tbuckley/cabot-search huggingface dataset:
Development of a clinicomolecular risk stratification system for nonmetastatic nasopharyngeal carcinoma using Epstein–Barr virus DNA and TNM stage: A “Big data” analysis of 9,160 endemic cases.
Authors: Fo-Ping Chen, Guan-Qun Zhou, Ying-Shan Luo, Kuan Rui Lloyd Tan, Sze Huey Tan, Yu Zheng, Li Lin, Ying Guo, Jun Ma, Melvin L.K. Chua, Ying Sun
Journal: Journal of Clinical Oncology (2019)

6043 Background: To construct a clinicomolecular index integrating circulating Epstein-barr virus (cfEBV) DNA with T- and N- categories for better prognostication in nasopharyngeal carcinoma (NPC). Methods: Clinical and treatment records of 9,160 biopsy-proven, non-metastatic NPC cases were identified from an institutional “Big-data” platform. Decision tree modeling (DTM), recursive partitioning analysis (RPA) and adjusted hazard ratio (AHR) methods were used to generate clinicomolecular risk models. Outcome prediction of the models were compared against 8 th edition TNM stage and two RPA-original models. Results: We observed linearity between cfEBV DNA and DFS; cfEBV DNA of &gt; 2,000 copies was consistent for risk discretisation (HR &gt; 1.0) for DFS, OS and DMFS in our cohort of 9,160 patients. DTM, RPA-new and AHR modelling using a two-tiered stratification by cfEBV DNA (≤2,000 and &gt; 2,000 copies) and T- and N- categories yielded five risk groups with significantly disparate DFS (P &lt; 0.001 for all subgroup comparisons). AHR model outperformed all other models and the TNM stage classification with better hazard consistency, hazard discrimination, explained variation, sample size balance and likelihood difference. Importantly, our clinicomolecular AHR groupings were significantly associated with the efficacy of different therapeutic regimes. Outcomes were comparable between concurrent chemoradiotherapy and intensity-modulated radiotherapy (IMRT) and IMRT alone for AHR1-2 (3-y DFS [AHR1] = 96.2% [IMRT] vs 95.3% [chemo-IMRT]; 3-y DFS [AHR2] = 91.1% vs 90.4%). Neoadjuvant chemotherapy and chemo-IMRT was superior to chemo-IMRT alone for AHR4-5 (AHR DFS 0.77[0.65-0.93], P = 0.005; 0.77[0.61-0.97], P = 0.027), but not for AHR3 (AHR DFS 1.07[0.86-1.34]). Conclusions: Here, we present a robust clinicomolecular risk stratification system that outperforms the TNM stage classification in non-metastatic NPC. Our clinicomolecular model is associated with the efficacy of different therapeutic regimes.
Glutaminase (GLS) expression in primary breast cancer (BC): Correlations with clinical and tumor characteristics.
Authors: Neelima Vidula, Christina Yau, Hope S. Rugo
Journal: Journal of Clinical Oncology (2019)

558 Background: Tumor cells rely on glutamine for growth. GLS is a mitochondrial enzyme that is necessary for glutamine catabolism, and is present as isoforms GLS1 and GLS2. A GLS1 inhibitor is being studied in triple-negative (TN) BC. We studied GLS1 expression in primary BC to understand associations with clinical and tumor characteristics in publically available databases. Methods: GLS1 mRNA levels were evaluated using expression data from the TCGA (n = 817) dataset, with confirmation in METABRIC (n = 1992). Associations between GLS1 levels and tumor subtype were assessed using ANOVA, followed by the post-hoc Tukey test for pairwise comparisons. Pearson correlations were used to study associations between GLS1 and selected genes. Correlations with overall survival (OS) were studied with Cox proportional hazard model. For all analyses, p &lt; 0.05 was considered significant. Results: In TCGA, the expression of GLS1 and its isoform GLS2 were significantly inversely correlated (r = -0.32). GLS1 expression was highest in TN compared to hormone receptor (HR)+ and HER2+ BC (p &lt; 0.001). In addition, GLS1 expression was higher in basal vs luminal A, luminal B, and HER2 enriched BC (p &lt; 0.001). GLS1 expression was significantly inversely correlated with ER (r = -0.45), PR (r = -0.34), and AR (r = -0.34), and these inverse correlations remained significant when restricted to TNBC (ER: r = -0.25, PR: r = -0.25, AR: r = -0.30). Consistent with previous reports of MYC upregulation of GLS1, GLS1 expression was significantly positively correlated with MYC (r = 0.26). Similarly, in METABRIC, GLS1 was most highly expressed in basal and TNBC, significantly inversely correlated with the expression of GLS2, ER, PR, and AR, and positively correlated with MYC expression. In METABRIC, higher GLS1 expression was associated with better OS (HR 0.91, p = 0.005); this association remained significant in the TN subset (HR 0.83, p = 0.03). Correlations between GLS1 and genes involved in metabolism and immune activation will be presented at the meeting. Conclusions: GLS1 expression is highest in basal and TNBC, is associated with MYC expression, and may have prognostic implications. These findings support ongoing trials of GLS1 inhibition in TNBC.
