tbuckley/cabot-search huggingface dataset:
The burden of disease of ovarian cancer in Spain: The OvarCost study.
Authors: Luis Angel Cordero, Laura Delgado-Ortega, Almudena Gonzalez-Dominguez, The Ovarcost Group, Margarita Jimenez, Alvaro Hidalgo, Amaya Gascó
Journal: Journal of Clinical Oncology (2016)

e18253 Background: Despite its relatively low prevalence and incidence in Spain (11.1 of one year and 10.2 per 100,000 habitants, respectively), ovarian cancer is associated with a high mortality rate in women. In Spain, it is the second most frequent gynecological malignant tumor, and the sixth leading cause of cancer death. Epithelial ovarian cancer represents 90% of total ovarian cancer cases.The economic burden of the disease in Spain was previously unknown. Methods: We developed a Markov model from a social perspective, simulating the natural history of epithelial ovarian cancer including its four stages, with a 10-year time horizon, 3 week cycles and a 3% discount rate. Direct healthcare costs, direct non-health costs (formal and informal care) and indirect costs (lost productivity) have been updated to 2015 euros. Epidemiological data and use of resources in all stages were first taken from a literature review including international studies, and then validated for Spain by the Ovarcost group (a Spanish multidisciplinary advisory board) using a Delphi process. Results: The total cost of epithelial ovarian cancer over 10 years in Spain is 3,089 million euros, of which 1,517 million are direct healthcare costs (49%), 1,501 million are direct non-healthcare costs (49%) and 71 million are indirect costs (2%). The mean cost per patient per year is € 30,332. Mean costs per patient per year by stage of disease are € 12,040, € 19,352, € 38,230 and € 43,893 in stages I, II, III and IV, respectively. Conclusions: Epithelial ovarian cancer imposes a significant burden to the national health system and to society as a whole in Spain. Investment in better early diagnosis techniques of epithelial ovarian cancer would represent a significant increase in survival and quality of life of patients, which would likely reduce costs of late stages of the disease leading in turn to a substantial reduction of the economic burden associated with this cancer.
Development and validation of a combined metabolic and immune prognostic classifier for head and neck cancer.
Authors: Hisham Mohamed Mehanna, Jill Brooks, Albert Menezes, Maha Ibrahim, Neeraj Lal, Lucinda Archer, Sandra . von Zeidler, Riyue Bao, Arun Khattri, Helen Valentine, Rachel Spruce, Nikolaos Batis, Jennifer Bryant, Andrew David Beggs, Daniel Tennant, Catharine West, Gary William Middleton, Jean-Baptiste Cazier, Benjamin Willcox, Tanguy Y. Seiwert
Journal: Journal of Clinical Oncology (2018)

6049 Background: Genomic characterisation of head and neck cancer (HNC) has identified 3-5 subgroups with distinct biological properties, including metabolic profile and immune status. Both facets could impact on response to standard and novel targeted therapies for HNC, but are not currently considered for treatment selection due to lack of validated biomarkers. Methods: A 54-gene metabolic-immune signature (MIGS) was constructed. Gene expression was analysed in silico using the TCGA HNC dataset (whole transcriptome RNA-Seq, n = 275) and validated using two independent cohorts (Chicago microarray [Agilent], n = 130; Birmingham targeted RNA-Seq [Illumina] on FFPE tissue, n = 123). We then evaluated MIGS in a cohort of anti-PD-1 treated R/M HNC patients. Immunohistochemistry (IHC) was used to investigate the utility of a surrogate protein signature. Spatial distribution of metabolic and immune markers was examined using Opal/Vectra multiplex immunofluorescent staining. Results: Analysis of TCGA dataset using unsupervised hierarchical clustering identified three patient subgroups with distinct metabolic-immune phenotypes and survival profiles: (1) immunehigh/metaboliclow, (2) metabolichigh/immunelow and (3) intermediate, with 5-yr overall survival (OS) rates of 71%, 51% and 49% respectively (p = 0.0015). The prognostic nature of MIGS was replicated in both validation cohorts (Table). Protein IHC signature was not prognostic. Metabolic and immune markers showed inverse expression patterns on multiplex staining. Preliminarily, presence of metabolichigh/immunelow signature was associated with ~ 20% worse OS at 1yr in PD-1 treated R/M HNC patients. Conclusions: We developed and validated a prognostic molecular classifier based on metabolic profile and immune status. This classifier may have clinical application to guide use of metabolic modification and targeted immunotherapies for HNC treatment. Cohort Subgroup 5year OS (%) p value p value adjusted for HPV status TCGA 1 71 0.0015 0.0005 2 51 3 49 Chicago 1 76 0.012 0.0025 2 65 3 60 Birmingham 1 80 0.097 0.0006 2 64
Charlson comorbidity index scores before and after prostate cancer diagnosis among a racially diverse cohort of men.
Authors: Alpana Kaushiva, Dana Sohmer, Anika Jenkins, Susan Hong
Journal: Journal of Clinical Oncology (2018)

