tbuckley/cabot-search huggingface dataset:
Correlation of cell-free circulating DNA, RNA, and PD-L1 from plasma with clinical response in patients with metastatic lung and breast cancers.
Authors: Luis E. Raez, Kathleen Danenberg, Aurelio Bartolome Castrellon, Joshua L. Usher, Yolanda S Jaimes, Brian Hunis, Michel E. Velez, Cheryl Habaue, Peter Danenberg
Journal: Journal of Clinical Oncology (2017)

11550 Background: There is an unmet need to evaluate tumor response by other means than radiology tests. Changes in gene expression, allele-fractions of mutations, PDL-1 expression and levels of cell free DNA [DNA] or RNA [RNA] in plasma might be useful for monitoring disease state and predicting outcome to anti-tumoral therapy. Methods: We measured serial levels of plasma DNA/RNA in metastatic patients (pts) with NSCLC and breast cancers undergoing treatment and correlated them with response (CR/PR/SD/PD) seen by CT scans. We also monitored PD-L1 expression in NSCLC pts treated with immunotherapy. DNA/RNA were extracted from plasma. RNA was reverse transcribed with random primers to cDNA. Levels of DNA/RNA were determined by RT-qPCR. Results: 52 pts were enrolled (28 breast/24 NSCLC). Breast group: 39% (11/28) were Caucasian (NHW) and 36% (10/28) Hispanic (H). 20 pts completed first two cycles of therapy: 2 pts had PR and showed no change (NC) or decrease (DEC) in levels of DNA/RNA. 11pts achieved SD, 9 had NC levels of DNA/RNA. Pts with PD: 5/6 underwent significant increase (INC) in DNA/RNA levels. Overall, among breast pts, there was an 84% (16/19) agreement between response and levels of DNA/RNA. These were correlated with one another ( r = 0.7002, p&lt; 0.0001). NSCLC group: 71% (16/24) were NHW and 25% (6/24) H. Non-SQCC were 87% (21/24). 20 pts had CT scans. One pt had PR with DEC levels of DNA/RNA. 10 pts achieved SD, all showed DEC or NC levels of DNA/RNA. 8 pts had PD, 6 of them had INC in DNA/RNA levels even 7 weeks prior to PD. Among NSCLC pts, there was a 90% (17/19) agreement in response and levels of DNA/RNA. These were correlated with one another ( r= 0.6231, p&lt; 0.0001). In 5 pts PD-L1 expression remained stable when CT scans showed SD or PR. Conclusions: There is a strong correlation between clinical responses with changes in plasma levels of DNA/RNA in pts with NSCLC (90%) and breast cancer (84%). Some of these were documented weeks before imaging was done. cfRNA is as effective as cfDNA as predictive tool for response. Plasma PDL-1 expression is a new tool to monitor immunotherapy response.
Abstract 18819: Adverse Pregnancy Outcomes and Their Prediction of Future Heart Disease
Authors: Paul-Ann Green, Dmitry Fridman, Heather Smith, Mary Rosser
Journal: Circulation (2015)

Objective: Pregnancy provides an opportunity for a natural stress test, with the physiological demands of pregnancy acting as a maternal stress test that can predict a woman’s health later in life. The 2011 Update of the American Heart Association’s Evidence-Based Guidelines for the Prevention of Cardiovascular Disease in Women identifies many complications of pregnancy as relevant in the determination of cardiovascular disease (CVD) risk. This is important because CVD is the leading cause of death in women worldwide. The purpose of this research was to determine if, in our diverse inner city population, pregnancies complicated by hypertensive disorders, gestational diabetes, intrauterine growth restriction, or abruption were associated with future development of CVD. Methods: We identified women who delivered at a large, urban hospital in Bronx, NY from 1997-2001 who were treated for gestational diabetes, hypertensive disorders of pregnancy, intrauterine growth restriction, and placental abruption (n=183). A hospital database was used to identify our cohort and electronic medical records were reviewed to determine if these patients developed CVD over 10 years since the index pregnancy. The end points were subsequent Hypertension, Myocardial Infarction, Cerebrovascular disease, Type 2 Diabetes Mellitus, and Thromboembolic events. The cohort was compared to controls delivered at the same institution. Results: The relative risk (RR) of subsequent type 2 diabetes mellitus was 1.93 [CI 1.00-3.75], if the exposed population was older than 35 at the time of the index pregnancy. The RR of subsequent hypertension was 2.21 [CI 1.3-3.77] in African Americans at any age of index pregnancy, regardless of exposure. When comparing all exposed population to our controls; there is an increased risk in our population of CVD with a RR of 1.58 (CI 1.12-.2.23), and a p value of 0.01. Conclusions: In our large, diverse, urban population, age or the presence of preeclampsia were associated with an increased risk for adverse CVD. These women may be appropriate for early CVD risk screening and intervention at younger ages than previously identified. Women with adverse pregnancy outcomes should be targeted for risk factor modification and prevention programs.
