tbuckley/cabot-search huggingface dataset:
Isocitrate dehydrogenase (<i>IDH</i>) mutation testing in the clinical management of acute myeloid leukemia (AML) - an international comparison.
Authors: Pieter De Richter
Journal: Journal of Clinical Oncology (2016)

e18530 Background: Several studies have previously identified IDH1 and IDH2 mutations as frequent genetic alterations in AML, with potential prognostic implications. We investigated the use of IDH mutation testing for AML by oncologists and pathologists in the clinical setting, in 9 different countries. We also measured the incidence of IDH mutations among the tested patient populations. Methods: A panel of oncologists/cancer-treating physicians and pathologists in the US (N = 64 treating physicians; 38 pathologists), France (N = 42;6), Germany (N = 36;11), Italy (N = 31;24), Spain (N = 41;11), the UK (N = 32;6), Brazil (N = 34;18), Argentina (N = 33;11) and Canada (N = 18;6) were asked to report on their practices relating to IDH mutation testing for AML patients, through the submission of online de-identified patient record forms (N = 712 AML patient records). Results: In all 9 countries, < 20% of AML patients had been tested for IDH mutations. Observed testing levels were the lowest in Argentina (6% of AML patients), Canada (6%) and Spain (7%), and highest in the US (15%) and France (14%). Whereas PCR-based testing dominated in Europe, Next Generation Sequencing was common in the US, and the use of immunohistochemistry was more frequently observed in Latin America. In both US and Europe, 15-20% of tested patients were found to have IDH mutations. Conclusions: IDH mutation testing in the clinical setting is currently only reserved for a small subset of AML patients across all 9 countries investigated. Furthermore, there is a lack of consistency in the methodologies used between regions. The observed mutation rates in the clinical setting were in line with previously reported rates in the literature.
Compliance with requirement to report results on the EU Clinical Trials Register: cohort study and web resource
Authors: Ben Goldacre, Nicholas J DeVito, Carl Heneghan, Francis Irving, Seb Bacon, Jessica Fleminger, Helen Curtis
Journal: BMJ (2018)

Abstract Objectives To ascertain compliance rates with the European Commission’s requirement that all trials on the EU Clinical Trials Register (EUCTR) post results to the registry within 12 months of completion (final compliance date 21 December 2016); to identify features associated with non-compliance; to rank sponsors by compliance; and to build a tool for live ongoing audit of compliance. Design Retrospective cohort study. Setting EUCTR. Participants 7274 of 11 531 trials listed as completed on EUCTR and where results could be established as due. Main outcome measure Publication of results on EUCTR. Results Of 7274 trials where results were due, 49.5% (95% confidence interval 48.4% to 50.7%) reported results. Trials with a commercial sponsor were substantially more likely to post results than those with a non-commercial sponsor (68.1% v 11.0%, adjusted odds ratio 23.2, 95% confidence interval 19.2 to 28.2); as were trials by a sponsor who conducted a large number of trials (77.9% v 18.4%, adjusted odds ratio 18.4, 15.3 to 22.1). More recent trials were more likely to report results (per year odds ratio 1.05, 95% confidence interval 1.03 to 1.07). Extensive evidence was found of errors, omissions, and contradictory entries in EUCTR data that prevented ascertainment of compliance for some trials. Conclusions Compliance with the European Commission requirement for all trials to post results on to the EUCTR within 12 months of completion has been poor, with half of all trials non-compliant. EU registry data commonly contain inconsistencies that might prevent even regulators assessing compliance. Accessible and timely information on the compliance status of each individual trial and sponsor may help to improve reporting rates.
Preliminary safety data from a randomized multicenter phase Ib/II study of neoadjuvant chemoradiation therapy (CRT) alone or in combination with pembrolizumab in patients with resectable or borderline resectable pancreatic cancer.
Authors: Matthew H. G. Katz, Gauri R. Varadhachary, Todd W. Bauer, Nicolas Acquavella, Nipun B. Merchant, Tri Minh Le, Milind M. Javle, Rachna T. Shroff, Michael J. Overman, David R. Fogelman, Gina R. Petroni, Craig L. Slingluff, Osama E. Rahma
Journal: Journal of Clinical Oncology (2017)