e18631 Background: We examined racial/ethnic differences in Charlson comorbidity index scores (CCI) pre and post prostate cancer (PC) diagnosis among Non-Hispanic White (NHW), Hispanic, and African-American (AA) men. Methods: We conducted a retrospective chart review to calculate CCI scores (excluding age and PC) for 379 men diagnosed with PC between December 2013 and June 2017 at the University of Illinois Hospital and Health Sciences System. Using all available electronic records, we used ICD 9/10 codes to determine presence or absence of a CCI condition pre and post PC diagnosis. Data was collected on race, ethnicity, stage, and age at diagnosis. Logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI) for associations between race/ethnicity and CCI among PC patients. Results: Of the 379 PC patients, 65% were AA, 15% were Hispanic, and 18% were NHW. Mean ages were 67, 67, and 64 years, respectively. 232 men had a CCI of 0, 93 men had a CCI ≥1 at their PC diagnosis (mean CCI 4.9), and 54 men developed at least one CCI condition after their PC diagnosis (mean CCI 5.1; with a mean duration of follow-up of 1.9 years). AA men were diagnosed with PC at a significantly younger age compared to NHW men (62 vs 65 years, p-val = 0.009). AA and Hispanic men had higher average CCI scores compared to NHW men (CCI = 3.3 versus 2.6, p = 0.017). At the time of their PC diagnosis, AA men were 2.6 times more likely to have a CCI ≥ 1 compared to NHW men [(AA vs NHW 95% CI (1.3-5.3), p = 0.008]. Men with late stage PC were 3.2 times more likely to develop another CCI condition as compared to those with early stage PC. Mean CCI score for men with late stage PC was 5.6 vs 4.7 for those with earlier stage PC (p = 0.05). Compared to NHW men, AA men were 3.4 times more likely to have chronic kidney disease [95% CI (1.01-11.4), p = 0.05]. Additionally, Hispanic men were 4 times more likely to have diabetes compared to NHW men [95% CI (1.01-11.4), p = 0.05]. Conclusions: AA and Hispanic men enter their PC diagnosis with higher mean CCI scores. Our findings suggest that the burden of chronic disease after PC diagnosis is greater for minority vs. NHW PC survivors. Future studies examining how this impacts longterm survivorship for minority men are warranted.
Chromatin regulator Asxl1 loss and Nf1 haploinsufficiency cooperate to accelerate myeloid malignancy
Authors: Peng Zhang, Fuhong He, Jie Bai, Shohei Yamamoto, Shi Chen, Lin Zhang, Mengyao Sheng, Lei Zhang, Ying Guo, Na Man, Hui Yang, Suyun Wang, Tao Cheng, Stephen D. Nimer, Yuan Zhou, Mingjiang Xu, Qian-Fei Wang, Feng-Chun Yang
Journal: Journal of Clinical Investigation (2018)

ASXL1 is frequently mutated in myeloid malignancies and is known to co-occur with other gene mutations. However, the molecular mechanisms underlying the leukemogenesis associated with ASXL1 and cooperating mutations remain to be elucidated. Here, we report that Asxl1 loss cooperated with haploinsufficiency of Nf1, a negative regulator of the RAS signaling pathway, to accelerate the development of myeloid leukemia in mice. Loss of Asxl1 and Nf1 in hematopoietic stem and progenitor cells resulted in a gain-of-function transcriptional activation of multiple pathways such as MYC, NRAS, and BRD4 that are critical for leukemogenesis. The hyperactive MYC and BRD9 transcription programs were correlated with elevated H3K4 trimethylation at the promoter regions of genes involving these pathways. Furthermore, pharmacological inhibition of both the MAPK pathway and BET bromodomain prevented leukemia initiation and inhibited disease progression in Asxl1Δ/Δ Nf1Δ/Δ mice. Concomitant mutations of ASXL1 and RAS pathway genes were associated with aggressive progression of myeloid malignancies in patients. This study sheds light on the effect of cooperation between epigenetic alterations and signaling pathways on accelerating the progression of myeloid malignancies and provides a rational therapeutic strategy for the treatment of myeloid malignancies with ASXL1 and RAS pathway gene mutations.
Correlation between gene expression and prognostic biomarkers in small cell bladder cancer (SCBC).
Authors: Vadim S. Koshkin, Andrew Dhawan, Ming Hu, Jordan Reynolds, Paul Elson, Jesse McKenney, Laura R. Saunders, Kumiko Isse, Summya Rashid, Aysegul Balyimez, Moshe Chaim Ornstein, Timothy D. Gilligan, Byron Lee, Jacob Gardinier Scott, Brian I. Rini, Jorge A. Garcia, Petros Grivas, Omar Y. Mian
Journal: Journal of Clinical Oncology (2018)

