tbuckley/cabot-search huggingface dataset:
Correlation of expression of TK1 in plasma-derived exosomes with clinical response to CDK4/6 inhibitors in breast cancer.
Authors: Marzia Del Re, Andrea Fontana, Stefania Crucitta, Ilaria Bertolini, Eleonora Rofi, Claudia De Angelis, Lucrezia Diodati, Diletta Cavallero, Barbara Salvadori, Alfredo Falcone, Riccardo Morganti, Romano Danesi
Journal: Journal of Clinical Oncology (2018)

12037 Background: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) improve PFS in patients with hormone receptor positive (HR+) advanced breast cancer (1). In order to better characterize the response to these agents and increase our knowledge on the pharmacogenetic profile of CDK4/6i, the aim of this study was to analyse the expression of targets relevant to the activity of CDK4/6i in plasma-derived exosomes. Methods: Blood samples were collected from patients affected by HR+, HER2- advanced breast cancer receiving a palbociclib in association with hormonal therapy. Three ml of plasma were taken at the beginning of treatment (baseline) and at the first clinical evaluation (after 3 months). Objective responses were defined following the RECIST criteria v.1.1. RNA from plasma-derived exosomes was extracted by the ExoRNeasy kit (Qiagen) and analysed for the expression of thymidine kinase 1 (TK1), CDK 4, 6 and 9 by digital droplet PCR (BioRad). Mann-Whitney test was applied. Results: Thirty-eight metastatic breast cancer patients were prospectively enrolled in this study. The comparison of mRNA levels of TK1, CDK4, 6 and 9 between baseline and the first clinical evaluation was available in 5 patients treated with letrozole + palbociclib and 11 patients given fulvestrant + palbociclib. Eight patients had newly diagnosed advanced breast cancer while 9 patients received > = 1 line of treatment. Objective responses were: 2 (12%) PR, 12 (70%) SD and 3 (18%) PD. The comparison of the expression between TK1, CDK 4, 6 and 9 at baseline and at first evaluation was statistically significant for TK1 (PR+SD vs PD p = 0.048). No association was found between the baseline levels of TK1, CDK 4, 6 and 9 and best response or number of disease sites. Conclusions: Exosomal TK1 expression may be useful to early identify patients who are likely to respond to CDK4/6i. Reference: Finn RS, et al. New England Journal of Medicine. 2016;375(20):1925-36.
Korean Cancer Patients’ Awareness of Clinical Trials: Perceptions on the benefit and willingness to participate.
Authors: Yoojoo Lim, Jee Min Lim, Won Jae Jeong, Kyung-Hun Lee, Bhumsuk Keam, Tae-Yong Kim, Sae-Won Han, Tae Min Kim, Do Youn Oh, Dong-Wan Kim, Se-Hoon Lee, Tae-You Kim, Dae Seog Heo, Yung-Jue Bang, Seock-Ah Im
Journal: Journal of Clinical Oncology (2016)

