tbuckley/cabot-search huggingface dataset:
Phase 1/1B trial to assess the activity of entrectinib in children and adolescents with recurrent or refractory solid tumors including central nervous system (CNS) tumors.
Authors: Giles W. Robinson, Amar J. Gajjar, Karen Marie Gauvain, Ellen M. Basu, Margaret E Macy, Luke Devon Maese, Amit J. Sabnis, Jennifer Haunani Foster, Suzanne Shusterman, Janet Yoon, Brian D. Weiss, Mohamed Abdelbaki, Mufiza Farid-Kapadia, Georgina Meneses-Lorente, Alison Cardenas, Katherine Hutchinson, Guillaume Bergthold, Edna Chow Maneval, Elizabeth Fox, Ami Vijay Desai
Journal: Journal of Clinical Oncology (2019)

10009 Background: Entrectinib is a CNS-penetrant oral inhibitor of TrkA/B/C, ROS1 and ALK tyrosine kinases. We report the efficacy of entrectinib in children with recurrent/refractory solid or CNS tumors. Methods: Patients ≤ 20y old with recurrent/refractory solid tumors were eligible. After determination of the recommended dose in all-comers, disease-specific expansion cohorts of CNS and solid tumors harboring target aberrations in NTRK1/2/3, ROS1 or ALK, and neuroblastoma (NBL), regardless of mutation spectrum, were enrolled. Response, assessed by Investigator, was classified as complete response (CR), partial response (PR), stable disease (SD) or progressive disease (PD) using RANO for CNS tumors, RECIST for solid tumors, and Curie score for NBL. Results: Between May 2016 and October 2018, 29 patients aged 4.9m–20y (median 7y) were enrolled and 28 were evaluated for response. Entrectinib was well tolerated. Dose limiting toxicities were elevated creatinine, dysgeusia, fatigue and pulmonary edema. The recommended dose was 550 mg/m 2 daily. All responses occurred at doses ≥ 400 mg/m 2 . In CNS tumors (n = 6), all high-grade with gene fusions: 1 achieved a CR ( ETV6-NTRK3); 3 achieved a PR ( TPR-NTRK1, EEF1G-ROS1, EML1-NTRK2); 1 achieved an unconfirmed PR ( GOPC-ROS1); and 1 has yet to be evaluated ( KANK1-NTRK2). In extracranial solid tumors (n = 8), 6 had a fusion of whom 1 achieved a CR ( DCTN1-ALK) and 5 achieved a PR ( TFG1-ROS1, EML4-NTRK3, ETV6-NTRK3, KIF5B-ALK, ETV6-NTRK3). In NBL (n = 15): 1 achieved a CR ( ALK F1174L). Median duration of therapy was 85d (6–592d) for all patients; 56d (6–338d) for non-responders; and 281d (56–592d) for responders. Median time to response was 57d (30–58d). Conclusions: Entrectinib produced striking, rapid and durable responses in all children with refractory CNS and solid tumors harboring NTRK1/2/3, ROS1 or ALK fusions (11 out of 11) as well as in an ALK-mutated NBL. No responses were seen in tumors lacking aberrations in target kinases. These results support the continued evaluation of entrectinib as a targeted therapeutic in solid tumors with NTRK1/2/3, ROS1 and ALK fusions, especially in high-grade CNS neoplasms. Clinical trial information: NCT02650401.
Previsit breast cancer educational microlearning videos: Impact on patient satisfaction and engagement.
Authors: Rachel M Hurley, Kirk Wyatt, Rachel F Johnson, Michael W O'Brien, Wendy J Zenz, Stacy R Anderson, Cheryl A Brugger, Kathryn Jean Ruddy, Judy Caroline Boughey, Sandhya Pruthi
Journal: Journal of Clinical Oncology (2019)

