bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tolerability of enzalutamide in prostate cancer: A meta-analysis.
Authors: Karawadia Tejas , Wu Shenhong 
Published: May 2020

e15629 Background: Enzalutamide, a second-generation androgen receptor inhibitor widely used in the treatment of prostate cancer, is often discontinued due to adverse events. A meta-analysis of randomized controlled trials was performed to examine the overall tolerability of enzalutamide in prostate cancer in comparison with controls. Methods: Databases including PubMed (up to December 2019) and Google scholar (up to December 2019) were searched to identify all phase II and III randomized controlled trials that compared enzalutamide with placebo (with or without other anti androgen drugs) along with reported data regarding drug discontinuation due to adverse events with enzalutamide and placebo. A random- or fixed-effects model was used to determine summary incidences, relative risks (RR), and 95% confidence intervals depending on the heterogeneity of included studies. Results: A total of 7 RCTs were eligible for analysis which included 7,343 patients (enzalutamide: n = 4116, control: n = 3227). The summary incidence of tolerability measured as discontinuation rate due to adverse events was 7.3% (95% CI: 6.1-8.7%) with enzalutamide and 5.7% (95% CI: 4.3-7.5%) with placebo or first-generation antiandrogens including bicalutamide, nilutamide or flutamide. The tolerability of enzalutamide varied with stage of prostate cancer with significantly higher incidence of discontinuation (9.8%, 95% CI: 8.0-11.9%) in non-metastatic prostate cancer group than metastatic prostate cancer group (6.7%, 95% CI: 5.8-7.6%). In comparison with controls, enzalutamide did not significantly affect the tolerability with an RR of 1.25 (95% CI: 0.95-1.66, P = 0.12). In addition, enzalutamide did not significantly affect the tolerability with an RR of 1.11 (95% CI: 0.80-1.53, P = 0.54) when compared to placebo. Conclusions: Enzalutamide may be comparable to placebo or first-generation antiandrogens in the tolerability for prostate cancer patients. Cautions should be taken to avoid unnecessary discontinuation.
Bevacizumab induced proteinuria and hypertension: A comparative analysis of anti-hypertensives utilized within a single institution.
Authors: Farooqui Marwah Wafa , Gustafson Nicholas , Patel Nisha , Danelski Erika , Patel Tirth , Srinivasan Krishnan , Stein Amy , Ghouse Masood 
Published: May 2020

e15631 Background: Bevacizumab (Bev) is a recombinant monoclonal antibody associated with hypertension and proteinuria commonly used in treatment of various malignancies. Often times, treatment is interrupted due to complications. Currently, there are no evidence based medication guidelines for Bev induced hypertension (htn) and proteinuria (pu). ACE inhibitors (ACE-I) and angiotensin II receptor blockers (ARBs) are known to reduce severity of proteinuria in other disease states. However, no studies on these drugs have been conducted to verify their efficacy for Bev associated htn and pu. This study aims to provide guidance on Bev induced htn and pu management. Methods: This is a retrospective analysis of oncology patients between 2018-2019 at a single community clinic. All patients receiving Bev were selected and the control arm was patients with similar malignancies on chemo without Bev. Data was collected for 10 cycles of treatment. A comparison for htn was done using the Chi-square test between the control and the Bev group. Within the Bev group different classes of meds were studied to determine superiority for htn and pu control with Chi-square tests or independent t-tests as appropriate. Results: The data set has a total of 82 observations. The demographics of the two groups are given in Table 1. In the Bev group, 16 (46%) of the patients were on ACE-I/ARB during treatment (10 [29%] on ARB), 10 [29%] were on a diuretic, 10 [29%] were on calcium channel blocker, and 13 [37%] of patients were on ARB/thiazide (combo). On average, patients receiving Bev had an average 11 point increase in SBP compared to control. ACE-I or ARB (p value 0.028) and CCB ( p value 0.025) had the best htn control . Patients on the ARB/thiazide combo had the least proteinuria. Our study shows a significant improvement in proteinuria in patients on an ARB/thiazide combo in comparison to patients on ACE-I or CCB alone. CCB was shown to be the worst for proteinuria but it did have some benefit with htn (p < 0.05). Conclusions: ACE-I, ARB, and CCB were all equally beneficial in treatment for Bev induced htn. Previous studies have shown the potential benefit of ARB/Thiazide combo in other nephropathies. This study gives us new insight on the combination of ARB/Thiazide for therapeutic benefit in Bev induced proteinuria. Further prospective studies are needed to help us guide with therapy.
Growth modulation index (GMI) as a comparative efficacy measure of larotrectinib versus prior systemic treatments for TRK fusion cancer patients.
Authors: Italiano Antoine , Hong David S. , Briggs Andrew , Garcia-Foncillas Jesus , Lassen Ulrik Niels , Vassal Gilles , Kummar Shivaani , Van Tilburg Cornelis M. , Keating Karen N , Reeves John A. , Fellous Marc Mardoche , Childs Barrett H. , Laetsch Theodore Willis , Drilon Alexander E. 
Published: May 2020

