tbuckley/cabot-search huggingface dataset:
Genetic variation in sex hormone receptor genes and association with enzalutamide response in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Ben Yiming Zhang, Moritz Binder, Brian Addis Costello, Fernando Quevedo, Manish Kohli
Journal: Journal of Clinical Oncology (2016)

e16606 Background: Enzalutamide has been shown to prolong overall survival in men with mCRPC. Given the modest response rate, high cost, and availability of alternative treatment options, it is crucial to identify predictive biomarkers for this drug. Therefore we investigated the association between common genetic variations in sex hormone receptor genes and response to enzalutamide. Methods: Germline DNA was extracted from peripheral blood mononuclear cells of 61 patients undergoing enzalutamide therapy for mCRPC. Twenty-six single nucleotide polymorphisms (SNPs) with minor allele frequency (MAF) ≥ 0.05 in AR, ESR1 and ESR2 genes were identified using a haplotype-based tagging algorithm to capture the common genetic variations. Genotyping was carried out on the MassARRAY iPLEX platform. The outcomes of interest included PSA response, defined as ≥ 50% decrease in PSA, time to PSA progression, defined as > 25% increase in PSA on two consecutive tests at least two weeks apart, and time to discontinuation of the drug. Logistic and Cox regression models were used to assess the associations with response and time to event, respectively. Effect measures were expressed as hazard ratio per minor allele. Results: The median age at initiation of enzalutamide was 73 years (50 - 90). Bone and soft tissue metastases were present in 57/61 (93%) and 21/61 (34%) of the men, respectively. 51/61 (83%) had received docetaxel prior to enzalutamide. After correcting for multiple testing the pathway adjusted α-level was 0.003. The genetic variant rs12881815 (G > A) in ESR2 (MAF 0.11) was associated with time to PSA progression (OR 4.06, 95% CI 1.69 - 9.71, p = 0.002) and time to discontinuation of the drug (HR 5.04, 95% CI 2.03 - 12.49, p = 0.001). No SNP in ESR1 was associated with the outcomes of interest. Due to genotyping failure, no data for the AR gene was obtained Conclusions: Presence of minor allele A in SNP rs12881815 of the ESR2 gene was found to be associated with shorter duration of response to enzalutamide. These promising results warrant validation in a larger independent cohort.
Chemotherapy-induced placental toxicity: The role of vascular toxicity.
Authors: Irit Ben-Aharon, Hadas Bar-Joseph, Mattan Levi, Fedro Peccatori, Ruth Shalgi, Tal Goshen-Lago, Fluvia Milena Cribiù
Journal: Journal of Clinical Oncology (2018)

e13097 Background: Several studies have addressed gestational and neonatal outcomes of chemotherapy during pregnancy (CDP) and demonstrated increased complications as pre-eclampsia and intrauterine growth retardation. We hypothesized that doxorubicin (DXR)-induced gestational complications may derive from direct vascular toxicity of the placenta vascular tree and aimed to study the role of vascular effect in a translational study. Methods: A retrospective cohort of 10 patients diagnosed with breast cancer during pregnancy (week 27-35) who were treated with DXR were matched to 10 chemo-naïve controls. Placentae FFPE sections were immunostained to evaluate apoptosis (TUNEL), vascular immunostaining (CD34) and proliferation (PCNA). In a preclinical study, we followed a cohort of pregnant ICR mice, starting at day 14 until delivery divided into 3: DXR-treated (8mg/kg), DXR+low molecular weight heparin (LMWH) combination, and saline-treated groups (two administrations q4days). Mice were imaged using real-time molecular bioimaging of uterine and placental blood flow every 4 days until delivery. On day 22 mice were sacrificed and the embryos and placentae are extracted for further analysis. Results: Histological analysis revealed that in DXR-treated patients, placentae depicted differential pattern of vascular landscape manifested by enhanced CD34 staining, representing neovascularization, and enhanced apoptosis compared with matched chemo-naïve placentae. In the preclinical study, following DXR administration, the placental Velocity-Time Integral (VTI) recorded by PW Doppler was compromised compared with control mice. The mean embryo weight in the DXR group was significantly reduced compared with control group, as well as reduced embryo/placenta weight ratio in the DXR group. In the DXR-LMWH group the measures resembled the control group. Conclusions: Chemotherapy-induced placental toxicity may derive from vascular insult. Elucidating the mechanism of chemotherapy-induced placental toxicity may shed light on the role of vascular impairment and enable applying protective measurements to reduce gestational complications in pregnant cancer patients.
Efficient lung cancer-targeted drug delivery via a nanoparticle/MSC system
Authors: Xusheng Wang, Haiyan Chen, Xiaowei Zeng, Wenpeng Guo, Yu Jin, Shan Wang, Ruiyun Tian, Yanjiang Han, Ling Guo, Jimin Han, Yaojiong Wu, Lin Mei
Journal: Acta Pharmaceutica Sinica B (2018)