Predictive molecular tumor response through circulating DNA (cDNA) measurements and correlation with established prognostic markers in a series of solid tumors treated with multitargeted epigenetic therapy (MTET).
Authors: Mohammad A. Nezami, Christian Klowsowski, Steven Jeffrey Hager
Journal: Journal of Clinical Oncology (2019)

e13015 Background: Epigenetic dysregulation of certain genes contribute to the progression of cancers. Plasma ctDNA concentrations can reflect these altered genes and have been shown to correlate well with tumor burden. Methods: We planned to assess the correlation value of c DNA on known factors for prediction of overall survival (OS), recognized as surrogates for survival. Ten( 10) genes of interest, namely NOTCH1, FGF2, MYC, RB1, ATM, MET, BRCA1, BRCA2, ATM and, VHL, were selected as being highly influenced by epigenetic control. We included 54 patients with reported cDNA on the genes of interest for this study evaluating the predictive impact of early changes in cDNA in response to multitargeted epigenetic treatment and the patient survival. There were 12 cases with NOTCH1 mutations, 20 cases with MYC mutations, 5 cases with RB1, 15 cases with BRCA1 or BRCA2 mutations, 26 cases with FGF2 mutations, 18 cases with MET mutations, 2 with VHL mutations and 2 cases with ATM mutations, for a total of 100 data points. Tests for statistical significance were completed using the Fisher Exact probability test calculator found at vassarstats.net/tab2x2.html. Significance level was set at α = .05. Results: There was statistically significant (p-value: .046) correlation on the response of the allele frequency of the observed NOTCH1 alteration with similar response in the angiogenesis biomarkers (Plasma VEGF) and presence of circulating tumor cells. There was a significant correlation (p-value: .014) between a decrease in AF of the observed MYC alteration and biomarker/imaging response on follow-up. In the group of 26 identified with FGF2 mutations, 22 saw cDNA alteration fraction(AF) reduction post therapy. 16/26 of them had either c Myc or NOTCH1 alterations. Also 8 /18 cases with c Met alterations shared NOTCH1 or Myc alteration. This represents a statistically significant (p-value: .0001) correlation on the response of the allele frequency of the observed FGFR2 alteration with the response of other biomarkers. Conclusions: There were a number of significant correlations observed between early changes in cDNA allele fractions of specific genes and the later observations of established prognostic markers. We conclude that changes in cDNA mutated allele fractions observed in liquid biopsy may provide an early useful independent prognostic marker for tumors carrying epigenetically influenced targets and their alterations.
Association of sex, age and ECOG performance status with cancer immunotherapy efficacy in randomized controlled trials.