6526 Background: Most patients diagnosed with breast cancer turn to the Internet to learn about their diagnosis; however, information online is often generic, challenging to navigate, and not expert-curated. To facilitate patient education and engagement in our breast clinic, we piloted the implementation of pre-visit education via brief microlearning videos organized within an online platform. Methods: Seventeen videos of 2-4 minute duration were developed by multidisciplinary content experts. Videos covered a variety of educational topics relevant to breast cancer, including treatment options. Patients received a link via email to create an account, which provided access to the platform. Aggregate viewing data and optional patient surveys (online after viewing 3 videos and at the clinical appointment) were used to assess opt-in rates, engagement, and satisfaction. Results: Between September 2018 and January 2019, 57.4% (240/418) of women with biopsy proven breast cancer who were sent an email invitation registered on the platform. On average, patients watched 11 of the 17 videos, with 93.7% of users (225/240) viewing at least one. Overall, 85% (168/198) of women recommend the microlearning format for patient education. The most-viewed video topics included types of breast cancer, breast abnormality and biopsy, understanding biopsy results, tumor markers, and staging. Seventy-eight percent (154/198) of women reported that they planned to share the videos with family or caregivers, and 67% (133/198) felt that the educational content increased their satisfaction with their overall experience. Barriers to video access were emails marked as junk, not having an email address, and difficulties with videos loading. Conclusions: The majority of patients participating in this pilot registered on the platform and watched pre-visit microlearning educational videos. These expert-curated videos contributed to high levels of satisfaction and engagement. Strategies to overcome barriers to access will be developed to expand the reach of this new valuable component of breast cancer care.
CDK 4/6 inhibitors (CDKi) + endocrine therapy (ET) in ER-positive metastatic breast cancer (mBC) patients according ET sensitivity: A systematic review and meta-analysis.
Authors: Michela Piezzo, Maria Riemma, Daniela Cianniello, Roberta Caputo, Giuseppina Fusco, Germira Di Gioia, Ivana Cerillo, Marina Licenziato, Gaetano Buonfanti, Stefania Cocco, Vincenzo Di Lauro, Michelino De Laurentiis
Journal: Journal of Clinical Oncology (2019)

e12532 Background: Addition of CDKi to ET in ER-positive mBC has proven effective in improving both progression-freesurvival (PFS) and Objective Response Rate (ORR). However, no randomized clinical trial (RCT) has so far shown a significant increase of Overall Survival (OS). We carried out a metanalysis of all RTCs to better characterize the efficacy of CDK4/6i in some relevant subgroups, with particular reference to OS. Methods: Literature search of main databases was carried out up to 08 Dec 2018. Hazard ratios (HRs) for PFS and OS and risk ratios (RRs) for ORR were extracted/calculated for each trial and then pooled by using both fixed and random effect model. Confidence intervals (CIs) at 95% were calculated for each statistics. Kaplan-Meier meta-curves were generated by pooling data of all trials, among ET sensitive and ET resistant pts. Results: Eight RCTs were included accounting for a total of 4580 pts, 2802 receiving a CDKi (palbociclib, ribociclib or abemaciclib) in association with ET (NSAI, tamoxifene or fulvestrant) and 1778 receiving ET alone or plus placebo. Pooled analysis of HRs showed a significant improvement in PFS, regardless ET sensitivity, disease site, number of metastatic sites and treatment free interval. Analysis of OS included 3 RCTs with a total of 1243 pts and showed a statistically significant improvement of OS (HR 0.769 [95% CI 0.638, 0.926], p-value 0.006). Pooled estimate for RR showed higher ORR in CDK 4/6 arm both in ET sensitive (RR 1.35 [95% CI 1.19, 1.52]) and ET resistant group (RR 2.19 [95% CI 1.66, 2.89]). Similarly, pts with measurable disease showed a RR of 1.34 (95% CI 1.20, 1.50) in ET sensitive group and 2.26 (95% CI 1.72, 2.96) in ET resistant group. Pooled survival curves showed an absolute benefit in PFS, both in ET sensitive (median PFS: NR vs 15 months) and ET resistant (median PFS: 19.2 vs 8.9 months). Conclusions: Our findings suggest that addition of CDKi to ET improve clinical outcome in terms of PFS, ORR and OS, irrespective of pts/tumor characteristics.
Effect of acid-reducing agents on the efficacy of capecitabine in metastatic gastrointestinal cancers.
Authors: Tonjeh Mary Stella Bah, Jill Comeau, Andrea Clarke, Arelis Robinson, Amanda Storer, Runhua Shi, Mindie Michelle Kavanaugh
Journal: Journal of Clinical Oncology (2019)