4125 Background: Pancreatic cancer (PC) is a challenging target for immunotherapy.Tumor-infiltrating lymphocytes (TILs) do not reach the PC cells in significant numbers due to the presence of stroma and a suppressive microenvironment. Neoadjuvant chemoradiation (CRT) can increase the presence of TILs in the PC microenvironment. We hypothesized that combination of CRT and pembrolizumab can lead to further increase in TILs and their activation. Methods: Patients with resectable or borderline resectable PC have been randomized 2:1 to the investigational treatment (Arm A) to receive pembrolizumab 200mg IV every 3 weeks on days 1, 22, and 43 during concurrent CRT with capecitabine (825 mg/m2 orally twice daily, Monday-Friday, on days of radiation only) and radiation (50.4 Gy in 28 fractions over 28 days) or Arm B to receive only concurrent CRT with capecitabine. Restaging CT scan or MRI is performed at 4-6 weeks after completion of neoadjuvant treatment, and patients with resectable disease will undergo surgical resection. Here we report the preliminary safety data based on 22 enrolled patients. Results: As of February 3-2017,22 patients have been enrolled (14 Arm A and 8 Arm B). 50% of the patients had resectable disease (7 arm A; 4 arm B) and the other 50% had borderline resectable disease (7 Arm A; 4 arm B). Post-neoadjuvant therapy, 6 patients had unresectable disease (3 on each arm), and 14 patients underwent surgery (10 arm A and 4 arm B). There were 7 grade 3 treatment-related toxicities in Arm A (5 patients): 2 grade 3 diarrhea attributed to CRT; 4 grade 3 lymphopenias attributed to pembrolizumab, CRT or the combination; and one patient had elevated alkaline phosphatase probably related to the combination that met the definition of DLT and resolved after holding the treatment and receiving steroids. There was only one grade 3 toxicity on Arm B: lymphopenia attributed to CRT. No grade 4 toxicities have been reported on either arm. There were no major surgical complications reported within 30 days post-surgery. Conclusions: The combination of CRT and pembrolizuamb is safe based on the presented data. Clinical trial information: NCT02305186.
Evaluation of clinical endpoints as surrogates for overall survival in patients treated with immunotherapies.
Authors: Howard Kaufman, Lawrence Howard Schwartz, William N. William, Mario Sznol, Michael del Aguila, Craig Whittington, Kyle Fahrbach, Yingxin Xu, Eric Masson, Sara Dempster, Andrea Leninka Vergara-Silva
Journal: Journal of Clinical Oncology (2017)

e14557 Background: In immuno-oncology (IO), the correlation between clinical trial endpoints, specifically, objective response rate (ORR), disease control rate (DCR) or progression free survival (PFS), and overall survival (OS) is poorly understood. The effect of IO agents as opposed to chemotherapy, is not on tumor cells, but on immune cells and OS benefit has been observed in absence of PFS benefit. However, decisions on registration trials often rely on PFS from Phase II trials. Methods: We conducted a systematic literature review with PubMed and Embase (Jan. 2005–Nov. 2016), supplemented with oncology conference proceedings (2014–2016). Eligible studies were randomized controlled trials (RCT) that investigated ≥1 immune checkpoint blockers (CBs) targeting programmed death proteins (PD-1/PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), and reported their relative effect on OS and on ≥1 of the clinical endpoints, DCR, ORR, and PFS. Log-transformed hazard ratios were fitted using weighted regression models to determine the power of relative effects on clinical endpoints to predict OS effects, with correlation coefficients estimated and presented with adjusted R 2 (high values indicating better goodness-of-fit). Results: This analysis included 18 RCTs involving 7140, patients. Most studies (10/18) evaluated the efficacy of CBs vs conventional chemotherapy, whereas 8 studies compared the efficacy of ≥1 CB. Among trials that evaluated anti-CTLA-4, the adjusted R 2 for the relative efficacy of CBs on DCR, ORR, PFS, and relative efficacy of CBs on OS were 0.160 ( P= 0.156), 0.016 ( P= 0.332), and 0.000 ( P= 0.623) respectively. Among trials that evaluated either anti-PD-1 or anti-PD-L1, the adjusted R 2 were 0.038 ( P= 0.401), 0.066 ( P= 0.251), and 0.432 ( P= 0.032), for DCR, ORR and PFS respectively. Among trials that evaluated CBs in melanoma, the adjusted R 2 were 0.030 ( P= 0.267), 0.028 ( P= 0.279), and 0.192 ( P= 0.154), for DCR, ORR, and PFS respectively. Conclusions: No clear correlations were observed between relative effects of conventional clinical endpoints and OS for CBs. New surrogate endpoints may be needed to better predict OS benefit for CBs and other forms of cancer immunotherapy.
TCT-496 Outcomes After Transcatheter Aortic Valve Replacement with the SAPIEN 3 - the VARC-2 composite endpoints at one year
Authors: Costanza Pellegrini, Oliver Husser, Tobias Rheude, Teresa Trenkwalder, N. Patrick Mayr, Michael Joner, Adnan Kastrati, Heribert Schunkert, Markus Kasel, Christian Hengstenberg
Journal: Journal of the American College of Cardiology (2018)
Assessing prognosis of neuroendocrine neoplasms: Results of a collaborative multinational effort including over 10.000 european patients—The ENETS registry.
Authors: Ivan Borbath, Damir Bikmukhametov, Sebastian Maasberg, Rocio Garcia-Carbonero, Paula Jiménez-Fonseca, Angel Castaño, Attila Kollar, Eva Sedlackova, Jaroslava Barkmanova, Beata Kos-Kudla, Daria Handkiewicz-Junak, Gregory Kaltsas, Anna Koumarianou, Massimo Falconi, Kjell E. Oberg, Bertram Wiedenmann, Holger Franz, Ruediger Lohmann, Ulrich-Frank Pape, Chris Verslype
Journal: Journal of Clinical Oncology (2018)

