tbuckley/cabot-search huggingface dataset:
Immune checkpoint inhibitor toxicity in the clinical practice setting.
Authors: Laura Schmidt, Brian McGuire, Wendy Hui, George W. Carro, Thomas A. Hensing, Daniel H. Shevrin, Nicholas Paul Campbell, Britt Erika Hanson, Bruce Brockstein
Journal: Journal of Clinical Oncology (2019)

e14128 Background: Immune checkpoint inhibitors (ICIs) are changing the landscape of treatment in oncology. The use of ICIs is growing rapidly as the indications for these medications broaden and new ICIs become approved. Given the rapid growth and relative infancy of the use of ICIs, much information stands to be gained on their use in the clinical practice setting, especially regarding toxicity. Methods: The primary objective of this project was to examine the incidence and severity of immune-related adverse events (irAEs), after treatment with single-agent or combination ICIs at a multi-site community cancer center. A retrospective chart review was conducted on all patients who had received ipilimumab, nivolumab, pembrolizumab, atezolizumab, or ipilimumab plus nivolumab from May 1, 2011 to June 30, 2017. Data collected included patient demographics, disease state, treatment information, preexisting autoimmune disease, previous immunotherapy, and adverse event details. The results were analyzed using descriptive statistics. Results: Data was collected on 383 patients. Dermatologic irAEs were common across single agent ICIs (overall incidence 23%). Diarrhea and/or colitis incidence was highest with CTLA-4 inhibitor ipilimumab (26% at 3 mg/kg and 22% at 10 mg/kg) versus the other monotherapy PD-1/PDL-1 inhibitors. Endocrinopathies were most common with ipilimumab 10 mg/kg (55%) and pneumonitis incidence was highest with nivolumab (6%). ICI toxicity occurred in 63% of patients with preexisting autoimmune disease versus 54% of those without a baseline autoimmune disease. Incidence of hospitalization and treatment holds due to irAEs was higher with combination therapy (57% and 66%, respectively) than with monotherapy (10% and 24%, respectively). Conclusions: Overall, there was increased incidence in ICI toxicity in patients at this oncology institution versus what has been reported in clinical trials. Patients with preexisting autoimmune diseases appeared to have mainly low-grade toxicities with slightly increased incidence of irAE compared with those without pre-existing autoimmune disease. Treatment holds and hospitalizations were higher in patients treated with combination therapy ICIs compared to monotherapy ICIs.
Randomized trial of text messaging (TM) to reduce early discontinuation of aromatase inhibitor (AI) therapy in women with breast cancer: SWOG S1105.
Authors: Dawn L. Hershman, Joseph M. Unger, Hillyer Grace, Anna Moseley, Kathryn B Arnold, Shaker R. Dakhil, Benjamin Esparaz, Ming C. Kuan, Mark Graham, Douglas M Lackowski, William Jeffery Edenfield, Zoneddy Ruiz Dayao, Julie Gralow, Scott Ramsey, Alfred I. Neugut
Journal: Journal of Clinical Oncology (2019)