e15058 Background: Recent retrospective and subgroup analyses have evaluated the effects of capecitabine with acid-reducing agents both in the adjuvant setting for colon cancer and in the palliative setting for stage IV gastroesophageal malignancies. Efficacy outcomes in these studies are contradictory. Acid-reducing agents are thought to reduce the absorption of capecitabine by increasing gastric pH leading to a concern of decreased efficacy. Studies thus far have not included stage IV colorectal cancers, a common population who receives capecitabine-based regimens. Methods: We conducted a retrospective chart review of patients diagnosed with stage IV Gastro Intestinal (GI) cancers treated with capecitabine-based therapies between 2012 and 2018. Electronic health records were used for data collection. Descriptive statistics and COX regression model were utilized for data analysis. Results: Of the 249 charts that were screened for inclusion, 58 were included in this review. Thirty-eight (65.5%) had a diagnosis of colon cancer, 11 (19%) had rectal cancer, and 9 (15.5%) had other GI malignancies. The most common capecitabine-based regimens included XELOX alone (29%) or with bevacizumab (36%). During capecitabine treatment, 20 (34.5%) patients received concomitant acid-reducing therapy. This included 19 patients taking a PPI and 1 patient taking a H2 Inhibitor. Patients who did not receive acid-reducing therapy had a 1-year PFS of 23.7% compared to 25% in patients who did not, (HR 0.55, p = 0.46). The 1-year OS was 68.4% in the non-acid-reducing agent group and 60% in the patients who did receive acid-reducing agents during capecitabine treatment, respectively (HR 0.17, p = 0.68). Conclusions: Receiving acid-reducing agents concomitantly with capecitabine-based regimens appears to not have an effect on 1-year PFS or OS in patients with Stage IV GI cancers. These outcomes may have been affected by the sample size, incomplete home medication lists, and compliance issues with capecitabine. Larger population studies are needed to validate these findings and identify the significance of utilization of acid-reducing agents in patients with Stage IV GI cancers receiving capecitabine.
Prognostic significance of NLR kinetics in operable triple negative breast cancer.
Authors: Ranga Raman Ganta, Srividya Nasaka
Journal: Journal of Clinical Oncology (2019)

e14201 Background: Inflammatory response exacerbates mechanisms linked to tumor growth and dissemination. As an index of systemic inflammatory marker, neutrophil lymphocyte ratio (NLR) may be a predictive biomarker of both prognosis and outcome in several malignancies. However very few reports have addressed the association of change in NLR and outcome in operable breast cancer. We evaluated preoperative NLR and postoperative NLR to assess which one would be predictive of disease outcome in triple negative breast cancer patients. Methods: This study included 67 stage I-III triple negative breast cancer patients diagnosed at HCG Cancer center, between 2013 to 2015. Those patients who underwent upfront surgery were included in the study. Patients who received neoadjuvant chemotherapy and those without adequate medical records were excluded. The NLR was calculated from the differential count by dividing neutrophil percentage with lymphocyte percentage. All preoperative NLRs were calculated from medical records, at the first visit. Postoperative NLR was obtained before first cycle chemotherapy. The NLR was divided into high if ratio is &gt; 3 and low if it is ≤ 3. We evaluated prognostic value of NLR on 3 year DFS. Results: The median preoperative NLR was 2.52 (Range 0.77-8.6). The pre op NLR was high in 19 patients (28%) and low in 48 patients (72%). There was no significant difference between two groups in baseline characteristics. Among the preoperative High and low NLR groups, 3 year DFS is statistically significant. The median postoperative NLR was 2.23 (Range 0.89-8.1). The post operative NLR was high in 7 patients (11%) and low in 60 patients (89%). Among the postoperative High and low NLR groups, 3 year DFS is statistically not significant. The 12 (63%) patients in the high preoperative NLR patients were converted to of the low NLR after surgery. Conclusions: Preoperative NLR correlated with outcome in operable triple negative breast cancer than postoperative NLR. The NLR kinetics might be an index of response to the treatment which needs to be evaluated in prospective studies. Drawbacks of the study: single centre, retrospective study and small sample size.[Table: see text][Table: see text]
Prognosis value of a genetic score based on germline genetic variants in a prospective cohort of early triple-negative breast cancer patients.
Authors: Elsa Curtit, Julie Henriques, Sophie Paget-Bailly, Sylvain Ladoire, Ariane Darut-Jouve, Marc Debled, Gilles Romieu, Claire Garnier-Tixidre, Jean-Philippe Jacquin, Patrick Soulie, Christelle Jouannaud, Maria Rios, Thierry Petit, Thomas Denis Bachelot, Céline Faure-Mercier, Laetitia Gambotti, Hélène Blanché, Jean-Francois Deleuze, David Cox, Xavier Pivot
Journal: Journal of Clinical Oncology (2019)