Authors: Fang Yang, Yucai Wang, Grzegorz S. Nowakowski, Michael Wang, Ashish V. Chintakuntlawar, Thorvardur Ragnar Halfdanarson, Lance C. Pagliaro, Jia Wei, Baorui Liu, Julian R. Molina, Svetomir Markovic
Journal: Journal of Clinical Oncology (2019)

6592 Background: Sex, age and ECOG performance status (PS) may affect immune response and the efficacy of cancer immunotherapy with immune checkpoint inhibitors (ICI). We did a meta-analysis to assess the potential sex, age and ECOG PS differences of immunotherapy efficacy in advanced cancer. Methods: PubMed was searched up to January 15, 2019 for randomized controlled trials (RCT) comparing overall survival (OS) in patients with advanced cancer treated with ICI immunotherapy vs control therapy (without ICI). For sex difference analysis, pooled hazard ratio (HR) of death for men and women was calculated separately, and the heterogeneity between the two estimates was assessed using an interaction test by pooling study-specific interaction HR. Age ( &lt; 65 vs ≥65) and ECOG PS (0 vs ≥1) difference was analyzed similarly. Subgroup analysis by cancer type and line of therapy (frontline vs subsequent) was explored. All analyses were done in Comprehensive Meta Analysis (v2) with random effects models. Results: Thirty phase 2/3 RCTs involving 17,728 patients were included. An OS benefit of immunotherapy was found for both men (HR 0.75, 95% confidence interval [CI] 0.69-0.81, P &lt; 0.01) and women (HR 0.79, 95% CI 0.69-0.90, P &lt; 0.01); for both younger ( &lt; 65; HR 0.75, 95% CI 0.68-0.83, P &lt; 0.01) and older (≥65; HR 0.76, 95% CI 0.69-0.83, P &lt; 0.01) patients; and for both ECOG PS 0 (HR 0.78, 95% CI 0.69-0.89, P &lt; 0.01) and PS ≥1 (HR 0.77, 95% CI 0.71-0.84, P &lt; 0.01) patients. No significant difference of relative benefit from immunotherapy over control therapy was found in patients with different sex ( P = 0.283), age ( P = 0.906) or ECOG PS ( P = 0.783). In melanoma RCTs, compared with women (HR 0.77, 95% CI 0.64-0.94, P &lt; 0.01), men (HR 0.56, 95% CI 0.42-0.76, P &lt; 0.01) had more OS benefit from immunotherapy ( P = 0.037). No significant difference was found in other subgroup analyses by cancer types or line of therapy. Conclusions: Overall we found no evidence of association of sex, age, or ECOG PS with cancer immunotherapy efficacy. However, in melanoma, men might benefit more from immunotherapy than women.
Tumor mutational burden reference materials for assay standardization.
Authors: Matt Butler, Yves Konigshofer, Omoshile Clement, Li Liu, Chen Zhao, Maria E. Arcila, Ahmet Zehir, Ravindra Kohle, Anthony Martin Magliocco, Keith Gligorich, Christian Gloeckner, Alexander F. Lovejoy, Feras Hantash, Carrie Sougnez, Niall Lennon, Bharathi Anekella, Russell Garlick
Journal: Journal of Clinical Oncology (2019)

e14746 Background: Next Generation Sequencing based assays are designed to detect genomic aberrations in a limited number of target regions. However, there is a need for accurate measurement of tumor mutational burden (TMB) as low as 4 to as high as 50. As TMB assessment is added to various targeted panels, consistent results between panels are required to advance the broad use of this biomarker. Properly designed reference materials aid measurement standardization and are required to demonstrate assay concordance. We developed reference materials that vary in TMB score, tumor content 5-50% and are prepared in FFPE format. Methods: Seven lung and two breast tumor cell lines as well as matched “normal” lymphoblastoid cell lines were expanded in cell culture. Genomic DNA (gDNA) from each cell line was extracted. Tumor/normal mixes were made by mixing DNA and by embedding cells in FFPE blocks. Whole exome sequencing (WES) results were obtained using Agilent SureSelectXT for library construction and an Illumina Novaseq for sequencing. The Friends of Cancer Research TMB consensus method for analyzing WES data was used to filter variants and calculate TMB scores. Results: The cell lines were grown at large scale to produce extractable gDNA. 100% gDNA tumor, 30% gDNA tumor mixes and 30% FFPE cell line mixes were prepared. Preliminary results show that a clinically-relevant range of TMB values ranging from 4 to 35 mutations per million bases. The several thousand mutations that were observed across the lines were found in a variety of genes, which may explain why TMB in targeted panels is influenced by the specific target regions. Also, the initial results show that 30% cell line mixes showed similar TMB results to 100% gDNA. Conclusions: Our approach with wide ranging TMB values as tumor normal mixes is flexible and can be used to test different tumors and assays. For this study we established WES as the ground truth measurement for comparison to other assay formats and obtained comparison data from other panels. This approach also allows laboratories to test additional variables including formalin fixation, sample extraction, gene panel size, target regions, sequencing depth, filtering and limits of detection.
