tbuckley/cabot-search huggingface dataset:
Clinical targeted next-generation sequencing to identify potentially actionable alterations in the majority of Asian cancer patients.
Authors: Song Ling Poon, Yen-Jung Lu, Ren-Shiang Jhou, Yi-Ting Yang, Pei-Ning Yu, Yen-Ting Liu, Yi-Lin Hsieh, Maarja-Liisa Nairismagi, Shu-Jen Chen, Kien Thiam Tan
Journal: Journal of Clinical Oncology (2018)

e24163 Background: Clinically innovative genomic diagnostics may expedite the development of effective targeting therapies if the patient can be stratified correctly based on their unique cancer driven events/ pathways during tumorigenesis. Here, we performed a pan-cancer analysis on the clinical utility of a targeted gene panel, ACTOnco+, in characterizing the prevalence of actionable mutations. Methods: A total of 229 formalin-fixed, paraffin-embedded (FFPE) tissues from 40 tumor types were subjected to next-generation sequencing (NGS) using the Ion Torrent Proton System. All coding exons in 440 cancer-related genes were assessed at average depth of > 800X. Therapeutic implications were based on information obtained from base substitutions, indels, and copy number alterations (CNAs). Results: 58.5% (n = 134) patients harbored at least one actionable mutation while CNAs, including homozygous and heterozygous deletions, were detected in 83.9% (n = 191) patients. Across all tumor types, the most frequently altered pathway that can either confer sensitivity or resistance to targeted therapies is PI3K/AKT/mTOR signaling, contributed by PIK3CA, AKT1 activating mutations as well as NF1, NF2, PTEN, TSC1, STK11, TSC2 inactivating mutations or deletions. In parallel, dysregulation of cell cycle was mostly owing to CCND1, CDK4, CDK6 amplification and/ or loss of CDKN2A. Notably, on tops of BRCA1/2 mutations, deletions of BRCAness-related genes (MRE11, RAD50, PALB2, FANCD2, ATM, ATR, CHEK1 and CHEK2) that may result in homologous recombination deficiency (HRD) was observed in 71.4% breast, 70.6% ovarian, 61.0% lung, 58.3% pancreatic, and 52.2% colorectal cancers. Other targetable alterations on receptor tyrosine kinase (RTK), angiogenic and hedgehog signaling pathways were also observed. Conclusions: A comprehensive pathway-based genomic profiling significantly characterized actionable alterations across different solid tumors that may play a role in tissue-agnostic tailored treatment.
Evaluating the link between T cell receptor beta variable gene polymorphism and immune mediated adverse events during checkpoint blockade immunotherapy.
Authors: Timothy Looney, Elizabeth Linch, Geoffrey Lowman, Lauren Miller, Jianping Zheng, Denise Topacio-Hall
Journal: Journal of Clinical Oncology (2018)

e15002 Background: Identifying predictive biomarkers for the emergence of immune mediated adverse events (IMAEs) during immunotherapy is a key objective of current immunotherapy research. The antigen specificity of the T cell receptor is determined in part by the sequence of the CDR and Framework regions encoded by the T cell receptor variable (TRBV) gene. Germline encoded polymorphism within the TRBV CDR1 and 2 regions can, among other things, modulate TCR interaction with HLA, potentially increasing the likelihood of autoantigen recognition. Here we use the Oncomine TCR Beta-LR assay to evaluate TRBV gene polymorphism as a potential predictive research biomarker for IMAEs following checkpoint blockade immunotherapy. Methods: Total RNA extracted from peripheral blood leukocytes from 55 individuals with graded adverse events following administration of checkpoint blockade for the treatment of cancer. 25ng RNA was used as input for long-amplicon TCRB repertoire sequencing via the Ion Torrent S5 using 530 chip (~1M reads per sample) to provide sequence coverage of all three CDR domains, enabling detection of the TRBV gene allele. Clonotyping and detection of variable gene alleles was performed using Ion Reporter software. Results: TRBV gene allele typing revealed the presence of distinct sets of TRBV alleles, which we classified into major TRBV allele groups. We then evaluated the frequency of severe adverse events within each group. We find that the frequency of adverse events varies markedly between groups: one group, accounting for nearly one third of the sample set, appears protected from severe adverse events (0% frequency), while other groups showed moderate to elevated frequency of adverse events. Conclusions: These data suggest that TRBV polymorphism may play a mechanistic or predictive role in autoimmune toxicity during immunotherapy, highlighting the potential for TRBV allele typing to enable personalized immunotherapy for the treatment of cancer.
A collaborative pilot model among Georgia oncologists to strengthen clinical trial enrollment and promote equity of care for minorities.
Authors: Sharad A. Ghamande, Guilherme Cantuaria, Anand P. Jillella, Vamsi Kota, Andrew Emmons Green, William Richards, James J Burke, Howard A. Zaren, Mark A. Taylor, Sreekanth Reddy, Melissa S. Dillmon, Andrew William Pippas, Frederick M. Schnell, Jayanthi Srinivasiah, Colleen H. McDonough, Joni Short, Geri Whitaker, Aprille Belgrave, Nancy M. Paris
Journal: Journal of Clinical Oncology (2018)