4546 Background: SCBC is a rare malignancy with poorly understood biology. TCGA data in BC underscores the presence of a neuronal subtype possibly misclassified by conventional histopathology. Increased small cell component (SC%) and protein expression (expr) of DLL3 and CD56 were previously shown to correlate with worse outcomes in SCBC. The association of gene expr data with available biomarkers has potential to improve risk stratification and inform treatment decisions. Methods: 63 patients (pts) at Cleveland Clinic diagnosed between 1993 and 2015 had SCBC histology independently reconfirmed. All pts had SC% quantified and 52 pts had immunohistochemistry (IHC) for DLL3 and CD56. A further subset of 39 pts had gene expr analysis using HTG EdgeSeq OBP. Expr of genes relevant in neuroendocrine tumors was evaluated with a panel including CHGA, DLL1, DLL3, DLL4, ENO1, HES1, HES5, HEY1, NCAM1, NOTCH1, NOTCH2, NOTCH4, RB1, SYP, and TP53. Associations between DLL3 and CD56 protein expr, SC%, and expr of relevant genes were assessed to identify biomarkers pertinent to molecular diagnostics (Spearman correlation, p < 0.05). Using these as seed-genes in a network-based approach we sought to develop a prognostic gene expression signature in SCBC. Results: Among 52 pts with IHC data, 79% had SC% > 50%, and protein expr of DLL3 and CD56 ( > 1% of tumor cells) was 68% and 81%, respectively. DLL3 protein expr correlated positively with mRNA expr of DLL3 (r = 0.70), CHGA (r = 0.55), DLL4 (r = 0.45), and negatively with NOTCH1 (r = -0.47), RB1 (r = -0.48) and ENO1 (r = -0.34). CD56 protein expr correlated positively with mRNA expr of NCAM1 (r = 0.61), DLL4 (r = 0.38), HEY1 (r = 0.42) and SYP (r = 0.34) and negatively with NOTCH1 (r = -0.34) and HES5 (r = -0.35). SC% correlated positively with DLL3 (r = 0.38) and NCAM1 (r = 0.41) and negatively with HES1 (r = -0.34). Conclusions: Expression of genes implicated in the pathophysiology of SC tumors correlated with protein expr of DLL3, CD56 and SC%, which were previously shown to be prognostic in SCBC. This supports a prognostic role for a novel gene expr signature in SCBC. Multi-institutional validation of this signature in external BC cohorts as well as comparison with BC TCGA and SC lung cancer datasets are ongoing.
A novel protein-coding and long non-coding RNA gene signature to predict prognosis of non-small cell lung cancer patients.
Authors: Mantang Qiu, Wenjia Xia, Jie Wang, Gaochao Dong, Youtao Xu, Rong Yin, Lin Xu, Siwei Wang
Journal: Journal of Clinical Oncology (2016)

e20032 Background: long non-coding RNAs (lncRNAs) are frequently aberrantly expressed in cancers and their expression patterns are more tissue specific than coding genes. We aimed to develop an mRNA-lncRNA gene signature to improve prognosis prediction of non-small cell lung cancer (NSCLC). Methods: Large NSCLC expression cohorts were identified from Gene Expression Ominus, including 894 samples. All samples were grouped by unsupervised consensus clustering and then differentially expressed genes among these subgroups were subjected to biomarker analyses. Results: We established a signature of 129 genes (41 lncRNAs and 88 protein-coding genes) that were significantly correlated with overall survival in the test series (N = 590). According to the gene signature, the test series could be categorized into high-risk and low risk subgroups with significantly different overall survival (HR = 5.036, 95% CI: 3.568-7.108, P < 0.01). The prognostic value of mRNA-lncRNA gene signature was validated in the external validation series (N = 394). Functional annotation suggested that mRNAs and lncRNAs in the signature were associated with cancer metastasis related pathways Conclusions: Our findings suggest that mRNA-lncRNA gene signature has both predictive value and biological relevance and might provide an efficient classification toll for prognosis evaluation of NSCLC.
Salvage use of Y90 coated hepatic arterial beads in the treatment of liver predominant metastatic colorectal cancer: Cancer Treatment Centers of America Southeastern Region experience.
Authors: Eyal Meiri, John Florin Isac, John P. Geisler, Kelly J Manahan, Henry J. Krebs, Charles Fulp
Journal: Journal of Clinical Oncology (2018)