Abstract 12824: Mortality Outcomes at 30 Days and 1 Year After Primary Percutaneous Coronary Intervention for Acute Myocardial Infarction Due to Unprotected Left Main Coronary Artery Occlusion
Authors: Ruth Chen, Siew P Chan, Poay H Loh, Joshua Loh, Edgar Tay, Mark Chan, Chi H Lee, Adrian Low, Huay C Tan, Koo H Chan
Journal: Circulation (2016)

Introduction: Patients with acute myocardial infarction (AMI) due to unprotected left main coronary artery (ULMCA) occlusion are often critically ill at presentation. Emergency surgical revascularization is often associated with significant time delay and high mortality risk, as such, primary percutaneous coronary intervention (PCI) has been advocated as the preferred form of reperfusion therapy. Data on the clinical outcomes in this setting however remains limited. Hypothesis: We hypothesised that primary PCI is a feasible revascularization therapy in AMI due to ULMCA occlusion and the identification of the predictors of outcomes would aid in clinical decision-making. Methods: From 2005 to 2015, 71 patients with AMI due to ULMCA occlusion who underwent primary PCI had their outcomes evaluated retrospectively. Given the complex data interrelationships, a generalized structural equation model was applied for identifying the predictors of 30-day and 1-year mortality. All statistical analyses were conducted at 5% level of significance. Results: Majority of the patients (mean age 58.0 ±11.5, 90.1% male) had cardiogenic shock (64.7%) and cardiac arrest (70.1%) and 71.8% were intubated. Procedural success was achieved in 87.3% of patients. Mortality at 30-day was 59.1%, including 16.9% intra-procedural deaths. Cardiogenic shock (Adjusted odds ratio [AOR] 12.1), cardiac arrest (AOR 12.0) and intubation (AOR 282.0) were significantly associated with 30-day mortality. Additionally, a QRS duration of &gt;130 milliseconds on the presenting electrocardiogram was also predictive of cardiogenic shock (AOR 4.5) and 30-day mortality (AOR 10.0). All-cause mortality at 1 year was 63.4% and for which QRS duration &gt;130 milliseconds (AOR 25.4), cardiac arrest (AOR 8.8) and intubation (AOR 16.9) remained predictive of mortality but not cardiogenic shock (AOR 1.8, p &gt;0.05). Conclusion: In conclusion, ULMCA occlusion is associated with a high incidence of 30-day mortality despite successful primary PCI. Patients presenting with a broad QRS complex, cardiogenic shock, cardiac arrest, or requiring intubation have a particularly poor prognosis. However, after thirty days, the mid-term survival rate of the remaining patients appeared favorable.
EV-103: Enfortumab vedotin plus pembrolizumab and/or chemotherapy for locally advanced or metastatic urothelial cancer.