Author Correction: The rate of meiotic gene conversion varies by sex and age
Authors: Bjarni V Halldorsson, Marteinn T Hardarson, Birte Kehr, Unnur Styrkarsdottir, Arnaldur Gylfason, Gudmar Thorleifsson, Florian Zink, Adalbjorg Jonasdottir, Aslaug Jonasdottir, Patrick Sulem, Gisli Masson, Unnur Thorsteinsdottir, Agnar Helgason, Augustine Kong, Daniel F Gudbjartsson, Kari Stefansson
Journal: Nature Genetics (2018)
FIGHT: A phase 3 randomized, double-blind, placebo controlled study evaluating (bemarituzumab) FPA144 and modified FOLFOX6 (mFOLFOX6) in patients with previously untreated advanced gastric and gastroesophageal cancer with a dose finding phase 1 lead-in.
Authors: Daniel V.T. Catenacci, Peter C. Enzinger, Anteneh A. Tesfaye, Mohamedtaki Abdulaziz Tejani, Janine Powers, Charlie Zhang, Neyssa Marina, Clarence Eng, Eric Cheung, Aaron James Scott, Peter D. Eisenberg
Journal: Journal of Clinical Oncology (2018)

TPS4135 Background: FGFR2b overexpression and FGFR2 gene amplification occurs in approximately 10% of patients with gastric cancer (GC) and is associated with a poor prognosis and the presence of metastases. Bemarituzumab, a first-in-class afucosylated, humanized IgG1 monoclonal antibody, selectively binds to FGFR2b, inhibiting ligand binding and blocking receptor activation and downstream signaling. Bemarituzumab is glycoengineered to enhance antibody-dependent cell-mediated cytotoxicity (ADCC). A phase 1 study of bemarituzumab monotherapy in solid tumors (Catenacci D, Rha S, Bang YJ, et.al. ASCO 2017) identified no dose-limiting toxicities. The reported response rate was 19% (4/21) with median duration of response of 15.4 weeks in patients with late-line GC and high FGFR2b overexpression. Based on the safety and activity profile of bemarituzumab monotherapy in GC, we designed a phase 3 trial with safety run-in of bemarituzumab in combination with mFOLFOX6. Methods: The FIGHT study (FPA144-004; NCT03343301) is a global, randomized, double-blind, placebo-controlled phase 3 trial evaluating bemarituzumab and mFOLFOX6 in first-line patients with advanced GC. Patients with unresectable locally advanced, or metastatic GC are eligible if tumors have FGFR2 amplification by circulating tumor DNA (ctDNA) or FGFR2b overexpression by immunohistochemistry (IHC). Eligible patients are randomized 1:1 to bemarituzumab + mFOLFOX6 versus placebo + mFOLFOX6. Bemarituzumab or placebo dosing will continue every 2 weeks until radiographic or clinical disease progression, or intolerable toxicity. The primary endpoint is overall survival (OS) and key secondary endpoints include investigator-assessed progression-free survival (PFS) and objective response rate (ORR). The primary analyses will be event-based. The FIGHT Phase 3 trial is preceded by a Phase 1 safety evaluation in gastro-intestinal tumors without selection for FGFR2b. This portion of the trial initiated in December 2017 and is currently in progress with accrual to phase 3 expected in mid-2018. Clinical trial information: NCT03343301.
