tbuckley/cabot-search huggingface dataset:
Results of a fifty-gene breast cancer RNA subtype classifier applied to 167 colorectal cancer (CRC) patients.
Authors: Sandeep K. Reddy, Tara Elisabeth Seery, Christopher Szeto
Journal: Journal of Clinical Oncology (2020)

20 Background: ERBB2 (HER2) is thought to be a target in &lt;10% of CRC patients versus 20% of breast cancers, 15% of gastroesophageal cancers, and 10% of biliary cancers, based on FISH or IHC. Intrinsic molecular subtype is used to classify cancers into distinct biologic subtypes (eg. CMS 1-4 in CRC). A 50-gene qPCR assay (PAM50) identifies 5 intrinsic biological subtypes: luminal A, luminal B, HER2-enriched, basal-like, and normal-like in breast cancer. The HERACLES trial (trastuzumab plus lapatinib) resulted a 32% ORR and median TTP of 5.5 months in heavily pre-pretreated HER2+ CRC patients. We determined molecular subtypes using the 50-gene breast cancer classifier to identify an expanded CRC patient population eligible for HER2 therapy. Methods: Retrospective analysis on Whole exome (WES) DNA tumor and paired germline and matched deep whole transcriptomic sequencing (RNA-Seq) (∼200x10 6 reads per tumor) data from NantHealth was performed. Breast Cancer Intrinsic Subtypes based on RNAseq was used to classify CRC into 5 BC subtypes. Results: 167 CRC patients were classified using the Nant50 Breast Cancer classifier: 15.0% as Luminal B, 13.1% as Luminal A, and 1.8% as Basal-like. Surprisingly, 117/167 (70%) classified as HER2-enriched (HER-E). 15/167 (9.0%) had over-expression of ERBB2 by RNAseq or CN gain, which is consistent with published data of HER2+ CRC. ERBB2 is very significantly differentially expressed in HER2-E subtyped CRC (p=&lt;0.001), more than ERBB2 CN gain, suggesting that HER2-E may be more HER2 driven. Across subtypes APC and TP53 were the most commonly mutated genes at 65.3% and 52.6% respectively, however both were more enriched in HER2-E CRC (APC OR=3.3, p=0.001, TP53 OR=2.6, p=0.007). Other known drivers of CRC such as PIK3CA, KRAS, and BRAF, were not differentially mutated in HER2-E CRC, however NRAS mutants were significantly more enriched in non-HER2-E CRC (OR=4.6, p=0.02). Conclusions: Even after excluding known HER2 over-expression and CN gain, PAM50-like gene classifier identifies a far higher than expected percentage of HER-E subtype CRC (99/167 = 59%) which may represent an under appreciated population for HER2 directed therapy and clinical trials.
Neoadjuvant therapy guideline adherence for locally advanced rectal cancers in a region with sociodemographic disparities.
Authors: Denise Wong, Leah E. Hendrick, Whitney M. Guerrero, Justin J. Monroe, Nathan M. Hinkle, Jeremiah Lee Deneve, Evan Scott Glazer, David Shibata
Journal: Journal of Clinical Oncology (2020)

71 Background: Quality and practice guidelines from the American College of Surgeons Commission on Cancer (CoC) and the National Comprehensive Cancer Network (NCCN) recommend neoadjuvant chemoradiation (NCR) for locally advanced rectal cancer (LARC). We examined guideline adherence in a healthcare system serving a region with significant socioeconomic disparities and poor cancer outcomes. Methods: We performed a retrospective analysis of patients from 2005-2014 with stage II and III rectal cancer in our local 5- hospital healthcare system in the Mid-South region of the US. We examined the associations between guideline adherence and patient demographic, socioeconomic, and clinicopathologic data. Results: Of 157 stage II/III RC patients, 96 (61.1%) received NCR. By univariate analysis, factors associated with receipt of NCR included white race versus non-white (OR = 2.14, p = 0.024), private insurance versus no or public insurance (OR = 2.70, p = 0.005), employed status versus unemployed (OR = 2.29, p = 0.031), age at diagnosis (OR = 0.74, p = 0.032), and appropriate local staging with EUS or MRI (OR = 6.67, p = &lt; 0.0001). Those who were diagnosed and treated later in the study period were more likely to get NCR (OR per 1 year = 1.20, p = 0.006). In addition, receipt of NCR was protective against death at time of follow up (OR = 0.41, p = 0.009). By multivariate analysis, those with private insurance (OR = 2.51, p = 0.023), younger age at diagnosis (OR per 10 years = 1.39, p = 0.048) and with appropriate local staging (OR = 6.67, p &lt; 0.0001) were more likely to have received NCR. Conclusions: Guideline adherence for LARC in our system, which serves a population with socioeconomic disparities, is relatively low. Sociodemographic factors such as employment and race influenced receipt of NCR, while insurance status and age were independent determinants. Despite some increase in compliance over time, adherence to NCR for LARC remains lower than expected and represents an important target for improvement efforts.
Relationship of periodic methylation patterns in the gastric mucosa and periodic stem cell replacement.
Authors: Jung-Hwan Oh, Seung Jin Hong
Journal: Journal of Clinical Oncology (2020)