Low targeting efficiency limits the applications of nanoparticles in cancer therapy. The fact that mesenchymal stem cells (MSC) trapped in the lung after systemic infusion is a disadvantage for cell therapy purposes. Here, we utilized MSC as lung cancer-targeted drug delivery vehicles by loading nanoparticles (NP) with anti-cancer drug. MSC showed a higher drug intake capacity than fibroblasts. In addition, MSC showed predominant lung trapping in both rabbit and monkey. IR-780 dye, a fluorescent probe used to represent docetaxel (DTX) in NP, delivered
Economic burden of clinical trials in lung cancer in a German comprehensive cancer center.
Authors: Florian Kron, Anna Kostenko, Matthias Scheffler, Jan Peter Glossmann, Rieke Nila Fischer, Sebastian Yves Friedrich Michels, Lucia Nogova, Michael J. Hallek, Thomas Zander, Juergen Wolf
Journal: Journal of Clinical Oncology (2016)

e18278 Background: Recent success of individualized lung cancer therapy has triggered fundamental changes in clinical research strategies. To date there is a strong focus on early proof of concept trials in genetically preselected, often rare, patient subgroups. From a hospital management perspective, this analysis focuses on the economic burden caused by such trials for advanced lung cancer patients in a German Comprehensive Cancer Center (CCC). Methods: Clinical and economic data from trials for advanced lung cancer (LC), pharma-sponsored trials (PhST) as well as investigator initiated trials (IIT), conducted between 2011 and 2015 at the Center for Integrated Oncology (CIO) Cologne, were analyzed using a profit-center calculation model. Results: 161 patients were enrolled in 27 clinical trials including 2,173 trial visits in total (PhST: 1,319, IIT: 854). We have identified ‘trial visit’ as a key economic parameter determining costs and payments. By comparison of two groups (A ≤ 3; B > 3 patients enrolled) we found negative profit margins of €-1,444 per patient (PP) in A and positive in B (€217). Significant differences were found between PhST and IIT (p = 0.009) concerning the number of visits PP, not, however, with regard to duration of treatment PP. Additionally, subanalysis show structural differences in cost composition by conducting PhST and IIT. Conclusions: The development of individualized, genomically targeted LC therapies goes along with an increase of early phase trials in rare genetic subgroups and, consequently, low patient recruitments. For trials with low patient numbers and IIT, it is difficult to break even with the costs. These observations demonstrate the need for CCC to thoroughly calculate the costs of such trials in order to receive adequate, cost-covering compensation by pharmaceutical companies. They also underline the need for novel structures in public funding for investigator-initiated clinical trials in precision medicine.
EZH2 copy number gain as a therapeutic target in mucosal melanoma.
Authors: Huan Yu, Yan Kong, Junya Yan, Meng Ma, Longwen Xu, Jiayi Yu, Tianxiao Xu, Jie Dai, Huan Tang, Xiaowen Wu, Zhihong Chi, Lu Si, Xinan Sheng, Bixia Tang, Bin Lian, Xuan Wang, Siming Li, Xue Bai, Jun Guo
Journal: Journal of Clinical Oncology (2018)