Worse prognosis in young female patients with non-metastatic colorectal cancer: A hospital-based analysis of 5,295 patients in China.
Authors: Ji Zhu, Lijun Shen, Miao Mo, Ye Xu, Xinxiang Li, Zhen Zhang, Sanjun Cai
Journal: Journal of Clinical Oncology (2016)

e15119 Background: The impact of young age and female on the outcome remains controversial and varies in different regions. We aimed to compare the survival of different age group between male and female cases with non-metastatic CRC. Methods: We identified 5,295 cases diagnosed with non-metastatic CRC from Jan. 2008 to Jul. 2013 in Fudan University Shanghai Cancer Center. Clinicopathological characteristics including age, gender, tumor site, pathological TNM stage, tumor differentiation, lymphatic or vascular invasion and neural invasion were evaluated for DFS and OS analyses using univariate and multivariate analyses. We also analyzed the interaction of age group and gender differences. Results: When DFS and OS were stratified in every 10 years’ age groups, female patients ≤ 35 and > 75 years old had worst DFS and OS, while OS seemed get worse with the increase of age in male patients, but the middle groups didn’t show significant difference. We combined age groups into ≤ 35, 36-75 and > 75 years old in further analysis. When DFS and OS in 3 different age groups stratified by gender, young female CRC patients ( ≤ 35 years old) had worse survival than young male patients (DFS: P = 0.032; OS: P = 0.0226), while there was no difference in other two groups.In multivariate analysis, male CRC patients had worse OS with the increase of age (36-75 vs. ≤ 35, HR, 2.17; 95% CI, 1.03-4.61, P = 0.043; > 75 vs. ≤ 35, HR, 4.60; 95%CI, 2.08-10.19, P = 0.000), but not related to DFS. Female patients between 36 and 75 years old had better DFS than young patients ≤ 35 years old (HR, 0.66; 95% CI, 0.43-1.00, P = 0.049), and there was no similar result for OS. Female patients younger than 35 years old were in more advanced stage with 61.5% patients in stage III. For both male and female patients, patients elder than 75 years old had worst OS. Conclusions: Young female patients had worse DFS than elder female patients (36-75 years old) and young male patients. These ﬁndings emphasize the need for health care providers to have a heightened awareness when caring for this young female CRC population. The effect of higher TNM staging, sex hormones and pregnancy might be the most plausible explanation for the observed patterns.
Molecular profiling comparison of breast cancer subtypes in young women and older women.
Authors: Antoinette R. Tan, Rebecca Feldman, James Thomas Symanowski, Julie Gottlieb Fisher, Lejla Hadzikadic-Gusic, Richard L. White, Edward S. Kim
Journal: Journal of Clinical Oncology (2017)

11581 Background: Young women with breast cancer (YWBC; ≤40 years) have a more aggressive clinical course and is associated with a poorer prognosis. In this analysis, we explore molecular features in tumors of YWBC and older women with breast cancer (OWBC; ≥65 years) by subtype. Methods: Somatic genomic profiles of 1879 breast tumors collected from 2013-2017 were assessed retrospectively and included in a de-identified data analysis if ER, PR and HER2 (immunohistochemistry [IHC] and/or in situ hybridization [ISH]) were available. Testing included IHC, ISH and massively parallel sequencing assays (next-generation sequencing [NGS]) at a CLIA-certified laboratory (Caris Life Sciences, Phoenix, AZ). Pearson’s chi-square was utilized for comparisons and significance defined as p &lt; 0.05. Results: Frequency of subtypes in YWBC (n = 536) and OWBC (n = 1343) were 45% and 55% HR+HER2-, 38% and 36% triple-negative (TN), 7% and 5% HER2+HR-, and 10% and 4% in HER2+HR+, respectively. Specimens tested were breast (53%, 43%) and a metastatic