333 Background: The role of Helicobacter pylori-associated methylation in the inactivation of tumour-suppressor genes has been previously investigated. However, the relationship between H. pylori-associated methylation and gene inactivation is unclear. Stem cells are replaced periodically every 8 years in the gastrointestinal mucosa. Hence, age-related methylation in the gastric mucosa was studied to understand the stabilization of new stem cell phenotypes. Methods: Endoscopic biopsy specimens of the antral mucosa were obtained from 148 H. pylori-negative and 124 H. pylori-positive subjects. The methylation-variable sites of 4 housekeeping genes ( CDH1, ARRDC4, MMP2, and CDKN2A) and 2 stomach-specific genes ( TFF2 and TFF3) were examined using radioisotope-labelled methylation-specific polymerase chain reaction. Age-related methylation was evaluated at an interval of 2 years. Results: The 4 housekeeping genes were more frequently methylated in H. pylori-positive subjects than in H. pylori-negative subjects. Periodic changes in the housekeeping gene methylation were obscure. TFF2, which is highly expressed in the stomach, was periodically methylated to attain peaks at the age of 40–41, 48–49, 56–57, and 64–65 years in both H. pylori-negative and -positive subjects. TFF3, which is weakly expressed in the stomach, was methylated at the age of 46–47, 54–55, 66–67, and 72–73 years in H. pylori-negative subjects. The methylation of stomach-specific genes periodically fluctuated approximately at 8-year intervals in the gastric mucosa. Conclusions: Periodic methylation changes in the gastric mucosa may be used to estimate the replacement of new stem cells.
Abstract 9670: Health Related Quality of Life Mediates the Relationship Between Medication Adherence and Cardiac Event-free Survival in Patients With Heart Failure
Authors: Jia Rong Wu, Debra Moser
Journal: Circulation (2019)

Background: Poor medication adherence predicts hospitalization and death. Health-related quality of life (HRQOL) is an important patient-reported outcome. It is unknown whether better medication ad...
Understanding the expanding armamentarium for GIST: Engaged learning outcomes.
Authors: Michelle Arielle Worst, Emily Sherene Van Laar, Mindy Tanzola, Michael C. Heinrich, Victor Manuel Villalobos
Journal: Journal of Clinical Oncology (2020)

837 Background: Gastrointestinal stromal tumors (GIST) are rare soft-tissue sarcomas that harbor specific genomic alterations, making GIST an ideal model for targeted therapy. Common oncogenic drivers include mutations in the KIT and PDGFR tyrosine kinase. Due to varying resistance patterns to existing TKIs, clinicians are challenged to stay current with new data and how best to integrate new agents into treatment paradigms. The objective of this study was to assess the changes in oncologists’ and gastroenterologists’ knowledge, competence, and confidence through participation in education regarding optimal GIST treatment. Methods: The educational activity consisted of a 30-minute online, 2 faculty, video discussion with synchronized slides. Educational effect was assessed with a repeated pairs pre-/post-assessment study with a 3-item, multiple choice, knowledge/competence questionnaire and one confidence assessment question. For all questions, each participant served as his/her own control. Pre- and post-assessment scores were compared to determine the relative changes in the proportion of correct responses. A chi-square test assessed statistical significance at the P &lt; 0.05 level. The activity launched 25th June 2019; data were collected until 19th August 2019. Results: Overall significant improvements were seen after education for oncologists (N=52, P &lt; 0.001) and gastroenterologists (N=127, P &lt; 0.01). The relative improvement was 79% for oncologists and 44% for gastroenterologists (pre-/post-assessment average correct response rates were 24%/43% and 23%/33%, respectively). Following the activity, 44% of oncologists and 37% of gastroenterologists were more confident in their ability to select appropriate therapy for patients with metastatic GIST. Conclusions: Participation in an online, 30-minute video discussion CME intervention resulted in statistically significant improvements in knowledge, competence, and confidence of oncologists and gastroenterologists, that may lead to improvements in clinical care. As new data and agents emerge, new educational activities are necessary to reinforce knowledge, close persistent gaps, and increase oncologists’ confidence in this clinical setting.
Outcomes and efficacy of neoadjuvant chemoradiation versus chemotherapy in localized pancreatic cancer.
Authors: Asmita Chopra, Jacob C. Hodges, Adam Olson, Steven A. Burton, Kenneth K. Lee, Nathan Bahary, Aatur D. Singhi, Brian A. Boone, Michael T. Lotze, Melissa E. Hogg, Herbert Zeh, Amer H. Zureikat
Journal: Journal of Clinical Oncology (2020)