e21530 Background: EZH2 aberrations have been described in divers cancer types. However, the status and the clinical significance of EZH2 copy number variation have not been investigated in Asian melanoma patients on a large scale. Methods: This study involved tumor samples from 558 Chinese melanoma patients, including 252 acral melanomas, 148 mucosal melanomas, 61 melanomas on skin with chronic sun-induced damage and 86 melanomas on skin without chronic sun-induced damage. EZH2 copy number was examined using the QuantiGene Plex DNA assay. The effect of EZH2 inhibitors were evaluated in melanoma cell lines and patient-derived xenograft models containing EZH2 gain. Results: The overall incidence of EZH2 gain was 30.6% (171/558). The incidence of EZH2 gain was higher in mucosal melanoma subtype than other subtypes (43.2%, p < 0.001). The median survival time for melanoma patients with EZH2 gain was significantly shorter than that for patients with normal EZH2 copy number only in mucosal subtype (p = 0.030). EZH2 inhibitors effectively inhibited the proliferation of mucosal melanoma cells and the tumor growth of mouse models with EZH2 gain. Conclusions: EZH2 gain is a frequent event in mucosal melanoma tumorigenesis and can serve as a predictive factor of poor outcome. Targeting EZH2 is sufficient to suppress mucosal melanoma cell growth in vitro and in vivo, implicating EZH2 inhibition as a novel approach for attenuating tumor progression in EZH2-gain mucosal melanomas.
Multigene panel testing for hereditary breast and ovarian cancers: An analysis of 1303 <i>BRCA</i>-negative Chinese patients.
Authors: Ava Kwong, Vivian Shin, Chun Hang Au, Cecilia Ho, Tsun Leung Chan, Edmond Ma
Journal: Journal of Clinical Oncology (2018)

e13625 Background: Identification of other breast cancer susceptibility genes, other than BRCA1/2, in hereditary breast and ovarian cancers (HBOC) using multigene panels could help to assess cancer risk in patients. The spectrum and frequency of variants are different across ethnicity, it is therefore imperative to identify other HBOC genes in Chinese patients. Methods: 1,303 high-risk patients (negative for BRCA1, BRCA2, TP53 and PTEN) were selected from Hong Kong Hereditary Breast Cancer Family Registry and subjected to 30-gene panel by next-generation sequencing (Color Genomics). All detected pathogenic mutations were further validated by bi-directional DNA sequencing and co-analyzed by our in-house developed bioinformatics pipeline. Results: Sixty-one pathogenic or likely pathogenic variants were identified (4.68%), which correspond to 12 different cancer predisposition genes. Majority of the carriers (77.05%) had early-onset of breast cancer (age <45), 29.51% had family members with breast cancer and 13.11% were triple-negative. The most common mutated genes were PALB2 (1.38%), RAD51D (0.84%) and ATM (0.77%). Moreover, over 29% of patients had variant of unknown significance (VUS) in these genes, which account for 323 types. Conclusions: Additional preventive measures and clinical management are recommended in 90% of the mutation-positive cases. Multigene panel testing is an alternative strategy in the diagnosis of HBOC, this could help to estimate the cancer risk and aid the development of effective treatments.
The serum albumin and gender in patients with low risk NCCN-IPI diffuse large B-cell lymphoma.
Authors: Branimir Spassov, Donka Vassileva, Svetoslav Nikolov, Georgi Mihaylov, Georgi Balatzenko, Margarita Guenova
Journal: Journal of Clinical Oncology (2016)

