Shim, Kyung Hwan Kim, Eui-Cheol Shin, Hong Kwan Kim
Journal: Journal of Clinical Oncology (2019)

8520 Background: The standard treatment option for stage IIIA-N2 subgroup is still under discussion with controversies. We hypothesize that immune checkpoint inhibitor consolidation therapy could have an additional role in prolongation of the disease-free survival (DFS) for stage IIIA-N2 NSCLC treated with tri-modalities therapy. Methods: This is a phase 2 study evaluating the clinical efficacy of pembrolizumab treatment after CCRT with curative resection in stage IIIA-N2 NSCLC pts. Pathologically confirmed pts were treated with five cycles of CCRT, weekly paclitaxel (50mg/m 2 ) and cisplatin (25mg/m 2 ) combined with radiotherapy (total of 44Gy over 22 fractions) followed by curative resection. Adjuvant Pembrolizumab (200mg fixed dose) is applied every three weeks up to 2 years or until disease recurrence. The primary objective is disease-free survival of more than 20 months. The first patient was recruited in October 2017, and the data for this abstract was locked at 20 th of January, 2019. Results: Total of 40 pts were screened, and 37 pts received treatment. Median age was 64 years (range 39-74), and twenty-three pts were male (62.2%). As a curative surgery, pts received lobectomy (n=34), bi-lobectomy (n=2), or pneumonectomy (n=1). Adenocarcinoma was predominant (n=27, 73.0%). After the neoadjuvant CCRT, down-staging were observed in nine pts (24.3%). The median follow-up duration was 10.6 months (range 3.1-17.2), and pts received a median of 11 cycles (range 1-22) of adjuvant pembrolizumab. DFS is not reached. Fourteen patients discontinued treatment due to disease progression (n=9), adverse events (n=4) and withdraw consent (n=1). There was a case of grade 4 pneumonitis and a case of grade 3 autoimmune hepatitis which lead to discontinuation of the treatment. Otherwise, grade 1-2 hypothyroidism (n=6), pneumonitis (n=5), skin rash (n=3) were observed. Patients with sever immune-related adverse event showed a significantly high percentage of Ki-67 + cells among CD8 T-cells in peripheral blood. Conclusions: This study is the first study to demonstrate the feasibility of adjuvant pembrolizumab monotherapy in stage IIIA-N2 patients. Updated and detail clinical and exploratory biomarker outcome will be presented at the annual meeting. Clinical trial information: NCT03053856.
Human model to predict the outcome of cancer vaccine clinical trials.
Authors: Orsolya Lőrincz, Eniko Rita Toke, Eszter Somogyi, Zsolt Csiszovszki, Mónika Megyesi, Kata Pantya, József Tóth, Levente Molnar, István Miklós, Franco Lori, Julianna Lisziewicz
Journal: Journal of Clinical Oncology (2019)

e14298 Background: Cancer vaccines activate T-cells with peptides presented by HLA alleles. We hypothesized that peptides binding to multiple HLA alleles of a patient are more likely to induce T-cell responses than epitopes presented by a single HLA. To prove this hypothesis we predicted the outcome of vaccine clinical trials in a Model Population of subjects with complete HLA genotype. Methods: We collected the immune- and objective response rate (IRR, ORR) results from 64 clinical trials conducted in 1,790 patients treated with 42 different vaccines. From these 42 vaccines, we identified personal epitopes (PEPIs) with strong binding affinity to at least 3 HLA alleles of each subject in the Model Population and calculated the proportion of subjects with PEPIs (PEPI Score), multiple PEPIs (MultiPEPI-Score) and PEPIs against multiple vaccine antigens (MultiAg PEPI-Score). Results: Highly significant correlation between the PEPI Score and IRR (p = 0.001) suggests that peptides binding to at least 3 HLA alleles of the subject induce T-cell responses. MultiPEPI-Score correlated with ORR when the tumor of patients expressed the target antigen (p = 0.01). MultiAg PEPI-Score correlated with ORR of clinical trials conducted with vaccines containing multiple antigens (p = 0.01). Conclusions: Our results suggest that (i) a patient’s HLA genotype is the main determinant of vaccine response and (ii) T-cell responses against multiple antigens expressed in the patient’s tumor favors tumor shrinkage. We introduced a novel pre-clinical human model that accurately predicts the outcome of clinical trials, will reduce the risk, cost and time of vaccine development for the prevention and treatment of cancer.
Niraparib in metastatic pancreatic cancer after previous chemotherapy (NIRA-PANC): A phase 2 trial.
Authors: Anup Kasi, Prabhakar Chalise, Stephen K. Williamson, Joaquina Celebre Baranda, Weijing Sun, Raed Moh'd Taiseer Al-Rajabi, Anwaar Saeed, Sean Kumer, Timothy Schmitt, Carolyn Foster, Ziyan Y. Pessetto, Malgorzata A. Witek, Steven A. Soper, Andrew K. Godwin
Journal: Journal of Clinical Oncology (2019)