site (43%, 57%) in YWBC and OWBC, respectively. HR+HER2- YWBC exhibited higher rates of pathogenic mutations in TP53 (34%, 24.4%; n = 748; p = 0.008), BRCA1 (9%, 4.5%; n = 503; p = 0.047), BRCA2 (14.8%, 8.4%; n = 501; p = 0.032), gene amplifications in FGF3 (26.7%, 10.4%; n = 107; p = 0.034), FGF4 (26.7%, 9.1%; n = 107; p = 0.019), FGF19 (29.6%, 11.6%; n = 96; p = 0.033), CCND1 (36.7%, 18.2%; n = 107; p = 0.042), and overexpression of EGFR (18.6%, 8%; n = 364; p = 0.004). TN YWBC had higher rates of alterations in TP53 (80.2%, 67.4%; n = 577; p = 0.002) and BRCA1 (13.3%, 5.9%, n = 375; p = 0.015). YWBC that was HER2+HR+ exhibited a higher rate of APC mutations (10%, 0%; n = 84; p = 0.03). In OWBC, there were higher rates of PD-L1 expression in HER2+HR- (22.7%, 0%; n = 70; p = 0.009) and TN (13%, 6.3%; n = 458; p = 0.035). There were also higher PIK3CA mutations in HER2+HR+ (43.4%, 18.8%; n = 101; p = 0.008) and CDH1 mutations (12.8%, 0%; n = 85; p = 0.022) in TN. Conclusions: There were distinct molecular aberrations and significantly different frequency of alterations in subtypes of YWBC compared to OWBC. These molecular changes may contribute to increased understanding of breast cancer tumor biology and refinement of treatment strategies in YWBC and OWBC.
Economic evaluation of carfilzomib + lenalidomide + dexamethasone (KRd) vs. lenalidomide + dexamethasone (Rd) in relapsed or refractory multiple myeloma (R/RMM).
Authors: Andrzej J. Jakubowiak, Agnes Benedict, Sumeet Panjabi, Ivan Houisse, Marco Campioni, Andromachi Giannopoulou, Sanjay Aggarwal, Rafael Fonseca
Journal: Journal of Clinical Oncology (2016)

8021 Background: In ASPIRE, KRd achieved superior progression free survival (PFS) (HR = 0.69; p = 0.0001) and improved quality of life (QoL) (p < 0.001) over Rd in patients (pts) with R/RMM. We assessed the cost-effectiveness (CE) of KRd vs Rd from a US payer perspective with data from ASPIRE and long-term overall survival (OS) data from the Surveillance, Epidemiology, and End Results Program (SEER). Methods: A partitioned-survival model with progression-free (PF), post-progression (PP) and death states was built with a 30 year horizon. Treatment (Tx) effect for PFS and OS was estimated with parametric regression models and applied over the time horizon. Since 60% of pre-specified OS events were observed, post-trial OS transition probabilities were estimated by matching SEER data to ASPIRE pts. Grade ≥ 3 adverse events (AEs) with > 2% incidence in any ASPIRE arm were included. Utilities were derived from literature and adjusted for the relative improvement in QoL increase observed when pts were PF in ASPIRE. Costs related to drug (WAC prices) as well as wastage (30% for carfilzomib), administration, monitoring, AE management, and subsequent Tx were considered. Tx duration was derived fitting ASPIRE data and carfilzomib was dosed upto 18 cycles. The base case assessed the CE of adding carfilzomib to Rd, and considered only additional costs of carfilzomib, i.e. neglecting Rd drug costs in both arms. A scenario including Rd costs in both arms was conducted. A 3% discount rate was applied to costs and outcomes. Results: KRd was more effective compared to Rd, providing 1.134 PF life year, 1.927 life year, and 1.616 quality-adjusted life year (QALY) gains over the modelled horizon. KRd incurred $123,524 in total additional costs. Incremental CE ratio (ICER) was 76,416$/QALY. With the inclusion of Rd costs, KRd incurred $179,863 additional costs with an ICER of 111,270$/QALY. Conclusions: The model predicts that KRd delivers nearly 2 additional life year’s over the standard of care (Rd), and is cost-effective vs. Rd at a willingness-to-pay threshold of 120,000$/QALY. Therefore, carfilzomib when added to Rd delivers considerable incremental value to patients and payers.
