tbuckley/cabot-search huggingface dataset:
BTC1.04 Genomic profiling of IDH-wildtype and IDH-mutant initial and matched recurrent glioblastomas reveals clinically actionable mutations (e.g. BRCA1/2) and resistance signatures
Authors: C E McInerney, H P Ellis, D Schrimpf, F Sahm, A Stupnikov, M Wadsley, C Wragg, P White, K M Prise, D G McArt, K M Kurian
Journal: Neuro-Oncology (2018)

Glioblastomas account for 90% of all adult brain tumours. Patient survival remains low because treatments are ineffective against this lethal disease. Understanding the genes and pathways altered in subtypes is necessary for therapeutic intervention. Tumours from 41 patients, 8 with matched initial and recurrent glioblastomas were genomically profiled. Some 130 clinically relevant neuro-oncology genes were assessed using an NGS-based diagnostic panel. Single nucleotide variants (SNVs), copy number variations (CNVs) and potentially clinically actionable mutations were described for initial and recurrent IDH-wildtype (n=38) and IDH-mutant glioblastomas (n=3). The mutational landscape revealed discrete differences and similarities between subtypes. TSC2, MSH6, TP53, CREBBP and IDH1 were co-mutated and putatively pathogenic in both subtypes, suggesting they are driver mutations. Recurrent tumours were not hypermutated and matched analysis revealed inter-tumour heterogeneity. SNVs (145) impacted 55 genes in the RTK/Ras/PI(3)K (82%), p53 (63%), WNT (58%), SHH (13%), NOTCH (11%), Rb (5%) and G-protein (8%) pathways. SNV burden was a predictor of overall survival (P=0.003) but no particular pathway was individually responsible. SNVs (40) in BRAF, DAXX, EGFR, FGFR2, JAK2, MYB, PIK3CA, PIK3R1, PTEN, ATM, BRCA1, CHEK2, PPM1D, PTCH1 and SMO were also putatively pathogenic. Many initial tumours had BRCA1 (21%) and BRCA2 (18%) variants, including previously confirmed somatic mutations in haemangioblastoma, and also WNT variants (58%). Recurrent tumours had fewer pathways (RTK/Ras/PI(3)K, p53, WNT, G-protein) impacted by genetic alterations. Possible tumour resistance signatures included a private SNV in PIK3C2G and CNV gains (BRCA2, GNAS, EGFR) and losses (TERT, SMARCA4). Survival analysis suggested GNAS variation was prognostic (P<0.001). Recurrent tumours (57%;4/7) harboured potentially actionable variation in PTEN, BRCA1/2, ATR and EGFR. Combination therapies with erlotinib, everolimus or dasatinib, olaparib, ATR inhibitors and EGFR-targeting antibodies, vaccines or TK inhibitors could provide therapeutic intervention. SNVs (15) impacted 11 genes in the RTK/Ras/PI(3)K (66%), p53 (100%) and WNT pathways (33%). SNVs were also putatively pathogenic in KLK1 exclusively in this subtype. The recurrent tumour had fewer pathways (p53, WNT, G-protein) impacted by genetic alterations and a private SNV in TCF4. Potentially actionable variation in ATR could be targeted using ATR inhibitors. TCGA-GBM and GDC datasets corroborated results confirming the clinical significance of findings. Combination therapies targeting the potentially clinically actionable mutations described for IDH-wildtype and IDH-mutant subtypes may hold the best promise for patient oncological management.
Whole BRCA1/2 exome screening in breast cancer tissue: Preliminary study on 45 patients negative in preventive screening analysis in Poland which cover the most common mutations in BRCA1/2 tested in blood.
