tbuckley/cabot-search huggingface dataset:
An explorative phase 2 study of afatinib for advanced cancers carrying an EGFR, a HER2 or a HER3 mutation: A Precision trial of the Belgian Society of Medical Oncology.
Authors: Lore Decoster, Nadia Cappoen, Philippe Georges Aftimos, Gordana Raicevic, Christian Diego Rolfo, Sylvie Rottey, Francois P. Duhoux, Joelle Collignon, Aline Hebrant, Marc Vandenbulcke, Jacques De Greve
Journal: Journal of Clinical Oncology (2018)

TPS2615 Background: Next generation sequencing of solid tumors will increasingly reveal mutations in cancer genes, including EGFR, HER2 and HER3 mutations. Afatinib is a small molecule, which selectively and irreversibly inhibits EGFR, HER2 and HER4 and which blocks transphosphorylation of HER3. Afatinib monotherapy has shown activity in EGFR and HER2 mutated lung cancer and preclinical activity in rare HER3 mutated lung cancer. In addition, synergy has been reported between afatinib and paclitaxel. The aim of this Belgian multicentre multicohort basket trial is to study the activity of afatinib in cancers of any type with an EGFR, a HER2 or a HER3 mutation and to study the efficacy of adding paclitaxel to afatinib at disease progression, regardless of tumor type. Methods: Methods: This is a multicenter, open-label, phase 2 study of afatinib in three cohorts of patients with advanced cancer harbouring an EGFR mutation, a HER2 mutation or a HER3 mutation. For each cohort an optimal Simon’s two-stage design is used (p0 = 0.10; p1 = 0.30; alpha = 0.05; power 80%). The primary endpoint for each cohort is objective response as determined according to RECIST 1.1. Secondary endpoints are progression free survival, overall survival and toxicity. At progression, paclitaxel weekly will be added to afatinib and response rate, progression free survival and toxicity will be evaluated. In addition to genotype specific response determination, the activity of afatinib in each cancer type will also be evaluated. Rebiopsy will be performed at progression. Major eligibility criteria are: Patients with locally advanced or metastatic cancers harbouring an EGFR, HER2 or a HER3 mutation, excluding EGFR mutated lung cancer. Failure of at least one line of standard systemic therapy. ECOG performance status ≤2. Adequate organ function. This study is in progress and has currently recruited 4 patients (2 lung cancers, 2 breast cancers) in the HER2 mutated cohort. No patients have yet been recruited in the EGFR or HER3 mutated cohorts. EudraCT No.: 2016-003411-34 Clinical trial information: 2016-003411-34.
Health resource utilization and costs for stage IV bladder cancer in community oncology settings.
Authors: Rahul A. Shenolikar, Maxine D. Fisher, Paul J. Miller, Mark Stephen Walker, Moon Jung Fenton
Journal: Journal of Clinical Oncology (2017)

e16032 Background: Current real-world data on patients with metastatic bladder cancer in the community setting are limited. This study describes patient characteristics, health resource utilization (HRU), and costs for this population. Methods: Medical records data from adults diagnosed with stage IV bladder cancer (T4b, node-positive, or distant metastatic disease) between 1/1/2008 and 6/1/2015 were retrospectively collected from a network of 10 US community oncology practices. Patient characteristics, HRU, and costs were assessed. Regression models were used to estimate group effects on utilization and costs through three progression-based lines. Results: Of 508 patients, 75% were male, 79% white, 15% African American, and 71.5% were aged ≥65 years (median age, 71 years; range 35-92 years). Overall, 76.4% were current or past tobacco users. The most prevalent comorbidities were diabetes (23.4%), renal disease (16.5%), and chronic obstructive pulmonary disease (COPD; 12.4%). Overall, 70.1% had distant metastases at diagnosis, including bone (24.0%), lung (23.4%), and liver (14.6%). Of 341 patients analyzed for HRU and cost, 58.9% had hospital visits and 11.7% had emergency department (ED) visits. Age, smoking history, and presence of diabetes were predictors of hospitalization (all P&lt; 0.05). Overall mean monthly total healthcare cost was $18,778 ± $47,006 (median $6285), which was driven by hospitalizations ($14,660 ± 44,686, median $1717). Mean monthly ED cost was $776 ± $5530, median $0. Mean monthly cost for office visits was $186 ± $189, median $152. Procedures in the medical oncology setting had a mean monthly cost of $707 ± $1179, median $395. Other costs included systemic therapy ($267 ± $704, median $117), infused supportive care drugs ($758 ± $1458, median $0), and other drugs ($1422 ± $3745, median $136). Age, presence of diabetes, presence of any comorbidities, body mass index, and impaired composite performance status were predictors of healthcare costs (all P&lt; 0.05). Conclusions: This study showed significant HRU and costs for metastatic bladder cancer patients suggesting high unmet need.
Abstract 14338: Functional Tricuspid Regurgitation Associated With Degenerative Mitral Valve Disease: Critical Role of Atrial Fibrillation
Authors: Clemence Antoine, Giovanni Benfari, Hector I Michelena, Joseph F Malouf, Vuyisile T Nkomo, Maurice Enriquez-Sarano
Journal: Circulation (2016)