6516 Background: Non-adherence to AI’s for breast cancer is common and increases risk of recurrence. Text messaging (TM) has been shown to increase adherence to medications for chronic conditions. We conducted a multicenter randomized trial to evaluate if TM reminders improve AI adherence. Methods: Patients taking an AI for ≥30 days and having ≥36 mos of planned therapy were eligible. Patients were randomly assigned 1:1 to receive either TM or NO-TM twice a week for 36 mos. Randomization was stratified by length of time on prior AI therapy ( &lt; 12 (64%) vs. 12-24 mos (36%)) and AI class (anastrozole, letrozole, exemestane). Content themes of the 36 TMs focused on overcoming barriers to adherence. Patients were assessed for discontinuation of AIs every 3 mos for 36 mos. The primary outcome was time to non-adherence, where non-adherence was defined as urine AI metabolite assay results satisfying the following: &lt; 10 [units], undetectable, or no submitted specimen. A stratified Log-rank test was conducted. Multiple sensitivity analyses were performed using Cox regression. Results: In total, 724 patients were registered between May, 2012 and September, 2013, among whom 696 (338/360 (93.9%) on TM and 338/364 (92.9%) on NO-TM) were eligible and adherent at baseline. Observed (time-independent) adherence at 36 mos was 55.4% for TM and 55.4% for NO-TM. The primary analysis showed no difference in time-to-adherence failure between patients on the TM and NO-TM arms (HR = 0.89, 95% CI:0.76,1.05 p = .18). An analysis of negative urine tests alone resulted in similar non-significant results. With missed appointments not counted as failures, time to self-reported discontinuation (89.6% vs. 89.7%; HR = 1.17, 95% CI:0.69-1.98, p = .57) and site reported discontinuation (78.1% vs. 81.1%; HR = 1.31, 95% CI:0.86-2.01, p = .21) were also similar between the 2 groups. Conclusions: As the first large long-term randomized trial of an intervention directed at improving AI adherence, we found high rates of AI discontinuation. Bi-weekly text reminders did not improve adherence to AIs compared to usual care. Improving long—term adherence will likely require sustained behavioral interventions and support. Clinical trial information: NCT01515800.
Evaluation of Ki67 and other predictors of survival in metastatic neuroendocrine tumor (NET) to the liver treated with Y90 radioembolization.
Authors: Julie Cronan, Bernadette White, Robert Mitchell Ermentrout, Zachary Louis Bercu, Walid Labib Shaib, Janice Newsome, Nima Kokabi
Journal: Journal of Clinical Oncology (2019)

e15687 Background: Ki67 index is a predictor of survival in patients with metastatic neuroendocrine tumor (NET). The purpose of this study is to evaluate Ki67 index and other potential predictors of overall survival (OS) in patients with NET metastases to the liver treated with Y90 radioembolization. Methods: In an institutional review board-approved retrospective study, consecutive patients with NET metastases to the liver who were treated with Y90 radioembolization from 2013-2018 at a single institution were evaluated. Patients with documented Ki67 index were stratified according to 2017 World Health Organization (WHO) grading based on Ki67 index (G1: &lt; 3%, G2: 3-20%, G3: &gt; 20%). Age, gender, and objective tumor response on post Y90 imaging were also evaluated as potential predictors of survival after Y90. Objective tumor response was evaluated at 1 and/or 3 months post Y90 with multiphase MRI utilizing Response Evaluation Criteria for Solid Tumors (RECIST). Overall survival (OS) from time of Y90 was analyzed using Kaplan-Meier estimation. Predictors of survival were evaluated using log-rank test with p &lt; 0.05 as the statistically significant level. SPSS software v. 25 (IBM Corporation, Armonk, NY) was used for all statistical analysis. Results: A total of 77 patients were identified; 36 (47%) had a documented Ki67 index from either their primary tumor, liver metastasis, or both. Primary tumor site included pancreatic (n = 10), small bowel (n = 7), pulmonary (n = 5), gastric (n = 3), large bowel (n = 3), and renal (n = 1). A primary site was not identified in several patients (n = 7).G1 tumors comprised 31% (n = 11) of patients, while G2 and G3 tumors made up 50% (n = 18) and 19% (n = 7) of the cohort, respectively. Median overall survival (OS) of the entire cohort was 51.1 months. Median OS in patients was 63.0 months in G1 tumors, 51.1 months in G2 tumors, and 3.1 months in G3 tumors (p &lt; 0.001). Objective response on initial MRI follow-up after Y90 radioembolization also predicted prolonged OS (51.2 months versus 17.9 months, p &lt; 0.001). Age at time of diagnosis and gender were not predictors of survival after Y90 radioembolization. Conclusions: WHO grading based on KI67 index and objective tumor response appear to be predictors of prolonged survival in patients with metastatic NET to the liver treated with Y90 radioembolization.
Digital Breast Tomosynthesis for Women Older Than 70 Years—Reply
Authors: Ilana B. Richman, Cary P. Gross
Journal: JAMA Internal Medicine (2019)