Authors: Marzena Anna Lewandowska, Ewelina Nalejska, Katarzyna Kaminska, Bogdan Zurawski, Tomasz Mierzwa, Krzysztof Roszkowski, Janusz Kowalewski
Journal: Journal of Clinical Oncology (2018)

e13615 Background: The standard genetic preventive test in Poland covered 3-5 of the most common mutations, including BRCA1: c.5266dupC, c.181T > G, c.4034delA and BRCA2: c.6174delT, c.5972C > T. Recent NGS analysis showed that this screening test misses up to 35% of germline BRCA1/2 mutations. Furthermore, identification of BRCA1/2 somatic mutations is important prior to treatment with PARP inhibitors. Our aim is to evaluate percentage of mutation using NGS in patients, who had been defined as BRCA1/2 negative with the standard panel, but developed breast cancer. Secondly – we determine the quality metrics of archival DNA which are suitable for NGS Methods: A total of 45 breast cancer patients diagnosed between 2009-2017 (F.Lukaszczyk Oncology Center,Poland) BRCA1/2 negative for 5 common mutations observed in the Polish population were referred after informed consent. Isolated DNA (Qiagen) was quantified using the qPCR-based Fragmentation Quantification Assay–FQA (EntroGen) and calculated using two F-ratios (150bp/37bp and 300bp/37bp) per sample. NGS libraries were prepared using the BRCA Complete™ CE-IVD (EntroGen) with DNA qualified equally or below FQA standards recommended by manufacturer. Sequencing results were analyzed using EntroGen Variant Reporter v1.3 and Illumina Variant Studio 3.0 Results: The average patient age at diagnosis was 43 years (range: 25-69 years old). We detected 6.7% pathogenic nonsense mutation among patients diagnosed with breast cancer at age 34 to 41. Detected VUS and putative novel changes are still under evaluation to confirm percentage of germline and somatic variants using capillary sequencing. In addition, we looked deeply into DNA quality, to better understand where is the limit, how much DNA can be degradated in order to still have readable NGS data. For archival fragmented DNA: samples with a 150bp/37bp F-ratio 0.8 or higher have uniformity of coverage > 85%. Conclusions: Our preliminary results indicates the need for NGS in breast cancer diagnostic algorithm. We recommend FQA analysis as an obligatory step to decrease cost of NGS analysis.
TCT-192 The comparison of healing 1-month and 1-year after percutaneous coronary intervention among cobalt chromium everolimus eluting stent(EES), biodegradable polymer(BP)-EES and BP-sirolimus eluting stent:Insights from optical coherence tomography and coronary angioscopy
Authors: Takao Sato, Yuji Taya, Yuta Sakaguchi, Sho Yuasa, Masaaki Okabe, Yoshifusa Aizasa
Journal: Journal of the American College of Cardiology (2018)
A clinical prediction model to assess risk for pancreatic cancer among patients with new-onset diabetes.
Authors: Ben Boursi, Brian S. Finkelman, Bruce J. Giantonio, Kevin Haynes, Anil K. Rustgi, Andrew Rhim, Ronac Mamtani, Yu-Xiao Yang
Journal: Journal of Clinical Oncology (2017)

e15780 Background: Approximately 50% of all patients with pancreatic ductal adenocarcinoma (PDA) develop diabetes mellitus (DM) prior to cancer diagnosis. Targeted screening for PDA among those with new-onset diabetes may allow earlier diagnosis. We sought to develop and validate a PDA risk prediction model to identify high-risk individuals among those with new-onset diabetes. Methods: We conducted a retrospective cohort study in a population representative database from the UK. Individuals with incident diabetes after the age of 35 and ≥3 years of follow-up after DM diagnosis were eligible for inclusion. Candidate predictors consisted of epidemiological and clinical characteristics available at the time of diabetes diagnosis. Variables with p-value&lt;0.25 in the univariable analyses were further evaluated using backward stepwise approach. Model discrimination was assessed using ROC curve analysis. Calibration was evaluated using the Hosmer–Lemeshow test. Results were internally validated using a bootstrapping procedure. Results: The study included 109,385 patients with new-onset diabetes. Among them, 390 (0.4%) were diagnosed with PDA within 3 years. The final model (AUC 0.82, 95% CI: 0.75-0.89) included age, BMI, BMI change, smoking, HbA1C, cholesterol, hemoglobin, creatinine and alkaline phosphatase, and use of PPI and anti-diabetic medication. Bootstrapping validation showed negligible optimism. If the predicted risk threshold for definitive PDA screening was set at 1% over 3 years, only 6.19% of the new-onset diabetes population would undergo definitive screening, and the corresponding sensitivity, specificity and positive predictive value would be 44.7%, 94.0%, and 2.6% respectively. Conclusions: A risk model based on widely available clinical parameters can help target PDA screening in patients with new-onset diabetes.