727 Background: Neoadjuvant therapy is increasingly used for pancreatic cancer (PDA). The comparative efficacy of neoadjuvant chemotherapy (NC) versus chemoradiation (NCRT) remains uncertain. We aimed to compare NC and NCRT on survival outcomes and pathologic endpoints of PDA. Methods: Single-center analysis of PDAs treated with NC or NCRT between 2008-2018. Average treatment effects (ATE) were estimated after matching cases to controls using Mahalanobis distance nearest-neighbor matching. Competing risk survival analysis and inverse probability weighted estimates (IPWE) were used for disease free survival (DFS) and overall survival (OS) respectively. Results: Of 418 patients (median age 67yrs, 51% females), 327 received NC and 91 received NCRT. NCRT patients had more locally advanced disease, cross-over NC regimens (gemcitabine &amp; 5-FU based), longer neoadjuvant therapy duration, open surgery and vascular resection (all p &lt; 0.05). NCRT was associated with lower LN positivity, LNR, LVI and PNI, higher R0 rates, and higher near complete and complete pathologic responses (all p &lt; 0.05, table). After adjustment, NCRT was associated with a significant reduction in LN positivity [95%CI = (-)0.41-(-)0.07; p = 0.007] and LVI [95%CI = (-)0.36-(-)0.03; p = 0.02]. While NCRT was associated with improved OS on UVA (25.5 vs. 21.6 months; p = 0.04), it was not significantly associated with OS by IPWE after adjusting for adjuvant therapy [95%CI = (-)5.02-16.3; p = 0.3] or DFS on competing risk analysis (95%CI = 0.78-1.31; p = 0.96). Conclusions: Although NCRT is associated with improved pathologic surrogates, it is not associated with improved survival in PDA. [Table: see text]
PCRT16-001: Phase II study of PEGPH20 plus pembrolizumab for patients (pts) with hyaluronan (HA)-high refractory metastatic pancreatic ductal adenocarcinoma (mPDA).
Authors: E. Gabriela Chiorean, Paul S. Ritch, David Bing Zhen, Elizabeth Poplin, Ben George, Andrew Eugene Hendifar, Tomislav Dragovich, Andrew L. Coveler, Amy C. Stoll-D'Astice, Stephanie Edwards, Adam Rosenthal, Shelley M. Thorsen, Sunil R. Hingorani
Journal: Journal of Clinical Oncology (2020)