e15554 Background: Resin Yttrium-90 hepatic arterial liver directed treatments are commonly used in the treatment of liver predominant metastatic colorectal carcinoma. Although its role in first line therapy of patients is questionable, it’s use as a second or third line has been well studied. The utility of the procedure has not been fully characterized. We sought to determine what characteristics are related to overall survival (OS) and post- Yttrium-90 (Y90) treatment survival (PTS) in patients with hepatic metastases from colorectal carcinoma. Methods: Data was collected from hospital/patient records for patients seen from August 2012 to May 2017 with colorectal cancer (CRC) hepatic metastases treated with Y90. Liver predominant disease was defined as individuals with at least 80% of total tumor volume confined to the liver. No patients were knowingly excluded. Results: One hundred twelve patients met the inclusion criteria. Half of the patients were female. While 57% of the patients were Caucasian, 42% were African American. The mean number of prior lines of therapy was 2.3. The mean (and median) PTS and OS were as follows: 16.8 months (12.2 months) and 38.1 months (31.9 months), respectively. PTS and OS were not related to gender, race, body surface area (BSA), or site of origin in the colon (right, left, rectum). Absence of extra-hepatic metastases was not predictive of a longer PTS or OS (p = 0.29; 0.79, respectively). The presence of a kras mutation was predictive of a shorter OS but not PTS (p = 0.024; 0.35, respectively). Similarly, the presence of a BRAF mutation was predictive of a shorter OS but not PTS (p = 0.029; 0.077, respectively). Conclusions: Salvage Y90 treatment for hepatic metastases from CRC is well tolerated and gives a similar PTS to patients with otherwise adverse predictors in this specific population (kras or BRAF mutation). Of note, site of origin and absence of extra-hepatic metastases did not affect PTS or OS.
Evaluating a novel oncologist-led BRCA1/2 mutation (BRCAm) testing counseling model for patients with ovarian cancer: Interim results from the ENGAGE study.
Authors: Gloria S. Huang, Ilian Tchakov, Yann Bourhis, Giovanni Scambia, Ettore Capoluongo, Begona Grana-Suarez, Jose Antonio Lopez-Guerrero, Andres Poveda, Sudeep Karve, Danielle Potter, David Lawrence, Jerzy E. Tyczynski, Eva Chalas
Journal: Journal of Clinical Oncology (2016)

e17048 Background: Genetic counseling is an important component of the BRCAm testing process. A novel streamlined oncologist-led BRCAm testing and counseling model was first used at the Institute of Cancer Research (ICR) in the UK, resulting in shortened BRCAm testing turnaround time (TAT). Our study assessed overall testing TAT, pre- and post-test counseling quality and patient satisfaction. Methods: This ongoing prospective observational study, conducted across 30 sites in the US, Italy and Spain, aims to include ~400 adult patients with epithelial ovarian, fallopian tube or primary peritoneal cancer. Physicians completed a BRCAm counseling training module. Interim analyses conducted on 132 patients enrolled at 10 US sites focused mainly on description of patient characteristics. Baseline demographic, clinical and therapeutic data, outcome of BRCAm test and BRCAm testing TAT were collected. BRCAm testing TAT and satisfaction surveys about BRCAm testing model, completed by patients, clinicians and genetic counselors, were primary outcomes. Results: Mean age was 65.3 (±9.6) years. Mean time since diagnosis was 2.4 (±3.5) years. At diagnosis 18% of patients had stage I disease, 14% stage II, 53% stage III and 15% stage IV. Family history of breast or ovarian cancer was reported in 42% of patients. At baseline, 41% of patients were newly diagnosed, 39% in remission/stable and 20% had relapsed; 90% of patients had prior surgery and 82% prior chemotherapy. BRCAm was identified in 12 patients (9%), of whom 9 had family history of breast/ovarian cancer. Pre-BRCAm counseling was provided mainly by oncologists (44%) and nurse practitioners/physician assistants (21%). Mean TAT from initial counseling to BRCAm test results was 4.4 (±3.4) weeks. Patient satisfaction rate for BRCAm genetic test counseling was > 95%. Mean satisfaction scores were consistently higher than 3.5 (1: completely dissatisfied; 4: completely satisfied). Conclusions: Interim results provide first insights about characteristics of patients taking part in an oncologist-led BRCAm testing model. Consistent with the ICR pilot study, improved TAT and high patient satisfaction were highlighted. Clinical trial information: NCT02406235.
OVARIO: The phase 2, single-arm, open-label study of maintenance therapy with niraparib + bevacizumab in patients with advanced ovarian cancer following response on frontline platinum-based chemotherapy.
Authors: Joanie M. Hope, Jian Chen, Marisa Wainszelbaum, Divya Gupta
Journal: Journal of Clinical Oncology (2018)