Treatment, outcomes, and impact of racial disparities on young adults with pancreatic cancer.
Authors: Olatunji Boladale Alese, Renjian Jiang, Walid Labib Shaib, Christina Sing-Ying Wu, Madhusmita Behera, Bassel F. El-Rayes
Journal: Journal of Clinical Oncology (2017)

e18069 Background: Pancreatic cancer is a disease of the elderly. The treatment and outcomes of young adults with pancreatic cancer has not been well studied. The aim of this study is to describe the treatment, outcomes, and impact of race in young adults with pancreatic cancer. Methods: Data were obtained from all US hospitals that contributed to the National Cancer Database (NCDB) between 2004 and 2013. Univariate and multivariate testing was done to identify factors associated with patient outcome. Kaplan-Meier analysis and Cox proportional hazards models were used to assess the association between patient characteristics, time intervals and survival. Results: A total of 9,657 patients between 18 and 50 years of age were identified. The mean age was 45.4 years (SD±4.6), with a male preponderance (58.3%). Distribution across stages I-IV was 6.1%, 31.1%, 13.9% and 48.8% consecutively, and was similar across all racial groups. About 30.9% of patients underwent resection of the primary pancreatic tumor. Univariate analysis showed survival difference between ages 18-34 vs. 35-50 years old (HR 0.81; 0.71-0.92; p&lt;0.001). On multivariable analysis, Hispanics had significantly higher survival rates than non-Hispanic Whites (NHW) (HR 0.7; 0.64-0.76; p&lt;0.001). Compared to Blacks, Hispanics were more likely to benefit from surgical resection (HR 0.76; 0.61-0.94; p=0.011) and chemotherapy administration (HR 0.78; 0.69-0.88; p&lt;0.001). Overall, patients treated between 2009 and 2013 had higher survival rates compared to 2004-2008 (HR 0.86; 0.82-0.91; p&lt;0.001). The improvement in 5-year overall survival rates over time was highest in American Indians and Asian/Pacific Islanders (16.6% vs. 6.5%); Blacks (10.6% vs. 8.5%) and Hispanics (14.5% vs. 12.6%). NHWs marginally improved from 8.4% to 9.8%. Conclusions: Survival in pancreatic cancer patients younger than 50 years has improved over time, with major gains in minority populations. [Table: see text]
A first-in-class therapy for the treatment of advanced stage liver cancer.