Introduction: Functional Tricuspid Regurgitation (FTR) associated with Degenerative Mitral Valve Disease (DMVD) is mainly considered consequent to pulmonary hypertension (PHTN) or ventricular dysfunction. Recent reports linked presence of atrial fibrillation (AF) to FTR severity but large data in DMVD are lacking. Methods and results: Patients diagnosed with isolated DMVD (no aortic valve diseases, valve surgery or pericardial/myocardial disease) with mitral prolapse with or without mitral regurgitation (MR) and with FTR (excluding pace maker or tricuspid valve prolapse) were enrolled between 2003 and 2011 at Mayo Clinic. Among 5083 patients with isolated DMVD (age 63±16 years), 10% had moderate or severe FTR and 14% had AF. Compared to trivial/mild FTR, patients with moderate-severe FTR were older (76±12 vs 62 ±16 years, p<0.0001) and more likely to be female (54% vs 46% p 0.0007). Moderate-severe FTR was [VTN1] associated with more frequent dyspnea (55% vs 34%, p<0.0001), larger right ventricle (p<0.000...
TCT-675 Site versus Core Laboratory SYNTAX score variability
Authors: Carlos Collet, Yosuke Miyazaki, Daniele Andreini, Antonio Bartorelli, Jeroen Sonck, Johan De Mey, Bert Vandeloo, Taku Asano, Yuki Katagiri, Ulf Teichgräber, Torsten Doenst, Marie-Angele Morel, Yoshinobu Onuma, Patrick Serruys
Journal: Journal of the American College of Cardiology (2018)
Safety and efficacy of chemosaturation in patients with primary and secondary liver tumours: A single-centre experience after 54 treatments.
Authors: Martha Kirstein, Steffen Marquardt, Nils Jedicke, Silke Marhenke, Wolgang Koppert, Michael Manns, Frank Wacker, Arndt Vogel
Journal: Journal of Clinical Oncology (2017)

e15625 Background: Chemosaturation with percutaneous hepatic perfusion (CS-PHP; Hepatic CHEMOSAT Delivery System; Delcath Systems Inc, USA) is a novel medical device, which delivers high doses of melphalan directly to the liver in patients with primary and secondary liver tumours while limiting systemic toxicity through hemofiltration of the hepatic venous blood. The aim of this study was to analyse the safety and efficacy of the second generation CS-PHP after 54 treatments at Hannover Medical School, Germany. Methods: Overall response rates (ORR) were assessed according to Response Evaluation Criteria In Solid Tumours (RECIST1.1). Overall survival (OS), progression-free survival (PFS) and hepatic PFS (hPFS) were analysed using the Kaplan-Meier estimation. Results: A total of 29 patients were treated with CS-PHP as last-line therapy up to five sessions. 19 patients had unresectable hepatic metastases from solid tumors (ocular melanoma [OM] n = 11; colorectal carcinoma n = 2; pancreatic adenocarcinoma n = 2; periampular carcinoma n = 2; breast and endometrial cancer each n = 1) and 10 patients were diagnosed with hepatocellular or cholangiocarcinoma (HCC/CCA). ORR was 19.2%. Patients with OM had the highest ORR (33.3%). Similar to patients with OM, patients with hepatobiliary tumours had durable disease stabilisation (40%). Median OS, PFS and hPFS were 261, 117 and 135 days, respectively. Tumour volume negatively correlated with OS. Complications and toxicites included thrombopenia, cardiovascular events, ulcerous bleeding and edema. Conclusions: Second generation CS-PHP seems to be effective and tolerable. Patient selection based on tumour volume end entity is of importance. Particularly patients with OM and hepatobiliary tumours represent promising candidates for CS-PHP.
Early prediction of outcomes to PD1 inhibitors in non-small cell lung cancer (NSCLC) using next generation sequencing (NGS) of plasma circulating tumor DNA (ctDNA).
Authors: Nicolas Guibert, Greg Jones, John F. Beeler, Vincent Plagnol, Myriam Delaunay, Anne Casanova, Gilles Favre, Anne Pradines, Julien Mazieres
Journal: Journal of Clinical Oncology (2018)