TPS785 Background: PDA is characterized by invasiveness and therapeutic resistance in part due to a desmoplastic stroma and an immunosuppressive microenvironment ( Provenzano PP, Hingorani S. Br J Cancer 2013). PD1/PD-L1 inhibitors have no single agent activity in PDA, except for pts with mismatch repair defects. There is high need to overcome resistance to immune targeted therapies and develop biomarkers for pts selection. Stromal HA poses a physical barrier and protects tumor cells from immune surveillance ( Kultti A, et al Biomed Res Int 2014). By remodeling the tumor stroma, PEGPH20 allows infiltration of cytotoxic T lymphocytes, and improves delivery of chemotherapy and PD1/PD-L1 antibodies ( Singha NC, et al Mol Cancer Ther 2015). mPDA pts refractory to 1 st line therapy have median overall survival (OS) of 6 mos. We hypothesize that stroma remodeling with PEGPH20 sensitizes PDA to immune therapy, and stroma and immunologic biomarkers will identify pts most likely to benefit. In this trial we will evaluate the efficacy, safety and translational biomarkers of PEGPH20 plus pembrolizumab in HA-high refractory mPDA. Methods: Eligible pts have ECOG PS 0-1, ≤ 2 prior therapies for mPDA, life expectancy ≥ 12 wks, able/willing to have tumor biopsies at baseline and after 6 wks of treatment. PEGPH20 dosing is 3 µg/kg iv QW and pembrolizumab 200 mg iv Q3W (2-4 hrs after PEGPH20 on wk 1) in 3-wk cycles. All pts receive prophylactic low molecular weight heparin. Primary endpoint: progression-free survival (PFS). Secondary endpoints: safety, OS, response rates. Translational endpoints: flow cytometry of peripheral and intratumoral immune cells, T-cell receptor sequencing, immune transcriptome, immune subsets IHC, circulating cytokines, serial plasma and tumor HA levels. For the primary endpoint of PFS, with a sample size of 31 evaluable pts, a one-sided α-level of 0.05, assuming 12 mos of accrual and 6 mos of follow-up, this study has 80% power to detect a difference between the null hypothesis median PFS 3 mos, versus the alternative hypothesis median PFS 6 mos. The study was activated in May 2019 and is open to accrual; 6 pts were enrolled as of 24Sept 2019. Clinical trial information: NCT03634332.
A phase I/II study of veliparib (ABT-888) with radiation and temozolomide in newly diagnosed diffuse pontine glioma: a Pediatric Brain Tumor Consortium study
Authors: Patricia A Baxter, Jack M Su, Arzu Onar-Thomas, Catherine A Billups, Xiao-Nan Li, Tina Young Poussaint, Edward R Smith, Patrick Thompson, Adekunle Adesina, Pete Ansell, Vincent Giranda, Arnold Paulino, Lindsey Kilburn, Ibrahim Quaddoumi, Alberto Broniscer, Susan M Blaney, Ira J Dunkel, Maryam Fouladi
Journal: Neuro-Oncology (2020)

Abstract Background A Pediatric Brain Tumor Consortium (PBTC) phase I/II trial of veliparib and radiation followed by veliparib and temozolomide (TMZ) was conducted in children with newly diagnosed diffuse intrinsic pontine glioma (DIPG). The objectives were to: (i) estimate the recommended phase II dose (RP2D) of veliparib with concurrent radiation; (ii) evaluate the pharmacokinetic parameters of veliparib during radiation; (iii) evaluate feasibility of intrapatient TMZ dose escalation; (iv) describe toxicities of protocol therapy; and (v) estimate the overall survival distribution compared with historical series. Methods Veliparib was given Monday through Friday b.i.d. during radiation followed by a 4-week rest. Patients then received veliparib at 25 mg/m2 b.i.d. and TMZ 135 mg/m2 daily for 5 days every 28 days. Intrapatient dose escalation of TMZ was investigated for patients experiencing minimal toxicity. Results Sixty-six patients (65 eligible) were enrolled. The RP2D of veliparib was 65 mg/m2 b.i.d. with radiation. Dose-limiting toxicities during radiation with veliparib therapy included: grade 2 intratumoral hemorrhage (n = 1), grade 3 maculopapular rash (n = 2), and grade 3 nervous system disorder (generalized neurologic deterioration) (n = 1). Intrapatient TMZ dose escalation during maintenance was not tolerated. Following a planned interim analysis, it was concluded that this treatment did not show a survival benefit compared with PBTC historical controls, and accrual was stopped for futility. The 1- and 2-year overall survival rates were 37.2% (SE 7%) and 5.3% (SE 3%), respectively. Conclusion Addition of veliparib to radiation followed by TMZ and veliparib was tolerated but did not improve survival for patients with newly diagnosed DIPG. Trial Registration NCT01514201
A colorectal cancer screening initiative to assist the healthcare for the homeless program within the Harris Health Safety-net Health Care System.
Authors: Allison Rosen, Betsy Escobar, Gandhar Datar, Roshanda Chenier, Jane Montealegre, Maria Jibaja-Weiss
Journal: Journal of Clinical Oncology (2020)