Authors: Steve Brookes, Gary Levy, Jin Seo, Murray Cutler, Gord Adamson, David Bell
Journal: Journal of Clinical Oncology (2016)

e14061 Background: Hepatocellular carcinoma (HCC) is the second most common cause of death from cancer worldwide. Current standard of care provides only a modest improvement in overall survival and is associated with poor quality of life. Therapure has developed a novel drug delivery platform based upon the attachment of therapeutic drugs to hemoglobin (Hb) as a means of targeting the liver. TBI 302 is a hemoglobin-drug conjugate (HDC) designed to deliver the anticancer drug floxuridine (FUdR) to the liver to improve the effectiveness of treatment for HCC. Systemic toxicity associated with free FUdR restricts its use to locoregional administration (0.2-0.5 mg/kg/d) via continuous hepatic arterial infusion (HAI). Although HAI of FUdR can reduce tumor burden, toxicity from HAI FUdR and complications associated with direct hepatic infusion pumps can be significant. HDC technology uses Hb as an innovative drug carrier that exploits the natural pathway for hemoglobin clearance predominantly through the liver to provide selective drug targeting while preserving FUdR activity following intravenous (IV) infusion. Methods: To establish a safe starting dose for a first-in-human Phase 1 trial, a GLP-compliant repeat dose preclinical safety study of TBI 302 in cynomolgus monkeys was conducted. TBI 302 administered by 1-hour IV infusion once per week for 8 weeks at doses of 2, 5, and 10.5 mg/kg. Results: Increasing doses of TBI 302 resulted in proportional area under the concentration-time curve (AUC) and maximum concentration (Cmax) of total plasma FUdR. No clinical signs or biochemical toxicity was associated with IV infusion of TBI 302. The no-observed-adverse effect level (NOAEL) of TBI 302 was determined to be the highest dose level of 10.5 mg/kg. TBI 302 is estimated to have a half-life of 5 hours in humans. Conclusions: A Phase I safety study of TBI 302 as second line therapy in HCC has been approved by the US FDA. The primary objective is to determine safety and tolerability of TBI 302. The secondary objectives are to determine TBI 302 pharmacokinetics and effects on tumor burden. Therapure's HDC platform represents a new class of therapy that offers liver-specific targeting for a wide range of hepatic diseases, while potentially reducing drug toxicity.
Prognostic significance of neutrophil-to-lymphocyte ratio in racial minorities with hepatocellular carcinoma.
Authors: Santiago Thibaud, Santiago Aparo, Jennifer W. Chuy, Andreas Kaubisch
Journal: Journal of Clinical Oncology (2018)

e16154 Background: An elevated neutrophil-to-lymphocyte ratio (NLR) has been shown to portend poor prognosis in hepatocellular carcinoma (HCC). However, studies that evaluated the prognostic significance of NLR in HCC did not include large numbers of Blacks and Hispanics. This single-center, retrospective study conducted on a large, racially diverse cohort explores the utility of NLR in predicting outcomes in minority populations. Methods: We identified patients (pts) diagnosed with HCC at our institution between the years 2000 and 2016. Those with an acute infection at the time of diagnosis were excluded. We used MaxStat analysis to select optimal cutoff value for NLR. Pts were divided into high and low NLR according to cutoff. Demographics, clinical and treatment data were collected. Overall survival (OS) was analysed using the Kaplan-Meier method. Cox proportional-hazards model was used for multivariate analysis (MVA). Results: 727 pts with HCC were included. 525 (72%) were male. Median age was 62. 40% were Hispanic, 28% Black and 21% White. Optimal NLR cutoff was calculated to be 2.0. NLR was high in 391 pts (54%, mean 3.9 ± 1.8) and low in 336 pts (46%, mean 1.3 ± 0.4). 32% of pts were stage I, 27% stage II, 21% stage III and 7% stage IV. Median follow up was 23 months. OS was significantly lower in the high NLR group (median survival 32.3 vs 80.1 months, HR 1.8, 95% CI 1.4-2.2, P < 0.01). Difference in OS remained significant in Hispanics (HR 1.7, P < 0.01), Blacks (HR 2.1, P < 0.01) and Whites (HR 1.9, P < 0.01) on subgroup analysis. High NLR pts had a more advanced stage at diagnosis (P < 0.01), as well as significantly higher AFP levels (P < 0.01), MELD-Na (P < 0.01) and ALBI scores (P < 0.01). NLR > 2 remained significantly associated with worse OS on MVA after adjusting for age, gender, MELD-Na, AFP level, stage and treatment modality (HR 1.4; 95% CI 1.1-1.8; P < 0.01). Conclusions: NLR > 2 at the time of diagnosis had a strong correlation with poor OS in a large, racially diverse cohort of HCC pts. This correlation held true for both Hispanic and Black patients, who have been previously underrepresented in similar studies. This study updates the results that our group previously presented at ASCO GI 2018 by adding staging and treatment data.
