tbuckley/cabot-search huggingface dataset:
Detection of <i>EGFR</i> mutations in cfDNA and development of resistance.
Authors: Grainne M. O'Kane, Geoffrey Liu, Tracy Stockley, Muqdas Shabir, Tong Zhang, Lisa Le, Frances A. Shepherd, Penelope Ann Bradbury, Natasha B. Leighl
Journal: Journal of Clinical Oncology (2018)

e21072 Background: Peripheral blood sampling for T790M in patients (pts) failing initial EGFR-TKIs is now standard practice. The value of longitudinal sampling is unknown. Methods: A study of cell free (cf) DNA analysis in pts with EGFR mutated(m) non-small cell lung cancer (NSCLC) is ongoing at the Princess Margaret Cancer Centre. The ThermoFisher Oncominelung assay detecting single nucleotide variants and indels to a limit of 0.05-0.1% variant allele frequency (VAF) was used. Patient clinical details and outcomes were collected prospectively. Results: From Oct 2016-Feb 2017, 73 pts with EGFRm NSCLC enrolled and first blood samples were analysed. Most (92%) had mutations in del19 or L858R, including 1 pt with del19/S768I. Uncommon EGFRm were present in 6 (G718X, L861Q, exon20ins). Detectable levels of cfDNA were found in 50 pts (68%). Of 64 pts either starting an EGFR-TKI (n = 11,17%), receiving a TKI without progression (PD) (23, 36%) or with PD on a TKI (30, 47%), the presence of the primary EGFRm in 39 (61%) strongly associated with a new diagnosis or PD, p = 0.03. Of 53 pts receiving a TKI, the presence of T790M in 31 (58%) also associated with PD (p = 0.04). In this cohort, in the presence of the primary EGFRm and no radiologic PD, the median progression free survival (PFS), taken from blood draw, was 2.1 months (mths) versus 10 mths (HR 2.22, 95% CI: 0.89-5.54 p = 0.08). If T790M was detected in cfDNA, the median PFS was 3.0 months versus 9.7 mths, (HR 4.59, 95% CI: 1.43-14.73 p = 0.005). In univariable regression analyses the %VAF of the primary EGFRm correlated with PFS (HR 1.15, 95%CI: 1.02-1.29, p = 0.02) with a trend in the %VAF of T790M (HR 1.16 95% CI:0.99-1.37, p = 0.08). T790M was detected in 3 of 4 pts with T790M -ve tissue, and other co-occurring EGFRm were found in 10 pts including K745R in a pt receiving first-line osimertinib. TP53 (n = 10), KRAS (1), PI3KCA(1) and ALK(2) gene mutations were also detected. Interestingly, in 1 pt receiving chemotherapy with T790M+ disease, both the primary EGFRm and T790M were detected in blood at the time of PD. Conclusions: In addition to the emergence of resistance mutations, the presence of the primary EGFRm in pts receiving EGFR-TKIs may associate with a shorter PFS and therefore may be useful in longitudinal analyses of cfDNA to direct therapy.
Division of elderly patients in colorectal cancer: Korean national health insurance big data analysis.
Authors: Sun Kyung Baek, Ji Sung Lee, Sang-Cheol Lee, Sang-Byung Bae, Jong Gwang Kim, Tae Won Kim
Journal: Journal of Clinical Oncology (2017)

e15104 Background: This nationwide study was conducted to demonstrate the difference of the treatment and the survival of elderly patients with colorectal cancer (CRC) by the analysis of big data using the Korean National Health insurance service (NHIS). Methods: We analyzed the NHIS database of CRC patients admitted hospitals which received its quality assessment between 2011 and 2014. According to age, we divided patients into three groups, non-elderly patients ( &lt; 65 years old), borderline elderly patients (65-74 years old) and elderly patients (≥ 75 years old). Results: We included 70,701 CRC patients. Median follow-up duration was 3.2 years (range 0.003-5.5 years). Male patients were 60% and median age was 65 years old (range 18-102 years). Comparing with non-elderly patients, elderly patients more received emergency operation (p &lt; 0.001) and less received adjuvant therapy in stage I-III or palliative chemotherapy in stage IV (p &lt; 0.001). Survival probability at 3 year of borderline elderly patients and elderly patients showed worse survival rate than non-elderly patients [HR 1.55, 95% confidence interval (CI) 1.46 - 1.64, HR 3.19, 95% confidence interval (CI) 3.03 -3.37, respectively]. Conclusions: These results show the treatment and the poor survival of elderly patients with CRC according to age in Korea. More study to reveal the biology of them and to improve outcome is warranted. Our study was the first to describe these data for CRC at a nationwide level.
Clinical outcomes in genetically targeted cancer treatment.
Authors: John Michael Rozehnal, Celina Ang, Michael Donovan, Erdem Bangi, Caitlyn Yeykal, Ross L. Cagan, Yevgeniy Antipin, Andrew V. Uzilov, Marshall R. Posner, Krzysztof Misiukiewicz
Journal: Journal of Clinical Oncology (2016)