10067 Background: Patients’ proper understanding and consent to participate are crucial for successful conduction of clinical trials (CT). We have conducted a survey, to assess the current patients’ understanding, perception and willingness to participate in CTs. Methods: From December 2012 to August 2015, we have distributed questionnaire to cancer patients receiving chemotherapy at Seoul National University Hospital, Seoul, Korea. The questionnaire was composed of questions assessing patient’s levels of awareness of CT, perception of benefit/risk, and willingness to participate in CTs and the reasons for or against, as well as their demographic information. The level of awareness and perception of benefit/risk was assessed quantitatively, using visual analogue scale (VAS), scored from 0 to 10. Results: A total of 397 out of 520 requested patients (76.3%) responded to the survey. Among the 397 patients, 62.5% were female and median age was 52 years. 97.4% (387/397) answered that they have at least heard of CTs before. When asked for level of awareness, 23.8% (92/387) answered that they could more than roughly explain about CTs. The average VAS score of CT benefit in all patients was 6.43±2.20. The average score in patients who were only roughly aware of CT (VAS 1-6) was lower than that of patients who were unfamiliar with CT at all (VAS 0) (6.24±2.44 vs. 7.00±2.00, p < 0.001). On the question about willingness to participate in CTs, 56.7% (225/397) answered positively. Heavily treated patients showed more willingness to participate (p < 0.001), although they did not show more positive perception of benefit towards CTs. The perception of benefit of CTs were higher in the group willing to participate (p = 0.026). Willingness was not associated with perception of risks of CTs or other demographic factors including socioeconomic status. Conclusions: Although most of patients were familiar of CTs, a large proportion did not have accurate concept. The patients who had only rough idea of CTs had the least positive perception of CTs. Proper public education and patient explanation may improve the patients’ perception and eventually accrual rate to CTs.
Abstract 19809: Heparin Binding EGF-Like Growth Factor (HB-EGF) is a Novel Regulator for Hyperlipidemia
Authors: Sangderk Lee, Richard Lee, Mark Graham, Debra Rateri, Ryan Temel, Aldons J Lusis, Judith A Berliner
Journal: Circulation (2016)

Objective: Elevation of ApoB-containing lipoproteins in circulation a well-established risk factor for the development of cardiovascular diseases. HB-EGF, which is an endogenous ligand of EGFR and ...
Circulating tumor DNA profiling to identify patients with metastatic colorectal cancer with improved overall survival following Sym004 treatment.
Authors: Thomas Tuxen Poulsen, Michael Kragh, Cliff Ding, Mikkel W Pedersen, Trine Lindsted, Thorarinn Blondal, Rodrigo Dienstmann, Clara Montagut, Ivan David Horak, Scott Kopetz, Josep Tabernero
Journal: Journal of Clinical Oncology (2018)

e15577 Background: Sym004, an antibody mixture targeting EGFR, has demonstrated promising activity in patients (pts) with anti-EGFR refractory metastatic colorectal cancer (mCRC). A Phase 2b trial evaluating Sym004 activity in 254 patients with mCRC was recently completed. Methods: All patients had RAS wild type tumors at the time of initial diagnosis and had responded to and subsequently relapsed on anti-EGFR antibody treatment. Baseline circulating tumor (ct)DNA profiles were obtained from 193 patients and analyzed for genomic changes using Guardant360 (Guardant Health). Results: Markers of anti-EGFR resistance such as KRAS mutations were confirmed to impact overall survival (OS) in Sym004 treated pts. A subset of pts without high allele frequency RAS mutations and BRAF V600E mutation in ctDNA termed Double Negative (DN)mCRC, was found to have an OS benefit of 3.5 months when receiving Sym004 compared to Standard of Care (SoC) (HR 0.71; p = 0.134). Further exclusion of patients with mutations in the EGFR extracellular domain (ECD) termed Triple Negative (TN) mCRC increased OS benefit of Sym004 vs. SoC to 5.5 months (HR 0.59; p = 0.044). Patients with detectable mutation in the EGFR-ECD not only had a higher number of genomic alterations but also strikingly heterogeneous and complex genomic profiles including multiple markers of anti-EGFR resistance such as subclonal BRAF, KRAS, NRAS, MAP2K1, or PIK3CA mutations, as well as ERBB2, KRAS, MET, or EGFR copy number gain/amplification. Preclinical studies demonstrated partial loss of Sym004 activity against EGFR-ECD mutated cells due to diminished binding of one of the Sym004 antibodies to the mutated receptor. Conclusions: The heterogeneous mutation landscape in patients with EGFR-ECD mutations as well as the partially impaired function of Sym004 against mutated receptors argues against the use of Sym004 for treatment of this patient subpopulation. Collectively, our data demonstrate that anti-EGFR refractory mCRC patients with DNmCRC and/or TNmCRC assessed by ctDNA are likely to benefit from Sym004 treatment, supporting a randomized registration trial in this genomically defined patient population.
The prognostic significance of Notch 1 intracellular domain nuclear levels in head and neck squamous cell carcinoma.
Authors: Theodoros Rampias, Margaritis Avgeris, Maria Vassilakopoulou, Veronique Neumeister, Nikos Haralambakis, Panagiota Economopoulou, Lambrini Tsoutsi, Amanda Psyrri
Journal: Journal of Clinical Oncology (2016)