Phase II trial of consolidation Pembrolizumab following concurrent chemoradiation in patients (pts) with unresectable or inoperable stage III non-small cell lung cancer (NSCLC): initial safety data from HCRN LUN 14-179.
Authors: Greg Andrew Durm, Ebenezer A. Kio, William B. Fisher, Michael L. Titzer, Salma Jabbour, TIM Breen, Ziyue Liu, Nasser H. Hanna
Journal: Journal of Clinical Oncology (2016)

e20025 Background: A standard of care for pts with inoperable or unresectable stage III NSCLC is concurrent chemoradiation alone, but approximately 80% of pts will develop recurrent or metastatic disease. Pembrolizumab is a monoclonal antibody (mAb) against programmed-death-1 (PD-1) and helps promote a renewed host immune response against malignant cells. Pembrolizumab is FDA-approved for the second line treatment of patients with metastatic NSCLC whose tumors express PD-L1 by an FDA-approved test, and pre-clinical mouse models demonstrate a synergistic effect on tumor cell kill following radiation in combination with PD-1 blockade. Methods: Pts with inoperable or unresectable stage III NSCLC were treated with concurrent chemoradiation (using cisplatin/etoposide, carboplatin/paclitaxel, or cisplatin/pemetrexed); consolidation chemotherapy was permissible. Pts with non-PD 4-8 wks after completing therapy received Pembrolizumab consolidation 200mg IV every 3 weeks until progression or prohibitive toxicity for up to 12 months. The primary endpoint is time to metastatic disease defined as disease progression outside the radiated field. Secondary endpoints include progression free survival, overall survival, and toxicity. An exploratory analysis will correlate these endpoints and PD-L1 expression levels. This abstract reviews the DSMC analysis of the first 10 pts treated on study. Results: As of 1/31/16, 38 of a planned 93 pts have enrolled. Eight of the initial 10 pts remain on treatment with a median of 9 cycles (range 3 to 12) of Pembrolizumab. There have been no treatment-related deaths and no grade 4 toxicities. One pt had grade 3 urinary toxicity. One pt developed grade 1 pneumonitis, and there have been no episodes of esophagitis. Fatigue was the most commonly reported symptom in 5 pts followed by cough in 4 pts (all grade 1-2). Conclusions: This early safety analysis in 10 pts suggests that it is feasible to administer Pembrolizumab 4-8 weeks following the completion of concurrent chemoradiation in pts with stage III NSCLC. Clinical trial information: NCT02343952.
Capecitabine plus oxaliplatin versus capecitabine plus oxaliplatin with concurrent radiotherapy in the treatment of gastric cancer after D2 gastrectomy.
Authors: Congying Xie, Xiance Jin, Didi Chen
Journal: Journal of Clinical Oncology (2018)

4059 Background: The role of adjuvant chemoradiotherapy (CRT) in the treatment of gastric cancer patients after D2 resection has not been defined yet. This trial was designed to compare capecitabine plus oxaliplatin (XELOX) versus XELOX combined with concurrent CRT in the treatment of gastric cancer patients after D2 gastrectomy. Methods: Patients with histologically confirmed gastric cancer with T3-4/N1-3 after D2 gastrectomy were enrolled and randomly assigned to XELOX for 6 cycles (CT arm) or 2 cycles XELOX plus 45 Gy radiotherapy (RT) with capecitabine concurrently, and then followed by another 4 cycles of XELOX after RT (CRT arm). The primary end point was 3-year disease-free survival (DFS), and the secondary end point was 3-year overall survival (OS). Results: From January 2013 to June 2017, a total of 144 Patients were protocol eligible with 74 assigned to the CT arm and 70 to the CRT arm, respectively. With a median follow up of 25.6 months, the 3-year DFS and OS rates were 76.3% and 79.6% in the CT arm, versus 72.8% and 70.9% in the CRT arm, respectively. The addition of RT did not show significant differences on the DFS (P = 0.868) and OS (P = 0.683). The rate of local recurrence-free survival and distant metastasis at 3 years were 98.5% vs. 91.7% (p = 0.281) and 18.7% vs. 18.1% (p = 0.606) for the CT and CRT arms, respectively. For patients with positive lymph nodes (84.5%), the 3-year DFS rate was 70.7% and 71.1% in the CT and CRT arms, respectively. The DFS was a bit shorter in the CT arm than in the CRT arm but without statistical difference (p = 0.920). Common grade 3/4 AEs with chemotherapy and RT were leukopenia, neutropenia, thrombocytopenia. All patients finished at least 4 cycles of XELOX with 82.1% and 75.5% patients in the CT and CRT arms finished 5 cycles of chemotherapy. Conclusions: No significant benefits on DFS and OS of CRT observed in the treatment of gastric cancer after D2 gastrectomy. Addition of RT did not show significant on lowering the risk of local recurrence for gastric cancer patients. Adjuvant CRT needs further investigation with larger populations for gastric cancers patients after D2 gastrectomy. Clinical trial information: NCT01711242.