e18651 Background: Clinical trials promote excellence in cancer care but only 2 – 3 % of patients enroll on trials. 1Minorities who experience the greatest cancer burden are least likely to enroll, although research demonstrates they are as likely as whites to consent to participation2. Historic rates of minority participation in NCI trials are 9.2% and less than 5% in pharmaceutical trials4. Persistent under representation of minorities creates disparity in access to care, inability to generalize research findings and worse health outcomes2.These factors underscore need for effective strategies to increase minority accrual to tria Methods: The Georgia Center of Oncology Research and Education serves as a catalyst for collaboration among oncologists committed to increasing statewide access to trials. Goals of Georgia CORE include enhancing availability of NCI sponsored trials and increasing minority accrual. Between 2007 and 2017 four clinical trial initiatives were created by Georgia CORE investigators: Gynecologic Oncology Group Consortium, APL Investigator Initiated Study, GA NCORP and GA CaRes Minority NCORP. Strategies to enhance minority enrollment included investigator education, staff training, and outreach to churches and minority organizations. Results: 1,164 patients reported racial/ethnic status and enrolled in clinical trials conducted through 3 NCI initiatives and 1 investigator initiated trial that resulted in an ECOG-ACRIN trial EA9131. A significant percentage of minorities, ranging from 23 – 47%, were enrolled. Conclusions: In a state with significant disparities in cancer survival, collaboration between oncologists increased access to NCI sponsored trials in geographically and racially diverse centers. Collectively these efforts produced 32% minority accrual and improved equity of available treatment options. This endeavor can serve as model for other states to replicate and improve cancer outcomes for minorities and the generalizability of research for all patients. GOG APL study GA NCORP GA CaRes Total M NCORP 2007-13 2013-16 2014-17 2014-17 # Sites 8 4 6 4 # Pts 225 118 615 206 1164 # Minority 54/24% 46/34% 141/34% 94/47% 335/32% Enrollment
Chinese medicine based study of warm and removing decoction in combination with conventional therapy of hepatic cell carcinoma.
Authors: Yongling Gong, Ruoqu Wei, Guangmei Lv, Haijun Wan Wan, Ping Li, Chongfeng Niu
Journal: Journal of Clinical Oncology (2016)

e15625 Background: Aiming at starting the ball rolling and contributing humble effort to promote Chinese traditional medicine, we performed a Chinese medicine based study of Warm and Removing decoction in combination with conventional therapy of hepatic cell carcinoma (HCC). Methods: Select 42 hospitalized patients with histologically confirmed HCC from Jan 2012 to Dec 2014 randomly, including 22 cases in the control group for conventional therapy of surgical resection and/or chemoradiotherapy as usual; and 20 patients in the study group for combined treatment of “warm and removing” decoction (WRD) on the basis of standard care. In the meantime, evaluation of clinical characteristics and quality of life was assessed. Results: There was a significant difference (P < 0.05) in AFP(alpha feto protein)/ALT(alanine transaminase) indices between groups of control and WRD. The DCR（disease control rate） was 43% in the WRD group compared with 34% in the control group. PFS(Progression-Free-Survival) and TTP(Time-to-Progression) of three-month duration were 60%,35% for WRD patients and 45%,40% for control patients, respectively. Our retrospective clinical study showed no overall survival (OS) benefit for HCC patients treated with WRD combination treatment compared with conventional care, while the QOL(quality of life) evaluation seemed to predict survival better for WRD patients than those for control patients. Conclusions: It had been shown that WRD played an important role in the combination therapy of primary liver cancer, which suggested distinguished liver cancer progression and heterogeneity with individual therapy response. Chinese medicine based combination therapy might be an additional choice with its better benefits and tolerability in the treatment of HCC.
Association between density of tumor infiltrating lymphocytes and disease-free survival (DFS) in patients with resected stage I-III colorectal cancer in the FACS randomized trial.
Authors: Sian Alexandra Pugh, Karwan Moutasim, Nicholas Mark Jenkins, Bethany Shinkins, Gareth Thomas, David Mant, John Neil Primrose
Journal: Journal of Clinical Oncology (2018)