6061 Background: An impressive finding of whole-exome sequencing studies in head and neck cancer is a high incidence of loss-of-function mutations within the NOTCH1gene. The vast majority of these mutations occurred at the ligand binding domains and were predicted to inhibit the proteolytic cleavage of Notch1 receptor and the translocation of its intracellular domain (Notch1ic) to nucleus. Our aim was to investigate the prognostic significance of nuclear Notch1ic for HNSCC. Methods: Nuclear Notch1ic protein levels were evaluated in tumors in a cohort of 101 HNSCC patients using automated quantitative protein analysis (AQUA). Our immunofluorescence protocol was optimized to detect only the Notch1ic and also to create a cytoplasmic tumor mask for the strict quantification of Notch1ic levels that have translocated to nucleus. The objectives were to determine the association of nuclear Notch1ic with efficacy outcomes, in terms of patients' overall survival (OS) and disease-free survival (DFS), by Kaplan-Meier and Cox proportional regression analysis. Results: Median follow-up time was 90 months. Survival analysis highlighted the favorable prognostic significance of nuclear Notch1ic levels for patients’ outcome. Superior DFS and significantly lower risk for disease relapse was revealed for the patients with higher nuclear Notch1ic levels by Kaplan-Meier (p = 0.006) and univariate Cox regression analysis (HR: 0.398; 95% CI: 0.201-0.790; p = 0.008). Moreover, multivariate Cox regression models, adjusted for age, tumor stage, grade, nodal status, alcohol consumption, smoking behavior, age and gender highlighted the independent prognostic value of nuclear Notch1ic (HR: 0.304; 95% CI: 0.131-0.706; p = 0.006) for the favorable DFS of the patients. Finally, a trend between nuclear Notch1ic and OS of HNSCC patients was also observed. Conclusions: In the nucleus, Notch1ic binds the DNA binding protein RBPJ and recruits MAML resulting in formation of the NOTCH coactivator complex that activates transcription of genes involved in cell-cycle control and differentiation. Therefore, HNSCCs that retain nuclear Notch1ic levels may represent a district subgroup of tumors with less aggressive behavior.
Impact of multidisciplinary discussion on therapeutic decision in cancer patients: a prospective observational study.
Authors: Carla Pires Amaro, Larissa Gomes, Daniel Almeida, Kelly Reiner, Gustavo Fernandes Godoy Almeida, Marcelo Rocha S Cruz
Journal: Journal of Clinical Oncology (2017)

e18243 Background: Continued and rapid evolution of diagnosis and staging methods along with the development of new treatments has changed decision-making process of cancer patient into a more complex task. We evaluated the impact of multidisciplinary tumor board meetings (MTM) in the final decision of cancer patients approach in comparison to the initial decision based on clinical oncologist’s individual choice. Methods: Between April 2016 and January 2017, data were collected prospectively during the MTM held daily at the Antônio Ermírio de Moraes Cancer Center, Sao Paulo, Brazil. Data were gathered by filling out a questionnaire. The therapeutic plan initialy proposed by the physician was compared to the proposal offered by the multidisciplinary team. We evaluated data from breast, gastrointestinal (GI) and lung cancer MTM. Results: We evaluated 100 questionnaires: 39% GI tumors, 34% lung cancer, 27% breast cancer. The main theme for discussion was selection of systemic therapy (65%). The rate of change in therapy choice was 24.6%. The recommendation suggested by the MTM surgeons and radio-oncologists showed disagreement with the one initially proposed in 21 cases. The majority of discordant cases was related to the choice of therapeutic method (57%) with 42% changes in the chemotherapy protocol. Eight patients were submitted to genetic test and mutations search. Only two cases were recommended for clinical trial enrollment. Conclusions: The rate of therapy plan change after MTM is in accordance with international studies. The largest volume of discussions on systemic therapies reflects the large number of new therapies as well as new treatment strategies. This research highlights the potential of multidisciplinary discussions in changing decision-making in cancer cases, allowing a more comprehensive care with the patient. In addition, a MTM allows the access of more patients to new medications made available through clinical trials and protocols. The small number of patients referred to a clinical study reflects the lack of clinical protocols available in Brazil, a problem that needs to be acknowledged and become a priority for Brazilian medical societies and regulatory agencies.
Copper chelation as targeted therapy in a genetic mouse model of oncogenic <i>BRAF</i>-driven thyroid cancer.
Authors: Mengmeng Xu, Danielle Range, Julie Ann Sosa, Christopher Counter
Journal: Journal of Clinical Oncology (2017)