e23127 Background: The availability of commercial tumor molecular profiling services enables clinicians to identify and drug “actionable” targets, with the aim of personalizing therapy. However, it is unclear if this approach improves outcomes. Methods: Medical records of solid tumor patients were reviewed for Foundation One (F1) reports, their targeted drug recommendations (“hits”) and patients’ clinical course. Any F1-identified hit was included even if treatment preceded the F1 report but only off-label therapy that followed the F1 report was considered “acted upon”. Clinical benefit was defined as non-progression of disease by the first radiographic or clinical assessment after the initiation of a therapy. Where clinical benefit was equivocal, drug discontinuation was used as evidence of failure. Results: 52 F1 reports were identified, 4 (8%) of which were excluded due to assay failure or duplication. 46 (88%) reported at least one significant genetic aberration. 35 (67%) reports identified a drug “hit”, of which 34 (65%) identified only off-label drugs, 6 (12%) identified both off-label and approved drugs, and 1 (2%) identified only approved drugs. 7 off-label hits were acted upon, 6 of which are evaluable for outcomes. 3/6 (50%) resulted in clinical benefit. 2 of these 3 responders (66%) required dose adjustment due to toxicity. Conclusions: Of 52 tumor molecular profiles ordered, 3 provided additional therapeutic options with documented benefit to the patient. While our findings are limited by small sample size, they suggest that currently-available methods of identifying and drugging actionable seldom provide great benefit. Cancer Drug (* indicates FDA-approved drug) Clinical Benefit Colorectal Adenocarcinoma Panitumumab* Yes Renal Clear Cell Carcinoma Everolimus* No Renal Clear Cell Carcinoma Pazopanib* Yes Renal Clear Cell Carcinoma Axitinib* Yes Bladder Adenocarcinoma Lapatinib No Appendix Adenocarcinoma Everolimus Yes Bladder Neuroendocrine Cabozantinib No Bladder Transitional Cell Cabozantinib No Appendix Adenocarcinoma Trametenib Yes Bladder Adenocarcinoma Cetuximab Yes
Comprehensive evaluation on treatment and outcomes of grade II diffuse gliomas.
Authors: Catherine R. Garcia, Stacey A. Slone, Thomas A. Pittman, William H. St Clair, Donita D. Lightner, John L. Villano
Journal: Journal of Clinical Oncology (2018)

e14025 Background: Grade II gliomas include a variety of histologic features. Low grade gliomas are present in younger patients and have favorable prognosis. We aim to describe prognosis patterns of low grade diffuse gliomas using the largest cancer database in the United States. Methods: We analyzed the National Cancer Database from 2004-2015, for WHO grade II diffuse gliomas. Results: 14,592 cases were included. The median age was 40 years with 55% males. 88% were white and 7.8% Hispanic. The most common location was the cerebrum (78.6%). Younger cases had a higher frequency of brainstem/spine/ventricles (central) location (21.2%). Overall 74.8% received surgery, 34.5% radiation, and 27% chemotherapy. Treatment modalities included surgery only (42.6%), unknown (5.4%), chemotherapy + surgery (6.9%), chemotherapy only (3.4%), radiation + chemotherapy + surgery (10.2%), radiation + surgery (11%), radiation only (5.9%), radiotherapy + chemotherapy (6.5%), and no treatment (8.1%). Treatment varied with age, tumor location, and 1p/19q co-deletion. Radiation was preferred in older cases and was more frequent in 1p/19q co-deleted, and central location. Chemotherapy was more common in those 1p/19q non-co-deleted. Majority of patients lived in metropolitan areas with high socioeconomic status. Medicare covered over 85% of elderly patients. Survival was 144 months. Younger age, 1p/19q co-deletion, and cerebrum location offered survival benefits. Conclusions: Our analysis is the largest to date and highlights the good prognosis of low grade gliomas. Tumor location, 1p/19q co-deletion, and age were main determinants of treatment and survival, likely reflecting tumor biology. Outcomes based on upfront use of radiation treatment were limited. Table 1. Treatment combinations as determinants for overall survival Hazard ratiosa Confidence intervals p-value Surgery only 0.43 0.35-0.52 < 0.0001 Chemotherapy + surgery 0.52 0.42-0.65 < 0.0001 Chemotherapy only 0.77 0.61-0.97 0.02 Radiation + chemotherapy + surgery 0.81 0.66-1.0 0.05 Radiation + surgery 0.82 0.67-1.00 0.05 Radiation only 1.56 1.27-1.91 < 0.0001 Radiation + chemotherapy 1.59 1.31-1.95 < 0.0001 aCompared to no therapy
Perception and opinions of health professionals of an Italian academic hospital about complementary and alternative medicine in oncology.
Authors: Claudia Bozza, Fabio Puglisi, Lorenzo Gerratana, Debora Basile, Maria Grazia Vitale, Michele Bartoletti, Stefania Russo, Nicoletta Pella, Alessandro Follador, Mauro Mansutti, Alessandro Marco Minisini, Marika Cinausero, Giacomo Pelizzari, Cosimo Stanislao Pio Sacco, Roberta Sottile, Giampaolo Canciani, Gianpiero Fasola
Journal: Journal of Clinical Oncology (2018)