1529 Background: Triple-negative breast cancers (TNBC) are a heterogeneous group of tumors with poor outcome. In this study, the association between germline genetic variants and invasive disease-free survival (iDFS) was analyzed in TNBC patients. Methods: A genome wide-association study (GWAS) aimed to identify variants (single nucleotide polymorphisms – SNPs) associated with prognosis in 1121 patients with TNBC in the SIGNAL prospective cohort. Associations between gene variants and iDFS were assessed in univariate Cox regression models. Variants were combined in a score to identify risk categories. A prognostic model based on breast cancer stage and genetic variants was estimated using a multivariate Cox regression. Interaction between stage and genetic score was tested. Discrimination of the model was assessed by the Harrell’s C statistic and internal validity by bootstrap method. Results: The characteristics of the 1121 patients were representative of a population with early TNBC. Four SNPs on chromosomes 9 and 2 were found significantly associated to iDFS in univariate Cox models. Homozygous status for the most frequent allele was associated with poorer iDFS for two SNPs and this status was present in 50% and 57% of the population. For the two other SNPs, the most frequent allele was associated with more favorable iDFS. Three prognostic categories were derived from the genetic score. The following table presents the results from the multivariate Cox model including genetic score and disease stage. Clinical trial information: RECF1098. Conclusions: In a prospective cohort of 1121 patients with early TNBC, 4 genetic variants (SNPs) were associated with iDFS. A score involving SNPs provided similar prognostic indications as breast cancer stages. A search assessing the function and the role of the involved genes is ongoing.[Table: see text]
Association of plasma DNA repair deficient (DRD) status with clinical outcome of metastatic castration-resistant prostate cancer (mCRPC) patients (pts) treated with abiraterone acetate (AA) plus prednisone/dexamethasone (+P/D).
Authors: Dong Shen, Shibu Thomas, Florence Lefresne, Michael Gormley, Karen Urtishak, Marjolein Lahaye, Bertrand F. Tombal, Axel S Merseburger, Trilok V. Parekh, Deborah S. Ricci, Gerhardt Attard
Journal: Journal of Clinical Oncology (2019)

5066 Background: Somatic DRD deficiency in 15-30% of mCRPC pts have been observed and inhibition of enzyme poly ADP ribose polymerase (PARP) could prove beneficial. We aimed to define DRD status using plasma from pts treated on AA and evaluate associations with prospectively-collected outcome measures. Methods: Plasma DNA samples (128 baseline [BL], 134 cycle 2 day 1 [C2D1], 46 progression [PROG]) from chemotherapy-naïve mCRPC pts in a phase 2 study (NCT01867710) evaluating AA+P/D were subjected to custom target-capture next-generation sequencing. DRD assay was optimized and validated to detect pathogenic point mutations, small insertions/deletions, and copy number alternations (DRD+) in 8 DRD genes: BRCA1, BRCA2, FANCA, ATM, CHEK2, HDAC2, BRIP1, and PALB2. Analysis for genomic aberrations was a secondary exploratory objective. Associations with overall survival (OS), progression-free survival (PFS), and radiographic PFS (rPFS) were assessed using Cox regression models and Kaplan Meier analyses. Results: 11.7% of BL and 17.4% of PROG were DRD+. Bi-allelic was observed in 73.3% of BL DRD+ samples. Shorter PFS was observed in BL DRD+ vs DRD- (5.3 vs 15.5 mo; HR: 2.32; 95%CI:1.39-4.28; P &lt; 0.002). Median PFS for BL DRD biallelic + vs DRD biallelic- was 5.1 vs 15.4 mo (HR: 2.49; 95% CI: 1.23-4.38; P &lt; 0.0095). For multivariate analysis using DRD+, ALP, and LDH as covariates, DRD+ (HR: 2.1; 95% CI: 1.18-3.75; P &lt; 0.012) and high ALP (HR: 1.66; 95% CI: 1.08-2.56; P &lt; 0.021) were strongly associated with worse PFS. Median OS for BL DRD+ vs DRD- was 28.8 vs 41.3 mo (HR: 1.67; 95%CI:0.88-3.18; P = 0.116). Median rPFS for BL DRD+ vs DRD- was 16.2 vs 20.9 mo (HR: 1.64; 95%CI:0.83-3.21; P = 0.152). Of 39 Pts with BL, C2D1 and PROG samples, 3 were DRD+ (7.7%) at all 3 timepoints, 3 (7.7%) only at BL, 3 (7.7%) only at PROG (bi-allelic), 2 (5.1%) had extra deletion at PROG. Conclusions: Patients with mCRPC harboring DRD+ have worse outcomes with AA and represent a population with an unmet medical need.
Evaluation of monovalent versus biparatopic CD3xPSMA bispecific antibodies for t-cell mediated killing of prostate tumor cells with minimal cytokine release.
Authors: Ben Buelow, Starlynn Clarke, Kevin Dang, Jacky Li, Chiara Rancan, Yuping Li, Preethi Sankaran, Duy Pham, Aarti Balasubramani, Laura Davison, Katherine Harris, Brett Jorgensen, Ute Schellenberger, Nathan Trinklein, Harshad Ugamraj, Lawrence Fong, Wim Van Schooten, Shelley Force Aldred
Journal: Journal of Clinical Oncology (2019)