9078 Background: Patient selection for PD-1 inhibitors in NSCLC is still based on imperfect screening biomarkers, including PD-L1 tumor expression and tumor mutational burden. We hypothesized that pretreatment molecular profile of ctDNA and its early kinetics during treatment could represent a reliable and non-invasive approach to determine response. Methods: Up to 4 serial plasma samples were prospectively collected from patients with advanced NSCLC treated with nivolumab as second line therapy: i) pretreatment, ii) at 1 month, iii) at the first CT-scan, iv) at progression. Plasma NGS was performed using InVisionSeq, tagged amplicon sequencing of hotspots and coding regions from 36 genes. The early kinetics (1 month) of ctDNA through treatment was analyzed along with specific baseline alterations as early indicators of response to immunotherapy. Results: 80 specimens from 33 patients underwent NGS. Alterations in ctDNA were detectable in 25/33 baseline samples. The most frequently detected alterations at baseline were TP53 (54.4%); KRAS (33.3%); STK11 (24.2%); and NFE2L2 (9%). Lack of detectable ctDNA at baseline in 6/8 patients correlated with progressive disease (PD). Studying 23 patients for whom serial specimens were available with ctDNA detected at baseline, plasma response (kinetics of ctDNA between baseline and 1 month specimens) was correlated with clinical outcomes (RECIST) in 18/23 cases (11/13 with overall response (OR) or stable disease (SD) and 7/10 with PD). Furthermore, ctDNA demonstrated potential predictive ability on outcomes by analyzing specific alterations and type of nucleotide change (transversion vs transition). Transversions in KRAS and TP53 were detected in 13/14 baseline cases demonstrating clinical benefit (OR+SD) while 8/11cases from patients who went on to have PD were enriched with transitions or STK11 co-mutations with TP53 or KRAS transversions. Conclusions: Plasma cell-free DNA analysis using NGS could be an additional screening assay to identify patients likely to derive benefit from anti-PD-1 therapy, particularly when tissue is unavailable.
Tolerance and efficacy of BRAF plus MEK inhibition in patients with melanoma who have received PD-1 based therapy.
Authors: Karim Saab, Meghan Mooradian, Daniel Ying Wang, Jeewon Chon, Cathy Yi Xia, Angelica Bialczak, Kelly Abbate, Alexander M. Menzies, Douglas Buckner Johnson, Ryan J. Sullivan, Alexander Noor Shoushtari
Journal: Journal of Clinical Oncology (2018)

9540 Background: Combined BRAF and MEK inhibition (BRAF-MEK) is a standard therapy for BRAF V600 mutant melanoma, but doses and adverse event (AE) profiles were defined in trials conducted largely before the era of PD-1 based frontline therapy. The tolerance, AE profile, rates of hospitalization, and efficacy are not well defined for BRAF-MEK in the post-PD-1 setting. Methods: A sequential cohort of patients (pts) with BRAF V600 mutant melanoma who received combined BRAF+MEK following prior PD-1 based therapy was assembled from 4 tertiary care centers in the US and Australia. Dose modification (mod) was defined as a treatment break, dose reduction, or planned intermittent dosing due to AEs. Rates of hospitalization, emergency room (ER) visits, and discontinuation due to AEs were collected, and OS was calculated using Kaplan-Meier methods from time of BRAF-MEK start. Results: 78 pts were identified; 48 (62%) male, median age (range) was 58 (26-88). Most primaries were cutaneous (82%) or unknown (12%). V600 mutations were -E in 71 (91%) and -K in 7 (9%). Most pts had M1c or M1d stage (80%); performance status was 0 (22%), 1 (57%) and 2-3 (21%). LDH was high in 54%. 55 pts (71%) were BRAF-naïve. 81 total BRAF-MEK regimens were utilized; 68 (84%) dabrafenib-trametinib (DT); 12 (15%) vemurafenib-cobimetinib (VC); 1 other. Median (range) interval between last PD-1 dose and BRAF-MEK start was 35 days (1-410). Most common AE for DT was fever (88%) and for VC was rash (83%). Atypical AEs included cytopenias (12%) and central nervous system events (7%). 25 (31%) had an AE-related hospitalization and 18 (22%) an ER visit. 12 pts (15%) stopped BRAF-MEK for AEs. 68 of 81 regimens (84%) had ≥1 dose mod; median time to first dose mod was 14 days, 59 (87%) occurred within 90 days, and 70% involved fever. Among BRAF-naïve pts, after median follow-up of 12.5 months (mo), median time on BRAF-MEK was 6 mo and median OS was 15 mo. Conclusions: The majority of patients receiving BRAF-MEK inhibitors after PD-1 therapy require dose interruptions, and a significant minority require hospitalization or ER utilization for AEs. In this higher-risk population, median time on therapy and OS may be inferior to those in published Phase 3 trials.
Transcriptomic but not genomic variability confers phenotype of breast cancer stem cells
Authors: Mengying Tong, Ziqian Deng, Mengying Yang, Chang Xu, Xiaolong Zhang, Qingzheng Zhang, Yuwei Liao, Xiaodi Deng, Dekang Lv, Xuehong Zhang, Yu Zhang, Peiying Li, Luyao Song, Bicheng Wang, Aisha Al‐Dherasi, Zhiguang Li, Quentin Liu
Journal: Cancer Communications (2018)