e23148 Background: Over half of papillary thyroid cancers (PTC) contain the MAPK pathway activating, oncogenic BRAF V600E mutation. Early clinical trials using inhibitors to this mutant protein or its substrates, the MEK1/2 kinases, prolonged progression-free survival or stabilized disease in patients with advanced PTC. However, the toxicities of these inhibitors are uniquely highlighted in an indolent disease like PTC, which would require patients to endure toxicities long-term. Our goal was to determine if tetrathimoybdate (TM), a well-tolerated copper chelator we have previously shown to inhibit BRAF-mutated melanoma via MEK inhibition, can inhibit BRAF-driven PTC growth. Methods: We assessed TM in comparison to current standard of care (SOC), Lenvatinib and Sorafenib, and mutant BRAF inhibitor, Vemurafenib. Anchorage independent growth assays were used to test the inhibitory effect of these drugs on human BRAF-mutated PTC cell lines. We then confirmed these findings by treating a genetically engineered mouse model (GEMM) of aggressive BRAF-driven PTC. Results: TM inhibited 57.5% of colony growth in vitro, which was not significantly different from the 42.4% and 32.2% inhibition by Sorafenib and Lenvatinib, respectively. TM inhibition was less effective than the 70.3% inhibition by Vemurafenib ( p =0.04). We confirmed these results in vivo, where mice on the TM arm, on average, were observed to have 14.8% of their thyroid glands occupied by tumor, a statistically significant reduction from the mice in the control arm, whose tumor load averaged 23.6% ( p= 0.008). This 37.4% reduction in tumor burden was not statistically different from the 35.2% reduction measured in the Vemurafenib arm, where mice on average had 15.3% of their thyroid glands replaced by tumor. Conclusions: The copper chelator, TM, was as effective as the SOCs, Lenvatinib and Sorafenib, at inhibiting the growth of human PTC in vitro. Although TM was slightly less effective than Vemurafenib in vitro, TM was as effective as Vemurafenib at reducing tumor load in a GEMM of BRAF-driven PTC. Success of TTM in these PTC models may next inform a Phase I trial assessing TM in patients with advanced PTC.
A phase I clinical trial of CM082 (X-82) in combination with everolimus for treatment of metastatic renal cell carcinoma.
Authors: Xinan Sheng, Xieqiao Yan, Bixia Tang, Zhihong Chi, Chuanliang Cui, Lu Si, Li Li Mao, Bin Lian, Si Ming Li, Li Zhou, Xuan Wang, Xue Bai, Yan Kong, Jie Dai, Jun Guo
Journal: Journal of Clinical Oncology (2017)