TPS4168 Background: Attempts to improve therapy for patients with pancreatic adenocarcinoma with traditional chemotherapy have largely failed to meaningfully improve survival. Therefore, there is a critical need for identification of specific molecular changes that define prognosis and potentially guide therapy decisions. Defective DNA damage response pathways in pancreatic cancer represent a targeted opportunity for treatment. PARP inhibitors exert activity in tumor cells that may not be effectively able to repair initially single-stranded and cumulatively double-stranded DNA breaks and can have a heightened susceptibility in tumor cells over normal tissue. This concept is referred to as synthetic lethality. Niraparib is an orally available, potent, highly selective PARP-1 and -2 inhibitor. We are studying the efficacy of Niraparib in pancreatic cancer patients that harbor DNA repair defects. Methods: This study is funded by a research grant from TESARO. Pre-screening of patients to find biomarker positive patients is funded by KU Cancer Center. This is a phase II open label single arm trial in metastatic pancreatic cancer patients with germline or somatic mutations, either already known, or tested after consent to pre-screening tumor tissue analysis in BRCA1/2, PALB2, ATM, NBN, ATR, BRIP1, IDH1/2, RAD51, RAD51B/C/D, RAD54L, CDK12, BARD1, FAM175A, BAP1, CHEK1/2, GEN1, MRE11A, XRCC2, SHFM1, FANCD2, FANCA, FANCC, FANCG, RPA1, ARID1A. Patients are being treated with Niraparib 300mg or 200mg by mouth daily for 28 days (1 cycle = 28 days) (200mg dose is for participants whose baseline weight is &lt; 77 kg [169.756 lbs] or baseline platelet count is &lt; 150,000 µL). The primary objective is to assess antitumor efficacy of niraparib using Objective Response Rate per RECIST 1.1. Secondary objectives include PFS, OS, DCR, DOR, and safety. Eligible patients received &gt; 1 line of therapy, no prior PARP inhibitor(s), have measurable disease, and ECOG PS 0-1. Accrual target enrollment of 18 patients over a period of 24 months with a study duration of 30 months. Correlative studies include assessment of pharmacokinetics, circulating tumor cells and storing samples for future research. The trial is currently enrolling. Clinical trial information: NCT03553004.
Evolving natural history of metastatic prostate cancer.
Authors: Nellie Nafissi, Alan Haruo Bryce, Heidi E. Kosiorek, Richard Butterfield, Thai Huu Ho, Parminder Singh, Winston Tan, Brian Addis Costello
Journal: Journal of Clinical Oncology (2019)

5063 Background: The systemic therapies available to patients with metastatic prostate cancer (mPC) have improved dramatically over the past decade. Prior to 2010, the only agents with a proven survival benefit for patients with metastatic disease were androgen deprivation therapy and docetaxel. Since then, five new agents have been FDA approved and have proven survival benefit in phase III trials. Anecdotal experience suggests that the increased available lines of therapy have changed the profile of mPC to include a higher prevalence of visceral metastases. Methods: A retrospective review of 474 patients with prostate cancer who died in 2009 and in 2016 was performed. Patients with metastatic disease who had imaging within 6 months of death were included. A total of 164 patients were eligible for analysis. Results: Mean age at death overall was 77.4 years (SD 9.5) and did not differ signifiantly by cohort. Overall rates of visceral and distant metastases to include lung, liver, adrenal, brain, renal, spleen, and thyroid, were higher in patients who died in 2016 as compared to those who died in 2009 (40.0% and 26.1%, respectively, p = 0.07). Lung metastases were more prevalent in patients who died in 2016 versus in 2009 at 26.3% and 13.0%, respectively (p = 0.05). Patients who died in 2009 received a median of 3 (range 1-10) systemic treatments versus 4 (range 0-13) in those who died in 2016 (p = 0.005). Forty-four percent of patients who died in 2016 used five or more lines of systemic treatments compared to 26.1% of patients in 2009. Conclusions: The emergence of new systemic therapies for mPC is changing the natural history of the disease. Forty percent of patients now develop visceral metastases compared to 26% in the past. These changes will drive the need for new treatment approaches targeting visceral metastases. [Table: see text]
Distribution of urokinase-type plasminogen activator and its receptor in malignant tissues of gastric adenocarcinoma.
Authors: Larisa S. Kozlova, Oleg I. Kit, Elena M. Frantsiyants, Yuriy A. Gevorkyan, Natalya V. Soldatkina, Nikolay S. Samoylenko, Dmitry A. Kharagezov, Anton G. Milakin, Petr N. Gabrichidze
Journal: Journal of Clinical Oncology (2019)