4095 Background: Global European high quality epidemiologic data on Neuroendocrine Neoplasms (NEN) are lacking. There is limited knowledge on the contribution of prognostic factors on patient (pt) management. Methods: The multinational ENETS registry (www.enets.org/the_registry.html) was launched in 2015. To date, data from 7 countries (Belgium, Czech republic, Germany, Greece, Poland, Spain, Switzerland) were analyzed, including age, gender, primary site, functional syndrome, WHO grade, stage according to TNM/ENETS, treatment modalities and overall survival (OS). Results: High quality data from 10.102 pts are presented. Median age at diagnosis is 59 y (10-102y), female represent 48%. Pancreas (2722 pts, 26%) and small intestine (2132 pts, 21%) NEN are the most frequent primaries. Functional syndrome is present in 26.9% of pts, 80% being carcinoid syndrome. Stage at diagnosis (n = 6297 pts) is IV in 46%, III in 16%, II in 11% and I in 27%. WHO grading (n = 7400) is G1 in 48%, G2 in 36% and G3 in 16%. Among metastatic pts (46% of total), liver is the most frequent site (77%), followed by lymph nodes (44%), bone, lung and peritoneum (10-15%). Surgery was performed in 71%, somatostatin analogues were given to 1/3 of pts, chemotherapy to 20%, molecular targeted therapies to 8% and PRRT to 9%. Median OS of all pts is 178 months. Five-year and 10-year OS are 74.5% and 60.9% respectively. OS is influenced by grade (G1: 279 months, G2: 167m, G3: 18m) and stage (I: Not reached, II: 225m, III: 160m, IV: 75m). Multivariable analyses show that grade and stage are independent predictors of OS: grade 2 vs grade 1 (HR 1.49, p < 0.001), grade 3 vs grade 1 (HR 7.56, p < 0.001), stage 3 vs stage 1 (1.59, p = 0.001) and stage 4 vs stage 1 (HR 3.99, p < 0.001). Conclusions: This analysis represents the largest multinational dataset of NEN patients to date, and highlights the crucial role of WHO grading (Ki67) for predicting patients’ prognosis. In addition, it provides valuable information on patients’ demographics, tumor characteristics and applied therapies.
High prevalence of hereditary cancer syndromes and outcomes in adults with early-onset pancreatic cancer.
Authors: Maria Fernanda Montiel, Sarah A. Bannon, Jennifer Brooke Goldstein, Maureen E Mork, Pompeyo Rafael Quesada, Wenli Dong, Lei Feng, Ester Borras, Anirban Maitra, Gauri R. Varadhachary, Matthew H. G. Katz, Andrew Futreal, David R. Fogelman, Eduardo Vilar-Sanchez, Florencia McAllister
Journal: Journal of Clinical Oncology (2018)