4575 Background: CM082 is an oral multikinase inhibitor targeting VEGFR, PDGFR and CSF1R with a shorter half-life and limited tissue accumulation, designed to lower toxicity and enable combination with other therapies. This is a phase I study to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of CM082 in combination with everolimus in patients with metastatic renal cell carcinoma. Methods: A 3+3 dose escalation design with expansion cohort was utilized to determine the dose-limiting toxicities (DLT) and the maximum tolerated dose (MTD) of CM082 plus everolimus at 5 mg PO daily for patients with metastatic clear cell renal cell carcinoma. Eligibility include PS 0-1, age ≥18 y, measurable disease, adequate organ function. Results: 22 patients (M/F: 16/6; median age: 55 y [range 32-69]; 21/22 pts [95.5%] had received prior anti-VEGF treatment (tx); 2/22 pts [9.1%] had also received prior mTOR-targeted tx) were treated at 3 dose levels of CM082 (100 mg [n = 4]; 150 mg [n = 3]; 200 mg [n = 15]) in combination with everolimus 5 mg. One patient in cohort 1 was not evaluable for DLT due to consent withdrawal. DLT were observed in one patient: G4 thrombocytopenia at 200 mg. CM082 200 mg plus everolimus 5 mg did not exceed MTD, but was chosen as the optimal biological dose regimen. Median duration of tx was 24 wk (range 1-57, 7/22 [32%] pts ongoing. The most common tx-related adverse events (AEs), all grades, were proteinuria 96% (G3, 5%); leukopenia 77% (G3, 9%); neutropenia 59%, hypercholesterolemia 64%, anemia 50% (G3, 9%), hypertension 46% (G3, 14%), raised aspartate aminotransferase 41%, fatigue 45%, diarrhea 32%, hypertriglyceridemia 32% (G3, 5%) and thrombocytopenia 20% (G4, 5%). At 200mg, partial response (PR) was observed in 5/14 (36%) patients, durable stable disease (SD) (≥24 week) or PR were achieved in 10/14 (71%) patients. Median PFS was 170 days (5.7 months) at this cohort. Conclusions: CM082 200mg in combination with everolimus 5 mg appeared to be well tolerated when administered to pretreated patients with advanced RCC in this Ph1 study. The preliminary efficacy warrant further evaluationand and the follow-up Ph 2/3 study is underway. Clinical trial information: NCT02577458.
Non-optimal perceptual decision in human navigation
Authors: Mintao Zhao, William H. Warren
Journal: Behavioral and Brain Sciences (2018)

Abstract We highlight that optimal cue combination does not represent a general principle of cue interaction during navigation, extending Rahnev &amp; Denison's (R&amp;D) summary of nonoptimal perceptual decisions to the navigation domain. However, we argue that the term “suboptimality” does not capture the way visual and nonvisual cues interact in navigational decisions.
ACTR-49. PriCoTTF: A PHASE I/II TRIAL OF TUMOR TREATING FIELDS PRIOR AND CONCOMITANT TO RADIOTHERAPY IN NEWLY DIAGNOSED GLIOBLASTOMA
Authors: Martin Glas, Björn Scheffler, Lazaros Lazaridis, Ulrich Herrlinger, Daniela Pierscianek, Ulrich Sure, Martin Proescholdt, Peter Hau, Jörg Hense, Christoph Kleinschnitz, Anca-Ligia Grosu, Martin Stuschke, Sied Kebir
Journal: Neuro-Oncology (2018)