e19068 Background: Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous group of B-cell lymphomas, treated by rituximab-CHOP chemotherapy (R-CHOP). Prognostic stratification of DLBCL patients (pts) is done by the enhanced International Prognostic Index (NCCN-IPI) defining four risk groups [low (L), low-intermediate (LI), high-intermediate (HI) and high (H)]. Male gender is considered as an adverse risk factor only in young DLBCL pts. Recently serum albumin (SA), β2-microglobulin (B2M), peripheral blood lymphocyte/monocyte ratio (LMR) etc were proposed to have prognostic impact in DLBCL pts. However, the data regarding age and gender differences of these markers are limited. Therefore, we decided to investigate gender distribution of SA, B2M and LMR across the R-CHOP treated DLBCL NCCN-IPI age groups in an attempt to refine clinical assessment. Methods: We retrospectively reviewed the clinical outcome of 329 R-CHOP treated DLBCL pts. The median age was 58 years and 49.8% male. The pts in L, LI, HI and H groups were 26.1%, 48.4%, 18.5% and 7%, respectively. The best cut off values of SA, B2M and LMR to predict overall survival (OS) by Kaplan-Meier method were calculated by a receiver operating characteristic (ROC) curve analysis. Univariate and multivariate analyses were performed by the log rank and Cox proportional-hazards methods, respectively. Results: A61.9% 5-year OSwas observed in the entire population, and 89% (L), 62.7% (LI), 42.6% (HI) and 23% (H) across the NCCN-IPI risk groups, respectively. By applying the best cut off values SA, B2M and LMR 39.4 g/L, 2.4 mg/L and 2.16, respectively, also correlated with OS, however this was confirmed in multivariate analysis only for SA (hazard ratio 0.136; p = 0.028). No survival differences were found between genders, except in the 40-60 yrs age group. Compared to men women had a significantly longer 5-year OS (84.9% vs 58.6%, p = 0.017) and significantly higher levels of SA in L and LI risk NCCN-IPI groups (median 43 vs 39.4 g/L; p = 0.04). Conclusions: Our data confirmed pretreatment SA levels as an additional prognostic factor for OS in DLBCL patients that can discriminate high-risk patients in low risk groups and might also be gender associated which warrants further investigation.
Abstract 116: Loss of T-type Ca <sup>2+</sup> Channels Alters the Cardiac Response to Myocardial Infarction
Authors: Shavonn C Harper, Tao Wang, Yijun Yang, Steven R Houser
Journal: Circulation Research (2016)

Rationale: Cav3.1 T-type calcium channels are expressed during development and then re-expressed in ventricular myocytes after pathological stress such as myocardial infarction (MI). Our lab has previously shown that mice with cardiac specific overexpression of Cav3.1 have improved contractility, survival, and preservation of the myocardial mass post-MI. Hypothesis: Loss of the Cav3.1 subunit of the T-type calcium channel reduces the ability of the heart to adapt to MI due to alterations in the wound healing response. Methods and Results: Ischemia reperfusion (IR) injury was induced in 12-16 week old Cav3.1 -/- and wild type (WT) mice. Previously collected data from our groups showed that Cav3.1 -/- mice have decreased survival after permanent occlusion MI. In the present study there was no significant difference in the one week survival of these mice after IR (100% vs 90% for WT vs Cav3.1 -/- , respectively). Cav3.1 -/- mice had significantly increased heart weight to body weight (7.066 vs 5.452) and heart weight to tibia length ratios (9.284 vs 7.594) compared to WT mice at 7 days post IR. Echocardiography performed at baseline showed no significant differences between the two groups. At 1 week post-IR, Cav3.1 -/- mice had significantly lower ejection fraction (11.58% vs 21.77%) and fractional shortening (10.02% vs 17.46%) compared to WT mice. This decrease in function was accompanied by a significantly increased percentage of fibrosis in the Cav3.1 -/- mice (26.42% vs 11.17%) and this was associated with alterations in the infiltration of proliferative inflammatory cells. The left ventricular internal diameter was also significantly increased in Cav3.1 -/- mice compared to WT (4.766 mm vs 4.151 mm). Summary and Conclusions: Cav3.1 -/- mice have decreased cardiac function and increased pathological remodeling at 1-week post-IR. The mechanisms resulting in these pathological changes appear to involve alterations in post MI inflammatory cell infiltration and myocyte survival. These results suggest that loss of Cav3.1 T-type calcium channels alters the behavior of inflammatory responses and myocyte survival after MI.
A phase II multicenter trial of the multitargeted kinase inhibitor sulfatinib in advanced medullary thyroid cancer (MTC) and radioiodine (RAI)-refractory differentiated thyroid cancer (DTC).
Authors: Jiaying Chen, Qinghai Ji, Junning Cao, Dongmei Ji, Chunmei Bai, Yansong Lin, Bin Pan, Guofang Sun, Jing Li, Chuan Qi, Ye Hua
Journal: Journal of Clinical Oncology (2017)