4129 Background: Most patients with Pancreatic Ductal Adenocarcinoma (PDAC) are diagnosed over the age of 65. Individuals diagnosed under the age of 60 are considered to be early-onset and potentially at high risk for a genetic predisposition. We aimed to determine the prevalence of germline mutations among early-onset PDAC, as well as their influence in prognosis. Methods: A High Risk Cohort (HRC) and a General Cohort (GC) were included in this study. The HRC patients were patients with PDAC who met referral criteria for genetic counseling and were seen at The University of Texas MD Anderson Cancer Center (MDACC) from 2005-2016. The GC patients had metastatic PDAC and were seen at MDACC between 2010-2016. Either gene-specific (targeted) or panel DNA germline sequencing for the 13 most common genes associated with pancreatic cancer (ATM, APC, BRCA1, BRCA2, CDKN2A, MLH1, MSH2, MSH6, PMS2, PALB2, STK11, EPCAM, PMS2) was performed. Survival outcomes were analyzed with respect to germline mutational status and age by using Kaplan-Meier curves. Results: A total of 409 patients underwent genetic testing (277 from High Risk and 132 from General Cohort). As expected, the HRC had higher prevalence of germline mutations compared to the general cohort: 17.3% vs 6.81%. The most common mutations in both cohorts were in BRCA1/2 and MMR genes. Patients younger than 60 years old had significantly higher prevalence of germline mutations in both the HRC (OR: 1.93 +/-1.03-3.70, P: 0.039) and GC (4.78 +/-1.10-32.95, P: 0.036). With respect to clinical outcomes, the GC patients with germline mutations had significant higher median survival as compared to patients without mutations, 18.2 months vs 9.2 months respectively (HR: 0.44, 95% CI of HR: 0.25-0.76, P= 0.030). In the HRC, only patients older than 60 years old with mutations had better overall survival compared to the group without mutations (HR: 0.40, 95% CI of HR: 0.20-0.80, P= 0.038). Conclusions: Germline mutations are highly prevalent in patients with PDAC of early-onset and can be predictive of better outcomes. Considering emerging screening strategies for relatives carrying susceptibility genes as well as impact on therapy choices, genetic counseling and testing should be encouraged in young onset PDAC.
Involvement of miR-99a in resistance to chemotherapy in triple-negative breast cancer
Authors: I. Garrido-Cano, B. Pattanayak, A. Adam-Artigues, P. Cabello, B. Pineda, E. Tormo, J. Albanell, F. Rojo, A. Lluch, P. Eroles
Journal: Annals of Oncology (2018)

Background: Breast cancer is the most prevalent type of cancer among women worldwide, and also the leading cause of women death in developed countries. Among the different breast cancer subtypes, triple-negative breast cancer is the most aggressive one. Those patients can be treated with cytotoxic therapies, but the most of them develop resistance against those drugs. Due to this reason, it is important to study new therapeutic approaches to increase the efficacy of chemotherapy. Herein, microRNAs have a major role in tumoral cell regulation as well as in drug resistance. Our aim was to determine which microRNAs are differentially expressed by MDA-MB-231 cells and MDA-MB-231 cells with acquired resistance to doxorubicin. Methods: A microRNA microarray (Genechip miRNA 4.0 Array, Affymetrix) was performed to compare microRNA expression between MDA-MB-231 and MDA-MB-231 with acquired resistance to doxorubicin. Studies of gain/loss of function of miR-99a were carried out in MDA-MB-231 cells by transient transfection of mimic and inhibitors. Then, those cells were treated with doxorubicin, paclitaxel and cyclophosphamide to establish the role of miR-99a in sensitivity or resistance to those drugs. Viability was measured by flow cytometry. Results: Among the differentially expressed microRNAs, we found that miR-99a-5p was downregulated in MDA-MB-231 resistant cells vs MDA-MB-231 wild type. We confirmed these results by PCR. The study of its involvement in resistance to different chemotherapies (doxorubicin and paclitaxel) showed that inhibition of miR-99a-5p in wild type cells increased resistance to doxorubicin and paclitaxel. Moreover, when we overexpressed this microRNA, the sensitivity to doxorubicin was increased but there were no changes in paclitaxel. Conclusions: The present study provided that miR-99a-5p is involved in chemoresistance in triple-negative breast cancer. Nowadays we are performing microarray of mRNAs to find miR-99a-5p targets which are involved in the observed effects. The importance of this finding could be overcome the resistance to chemotherapy in triple-negative breast cancer patients, and can be a potential therapeutic target. Legal entity responsible for the study: INCLIVA Biomedical Research Institute. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
Adoption rates of immune checkpoint inhibitors in real world oncology practice.
Authors: Jennifer O. Nwankwo, Charles Lagor, Hemant Tiwari, Robert Fair, Tom Brasington, Douglas Terrell, Jeffrey Kaufman, Faith DeFreitas, Brigham Hyde, Edward J. Stepanski, Mark S. Walker
Journal: Journal of Clinical Oncology (2018)