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Preclinical characterization and efficacy of 4R9, a novel immune checkpoint blockade targeting CEACAM1 for cancer therapy.
Authors: Jae-Chul Lee, Minkyu Hur, Hye-Young Park, EunHee Lee, Hye In Yum, Hye-mi Nam, Mi-Young Oh, HyungSuk Choi, Jae-Hwan Kim, Byoung Chul Cho, Yang-Mi Lim, Jonghwa Won
Journal: Journal of Clinical Oncology (2019)

e14155 Background: CEACAM1 is one of the several immune checkpoint receptors expressed on T cells that mediate suppression of inflammatory T cell response. It is known that CEACAM1-CEACAM1 homophilic interaction induces downregulation of ZAP70 phosphorylation in response to T cell receptor (TCR) stimulation. Also, CEACAM1 is highly expressed on non-small cell lung cancer (NSCLC) and its expression correlated with cancer progression and poor prognosis. We developed a fully human monoclonal antibody 4R9, human CEACAM1-targeting antibody. Methods: T cell activation of 4R9 was determined by NFAT-luciferase reporter assay with CEACAM1 overexpressing Jurkat stable cells. In vitro efficacy of 4R9 was examined using NK-mediated tumor cell killing assay. The anti-tumor efficacy of 4R9 alone or in combination was studied in vivo in a humanized mouse model engrafted with NSCLC patient-derived tumor xenografts. Results: Anti-CEACAM1 antibody 4R9 binds to CEACAM1 overexpressed in HEK293 or Jurkat cells but not to other CEA family members. 4R9 blocks CEACAM1-CEACAM1 homophilic interaction by binding to N domain of CEACAM1. CEACAM1-CEACAM1 homophilic interaction induced downregulation of ZAP70 phosphorylation in response to TCR stimulation in CEACAM1 overexpressing Jurkat stable cell line, which was rescued by 4R9 resulting in augmentation of NFAT activity and IL-2 expression. NK cell-mediated tumor lysis was increased by 4R9 in a CEACAM1 expression-dependent manner. Out of 49 NSCLC tumor tissues, 20 cases exhibited dominant expression of CEACAM1 over PD-L1 with 6 cases showing &gt; 50% of CEACAM1 positivity. In a single mouse trial using NSCLC PDX-huNSG mouse model, 4R9 (20 mpk, 2qW) suppressed tumor progression more than 30% as monotherapy (10/19) as well as in combination (16/22) with pembrolizumab (5 mpk, 2qW). Moreover, PDX of adenocarcinoma origin with more than 50% of CEACAM1 expression were more efficiently prohibited for progression with 4R9, suggesting potential therapeutic use of 4R9 in patients with NSCLC. Conclusions: Anti-CEACAM1 antibody blocked CEACAM1-mediated negative regulation and restored T/NK cell activities. Different expression patterns of CEACAM1 compared with PD-L1 and efficacies in a single mouse trial support the rationale for developing anti-CEAEAM1 antibody as cancer therapeutics.
The inherited variations of a p53-responsive enhancer in 13q12.12 confer lung cancer risk by attenuating TNFRSF19 expression
Authors: Lipei Shao, Xianglin Zuo, Yin Yang, Yu Zhang, Nan Yang, Bin Shen, Jianying Wang, Xuchun Wang, Ruilei Li, Guangfu Jin, Dawei Yu, Yuan Chen, Luan Sun, Zhen Li, Qiaofen Fu, Zhibin Hu, Xiao Han, Xin Song, Hongbin Shen, Yujie Sun
Journal: Genome biology (2019)

Inherited factors contribute to lung cancer risk, but the mechanism is not well understood. Defining the biological consequence of GWAS hits in cancers is a promising strategy to elucidate the inherited mechanisms of cancers. The tag-SNP rs753955 (A>G) in 13q12.12 is highly associated with lung cancer risk in the Chinese population. Here, we systematically investigate the biological significance and the underlying mechanism behind 13q12.12 risk locus in vitro and in vivo.We characterize a novel p53-responsive enhancer with lung tissue cell specificity in a 49-kb high linkage disequilibrium block of rs753955. This enhancer harbors 3 highly linked common inherited variations (rs17336602, rs4770489, and rs34354770) and six p53 binding sequences either close to or located between the variations. The enhancer effectively protects normal lung cell lines against pulmonary carcinogen NNK-induced DNA damages and malignant transformation by upregulating TNFRSF19 through chromatin looping. These variations significantly weaken the enhancer activity by affecting its p53 response, especially when cells are exposed to NNK. The effect of the mutant enhancer alleles on TNFRSF19 target gene in vivo is supported by expression quantitative trait loci analysis of 117 Chinese NSCLC samples and GTEx data. Differentiated expression of TNFRSF19 and its statistical significant correlation with tumor TNM staging and patient survival indicate a suppressor role of TNFRSF19 in lung cancer.This study provides evidence of how the inherited variations in 13q12.12 contribute to lung cancer risk, highlighting the protective roles of the p53-responsive enhancer-mediated TNFRSF19 activation in lung cells under carcinogen stress.
The effects of wheatgrass juice administration in colon cancer patients during adjuvant chemotherapy and the treatment reflection on the extracellular vesicles.
Authors: Gil Bar-Sela, Adva Avisar, Talia Shentzer Kutiel, Miri Cohen, Anat Aharon
Journal: Journal of Clinical Oncology (2019)