Subgroup analyses of diffuse large B-cell lymphoma (DLBCL) and indolent lymphoma cohorts from a phase IIa study of single-agent MOR208 in patients with relapsed or refractory non-Hodgkin’s lymphoma (R-R NHL).
Authors: Wojciech Jurczak, Pier Luigi Zinzani, Gianluca Gaidano, Andre Goy, Mariano Provencio, Zsolt Nagy, Tadeusz Robak, Kami J. Maddocks, Christian Buske, Sumeet Vijay Ambarkhane, Mark Winderlich, Jan Endell, Kristie A. Blum
Journal: Journal of Clinical Oncology (2016)

7545 Background: There is a high unmet medical need for new therapies for patients (pts) with R-R NHL. CD19 is highly expressed by most B-cell NHLs; CD19 expression is maintained even when CD20 is downregulated following treatment with CD20 antibodies. Therefore, MOR208, an Fc-engineered, humanized monoclonal CD19 antibody may have clinical use as a new therapeutic agent in this setting. Methods: This is an open-label, multicenter, phase IIa study of MOR208 in R-R NHL pts progressing after at least one prior rituximab-containing therapy. Pts were enrolled into 4 cohorts of aggressive and indolent (i) NHLs. Pts received single-agent MOR208, 12 mg/kg IV, weekly; responders at week 12 qualified for treatment (every 2 or 4 weeks) until progression. The primary endpoint was overall response rate (ORR), investigator assessed. This analysis focused on DLBCL and iNHL cohorts. Results: In total,92 pts were enrolled including 35 (38%) with DLBCL and 45 (49%) with iNHL. ORR was 26% (36% in 25 evaluable pts; 2 complete responses [CR], 7 partial responses [PR]) for DLBCL, and 27% (30% in 40 evaluable pts; 5 CR, 7 PR) for iNHL cohorts. Median duration of response was 13.7 months for DLBCL pts (1.2–26, 3 ongoing) and 8.4 months for iNHL pts (2.5–20.3, 6 ongoing). In DLBCL responders, 5/9 were rituximab-refractory, of which 1 pt had a response duration of > 1 year and 2 of > 19.8 months. The incidence of grade ≥ 3 hematologic TEAEs was low (DLBCL: 9/35, 26%; iNHL: 4/45, 9%), including neutropenia, anemia and thrombocytopenia in 14%, 9% and 6% of DLBCL and 4%, 0% and 0% of iNHL pts. Infusion-related reactions were seen in 3/35 (9%) and 4/45 (9%) pts in the DLBCL and iNHL cohorts, mostly of grade 1–2 (with one grade 4 dyspnea). There were no treatment-related deaths and no trend towards late toxicity. Conclusions: Single-agent MOR208 was associated with a promising ORR including CRs and long-lasting responses in both DLBCL and iNHL, even in pts with rituximab-refractory disease. These efficacy data, and the excellent safety and tolerability profile of MOR208 further justify the development of MOR208 as part of a combination therapy in B-cell malignancies. Clinical trial information: NCT01685008.