Authors: Christopher J. Hoimes, Jonathan E. Rosenberg, Daniel Peter Petrylak, Anne-Sophie Carret, Amal Melhem-Bertrandt, Thomas W. Flaig
Journal: Journal of Clinical Oncology (2019)

TPS4593 Background: PD-(L)1-targeted immune checkpoint inhibitors (CPIs), such as pembrolizumab (P), are approved for patients (pts) with locally advanced or metastatic urothelial cancer (la/mUC) who progress after platinum, are ineligible for first-line (1L) cisplatin (PD-L1 positive), or are ineligible for 1L platinum. The ORR for CPI in all treated pts is ~25%, and a combination approach may provide additional benefit. Enfortumab vedotin (EV), an investigational antibody-drug conjugate, delivers the microtubule-disrupting agent monomethyl auristatin E to cells expressing Nectin-4, found in 97% of mUC pt samples (Petrylak ASCO 2017). In a phase 1 study (NCT02091999), EV (1.25 mg/kg) was generally well tolerated with a confirmed ORR of 43% in 112 mUC pts (Rosenberg ASCO-GU 2019). These encouraging results, with the potential for an enhanced immune response, suggest that EV+P may improve response rates and extend response durability. Methods: EV-103, a phase 1b trial for non–resectable la/mUC pts with no prior CPI, added an additional 4 cohorts (Parts 2 and 3) in an Oct 2018 amendment. It is now expected to enroll ~159 pts. Dose escalation pts (EV+P, 1L or 2L) must be ineligible for 1L cisplatin-based chemotherapy or have disease progression during/following treatment with ≥1 platinum-containing regimen. Dose expansion (Part 1) will evaluate EV+P in 1L (Cohort A) and 2L settings (Optional Cohort B). Part 2 will evaluate 1L EV+cisplatin (Cohort D), 1L EV+carboplatin (Cohort E), and 1L or 2L EV+gemcitabine (Optional Cohort F). Part 3 (Cohort G) will evaluate 1L EV+P+cisplatin or carboplatin, depending on pts cisplatin-eligibility. In all cohorts, pts receive EV on Days 1 and 8 of each 3-week cycle. In combination therapies, pts receive P, cisplatin, and carboplatin on Day 1 or gemcitabine on Days 1 and 8 of each cycle. The primary objective is to assess the safety/tolerability of EV+P and/or chemotherapy. Secondary objectives are establishing EV recommended dose for combination therapies, assessing ORR per RECIST for all cohorts and per iRECIST for therapies with pembrolizumab, as well as assessing disease control rate, duration of response, PFS, OS, PK, and biomarkers. The study opened Oct 2017. Clinical trial information: NCT03288545.
Phase 1 study of pasotuxizumab (BAY 2010112), a PSMA-targeting Bispecific T cell Engager (BiTE) immunotherapy for metastatic castration-resistant prostate cancer (mCRPC).
Authors: Horst-Dieter Hummel, Peter Kufer, Carsten Grüllich, Barbara Deschler-Baier, Manik Chatterjee, Maria-Elisabeth Goebeler, Kurt Miller, Maria De Santis, Wolfgang C. Loidl, Andreas Buck, Sabine Wittemer-Rump, Goekben Koca, Oliver Boix, Wolf-Dietrich Doecke, Sabine Stienen, Cyrus Sayehli, Ralf C. Bargou
Journal: Journal of Clinical Oncology (2019)

5034 Background: mCRPC has a poor prognosis and immunotherapies are largely ineffective. PSMA is a promising therapeutic target in mCRPC, and pasotuxizumab is a PSMA x CD3 BiTE that mediates tumor cell killing. Methods: NCT01723475 was a first-in-human, multicenter, dose-escalation study in patients (pts) with mCRPC refractory to standard therapy. Pts received pasotuxizumab as a continuous intravenous infusion in cohorts of 3–4 pts. Dose-escalation followed a continuous reassessment methodology design. The primary objective was to determine safety and maximum tolerated dose (MTD); secondary objectives included pharmacokinetics, biomarkers, and tumor response. Results: 16 pts were enrolled into 5 dosing cohorts (5 µg/d, n = 3; 10 µg/d, n = 4; 20 µg/d, n = 3; 40 µg/d, n = 4; 80 µg/d, n = 2). All pts had ≥1 AE of any grade; most common were fever (94%), chills (69%), and fatigue (50%). 