Molecular detection of ROS1-rearranged circulating tumor cells (CTC) in non-small cell lung cancer (NSCLC) patients.
Authors: Man Chun Leong, Tse Hui Lim, Yong Wei Chua, Chye Ling Tan, Daniel Shao-Weng Tan, Andrew Wu, Angela Takano, Kiat Hon Lim, Alvin ST Lim, Wan-Teck Lim
Journal: Journal of Clinical Oncology (2016)

e23086 Background: Fluorescence in-situ hybridization (FISH) is the reference assay for ROS1 gene rearrangement. Molecular detection of ROS1 rearrangement in lung cancer has therapeutic relevance in the clinic. We sought to determine the possibility of detecting ROS1-rearrangements in CTCs from patients with lung cancer. Methods: Metastatic lung adenocarcinoma patients (mean age: 46.8+11.7) identified with ROS1-rearrangement on tumor biopsy were recruited in this study. Peripheral blood samples (N = 6) were collected in 10ml K2 EDTA blood collection tubes. Approximately 8ml of blood were enriched for CTCs using ClearCell FX system (Clearbridge Biomedics). Enriched output from each sample was divided into four portions and transferred onto glass slides— one slide was sent for ROS1 FISH testing. ROS1 FISH was carried out using Vysis 6q22 ROS1 Break Apart FISH probes (Abbott Molecular). Blood samples from healthy donors (N = 5) were included as negative controls to establish the assay cut-off. The slides were read by trained cytogeneticists blinded to the origin of the sample. Results: Detection rate of ROS1-rearranged CTCs was 67% (4 out of 6 samples) among ROS1-rearranged NSCLC patients, with a frequency ranging from 0 – 10 cells/per 2ml blood: 0 cell– 33.3%, 1 cell – 16.7%, 2-10 cells – 50%. An assay cut-off of 1 cell/2ml blood was determined from the negative control cohort. The frequency of false-positive cells ranged from 0 – 1cell/per 2ml blood. Conclusions: Results from this study of a rare lung tumor subset confirm that circulating tumor cells can be recovered from peripheral blood and offer a potential alternative for the detection of ROS1-rearrangements among NSCLC patients.
Treatment outcomes of patients with mixed neuroendocrine-nonneuroendocrine neoplasms (MiNEN).
Authors: Leonidas Apostolidis, Frank Bergmann, Georg Martin Haag, Dirk Jaeger, Eva Caroline Winkler
Journal: Journal of Clinical Oncology (2018)

e16163 Background: Mixed neuroendocrine-nonneuroendocrine neoplasms (MiNEN) have been newly defined in the WHO 2017 classification of tumors of the endocrine organs. They are considered rare and are commonly treated in analogy to their nonneuroendocrine (nNE) or neuroendocrine (NE) component without systematic data regarding the optimal therapeutic strategy. The aim of this study was to analyze the treatment outcomes of MiNEN patients. Methods: Retrospective analysis of all patients with MiNEN who presented at the National Center for Tumor Diseases, Heidelberg University Hospital, between October 2001 and January 2018. Results: In the total of 101 patients identified, 86.1 % showed adenocarcinoma as nNE component and could be classified als mixed adenoneuroendocrine carcinoma (MANEC) according to the WHO 2010 classification of tumors of the digestive system. Overall survival (OS) from diagnosis was 44.5 months. 61 patients in a localized stage underwent surgery, median recurrence-free survival was 12.5 months. Multimodal treatment (including chemotherapy and/or radiotherapy) vs. surgery alone was associated with a significantly prolonged OS of 75.0 vs. 18.9 months (p = 0.0045). 57 patients received palliative first-line chemotherapy with nNE or NE regimens for metastatic disease. In 51 patients evaluable for response, overall response rate was 39.2 % and disease control rate was 60.8 %. Median progression-free survival (PFS) and OS was 4.7 and 17.4 months respectively without any significant difference between nNE and NE regimens. Of 31 patients receiving a second-line therapy, 2 (6.5 %) showed a partial remission (1 with FOLFIRI+bevacizumab, 1 with FOLFIRI), 5 (16.1 %) a stable disease (2 with FOLFIRI+bevacizumab, 2 with everolimus, 1 with cisplatin+irinotecan). Conclusions: Prognosis of localized MiNEN seems to be improved by multimodal treatment. In first-line therapy of metastatic MiNEN, both regimens for the nNE and NE component can be considered equally effective. Second-line therapy has only limited benefit, with some activity of irinotecan/bevacizumab-containing regimens and everolimus.