6037 Background: Sulfatinib is an oral tyrosine kinase inhibitor targeting Vascular Endothelial Growth Factor Receptor (VEGFR), Fibroblast Growth Factor Receptor 1 (FGFR 1), and Colony Stimulating Factor 1 Receptor (CSF1R). In a proof of concept (PoC) phase II study, sulfatinib showed promising efficacy in patients (pts) with neuroendocrine tumors (NETs). Methods: This is an open label, two cohorts phase II study using Simon's two-stage design. In stage I, 15 pts will be enrolled in each cohort (advanced MTC or iodine-refractory DTC), and 10 more pts will be enrolled in a cohort in stage II if at least 2 PR observed in that cohort in stage I. Pts are required to have progressive disease in the past 12 months, but could not have received &gt; 1 prior anti-angiogenesis therapy. Pts are treated with oral sulfatinib 300 mg once daily until disease progression, death, or intolerable toxicity. Primary endpoint is Objective Response Rate (ORR) by investigator per RECIST 1.1. Results: As of Dec 31 2016,the studyenrolled 18 pts (MTC: 6, DTC: 12), amongst whom 17 pts were efficacy evaluable. There were a total of 4 confirmed PRs, 1 in the MTC cohort and 3 in the DTC cohort, respectively. The others best response was stable disease (SD). 11 pts (61.1%) had dose interruption due to adverse events (AEs) and 5 pts (27.8%) had dose reduction. Two pts discontinued therapy (1 patient due to disease progression, another due to subject's decision). The most commonly reported AEs were proteinuria 72.2% (Grade 3-4: 22.2%), hypertriglyceridemia 50.0% (Grade 3-4: 0%), hypertension 44.4% (Grade 3-4: 16.7%), blood bilirubin increased 44.4% (Grade 3-4: 5.6%), and diarrhea 33.3% (Grade 3-4: 0%). No Grade 5 AE was reported by the time of data cut-off. Conclusions: Sulfatinib appears to be well tolerated in the pts with advanced MTC and RAI refractory DTC. Safety profile seems to be consistent to previous report, with mostly manageable AEs. Efficacy is encouraging in both indications. Further investigation is warranted. Clinical trial information: NCT02614495.
Genetic polymorphisms of CCL5 and CCR5 to predict efficacy of cetuximab-based treatment in metastatic colorectal cancer patients depending on primary tumor location.
Authors: Mitsukuni Suenaga, Shu Cao, Sebastian Stintzing, Wu Zhang, Dongyun Yang, Yan Ning, Satoshi Okazaki, Martin D. Berger, Yuji Miyamoto, Marta Schirripa, Roel Gopez, Elizabeth Melendez, Shivani Soni, Afsaneh Barzi, Toshiharu Yamaguchi, Volker Heinemann, Heinz-Josef Lenz
Journal: Journal of Clinical Oncology (2017)