3573 Background: Accumulating evidence demonstrates an association between density of tumor infiltrating lymphocytes and outcome in colorectal cancer (CRC). This study sought to assess the prognostic utility using an accurately staged cohort of patients followed up in a clinical trial. Methods: Observational analysis of data from the FACS (follow-up after CRC surgery) trial after 5 years of follow-up. All patients had undergone treatment with curative intent for stage I-III primary CRC, with microscopically clear margins, no evidence of metastases on axial imaging and CEA < 10μg/l following completion of treatment. Immune cell densities were quantified in the centre (CT) and invasive margin (IM) of all tumors for both CD3 and CD45RO. For each tumor region high (Hi) and low (Lo) CD3 and CD45RO densities were determined according to the median of the cohort to investigate association with disease free survival (DFS). Results: Tumor samples have been analyzed from 297 patients to date for which the combined 5 year DFS is 83% (left sided CRC 81%, right sided CRC 85%). High densities of CD3 and CD45RO positive cells in both tumor regions were associated with a superior outcome: CD3CTIMHiCD45ROCTIMHi 94% 5yr DFS vs CD3CTIMLoCD45ROCTIMLo 81%, HR 0.36 95% CI 0.15-0.89 p = 0.04. This difference was most notable in left sided CRC: CD3CTIMHiCD45ROCTIMHi 96% 5yr DFS vs CD3CTIMLoCD45ROCTIMLo 78%, HR 0.13 95%CI 0.04-0.41 p = 0.02. In right sided CRC the difference was not significant: CD3CTIMHiCD45ROCTIMHi 91% 5yr DFS vs CD3CTIMLoCD45ROCTIMLo 83%, HR 0.70 95%CI 0.17-2.89 p = 0.62. Conclusions: In a well characterized and followed up cohort of CRC patients within a clinical trial we have demonstrated that CD3CTIMHiCD45ROCTIMHi left sided tumors have a significantly better outlook. The potential for these data to impact on the need for clinical follow up in patients with left sided CRC should be examined in a prospective study. Clinical trial information: 61091474.
Reliability of administrative data for evaluating quality of systemic cancer treatment.
Authors: Monika K. Krzyzanowska, Melanie Lynn Powis, Nathan Taback, Christina Diong, Katherine Enright, Christopher M. Booth, Maureen E. Trudeau
Journal: Journal of Clinical Oncology (2017)

e18269 Background: There is ongoing interest in leveraging administrative data to examine quality but methodological concerns persist. We evaluated the reliability of a previously established panel of administrative data derived quality measures for systemic treatment. Methods: The cohort consisted of women diagnosed with early stage (stage I-III) breast cancer (ESBC) in Ontario, Canada, in 2010. Performance on 11 quality indicators evaluated using deterministically linked healthcare administrative databases has been reported previously. Sensitivity and specificity were examined using the chart as the gold standard. Results: The administrative cohort consisted of 6,795 women with ESBC from which a validation cohort of 705 patients was randomly selected from among patients who underwent cancer surgery at one of five hospitals chosen to balance feasibility and institutional characteristics.Sensitivity and specificity varied by indicator (Table 1). Reliability of some indicators may have been affected by suboptimal chart documentation in instances where care spanned multiple settings or the medical record was fragmented, or where the number of eligible patients for that indicator was low. Conclusions: Administrative data can be used to evaluate quality of systemic cancer therapy but understanding the reliability characteristics of individual indicators is essential to inform their appropriate use and interpretation. [Table: see text]
Phase III study of individualized intraperitoneal/intravenous/oral chemotherapy compared with standard intravenous/oral chemotherapy in patients with advanced gastric cancer.
Authors: Yang Yang, Jia Wei, Juan Du, Lixia Yu, Hanqing Qian, Yan Yang, Xiaoping Qian, Baorui Liu
Journal: Journal of Clinical Oncology (2017)