e15638 Background: Larotrectinib is a highly selective TRK inhibitor that demonstrated high response rates and durable disease control in three phase I/II single-arm studies of patients (pts) with TRK fusion cancer. While single-arm studies are often used for rare cancer populations, they do not provide comparative data. GMI utilizes pts as their own control and can be used in this setting. GMI is the ratio of progression-free survival (PFS) on the current therapy to time to progression (TTP) on the most recent prior line of therapy. A GMI ≥1.33 has been used as a threshold of meaningful clinical activity. We report GMI for TRK fusion cancer pts treated with larotrectinib. Methods: Data were pooled from 3 clinical trials of pts with TRK fusion cancer treated with larotrectinib. A retrospective, exploratory analysis of GMI was conducted in pts who had been on larotrectinib and followed up for ≥6 mos or pts who discontinued early, and had ≥1 prior line of systemic treatment for locally advanced or metastatic disease. TTP on the prior line of therapy was investigator assessed. PFS on larotrectinib was determined by independent review committee per RECIST 1.1. Pts who had not progressed were not censored from the analysis. Results: As of July 15, 2019, 122 pts were eligible for analysis. Fifteen different tumor types were represented, the most common being soft tissue sarcoma in 26 pts (21%), infantile fibrosarcoma in 22 (18%), and thyroid in 21 (17%). Median GMI was 3.35 (range 0.00–337.00; Table); In metastatic pts (n = 81), the proportion with a GMI ≥1.33 was higher in pts with a complete or partial response vs non-responders (88% vs 42%). In the whole analysis set (N = 122), median TTP on prior line of treatment was 2.7 mos (95% CI 2.0–3.1) and median PFS on larotrectinib was 33.4 mos (95% CI 13.8–NE; HR 0.20 [95% CI 0.14–0.29]). In metastatic pts (n = 81), median TTP on prior line of treatment was 2.3 mos (95% CI 1.9–3.0) and median PFS on larotrectinib was 23.4 mos (95% CI 10.9–NE; HR 0.24 [95% CI 0.16–0.36]). Conclusions: Greater than two-thirds of pts with TRK fusion cancer treated with larotrectinib had a GMI ≥1.33, demonstrating a clinically meaningful improvement in PFS compared to TTP on their prior treatment. Clinical trial information: NCT02122913, NCT02576431, NCT02637687.
A preclinical model for skin sensitization prediction of antineoplasic drugs.
Authors: Perez-Fidalgo Jose Alejandro , Montero Magallo Paula , Roger Laparra Ines , Ribera Alba Pilar , Poveda Ferriols Jesus , Milara Paya Javier , Cervantes Andres , Cortijo Gimeno Julio 
Published: May 2020

e15643 Background: Skin side effects are common manifestations of antineoplastic drugs that are frequently observed in early clinical trials. Therefore, there is a need to identify skin toxic agents before clinical development in order to predict severe skin manifestations. In many cases, skin toxicity is due to sensitization, a key immunologic process mediating redness, swelling and itching that can lead to more severe skin alterations. Methods: We adapted three skin cellular in vitro techniques for cutaneous drug sensitization assessment of the Organization for Economic Cooperation and Development (OECD, 2012) in order to predict antineoplastic drug skin sensitization: 1) Direct peptide reactivity assay (DPRA) was assessed by high performance liquid chromatography (HPLC) coupled to ultraviolet detector, to detect covalent binding of antineoplastic to skin proteins (haptenation). 2) KeratinoSense skin sensitization assay was evaluated in keratinocyte cell line (HaCaT) transfected with a selectable plasmid to quantify luciferase gene induction by chemiluminescence as a measure of activation of Keap1-Nrf2-antioxidant response element involved in the cellular processes in skin sensitization and 3) The human cell line activation test (h-CLAT) represents the activation of dendritic cells by the increase of CD86 and CD54 surface markers measured by flow cytometry. An antineoplastic was considered sensitizing when at least two of these three tests were positive. Antineoplastic tested were paclitaxel, erlotinib, imatinib, sunitinib, cetuximab, olaparib, palbociclib and everolimus. Results: Paclitaxel was positive for all the three tests; the DPRA formation, keratinoSense activation and h-CLAT expression showing the highest level of sensitization. Moreover sunitinib, and imatinib were positive for two of the three in vitro cellular tests, being considered sensitizing drugs. In contrast, erlotinib, cetuximab, olaparib, palbociclib and everolimus were considered non-sensitizing antineoplastic agents. In the case of erlotinib a high proportion of apoptosis of the keratinocytes during the keratinosense test was observed, suggesting that cutaneous toxicity could be due to cytolysis instead of sensitization. Conclusions: Results obtained in this work suggest that pre-clinical assays may predict skin sensitization and be of potential value to predict skin sensitization of antineoplastic drugs before clinical development. Further assessment with in vivo tests will help to identify the cutaneous toxic mechanisms of those non-sensitizing drugs as cetuximab
Antitumor activity of tipifarnib and PI3K pathway inhibitors in HRAS-associated HNSCC.
Authors: Burrows Francis , Malik Shivani , Wang Zhiyong , Chan Stacia , Gutkind Silvio 
Published: May 2020