e23045 Background: Adjuvant chemotherapy is recommended in stage II-III colorectal cancer (CC). Wheatgrass juice (WGJ), has high nutritional values may attenuate chemotherapy adverse events (AE). Extracellular vehicles (EVs) are subcellular membrane blebs that provide information on cellular processes. Aim: To evaluate the incidence of chemotherapy AE and to elucidate the effects of supportive treatment of WGJ on CC patients’ EVs characteristics. Methods: In a prospective trial between 3/2014- 7/2017, 99 patients stage II-III CC, treated with standard adjuvant chemotherapy were enrolled. According to patient preference, they were divided into: control group of 50 (CC-C) patients and intervention group of 49 patients who received chemotherapy plus consumption of daily 60cc frozen WGJ (CC-W). EVs were isolated from the blood samples of 15 healthy controls (HC) and 25 patients from each study group. Blood samples were taken before, during and at the end of chemotherapy, EVs characterized by membrane antigens/cytokine content Results: Study groups were well balanced. Median follow-up time was 15 months. Eleven patients had died at the time of analysis, 3 in the WGJ and 8 in the control ( p= 0.142). 11/50 (22%) and 8/49 (16.3%) had severe diarrhea in the control and WGJ groups, respectively ( p= 0.47). There was no difference between the groups in RFS (HR = 1.19 , p= 0.69). Higher levels of endothelial EVs (CD34 + 41, CD144), indicating vascular injury, were found in CC-C patients- compared to CC-W during and at the end of treatment. Increased EVs thrombogenicity in patients was documented, while EVs thrombogenicity was lowered in CC-W compared to CC-C during or at the end of treatment (TF, P = 0.029; TF/TF-pathway inhibitor (TFPI) ratio, p = 0.008; endothelial protein C receptor 0.005 and annexin-V 0.05). Following treatment, the majority of growth-factors/pro-inflammatory cytokines were found to be lower in CC-W than in CC-C. Conclusions: Daily consumption of WGJ during chemotherapy may reduce vascular damage and thrombogenicity. There was no statistical difference in overall survival. However, the large difference in death rate may relate to other long-standing effects of daily WGJ consumption. Clinical trial information: NCT01991080.
Lymphodepletion (LD), tumor-infiltrating lymphocytes (TIL) and high (HD-IL2) versus low-dose (LD-IL2) IL-2 followed by pembrolizumab (pembro) in patients (pts) with metastatic melanoma (MM).
Authors: Rodabe Navroze Amaria, Cara L. Haymaker, Marie-Andree Forget, Roland Bassett, Janice N. Cormier, Michael A. Davies, Adi Diab, Jeffrey E. Gershenwald, Isabella Claudia Glitza, Jeffrey Edwin Lee, Anthony Lucci, Jennifer Leigh McQuade, Sapna Pradyuman Patel, Richard Eldon Royal, Merrick I. Ross, Hussein Abdul-Hassan Tawbi, Jennifer Ann Wargo, Michael K.K. Wong, Chantale Bernatchez, Patrick Hwu
Journal: Journal of Clinical Oncology (2019)