Abstract Background Breast cancer stem cells (BCSCs) are considered responsible for cancer relapse and drug resistance. Understanding the identity of BCSCs may open new avenues in breast cancer therapy. Although several discoveries have been made on BCSC characterization, the factors critical to the origination of BCSCs are largely unclear. This study aimed to determine whether genomic mutations contribute to the acquisition of cancer stem‐like phenotype and to investigate the genetic and transcriptional features of BCSCs. Methods We detected potential BCSC phenotype‐associated mutation hotspot regions by using whole‐genome sequencing on parental cancer cells and derived serial‐generation spheres in increasing order of BCSC frequency, and then performed target deep DNA sequencing at bulk‐cell and single‐cell levels. To identify the transcriptional program associated with BCSCs, bulk‐cell and single‐cell RNA sequencing was performed. Results By using whole‐genome sequencing of bulk cells, potential BCSC phenotype‐associated mutation hotspot regions were detected. Validation by target deep DNA sequencing, at both bulk‐cell and single‐cell levels, revealed no genetic changes specifically associated with BCSC phenotype. Moreover, single‐cell RNA sequencing showed profound transcriptomic variability in cancer cells at the single‐cell level that predicted BCSC features. Notably, this transcriptomic variability was enriched during the transcription of 74 genes, revealed as BCSC markers. Breast cancer patients with a high risk of relapse exhibited higher expression levels of these BCSC markers than those with a low risk of relapse, thereby highlighting the clinical significance of predicting breast cancer prognosis with these BCSC markers. Conclusions Transcriptomic variability, not genetic mutations, distinguishes BCSCs from non‐BCSCs. The identified 74 BCSC markers have the potential of becoming novel targets for breast cancer therapy.
Massively parallel sequencing of cell-free DNA enriched from a single drop of urine.
Authors: Chen-Hsiung Yeh, Andrew Ford, Jonathan Spurgin, Ashlee Stamba, James Posey
Journal: Journal of Clinical Oncology (2016)

e23189 Background: The clinical application of urinary cell-free DNA (cfDNA) based testing is often cumbersome by difficulties in handling and analyzing large sample volumes, poor yield, ultra-short fragments, and low throughput. We have developed a proprietary cfDNA enrichment technology, designed for minimum sample volume, enabling molecular genetic analysis from a single drop of urine. A key feature of this method is its versatility, which potentially can be applied to a variety of body fluids. Non-invasive detection and monitoring of tumor mutations in urinary cfDNA thus can be realized by combining minimum volume of urine with the high throughput of next-generation sequencing (NGS). Methods: Cell-free DNA was enriched from 20 uL of urine and quantified by fluorometry. The performance of this sample preparation breakthrough was further evaluated by NGS analysis of urinary cfDNA collected from a prospective cohort of 12 subjects. All samples were tested for 2,855 hotspot mutations in 50 well-established cancer driver genes with deep coverage of 2,000X – 14,000X. Results: We have established a novel procedure for urinary cfDNA enrichment with excellent performance in 12 urine samples from volunteers of both genders. In proof-of-concept experiments, the deployment of this protocol provided efficient recovery of urinary cfDNA with yield ranging 382.5 – 6,720 ng by Qubit fluorometer dsDNA assay. The size distribution of the resultant DNA is between 100 – 500 bp. NGS studies demonstrated the consistency of our protocol in generating high usable, on-target, and high-quality ≥ Q20 sequencing reads with good uniformity. We found 100% success rate of sequencing runs by Ion Proton at the allele frequency ≥ 1%. Conclusions: Targeted deep-coverage NGS genomic profiling using cfDNA from a single drop of urine is a highly feasible platform well-suited for routine genetic testing, support of trials with molecularly defined populations, and companion diagnostics in therapeutics development.
Impact of baseline renal function on efficacy and safety of daratumumab plus bortezomib-melphalan-prednisone (VMP) in patients (Pts) with newly diagnosed multiple myeloma (NDMM) ineligible for transplantation (ALCYONE).
Authors: Michele Cavo, Meletios A. Dimopoulos, Jesus San-Miguel, Andrzej J. Jakubowiak, Kenshi Suzuki, Sung-Soo Yoon, Mark Cook, Mario Boccadoro, P. Joy Ho, Ludek Pour, Stefan Knop, Chantal Doyen, Tamas Masszi, Joan Blade, Jianping Wang, Susan Wroblewski, William Deraedt, Ming Qi, Maria-Victoria Mateos
Journal: Journal of Clinical Oncology (2018)