13 pts (81%) had ≥1 AE of grade ≥3; most common were decreased lymphocytes and infections (both 44%). No grade 5 AE occurred. A serious AE related to study drug was reported for 1 pt (fatigue, 20 µg/d). No anti-drug antibodies were observed. Recruitment was stopped before MTD was reached to facilitate initiation of a new study sponsored by Amgen. Antitumor activity as indicated by PSA serum level decline was dose dependent, with a mean best PSA change per dosing cohort versus baseline of +0.74% (5 µg/d), –17.9% (10 µg/d), –37.4% (20 µg/d), –42.5% (40 µg/d) and –54.9% (80 µg/d). PSA decreases of ≥50% occurred in 3 pts (n = 1 each in 20 µg/d, 40 µg/d, and 80 µg/d cohorts). One long-term PSA responder was treated for 14 months (40 µg/d) and one for 19.4 months (80 µg/d). The latter pt showed a complete regression of soft-tissue metastases and marked regression of bone metastases as assessed by PSMA-PET/CT, &gt; 90% reduction in PSA and alkaline phosphatase, and a significant and durable improvement in disease related symptoms. Conclusions: Pasotuxizumab had an acceptable safety profile and dose-dependent clinical activity in mCRPC pts. There were two long term responders in the dose escalation. This is the first clinical study showing that a BiTE immunotherapy can be efficacious in solid tumors. Clinical trial information: NCT01723475.
Nationwide shift in patterns of prophylactic cranial irradiation utilization for extensive-stage small cell lung cancer patients.
Authors: Olsi Gjyshi, Ethan B. Ludmir, Todd A. Pezzi, David Boyce-Fappiano, Timur Mitin, Steven H. Lin
Journal: Journal of Clinical Oncology (2019)

e20099 Background: A recent phase III trial (Takahashi et al., 2017) showed no overall survival (OS) benefit in patients with extensive-stage small cell lung cancer (ES-SCLC) treated with prophylactic cranial irradiation (PCI), casting doubt on the practice of PCI as established in a prior phase III trial (Slotman et al., 2007). We undertook a nationwide survey of radiation oncologists to ascertain the impact of the Takahashi trial on the utilization of PCI for ES-SCLC patients. Methods: A total of 3,646 ASTRO-registered radiation oncologists in the United States were invited to answer an anonymous survey on their use of PCI in ES-SCLC, and the impact of the recent Takahashi et al. trial on their practice. The survey consisted of 35 questions created using a branching logic system via RedCAP. Results: A total of 438 (12%) radiation oncologists completed the survey. Responders were well-distributed across geographic regions, practice environment, age, gender, practice size and lung cancer volume. Most respondents (92%) were aware of the Takahashi trial. While 71% routinely offered PCI to ES-SCLC patients prior to the publication of this trial, only 43% continue to do so after its publication (p &lt; 0.001). Most respondents (66%) had altered their practice in response to the study. There was no difference in post-publication practice patterns between academic and private practice radiation oncologists (43% vs. 44%, p = 0.81). While 43% of participants who were aware of the Takahashi trial still offered PCI after its publication, 82% of those unaware of the trial still continued to offer PCI (p &lt; 0.001). Additionally, 25% of participants noted that they have experienced a decrease in medical oncology referrals for PCI for ES-SCLC patients. Twenty-two percent of participants stated that the Takahashi trial impacted their practice with regards to limited-stage SCLC patients as well. Looking toward the future, 47% of respondents reported that they would be willing to enroll both LS- and ES-SCLC patients on a randomized trial comparing active MRI-surveillance to PCI; 15% stated that they would enroll only LS-SCLC patients on such a trial, and 20% would enroll only ES-SCLC patients. Conclusions: The phase III data from Takahashi et al. (2017) has markedly impacted the current practice patterns in the US by reducing PCI utilization for ES-SCLC patients across all practice settings and measured demographic variables. Most respondents expressed openness to a randomized trial comparing active MRI surveillance to PCI for SCLC patients.