9543 Background: TIL adoptive cell transfer (ACT) therapy can produce durable responses for MM pts although efficacy appears lower in the era of checkpoint inhibitors. Toxicities from HD-IL2, including sepsis physiology, limits widespread use of this regimen. Suppression of transferred TIL by either tumor cells or the tumor microenvironment could limit TIL responses. Pembro is known to promote T cell activation, thus, we evaluated the efficacy and safety of TIL with pembro with HD-IL2 versus LD-IL2. Methods: Pts with MM who had tumor harvested and cryopreserved TIL at MD Anderson with PS 0-1 and normal organ function were eligible. All pts received a standard LD regimen consisting of cyclophosphamide and fludarabine, followed by infusion of pooled ex-vivo expanded TIL and either HD-IL2 (Arm 1: 720,000 IU/kg IV q 8 hrs up to 15 doses) or LD-IL2 (Arm 2: 2 million IU SC for 14 d). Pts received pembro 200mg IV starting 21 d post T cell infusion every 3 wks for up to 2 yrs. Pts were randomized 1:1 based on stage and LDH. Paired blood and tumor biopsies were obtained prior to LD, prior to first and second dose of pembro and at time of progression. Results: A total of 36 pts were planned to enroll (18 in each arm); however, the protocol met pre-specified futility boundaries in Arm 1 which prompted early closure after treatment of 14 pts (7 in each Arm). Median age was 50 yrs, 6 were female, 8 had cutaneous melanoma, 2 mucosal, 2 uveal and 2 unknown primary. 86% were stage M1c, 14% M1D, 50% had LDH elevation. Median lines of prior therapy were 3 (range 1-6), including prior anti PD-1 in 13 pts. Best overall response was 1 PR (for 10 mos), 2 SD, 3 PD, 1 NE in Arm 1; 1 PR (ongoing over 36 mos), 1 SD, 5 PD in Arm 2. With median follow up of 9.2 mos, PFS was 3.9 mos for Arm 1 and 2.1 mos for Arm 2 (p = 0.99). Median OS was 9.7 mos for Arm 1 and 8.8 mos for Arm 2 (p = 0.71). Toxicity was similar in both Arms but with lower rates of grade 3 febrile neutropenia (57% vs. 71%) and shorter hospital stay (median 16 vs. 18 d) in Arm 2 vs. Arm 1. Conclusions: In a heavily treated pt population, TIL with pembro achieved low response rates. Use of LD-IL2 did not diminish efficacy and may be better tolerated than HD-IL2 for TIL ACT. Correlative studies are ongoing to determine mechanisms of treatment response and failure. Clinical trial information: NCT02500576.
iMETX (Individualized Metabolic RX): An environmental intervention to increase energy expenditure in breast cancer survivors.
Authors: Tarah Jean Ballinger, Sandra K. Althouse, Timothy P. Olsen, Kathy Miller, Jeffrey Sledge
Journal: Journal of Clinical Oncology (2019)

e23060 Background: Despite survival and quality of life benefits associated with physical activity (PA), many breast cancer survivors remain inactive. Effective, sustainable PA interventions must account for individual differences in capability, motivation, and environment. iMETX evaluated the feasibility, mechanics, and efficacy of delivering an individualized, dynamic intervention to increase energetic capacity and energy expenditure in breast cancer survivors. Methods: Stage 0-III breast cancer pts who had completed primary treatment were enrolled. Baseline PA patterns were collected using a wearable GPS/accelerometer for 4 weeks pre- intervention. Detailed movement data collection continued throughout the 12- week intervention, during which pts received tailored PA “prescriptions” every 1-3 days from an interactive web application, adjusted based on individual capability and environment to achieve pre- determined energy endpoints. Baseline and post- intervention, energetic capacity was assessed by power generation using a stationary bicycle protocol feasible in the clinic setting over a range of physical capabilities. Body composition by DEXA and quality of life questionnaires were collected. Results: 56 of 57 enrolled pts completed the intervention (98%). Median age was 60 (range 38 – 82), and pts were an average of 5.25 yrs from diagnosis (range 0.5 – 21 yrs). In the total population, energetic capacity (Watts/kg lean mass) increased significantly from 1.75 to 1.99 W/kg (p &lt; 0.01) post- intervention. Separated by baseline energetic capacity, the lowest performing tertile improved significantly (0.76 to 1.12 W/kg, p &lt; 0.01), while the highest performing tertile did not (2.75 to 2.96 W/kg, p = 0.30). Physical and functional well-being also improved (FACT-B TOI, pre: 72.26, post: 74.66, p = 0.02). Conclusions: iMETx is a feasible PA intervention with high adherence rates. Individualized PA prescriptions allowing pts to move in their typical environment resulted in improved energetic capacity and well- being. Results were particularly significant in those with the lowest baseline energetic capacity, a population most in need of effective and accessible PA interventions. Clinical trial information: NCT03158519.