4021 Background: Tumor mRNA expression levels may have a promising role as potential predictive biomarkers for chemotherapy. Intraperitoneal (IP) chemotherapy provides sustained high local concentrations, and its efficacy has been shown in ovarian cancer and gastric cancer patients with peritoneal metastasis. We developed a regimen combining IP/intravenous(IV)/oral chemotherapy for the treatment of advanced gastric cancer patients with individualized chemotherapeutics according to mRNA expression. This multicenter phase III study evaluated the efficacy of individualized multi-route chemotherapy compared to standard systemic chemotherapy. Methods: Eligibility criteria included pathologically confirmed advanced gastric adenocarcinoma, and no prior chemotherapy. Patients were randomized 3:1 to an individualized arm (IN) and standard arm (ST). Randomization was stratified by center. Patients in individualized arm first underwent mRNA expression (BRCA1/TOPO1/TS) to choose sensltive chemotherapeutics from oxaliplatin/cisplatin/docetaxel/irinotecan/S-1 and then received individualized IP/IV/oral chemotherapy. The primary endpoint was overall survival (OS). Secondary endpoints were response rate, progression-free survival (PFS), and safety. Results: Between April 2013 and December 2015, 231 patients were enrolled, and 218 patients were included in the efficacy analysis. Baseline patient characteristics were balanced between the two arms. The median OS for IN and ST were 16.3 and 14.1 months, respectively (adjusted hazard ratio [aHR] 0.77, 95% confidence interval [CI] 0.61-0.98, p &lt; 0.05). The overall response rate was 44.0% in the IN arm, and 33.9% in the ST arm (p &lt; 0.05). Both regimens were tolerable. Conclusions: The primary analysis showed the statistical superiority of the individualized multi-route regimen. It suggested clinical efficacy of this regimen in patients with advanced gastric cancer. Clinical trial information: ChiCTR-IPR-15006201.
<i>BRAF</i> mutation and PD-L1 expression in melanoma: Comparison between multiple PD-L1 IHC clones and <i>BRAF</i> mutation evalutated by FDA-approved kits versus NGS.
Authors: Dennis O'Malley, Sucha Sudarsanam, Vladislav Chizhevsky, Wanlong Ma, Shiping Jiang, Wayne Chen, Vincent Anthony Funari, Sally Agersborg, Maher Albitar
Journal: Journal of Clinical Oncology (2017)

e21050 Background: BRAF mutation and PD-L1 expression appear independent in melanoma. We have established that PD-L1 clones 22C3 and 28.8 show almost identical results. In this study we correlated between BRAF mutation and PD-L1 expression as detected by 22C3/28.8 and SP142 in melanoma clinical samples. Methods: Melanoma samples were tested for PD-L1 expression and BRAF mutation. IHC testing for PD-L1 22C3 or 28.8 were tested using FDA-approved kits as recommended. Testing with SP142 (Spring Biosciences; LDT) was performed using standard techniques. BRAF testing in combination with SP142 PD-L1 testing was performed using next generation sequencing covering exons 11 and 15. Samples tested with 22C3 and 28.8 clones were tested using FDA-cleared BRAF kits (Cobas, Therascreen) testing V600 only. Results: 68 samples were tested for PD-L1 expression with clone 22C3, 67 with 28.8, and 56 with SP142. There was no overall statistical difference between the three clones in PD-L1 expression (P = 0.41). For combined 22C3 and 28.8, 61 of 135 cases (45%) had PD-L1 expression and 31 (23%) had BRAF mutation detected using FDA kits (V600). There was no statistical correlation between PD-L1 expression and BRAF mutation in this group (P = 0.9) at any cut-off. In cases tested with SP142 clone, BRAF mutation was detected in 31 cases (55%) by NGS, higher than using the FDA kit (P &lt; 0.0001). In V600 mutations by NGS, 14 cases (25%) were positive, similar FDA kits. In SP142 cases, PD-L1 was positive in 45% of cases. There was no correlation between BRAF mutation and PD-L1 using SP142 expression as a continuous variable (P = 0.59) or cut-off points of 5% or 50%. When cut-off of 20% was used, significant inverse correlation with BRAF mutation (P = 0.004) was identified and was maintained if V600 codon only was evaluated. Conclusions: There is no correlation between BRAF mutation and PD-L1 expression as detected using clones 22C3 and 28.8. With SP142, a negative correlation between PD-L1 expression and BRAF mutation is identified with a 20% cut-off. The rate of BRAF mutations practically doubles when NGS is used and exons 11 and 15 are included in the testing, in contrast to FDA approved testing.
Abstract 18803: Abnormal Right Ventricular Longitudinal Strain With Exercise Stress Echocardiography in Systemic Sclerosis
Authors: Monica Mukherjee, Susan A Mayer, Ryan J Tedford, Stephen C Mathai, Laura K Hummers, Fredrick M Wigley, Theodore P Abraham, Ami A Shah
Journal: Circulation (2016)