e20024 Background: In the phase 3 ALCYONE study, daratumumab (D) in combination with VMP (D-VMP) prolonged progression-free survival (PFS) vs VMP alone, and exhibited favorable tolerability in pts with NDMM. We conducted a subgroup analysis of the efficacy and safety of D-VMP vs VMP according to baseline creatinine clearance (CrCl; ≤60 mL/min [moderately impaired] and > 60 mL/min). Methods: Randomized pts were ineligible for high-dose chemotherapy with ASCT and had baseline CrCl ≥40 mL/min. Up to nine 6-week VMP cycles (V 1.3 mg/m2 SC on Days [d] 1, 4, 8, 11, 22, 25, 29, 32 in Cycle [C] 1 and d 1, 8, 22, 29 in C 2-9; M 9 mg/m2 PO and P 60 mg/m2 PO on d 1-4 in C 1-9) with or without D (16 mg/kg IV QW for C1, Q3W for C 2-9, and Q4W for C 10+ [post VMP-treatment phase] until progression) were received. Minimal residual disease (MRD) at 10–5threshold was evaluated using clonoSEQ (Adaptive Biotechnologies). Results: Among 706 (350 D-VMP; 356 VMP) randomized pts, 295 (150 D-VMP; 145 VMP) had baseline CrCl ≤60 mL/min (≤60) and 411 (200 D-VMP; 211 VMP) had baseline CrCl > 60 mL/min ( > 60). D-VMP prolonged PFS vs VMP in ≤60 (median not reached [NR] vs 16.9 mo; HR 0.36; 95% CI 0.24-0. 56) and > 60 (median NR vs 18.3 mo; HR 0.63; 95% CI 0.45-0.88) subgroups after median follow-up of 16.5 mo. ORR benefit was maintained for D-VMP vs VMP in the ≤60 (89% vs 73%; ≥complete response [CR]: 43% vs 24%) and > 60 (92% vs 74%; ≥CR: 43% vs 25%) subgroups; similar findings were observed with MRD-negative rates in the ≤60 (25% vs 8%; odds ratio [OR] 4.13; 95% CI 2.02-8.46) and > 60 (20% vs 5%; OR 4.55; 95% CI 2.26-9.14) subgroups. Safety findings for D-VMP vs VMP are summarized in Table 1. In the ≤60 and > 60 subgroups, infusion reactions were observed in 27% (Grade 3/4: 5%/0.7%) and 29% (Grade 3/4: 4%/0.5%), respectively. Conclusions: D plus VMP prolongs PFS, induces deep responses, and demonstrates tolerability regardless of baseline CrCl. Clinical trial information: NCT02195479.Grade 3/4, % CrCl ≤60 mL/min CrCl > 60 mL/min D-VMP VMP D-VMP VMP Most common (≥10%) TEAEs Neutropenia 47 38 35 39 Thrombocytopenia 43 42 28 34 Anemia 21 29 12 13 Pneumonia 15 6 9 2 Peripheral sensory neuropathy 2 4 1 4
Abstract IA20: Lineage plasticity in antiandrogen resistance
Authors: Wassim Abida
Journal: Cancer Research (2018)

Abstract Resistance to the novel androgen receptor (AR)-directed therapies enzalutamide and abiraterone acetate can evolve with an aggressive clinical phenotype and atypical histology, including neuroendocrine features. Genomic studies have also revealed enrichment in TP53 and RB1 alterations in advanced metastatic CRPC when compared with primary disease. In recent work, the Sawyers and Goodrich groups have independently shown that concurrent loss of TP53 and RB1 confers resistance to antiandrogen and lineage plasticity through upregulation of the transcription factor SOX2. These studies implicate key tumor suppressors in lineage switching in resistant prostate cancer, and suggest that antiandrogen resistance may be targeted by epigenetic agents in advanced disease. Citation Format: Wassim Abida. Lineage plasticity in antiandrogen resistance [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr IA20.