3594 Background: EGFR signaling blockade increases CCL5 expression, which attracts with tumor-infiltrating leukocytes regulating either the host-derived anti-tumor immunity or tumor progression. We tested whether genetic polymorphisms in the CCL5/CCR5 axis could predict efficacy of cetuximab (CET)-based first-line treatment in metastatic colorectal cancer (mCRC) patients (pts). Methods: Genomic DNA was extracted from 491 samples of two different cohorts with KRAS wild-type mCRC in the FIRE-3 study: an evaluation cohort of 244 pts receiving CET plus FOLFIRI (median age 64 yrs; median follow-up 34.1 mos); and a control cohort of 247 pts receiving bevacizumab plus FOLFIRI (median age 65 yrs; median follow-up 39.4 mos); Single nucleotide polymorphisms (SNPs) of CCL5 and CCR5 genes were analyzed by PCR-based direct sequencing. Results: Pts in the evaluation cohort with any CCL5 rs2280789 G allele had shorter OS compared to those with the A/A variant (19.9 vs. 33.4 mos, HR 1.56, 95%CI: 1.05–2.30, P= 0.024), which was confirmed in multivariable analysis (HR 1.64, P= 0.015). Pts carrying any CCR5 rs1799988 T allele had a trend lower response rate than those with the C/C variant (68 vs. 81%, P= 0.078). Statistically significant differences in efficacy were shown between the groups consisting SNPs and tumor location (Table). The findings were not confirmed in the control cohort. Conclusions: Genetic variants of CCL5 and CCR5 SNPs may predict outcomes in mCRC pts receiving CET-based first-line treatment depending on tumor location. [Table: see text]
A phase I, open, multiple dose, dose escalation and expansion study to evaluate the safety, tolerability, and pharmacokinetics of KN035 (anti-PD-L1 antibody) administered in subcutaneous injection as a single agent to Chinese subjects with advanced solid tumors.
Authors: Jianming Xu, Shukui Qin, Yun Zhang, Yaoyue Zhang, Ru Jia, Rongrui Liu, Yan Wang, Gairong Zhang, Chuanhua Zhao, Ni Lu, Xiaoyu Ma, Yue He, Liwei Yuan, Yihui Lin, Wenlian Xu, Xiaoxiao Wang, Pilin Wang, Ting Xu, RuiPing Dong, John Gong
Journal: Journal of Clinical Oncology (2018)

e15138 Background: KN035 is a novel programmed death-ligand 1(PD-L1) antagonist and formulated to high protein concentration (200 mg/ml) and provided as a transparent liquid solution for subcutaneous injection. This phase I dose escalation and dose expansion study was performed to evaluate and characterize the tolerability and safety, maximum tolerated dose (MTD), recommended dose (RD), pharmacokinetics, and antitumor activity of single agent KN035 in Chinese subjects with locally advanced or metastatic solid tumors. Methods: A modified 3 + 3 dose-escalation design was adopted with a 28-day per cycle in dose escalation study. Six dose levels were planned at: 0.1, 0.3, 1.0, 2.5, 5 and 10 mg/kg subcutaneously weekly. Dose expansion phase was planned to investigate the efficacy and safety in advanced HCC patients at 2.5 mg/kg and 5 mg/kg dose levels respectively after confirmed safety in dose-escalation phase. Results: As of Jan 19, 2018, 11 pts with various tumors had already been completed enrollment at 0.1-2.5 mg/kg dose level. Additionally, 2 pts were enrolled at 5 mg/kg dose level. No DLT was observed. The common treatment-related AEs were grade 1/2, such as alanine aminotransferase increased. The only one treatment–related grade 3 AE was autoimmune dermatitis (n = 1) which occurred at 0.3 mg/kg cohort and was resolved in about one month after symptomatic treatment. Overall, the emergence of AEs is not dose related. The exposure to KN035 was dose dependent and proportionally increased, the steady state was not achieved yet up to Dose 5 and the PK exposure continued to increase. The average elimination half-life of KN035 is approx. 200 hrs or 8.3 days. Among 10 evaluable pts, 1 pt had partial response (Renal Cell Carcinoma) at 2.5mg/kg cohort, and 3 pts achieved stable disease (1 Hepatocellular Carcinoma and 1 Renal Pelvis Carcinoma at 1.0 mg/kg cohort; 1 Renal Cell Carcinoma at 2.5mg/kg cohort). The pt with PR still has ongoing response. Conclusions: KN035 exhibited favorable safety and PK profiles in human and preliminary anti-tumor activity. Clinical trial information: NCT03101488.