e18865 Background: Cancer patients are interested in complementary and alternative medicine (CAM) and frequently use it but they are reluctant to talk about this topic with their oncologist. On the other hand, health staff often does not ask the patients about the use of CAM and is lacking information about CAM. Therefore, we conducted a survey in order to know perception and attitude about CAM of different professionals of an Italian academic hospital. Methods: From June to December 2017 a survey was conducted among the employees of the Academic Hospital of Udine, through the web-based platform SurveyMonkey. Participation was voluntary and anonymous. The questionnaire included sections regarding demographic data, interest in CAM and knowledge about it, and statements for which respondents were asked to express a level of agreement. Results: Overall, 1008 employees (about 20% of total) have joined the survey, 773 females (76.7%) and 235 males (23.3%). Median age was 47 years. A total of 52% of respondents declared they were interested in CAM before the survey; 62 respondents (7.5%) said that they would propose an alternative treatment to cancer patients, while 212 respondents (25.7%) would propose a complementary treatment. Notably, 547 respondents (54.3%) agreed with the statement: “Alternative therapies could be dangerous and their side effects not known.” Females and nurses seemed to be more in favor of CAM than males and physicians, especially regarding the statements “CAM can help quality of life even if they are not as effective as traditional therapies” (p < 0.0001), “Even if probably ineffective, alternative therapies are not harmful” (p < 0.0001). Conclusions: Health-related workers are often faced with cancer patients who need information on the CAM or who use it. Therefore, their role in promoting appropriate use (i.e. complementary medicine with scientific evidence) and in curbing inappropriate use (i.e. alternative medicine without scientific evidence) of CAM is crucial. The present study offers a starting point for better calibrate awareness campaigns and educational activities on this topic for both patients and health-related workers.
Overall survival for men with high risk prostate cancer and co-morbidities after treatment with external beam radiotherapy and androgen deprivation therapy.
Authors: Nicolette Taku, Vivek Narayan, Neha Vapiwala
Journal: Journal of Clinical Oncology (2018)