Introduction: Cardiac involvement in systemic sclerosis (SSc) is associated with increased morbidity and mortality, due to the development of right ventricular (RV) dysfunction and associated pulmonary arterial hypertension (PAH). Current screening tools are insufficent to detect early cardiac involvement in SSc. We sought to assess the utility of exercise bicycle echocardiography (BE) in conjunction with speckle derived strain to detect occult abnormalities in regional and global RV contractility in SSc patients at high risk of PAH. Methods: SSc patients were referred for supine BE. Inclusion criteria included: RV systolic pressure (RVSP) ≥40mmHg with dyspnea, RVSP ≥45mmHg regardless of symptoms, isolated decline in diffusing capacity (DLCO) ≥10% predicted from baseline, or new onset unexplained dyspnea. Patients initiated exercise at 25 Watts and increased by 25 watts every 3 minutes until achieving 85% of the their age-predicted maximum heart rate or were limited by symptoms. Standard 2D assessment of ...
GEIS-21: A multicentric phase II study of intensive chemotherapy including gemcitabine/docetaxel for the treatment of Ewing sarcoma of children and adults: A report from the Spanish Group of Sarcoma Investigation (GEIS).
Authors: Jaume Mora, Alicia Castaneda, Essy Madariegue, Antonio Lopez-Pousa, Claudia María Valverde, Javier Martin Broto, Xavier Garcia del Muro, Javier Martinez Trufero, Josefina Cruz, Joan Maurel, Maria Angeles Vaz, Sara Perez-Jaume, Enrique Alava, Carmen de Torres
Journal: Journal of Clinical Oncology (2016)

11002 Background: This is the first Spanish trial of Ewing sarcoma (ES) with the aim to reproduce the mP6 results and test the efficacy of the Gemcitabine/Docetaxel (G/D) regimen. Methods: Prospective, multicentric, non-randomized study of ES pts ≤40 years with tumor rearrangements of EWSR1. Centralized bone marrow screening for micrometastatic spread and radiological review was performed. All pts received 5 mP6 courses of chemotherapy; surgical resection after course 3; and radiotherapy after course 5. High-risk (HR) pts received 2 window cycles of G/D, Gemcitabine 1000 mg/m2 IV on days 1 and 8, and Docetaxel 100 mg/m2 on day 8 of a 21-day cycle. HR pts with an objective response (OR) to G/D received 12 monthly cycles of G/D after mP6. Results: 43 (22 SR, 21 HR) pts were enrolled, median age 17y (range, 3 - 40). 10/21 HR pts evaluable for G/D window therapy response showed 1 complete (CR) and 3 partial (PR) responses, 3 stable disease (SD). 30/43 pts were evaluable at the end of mP6. 24 (80%) CR; 3 (10%) PR; 1 SD (3%); and 2 (7%) progressed. 11 HR entered maintenance and 1 year later 5 remain CR. Grade 4 adverse events during mP6 occurred in 28/39 (72%) and did not correlate with age. Statistically significant differences were detected for risk groups: SR 4-y OS 74% (CI=51,100) and 4-y EFS 67% (CI=47,95); HR 4-y OS 42% (CI=25,73) p=0.011 and EFS 27% (CI=13,56) p=0.0028; and age: <18y 4-y OS 78% (CI= 58,100) and 32% for >18y (CI= 15,69) p<0.001; 4y-EFS 62% (CI= 43,89) <18y and 28% (CI= 13,61) >18y, p=0.0087. Multivariate analysis for OS showed HR and < 18y vs HR >18y, p= 0.0070; HR and >18y vs SR and < 18y, p <0.001. Cox model for HR and >18y vs SR and <18y, p<0.001; 18y vs same risk group, p= 0.0021, superior to same age vs risk group, p=0.014. Conclusions: The G/D regimen resulted in objective responses to 70% HR-ES. Age is stronger predictive marker than risk group. Monthly G/D benefited 50% of HR-ES providing a backbone regimen for managing minimal residual disease. Clinical trial information: EudraCT 2009-016027-62.