Metformin and stage IV colorectal cancer in elderly.
Authors: Rohit Bishnoi, Chintan Shah, Jessica Marie Schmit, Jinhai (Stephen) Huo
Journal: Journal of Clinical Oncology (2018)

e15636 Background: It is well reported that patients with diabetes have higher risk of developing new malignancies including colorectal cancer (CRC), and previous studies also reported that antidiabetic drugs may positively impact survival in cancer patients, including CRC. The objective of this study was to determine the effect of antidiabetic drug metformin on the survival of metastatic CRC patients with type 2 diabetes. Methods: Using SEER-Medicare-linked database, we performed a retrospective study in a cohort of diabetic patients 65 years and older diagnosed with stage IV CRC from January 1, 2007 to December 31, 2013. We used multivariable regression analyses to identify factors predicting the use of metformin. Cox proportional hazards models were used to analyze the association of metformin with overall survival. Results: We identified 1804 patients with preexisting diabetes and stage IV CRC, of these 35.9 % (n = 647) patients were on metformin for diabetes. Metformin utilization increased from 7.6% in 2007 to 17.3% in 2013. Overall survival was better for patients who were on Metformin (hazard ratio [HR] 0.85, 95% CI 0.76–0.94; p = 0.002). Patients who received any cancer directed therapy including surgery, chemo or radiation were associated with improved survival (p < 0.05). The other significantly predictors of better survivals include younger age, females, Hispanic, and being married (p < 0.05). Higher comorbidity (Charlson comorbidity index 2+ vs 0) were associated with worse overall survival (P < 0.003). See table for details. Conclusions: This analysis on stage IV CRC patients based on large population-based data endorses anti-cancer effects of metformin, until confirmed by prospective studies. This analysis also highlights some other important factors and their effect on survival, which can be used for prognostication. Variables Hazard Ratio 95% CI p-value Metformin use Yes vs. no 0.85 0.76 0.94 0.002 Surgery Yes vs. no 0.67 0.60 0.74 < .0001 Radiotherapy Yes vs. no 0.63 0.49 0.81 < .001 Chemotherapy Yes vs. no 0.57 0.51 0.64 < .0001 Age Group 80+ 1.59 1.37 1.85 < .0001 Gender Female 0.87 0.78 0.97 0.013 Race Hispanic 0.80 0.66 0.97 0.021 Marital Status Married 0.77 0.67 0.88 0.000 Comorbidity Score 1 1.13 0.95 1.35 0.182 2 1.33 1.10 1.60 0.003 3 + 1.31 1.10 1.57 0.003
TCT-648 The Prevalence of Computed Tomography-Defined Leaflet Thrombosis in Intra- versus Supra-Annular Transcatheter Aortic Valve Prostheses
Authors: Hashrul Rashid, Michael Michail, Abdul Rahman Ihdayhid, Arthur Nasis, Robert Gooley, Paul Thein, James Cameron, Adam Brown
Journal: Journal of the American College of Cardiology (2018)