e17047 Background: For men diagnosed with high-risk prostate cancer (HRPC), external beam radiotherapy (EBRT) plus androgen deprivation therapy (ADT) is a standard treatment approach. However, for men with moderate to severe baseline co-morbidities, there may not be an overall survival (OS) benefit to EBRT + ADT when compared to treatment with EBRT alone. We report co-morbidity-related OS for men included in the National Cancer Database who were diagnosed with HRPC and treated with EBRT + ADT or EBRT alone from 2004 to 2012. Methods: HRPC was defined as clinical stage T3a or Gleason score ≥ 8 or PSA ≥ 20 ng/ml, in accordance with National Comprehensive Cancer Network guidelines. Cases were limited to those that received EBRT and had 1) known ADT status, 2) baseline Charlson co-morbidity score (CCS) of 1 or more, and 3) documented survival outcome. The Kaplan-Meier method and log rank test were used to estimate the OS and difference between the treatment groups. Cox regression models were used to evaluate the effects of covariates on OS. Results: At median lengths of follow-up of 42.1 months (IQR, 24.4 – 67.9) for EBRT + ADT and 46.5 months (IQR, 27.5 – 70.4) for EBRT alone, there were 3,599 deaths (33.6%) and 1,049 deaths (25.5%) in the respective treatment groups (Log rank p < 0.001). In the EBRT + ADT treatment group, estimated median time to death was 8.5 years (95% CI 8.2-8.7) for men with CCS of 1 and 5.8 years (95% CI 5.4-6.2) for men with CCS of 2 (Log rank p < 0.001). On multivariate testing adjusted for income, insurance status, and treatment facility type there was a significant increase in the risk of death when men with CCS of 2 were compared to those with CCS of 1 (hazard ratio = 1.75, 95% CI 1.63-1.89, p < 0.001) There was no race-related increase in mortality when OS for black men was compared to that of non-Hispanic white men. Conclusions: Treatment with EBRT + ADT is associated with increased mortality when compared to EBRT alone for men with baseline co-morbidities. Among men treated with EBRT + ADT, greater number of co-morbidities is associated with decreased OS.
Abstract 16260: On-transient Vo2 Kinetics During Submaximal Exercise Are Influenced by Intrathecal Fentanyl Inhibition of Group III/IV Locomotor Afferents in Heart Failure Patients
Authors: Erik H Van Iterson, Bruce D Johnson, Michael J Joyner, Timothy B Curry, Thomas P Olson
Journal: Circulation (2016)

Introduction: Peak oxygen uptake (VO2) is the gold standard measure of exercise tolerance in heart failure (HF). The pathophysiology of low peak VO2 in HF is incompletely understood. Thus, physiolo...
Comparison of expression of microRNAs which regulate metastasis genes in breast cancer stem cells and primary breast cancer tissues
Authors: M. Rahimi, M. Ebrahimi, E. Alizadeh
Journal: Annals of Oncology (2018)

Background: Recently in cancer research has shown that tumors are highly heterogeneous. Cancer developments are driven by specific cells-cancer stem cells (CSCs)-which are also responsible for metastases and drug resistance. Many studies have proved the significant role of miRNAs in controlling the Metastasis in CSCs. So, the present systematic analysis based on literature mining and bioinformatics approaches was performed to find the miRNAs in breast cancer. Methods: After systematic analysis, we found miR-200c and miR-30c as regulators of metastasis in breast cancer. Then, using mammosphere formation in serum-free condition and colony formation assay were conducted to check the stemness properties of MDA-MB231 breast cancer cells. After RNA extraction of mammosphere and primary breast cancer tissue, real-time PCR analysis was performed for metastasis genes (CDH1/2, SNAI1, TWIST1/2 and ZEB1) and the prior selected miRNAs. Finally, differentially expressed genes and miRNAs in mammospheres have been determined and compared with seven malignant breast tissues. Results: Mammospheres demonstrated higher colony-forming ability and has higher expression of metastasis genes in comparison to their parental. Also, they have shown down regulated miR-200c and up regulated of miR-30c. Interestingly, 3 metastatic patients with grade II/III who received neo adjuvant therapy have higher expression of metastasis and have shown down regulated miR-200c and up regulated of miR-30c in comparison to primary breast normal tissue like mammospheres. Conclusions: This study validates the use of breast cancer cell lines as models to elucidate the nature of BCSCs that may represent a novel target for therapy. Additionally, by correlating EMT genes with two miRNAs expression we suggest that simultaneous reduction of miR-200c and increasing in miR-30c could be an indicator for resistance to treatment or secondary metastasis. Legal entity responsible for the study: Department of Stem Cells & Developmental Biology at Cell Science Research Center, Royan Institute for Stem Cell Biology & Technology, ACECR, Tehran, Iran. Funding: Department of Stem Cells & Developmental Biology at Cell Science Research Center, Royan Institute for Stem Cell Biology & Technology, ACECR, Tehran, Iran. Disclosure: All authors have declared no conflicts of interest.
Correlation of pre-CAR CD19 expression with responses and relapses after CAR T cell therapy.
Authors: Vinodh Pillai, Jaclyn Rosenthal, Kavitha Muralidharan, Gerald B Wertheim, Michele Paessler, Shannon L. Maude, Susan R. Rheingold, Stephan A. Grupp
Journal: Journal of Clinical Oncology (2018)