e16519 Background: Castration resistant prostate cancer (CRPC) remains an incurable disease and new treatments are needed. Therapies directed against Prostate specific membrane antigen (PSMA) -such as radiolabeled antibodies, chimeric antigen receptor T cells (CAR-Ts) and T-cell engaging bispecific antibodies (T-BsAbs)- have shown promising efficacy but also induce significant toxicity. In particular T-cell redirection leads to efficient killing of tumor cells but induces cytokine release-related toxicities. We have developed a panel of monovalent and biparatopic CD3xPSMA bispecific antibodies that eliminate prostate tumor cells while minimizing cytokine release. Methods: Antibodies targeting CD3 and PSMA were generated in transgenic rats (UniRat™, OmniFlic™) followed by deep sequencing of the antibody repertoire from draining lymph nodes in immunized animals, and high-throughput gene assembly/expression. PSMA x CD3 T-BsAbs were assembled and evaluated for stability, pharmacokinetics, and T cell activation and ability to eliminate PSMA+ tumor cells in vitro and in vivo. Results: Bispecific CD3xPSMA Abs. incorporating either monovalent or biparatopic anti-PSMA binding domains activated T-cells in the presence of PSMA (plate-bound or cell surface), while no T cell activation occurred in the absence of either PSMA antigen or bispecific antibody. Potent/selective cytotoxicity against PSMA+ cells was observed in co-cultures of primary human T cells and tumor cells treated with CD3xPSMA T-BsAbs. Similar results were observed in in vivo Xenograft models of prostate cancer. Strikingly, CD3xPSMA bispecifics containing a novel low affinity anti-CD3 domain produced similar levels of tumor cytotoxicity compared to those with a traditional high affinity anti-CD3 domain, but with reduced cytokine production. Conclusions: We have created novel CD3xPSMA bispecific antibodies incorporating both monovalent and biparatopic anti-PSMA binding domains that mediate T-cell killing of PSMA+ tumor cells with minimal production of cytokines. Such T-BsAbs may improve safety, efficacy, and opportunities for combination therapy to treat CRPC.
Effect of ligand binding domain activating mutations of ESR1 on cellular metabolism, liver tropism, and chemotherapy resistance.
Authors: Ido Wolf, Lotem Zinger, Keren Merenbakh-Lamin, Anat Klein Goldberg, Adi Elazar, Shani Journo, Tomer Boldes, Marwa Taya, Metsada Pasmanik-Chor, Avishay Spitzer, Tami Rubinek
Journal: Journal of Clinical Oncology (2019)

e14506 Background: Mutations in the ligand binding domain (LBD) of estrogen receptor α (ER) confer constitutive transcriptional activity and resistance to endocrine therapies in breast cancer patients. Accumulating clinical data suggest adverse outcome for patients harboring tumors expressing these mutations. We aimed to elucidate mechanisms conferring this aggressive phenotype. Methods: Cells constitutively expressing physiologic levels of ER harboring activating LBD mutations were generated and characterized for viability, invasiveness and tumor formation in vivo. Gene expression profile was studied using RNAseq. Metabolic properties were assessed using global metabolite screen and direct measurement of metabolic activity. Response to chemotherapies was assessed using viability assays. Results: Cells expressing mutated ER showed increased proliferation, migration and in vivo tumorogenicity compared to cells expressing the WT-ER, even in the presence of estrogen. Experiments in mice revealed a more aggressive phenotype of the Y537S mutant compared to D538G as well as unique tissue predilection. Thus, 538G-ER cells exhibited liver tropism while Y537-ER cells mainly metastasized to the lungs and lymph nodes. Importantly, both mutations conferred resistance to paclitaxel and doxorubicin. Further studies indicated association of the mutated ER with upregulation of genes involved in tumor cell metabolism. Indeed, a global metabolic screen revealed distinct metabolic profile for cells harboring activating mutations, including the ability to utilize glutamine as an alternative carbon source. Moreover, we observed unique metabolic activities enabling cells to thrive in urea-reach environment of the liver, and overcome doxorubicin-induced stress responses. Conclusions: Taken together, these data indicate estrogen-independent rewiring of breast cancer cell metabolism by LBD-activating mutations, enabling aggressivene clinical behavior and chemotherapy resistance. Importantly, These unique metabolic activities may serve as a potential vulnerability and aid in the development of novel treatment strategies to overcome endocrine resistance.