e15530 Background: Peritoneal metastases are the most common recurrence of gastric cancer, even after radical surgery. Urokinase-type plasminogen activator (uPA) system, including its receptor uPAR, is crucial in the proteolysis activation for the cleavage of the extracellular matrix and basement membrane. The purpose of the study was to determine the antigen form uPA-Ag, active form uPA-act and the uPAR receptor in tissues of adenocarcinoma of the stomach, its perifocal tissues (PT), greater omentum and peritoneum in patients with stomach cancer T 3-4 а N 0-3 M 1 and T 3-4 а N 0-3 M 0 . Methods: Tissues of patients with gastric adenocarcinoma T 3-4 а N 0-3 M 1 (n = 21: 10 men, 11 women) and T 3-4 а N 0-3 M 0 (n = 24: 15 men, 9 women) aged 61.23±4.8 years were studied. Controls: non-cancer patients aged 39.1±3.2 years (n = 17: 6 men, 11 women). Levels of uPA-act, uPA-Ag and uPAR were determined by ELISA using standard test systems. Statistical analysis was performed using the SPSS 11.5 software package for Windows. Results: In T 3-4 а N 0-3 M 1 , the highest uPAR levels were observed in tissues of the tumor, greater omentum and peritoneum, compared to T 3-4 а N 0-3 M 0 and controls (p &lt; 0.01). In PT of T 3-4 а N 0-3 M 1 , uPAR levels were lower than in tumor (p &lt; 0.01) but higher than in resection line tissues. Tumor levels of uPA-act in T 3-4 а N 0-3 M 1 and T 3-4 а N 0-3 M 0 were similar and in both cases higher than in PT. In the greater omentum in T 3-4 а N 0-3 M 1 , uPA-act levels were similar to tumor levels and exceeded the values in T 3-4 а N 0-3 M 0 (p &lt; 0.01). Peritoneal uPA-act did not differ in T 3-4 а N 0-3 M 1 and T 3-4 а N 0-3 M 0 but was higher than in controls (p &lt; 0.05). Tumor levels of uPA-Ag in T 3-4 а N 0-3 M 1 exceeded the levels in T 3-4 а N 0-3 M 0 and in both PT (p &lt; 0.05). Levels of uPA-Ag in the greater omentum in T 3-4 а N 0-3 M 1 were higher than in T 3-4 а N 0-3 M 0 and lower than in controls (p &lt; 0.01). Comparable uPA-Ag levels in T 3-4 а N 0-3 M 1 and T 3-4 а N 0-3 M 0 were lower than in controls (p &lt; 0.01). Conclusions: Gastric adenocarcinoma secretes uPAR and uPA, and uPAR levels in the tumor are associated with omental or peritoneal metastases. Levels of uPAR and uPA-act in the greater omentum and peritoneum in T 3-4 а N 0-3 M 1 are increased even higher than in T 3-4 а N 0-3 M 0 ; uPAR can serve as a marker of a pre-metastatic niche in peritoneal tissues.
Patients’ perspectives and outcomes on an oral chemotherapy education and electronic monitoring program.
Authors: Noah Xavier Tocci, Jim Doolin, Daniel Aaron Roberts, Christina Cibotti, Rebekah A Hartwell, Jennifer Espiritu, Scott M Devlin, Holly Dowling, Kelsey Trillo, Mary Yenulevich, Jessica A. Zerillo, Meghan Shea
Journal: Journal of Clinical Oncology (2019)

e18007 Background: Patients on oral chemotherapy (OC) often lack consistent education and monitoring, risking toxicity and poor adherence. We developed an OC management program including education and an online tool for active outreach. Methods: In November 2017, we initiated pharmacist-led education for patients newly prescribed OC at a community practice and in the gastrointestinal oncology group at an academic medical center (AMC). An online tool assessing adherence, symptoms, and financial toxicity was emailed to patients three days after starting OC. Non-responders were contacted for phone interviews. A random sample of 28 patients newly started on OC at both sites before the intervention in 2017 was analyzed at baseline. A retrospective chart analysis was done to collect time to symptom assessment, identification and action. A report generated date of first emergency department (ED) visit or hospitalization within the AMC. We conducted a Mann Whitney U-Test, using a one-sided p value of 0.025 with Bonferroni correction. Results: Sixty-nine of 106 eligible patients (66%) received education, of whom 36 (52.1%) received the online tool, and 13 (36.1%) responded. There was a significant difference between the intervention and baseline median times to first new/worsening symptoms (p = 0.0105) but otherwise there were no outcome improvements. Eight of 23 patients who did not respond to the electronic tool were interviewed and indicated that their illness impeded their ability to check email (n = 2), and that they never check email (n = 2). Conclusions: This OC management program improved time to detect new/worsening symptoms and could potentially improve outcomes after further patient accrual. Future investigation should examine ways to improve patient responsiveness to electronic patient-reported symptom tools. [Table: see text]