3051 Background: Chimeric antigen receptor (CAR) T cells targeting CD19 have shown excellent responses in patients with relapsed/refractory B-ALL. However, a subset of patients either do not respond or relapse after CAR T cell therapy, the causes of which are unclear. The use of CD19-directed therapy has increased the incidence of CD19 dim or CD19 negative B-ALL. We assessed whether pre-treatment CD19 expression level or prior targeted therapy impacts response to CAR therapy. Methods: Cases of B-ALL treated with CAR therapy from 2012-2017 at Children’s Hospital of Philadelphia were evaluated. CD19 in blasts was classified as dim, normal or bright compared to normal B cells by flow cytometry. CD19 expression and immunophenotype of blasts pre and post-CAR therapy were correlated with responses to CAR T cell therapy. Failure to reach an MRD-negative remission was considered as non-response. Presence of aberrant blasts ( > 0.01%)at any time point after remission was considered as relapsed disease. Results: 150 cases treated with CAR therapy were evaluated of which 10 were non-response (NON), 20 were CD19 positive relapses (CD19PR) and 33 were CD19 negative relapses (CD19NR). 15 patients received prior CD19 targeted therapy. Rate of responses and relapses in CD19dim B-ALL were not significantly different from the CD19 normal/bright group. However, prior CD19-targeted therapy was associated with a significantly higher rate (60%; p = 0.014) of NON and CD19NR compared to 25% in patients who did not receive any prior CD19 targeted therapy. Immunophenotype of CD19PR were identical to that of pre-therapy disease in 85% of cases, consistent with loss of CAR T cells as the etiology of those relapses. Blasts from CD19NR patients did not show any CD19-negative events by flow prior to CAR T cell therapy in 75% of cases suggesting that CD19-negative blasts may be de novo events. Conclusions: CAR T cell therapy is effective in B-ALL with dim CD19 expression. Prior targeted therapy is associated with increased non-response and relapse, likely due to CD19 escape. CD19PR after CAR T cell therapy are due to early loss of CAR T cells while CD19NR are likely due to expansion of de novo CD19-negative B lymphoblasts under treatment pressure.
Cerdulatinib (PRT062070): A dual SYK/JAK inhibitor in patients with relapsed/refractory b-cell malignancies—Pharmacokinetic and pharmacodynamic outcomes with twice-daily (BID) vs once-daily (QD) dosing.
Authors: Paul A. Hamlin, Ian Flinn, Nina Wagner-Johnston, Jan Burger, Glenn Michelson, Anjali Pandey, Matt Birrell, Greg Coffey, Janet Leeds, Alice sabalvaro-Torres, Yvonne Kim, John T Curnutte, Manish R. Patel
Journal: Journal of Clinical Oncology (2016)

7557 Background: Subsets of B cell malignancies demonstrate a reliance on BCR and/or cytokine JAK/STAT signaling for survival. Cerdulatinib is a dual SYK/JAK inhibitor, currently in a phase I dose escalation study. Pre-clinical tumor models suggested a target therapeutic exposure of 1.5 µM at steady-state Cmin . However, PK analysis from our first-in-human study has indicated an exposure plateau with daily (QD) dosing from 40-100 mg, resulting in sub-micromolar exposure (~0.7 µM) at steady-state Cmin . We utilized a physiological-based PK model to understand the nature of the exposure plateau. Analysis suggested BID dosing would achieve higher exposures, which were explored clinically and achieved. Methods: 3+3 dose escalation study with 28-day cycles and doses ranging from 15-100mg QD, and up to 45mg BID. PK, PD, and safety were monitored. Clinical response was assessed by standard criteria. Results: : As of January 7, 2016, 41 patients (pts) with CLL/SLL or B cell NHL were dosed. In general, cerdulatinib has been well tolerated. One DLT of pancreatitis was observed in the 45mg BID cohort and the cohort will now expand to 6 pts. QD dosing of 40-100mg resulted in 50 to 100% inhibition of SYK and JAK signaling at steady-state Cmin to Cmax , respectively, in peripheral blood of patients. At the 45mg BID dose level, complete inhibition of SYK and JAK at steady-state Cmin in peripheral blood assays was observed, consistent with an approximate doubling in exposure (steady-state Cmin of 1.5µM was achieved). Partial responses (n = 4) have been observed in FL, transformed FL, and CLL. Tumor response correlates with serum exposure and target kinase inhibition. Ten pts on drug for > 200 days; 15 pts on drug > 100 days. Conclusions: Cerdulatinib has demonstrated a favorable PK profile and good tolerability at high levels of SYK and JAK inhibition. BID dosing overcomes the previous exposure plateau. Clinical responses seen to date support further development and dose escalation continues to identify the MTD. Phase II expansion cohorts are open or planned for CLL, FL, aggressive NHL (DLBCL), and a combination with rituximab. Clinical trial information: NCT01994382.