Tumor Treating Fields (TTFields) in combination with adjuvant temozolomide (TMZ), applied after completion of radiochemotherapy, showed significantly improved clinical outcome in newly diagnosed glioblastoma (GBM) patients in the EF-14 trial. In preclinical settings, TTFields synergistically enhanced efficacy of radiotherapy in GBM, hypothetically by inhibiting DNA damage repair in irradiated cells. The presented phase I/II trial will evaluate safety and feasibilty of TTFields initiated prior and concomitant to combined radiochemotherapy in newly diagnosed GBM. In arm A of this prospective multi-center trial, seven eligible patients with newly diagnosed GBM will be enrolled initially. Provided that treatment is tolerated well, enrollment will continue for up to 20 patients. Patients will be subjected to TTFields after complete wound-healing following surgery. TTFields treatment will be continued throughout radiochemotherapy and adjuvant chemotherapy for six cycles. In total, patients will receive TTFields therapy for approximately nine months. In arm B, elderly patients with a reduced KPS (50 or 60) will be treated with postsurgical TTFields therapy followed by TTFields therapy concomitant to hypofractionated radiotherapy with 40 Gy for three weeks. TTFields therapy will continue throughout adjuvant chemotherapy for a total of nine months. In the first stage, six patients will be accrued. Under the provision of an acceptable safety profile, seven additional patients will be accrued. The primary endpoint of the trial is safety and tolerance based on the frequency of a set of predefined treatment-limiting toxicities (TLTs). Secondary endpoints consist in particular of PFS, OS, radiologic response and frequency of adverse events. First experiences will be presented. CONCLUSION: The objective of this trial is to demonstrate that the administration of TTFields therapy prior and concomitant to radiotherapy and adjuvant chemotherapy is feasible and safe. Moreover, first data obtained on efficacy may serve as a basis for a potential randomized phase III trial.
Association of clinical factors and biological subtypes with different Ca15-3 levels in metastatic breast cancer.
Authors: Marta Bonotto, Lorenzo Gerratana, Giacomo Pelizzari, Debora Basile, Marika Cinausero, Maria Grazia Vitale, Elisa Bertoli, Alessandro Bettini, Michele Bartoletti, Vanessa Buoro, Elena Poletto, Gaetano Pascoletti, Stefania Russo, Claudia Andreetta, Alessandro Marco Minisini, Mauro Mansutti, Gianpiero Fasola, Fabio Puglisi
Journal: Journal of Clinical Oncology (2018)

e24014 Background: The role of serum tumor markers (TM), such as Ca15-3 and CEA, in early intercepting breast cancer (BC) recurrences is still debated. Due to lack of sensitivity and specificity, TM measurement is recommended only to support monitoring of treatment benefit in patients (pts) with metastatic BC (MBC). We aimed to investigate whether TM levels at diagnosis of metastatic disease were linked to BC biological subtypes and pts’ characteristics. Methods: We retrospectively analyzed 396 consecutive women with MBC, treated between 2010 and 2016 at the department of oncology, Academic Hospital of Udine, Italy. Demographic and clinico-pathological data were collected with TM levels. Multivariate logistic regression was performed to identify factors associated with TM levels. Results: Overall, 14% of pts had luminal A disease, 49% had luminal B disease, 14% and 11% had respectively luminal HER2 and HER2 positive (HER2+) disease and 12% had triple negative (TN) BC. Median follow up was 53 months, median overall survival and progression free survival was 31 and 9 months, respectively. At diagnosis of MBC, 51% of pts presented bone localizations and 26% had liver involvement; of note, 20% had ≥3 sites involved. An increase of Ca15-3 and CEA baseline serum levels was present in 61% and 29% of pts, respectively. At multivariate analysis, the involvement of ≥3 sites was associated with higher baseline Ca15-3 serum levels (OR = 2.56, 95%IC = 1.11-5.87, p = 0.027) while HER2+ and TN subtypes were associated with a lower probability of high Ca15-3 levels (OR = 0.24, 95%IC = 0.08-0.76, p = 0.015 and OR = 0.14, 95%IC = 0.04-0.44, p = 0.001 respectively). Regarding CEA, only liver (OR = 1.93, 95%IC = 1.06-3.52, p = 0.030) and bone (OR = 2.03, 95%IC = 1.17-3.52, p = 0.011) involvement were related with high baseline CEA serum levels. Conclusions: High Ca15-3 levels are less likely associated with HER2+ and TN BC, contrary to what is observed for luminal subtypes and for tumor burden. The present study provides initial hints on preferential use of TM for surveillance of pts with BC, waiting for their potential integration with emerging liquid biopsy techniques (i.e. CTC and ctDNA) in blood-based multi-parametric assessments.