TPS5606 Background: Niraparib (Zejula) a selective poly(ADP-ribose) polymerase (PARP) 1/2 inhibitor, significantly improved progression-free survival (PFS) as a single agent for patients with recurrent ovarian cancer (OC) relative to placebo in the ENGOT-OV16/NOVA trial, regardless of BRCA or HRD status. The ongoing AVANOVA trial (NCT02354131) has shown that niraparib can be safely combined with bevacizumab (bev). This combination is being explored in AVANOVA, as a strategy to increase tumor sensitivity to PARP inhibition. As an anti-angiogenic agent, bev can induce tumor hypoxia, leading to downregulation of BRCA and RAD51, which could sensitize tumors to PARP inhibition, and lead to apoptosis via contextual synthetic lethality. While BRCA and HRD status was insufficient to predict responders to niraparib in NOVA, a longer median PFS was observed for the cohorts with these biomarkers. In the phase 2 OVARIO study (NCT03326193), niraparib plus bev will be evaluated as a maintenance treatment in patients with advanced OC who have recovered from primary debulking surgery and have responded to frontline platinum-based chemotherapy with bev. Methods: Target enrollment is 90 patients, regardless of BRCA or HRD status, with stage 3b and 4 epithelial ovarian, fallopian tube, or peritoneal cancer. Patients must achieve complete response, partial response or no evidence of disease after the frontline platinum-based chemotherapy. The primary objective for OVARIO will be PFS at 18 months landmark. Secondary objectives include evaluation of PFS, overall survival, time to first subsequent therapy, and safety and tolerability. Exploratory objectives will be PFS at 6 and 12 months and patient-reported outcomes. The starting dose of niraparib will be based on the patient's baseline body weight and/or platelet count. Patients weighing ≥77 kg with a platelet count of ≥150,000/μL will receive 300 mg qd. Patients weighing < 77 kg or with a platelet count of < 150,000/μL will receive 200 mg qd. The bev dose will be 15 mg/kg q3w up to 15 months. Patients will be treated continuously until disease progression or unacceptable toxicity. Clinical trial information: NCT03326193.
Validation of a software-based clinical trial matching platform for oncology using comprehensive clinical information.
Authors: Denise Mitchell, Anna Lewis, Andrew Schaer, Sameer Soi, James L. Gulley, Petros Giannikopoulos
Journal: Journal of Clinical Oncology (2018)

e18589 Background: Despite the critical need for cancer patients to participate in clinical trials, only 3% of US cancer patients actually do so, and 40-60% of oncology clinical trials fail to recruit enough patients to meet their statistical endpoints (1). One of the fundamental causes of this issue is that traditional manual eligibility determination is inefficient and costly. To address this, Driver has developed a scalable software platform that accelerates clinical trial eligibility screening for individual cancer patients and conducted a validation of the platform’s clinical performance with the NCI Center for Cancer Research (CCR). Methods: Medical records from 21 metastatic prostate cancer patients who were enrolled on a therapeutic clinical trial at the CCR within the last 5 years were processed by the Driver platform. The CCR provided Driver with all relevant retrospective clinical data available before these patients were screened. Eligibility results produced by Driver were compared to the trials the patients were enrolled in. Results: Of the 21 patients who were enrolled on CCR trials, Driver correctly predicted that 20 of them were “Potentially Eligible” for the trial that they were actually enrolled in. Conclusions: This study demonstrated the feasibility of a software-based eligibility screening platform. The patient that Driver deemed ineligible was indeed ineligible on the basis of his medical records, but had become eligible by the point of screening. The existence of such cases has led Driver to introduce a new category, “Eligibility Concerns”. References: 1. IOM, 2010, A National Cancer Clinical Trials System for the 21st Century: Reinvigorating the NCI Cooperative Group Program.