65 Background: The homeless population presents unique challenges for Colorectal Cancer (CRC) screening and follow-up, due to difficulty completing at home procedures such as stool-based screening and prepping for a colonoscopy. Harris Health System’s Healthcare for the Homeless Program (HHS-HHP) screens patients for CRC using strategies such as on-site stool collection to promote completion of fecal immunochemical tests (FIT). According to the HHS screening algorithm, there are currently no targeted interventions at HHS-HHP to address diagnostic follow-up of FIT-positive patients who require colonoscopy Homeless patients face barriers to colonoscopy, notably the structure of shelters, which makes it difficult to prep for a colonoscopy; and the lack of a companion to accompany patients to and from their procedures. Methods: We reviewed data regarding FIT screening and colonoscopy completion from Harris Health for the 2016-2017 fiscal year. We convened meetings with administrators of the Star of Hope Cornerstone Community and HHS-HHP to examine barriers faced by this population and identify potential interventions to address them. Results: For the 2016-17, fiscal year the average FIT completion rate for the entire population was 72% versus the homeless population was 38%. In the colonoscopy database, 173 homeless patients had positive FITs, but only 43 got their colonoscopy (25%). Reasons for not getting the colonoscopy were poor prep, not being able to reach the patient, and no-shows. There is an obvious need for an intervention to assist homeless patients in completing a colonoscopy after a positive FIT. Conclusions: Our project will assist with the care coordination for the homeless patients requiring a colonoscopy. We plan to coordinate care with the homeless shelters to schedule the use of a private, subacute care room (respite unit), if available, to ensure the patients appropriately prep the night before their procedure. In addition, medical student volunteers will be serving as companions for this project; thus, we plan to work with the patient and shelters to provide volunteers accompany patients to and from their procedures.
GINA recommendations in adults with symptomatic mild asthma and a smoking history
Authors: Neil C. Thomson, Rekha Chaudhuri
Journal: European Respiratory Journal (2020)

<b>The GINA recommendation to use as-required ICS-formoterol in symptomatic mild asthma is applicable to smokers with a low cumulative smoking history, but evidence is lacking for its effectiveness in smokers with medium and high tobacco use</b>http://bit.ly/2Xqqluu
Osimertinib plus savolitinib in patients with EGFR mutation-positive, MET-amplified, non-small-cell lung cancer after progression on EGFR tyrosine kinase inhibitors: interim results from a multicentre, open-label, phase 1b study
Authors: Lecia V Sequist, Ji-Youn Han, Myung-Ju Ahn, Byoung Chul Cho, Helena Yu, Sang-We Kim, James Chih-Hsin Yang, Jong Seok Lee, Wu-Chou Su, Dariusz Kowalski, Sergey Orlov, Mireille Cantarini, Remy B Verheijen, Anders Mellemgaard, Lone Ottesen, Paul Frewer, Xiaoling Ou, Geoffrey Oxnard
Journal: The Lancet Oncology (2020)
Long-term outcome after combined carbon-ion radiotherapy and chemotherapy for locally advanced pancreatic cancer.
Authors: Makoto Shinoto, Hidenari Hirata, Hiroaki Suefuji, Shingo Toyama, Minoru Ueda
Journal: Journal of Clinical Oncology (2020)

671 Background: Carbon-ion radiotherapy (C-ion RT) has the potential advantages in terms of improved dose localization and enhanced biological effectiveness compared to conventional radiotherapy or proton therapy. C-ion RT is expected to contribute to the prolongation of survival in patients with pancreatic ductal adenocarcinoma (PDAC). We started C-ion RT for pancreatic cancer at SAGA HIMAT since April 2014. The aim of this study is to evaluate the long-term clinical results of C-ion RT for locally advanced PDAC. Methods: From April 2014 to March 2018, 144 patients with pancreatic cancer were treated with definitive C-ion RT. 80 patients who were confirmed as unresectable locally advanced PDAC were included in this retrospective analysis. C-ion RT was performed with 55.2 Gy (RBE) at 12 fractions in 3 weeks. Overall survival (OS) and prognostic factors were analyzed. Toxicities were evaluated using the CTCAE ver. 5.0. Results: The median follow-up period for survivors was 38 (range 13-59) months from the initiation of C-ion RT. In all patients, planned C-ion RT was completed. Induction chemotherapy was performed in 64 patients (80%) and the median duration time was 3 (range 1-19) months. Seventy patients (86%) underwent concurrent chemotherapy with gemcitabine or S-1. 2y-, 3y-, and 4y-OS from C-ion RT were 47% (95%CI, 37-59%), 25% (95%CI,16-37%), and 18% (95%CI, 10-30%), respectively. 2y-, 3y-, and 4y-OS from initial treatment were 55% (95%CI, 45-66%), 33% (95%CI, 24-45%), and 20% (95%CI, 12-32%). Multivariate analysis showed that PS 1-2, CA19-9 ≥350, and the absence of concurrent chemotherapy were independent prognostic factors on OS. Only seven patients (9%) experienced grade 3 toxicities that were gastrointestinal ulcer/bleeding (n = 4), anorexia (n = 1), leukopenia (n = 1), and neutropenia (n = 1). There was no grade 4 or 5 toxicity. Conclusions: C-ion RT for locally advanced PDAC was effective and well-tolerated.