e15103 Background: Inhibition of immune checkpoints such as PD-1, PD-L1, and CTLA-4, has become an important option in unleashing the immune system to fight cancer. However, there is limited information about the use of immune checkpoint inhibitors (ICIs) in real world oncology practice. Methods: We performed a multicenter analysis of the use of ICIs in the real world using the ASCO CancerLinQ Discovery™ dataset. From a starting population of 640,413 patients with a tumor diagnosis, we selected and analyzed a cohort of 17,964 stage IV patients who met the following criteria during our observation period of April 1, 2016 to September 30, 2017: i) were not known to be deceased, ii) had 1 of the 9 cancer types for which ipilimumab, pembrolizumab, nivolumab, and atezolizumab have received FDA approval, and iii) received at least 1 dose of either ipilimumab, pembrolizumab, nivolumab, or atezolizumab. Results: Of the 17,964 stage IV patients in the cohort, 1,850 had received an ICI, of which the percentage that received at least 1 dose of each ICI were: nivolumab (57.7%), pembrolizumab (27.0%), atezolizumab (7.6%), ipilimumab (0.5%), and 7.2% with a combination of 2 or more ICIs for 1 of 9 cancer types – colon cancer, gastric cancer, Hodgkin’s lymphoma, liver cancer, lung cancer, metastatic melanoma, bladder cancer, head and neck cancer, and kidney cancer. We determined that the top 5 FDA approved cancer types with ICI usage in stage IV were metastatic melanoma (23.6%), kidney cancer (16.5%), lung cancer (14.9%), bladder cancer (10.0%), and head and neck cancer (6.1%). Stage IV ICI usage in the 4 remaining FDA approved cancer types were 3.0% or lower. Temporal changes in usage patterns by month will be presented. Conclusions: Our results demonstrate that overall, 10.3% of prevalent stage IV patients across 9 cancer types received at least 1 dose of an ICI during the observation period. Nivolumab was by far the most widely used ICI, while metastatic melanoma was the most commonly treated cancer indication for ICIs. Subsequent studies should evaluate how these usage patterns correlate with patient and provider characteristics.
Graft-versus-host disease (GVHD) risk with daratumumab (Dara) therapy post allogeneic transplantation (alloHCT) for multiple myeloma (MM).
Authors: Liana Nikolaenko, Saurabh Chhabra, Parameswaran Hari, Amrita Y. Krishnan, Joshua Ryan Richter
Journal: Journal of Clinical Oncology (2018)

8028 Background: Daratumumab (Dara) is an antibody targeting CD38+ MM cells that also affects CD38+ non-myeloma cells, including T cells, which mediate GVHD. Regulatory T cells (Tregs) are reduced while helper and cytotoxic T cells are increased in Dara-treated patients. Decreases in Tregs are associated with the development of GVHD. The association between Dara therapy post alloHCT and GVHD was evaluated. Methods: Multicenter, retrospective study. All patients who received alloHCT for MM were cross referenced with patients receiving Dara. Demographic data, details of prior MM therapy, conditioning regimen, time from transplant to Dara and time to GVHD were collected. Results: AlloHCT were performed between 2001 to 2016. Median time from alloHCT to first dose of Dara was 1.8 years (3.5 months to 15.3 years). Patient demographics are shown in Table 1. Median number of Dara infusions was 12 (range 1-19). A total of 14 patients (41%) developed GVHD post alloHCT: 9 patients had GVHD prior to Dara without relapse of GVHD after Dara, 5 patients developed GVHD after Dara (15%) with 4 of these 5 patients having no prior history of GVHD before Dara. One patient developed acute GVHD during Dara therapy while having history of chronic GVHD. Median time to onset of GVHD from first dose of Dara was 149 days (36 to 149 days). Overall response to Dara-based therapies was 38% (13/34), including 12 SD, 3 MR, 9PR, 2VGPR, 2CR, 4PD and 2 unavailable. Median follow up was 33.2 months (6.4 months to 16.5 years). Conclusions: Dara therapy post-alloHCT was well tolerated and did not increase risk of GVHD. These data suggest that Dara is an effective and safe option for use after alloHCT and could be considered in studies of salvage and maintenance post alloHCT. Age at diagnosis 55 (33-70) Sex Female 14 (41) Male 20 (59) Race Caucasian 24 (70) Hispanic 6 (18) Asian 2 (6) African-American 2 (6) Conditioning Cy/TBI 2 (6) Flu/Cy 1 (3) Flu/Cy/TBI 5 (15) Flu/Mel 8 (24) Flu/Mel/ATG 3 (9) Flu/Mel/Bort 5 (15) Flu/Mel/Vel/ATG 4 (12) Flu/Mel/TBI 1 (3) TBI 3 (9) Flu/Mel/Bort/TMI 1 (3) Flu/Bu 1 (3) GVHD Prophylaxis FK/MTX 9 (26) MMF/Cyclosporine 3 (9) Tacro/MMF/Cy 5 (15) Tacro/MTX 13 (38) Tacro/Siro 2 (6)