e15658 Background: HRAS is an important driver oncogene in HNSCC and other squamous cell carcinomas (SCCs). HRAS mutations are observed in 6-10% of HNSCC cases and appear to define a unique subset of HNSCC associated with wild-type TP53, co-mutations in caspase 8 and a characteristic methylation pattern. RAS proteins undergo several posttranslational modifications that facilitate their attachment to membranes. The first and most critical modification is the addition of a farnesyl isoprenoid moiety by the enzyme farnesyltransferase (FT), prompting the development of FTIs for the treatment of RAS-driven cancers. Tipifarnib is a potent and selective FTI that has demonstrated compelling antitumor activity in a heavily pretreated cohort of recurrent/metastatic HNSCC carrying HRAS mutations. Based on these data, a pivotal study (NCT03719690) evaluating the efficacy of tipifarnib in HRAS mutant HNSCC (AIM-HN) is currently ongoing. Methods: HRAS is the predominant RAS in squamous epithelial cells and SCCs commonly overexpress the protein. In TCGA PanCancer Atlas, approximately 30% of HNSCC cases have elevated HRAS gene expression, raising the possibility that some HRAS wild-type (WT) HNSCCs may also display a degree of dependence on this oncoprotein. The PI3K-AKT-mTOR pathway is another prominent driver in HNSCC, and reports suggest HRAS and PI3K can each drive resistance to inhibitors of the alternative pathway. In this study we explored the activity of tipifarnib in cellular models and six HRAS-mutant and twelve HRAS WT HNSCC patient-derived xenograft (PDX) models alone and in combination with inhibitors of PI3K-a (BYL-719), AKT (GSK2141795) and mTORC1/2 (INK128). Results: Tipifarnib induced regression in several HRAS WT-overexpressing models. In those cases where the FTI was only moderately active, robust inhibition of tumor growth was observed in the majority of animals treated with the combination of tipifarnib and the PI3K-a inhibitor BYL-719. Similar activity was noted in a smaller panel with GSK2141795 & INK128. Regressions with the FTI-PI3K-a inhibitor doublet were observed both in tumors that were WT or harbored hotspot mutations or amplification of the PIK3CA gene and in HRAS mutants that carried or lacked PIK3CA mutations. Conclusions: Concomitant blockade of both targets may have surprisingly broad and potent anti-tumor activity in HNSCC. Additional biomarkers associated with sensitivity or resistance and alterations in gene expression (by RNAseq) and oncogenic signaling following treatment either as a monotherapy or in combinations will also be described.
Drugging the undruggable: A market readiness analysis for KRAS-G12C.
Authors: Loupakis Fotios , Bloom Kenneth Joel , Allen Wendy , Scanlon Enya , Stacey Isabel , Keeling Derry Mae , Patel Nital , Clark Jordan 
Published: May 2020

e15667 Background: KRAS G12C is a distinctively aggressive, poor survival, tumor genotype conferring resistance to anti-EGFR therapies in lung, colorectal (CRC) and pancreatic cancers. Prospective therapies targeting G12C have demonstrated promising activity in Phase I trials. In the advent of potentially transformative novel inhibitor therapies, we assess the need for earlier and repeated tumor profiling between treatments to accurately guide further therapeutics and assess market readiness for specified testing. Methods: Treatment-naïve patients and cell-lines were assessed for genomic change by consensus molecular classification in CRC pre/post treatment with standard chemotherapy. Assessing mutation occurrence, prevalence and testing rates, we aimed to identify areas of translational potential for testing within common cancers. A laboratory and prescriber mapping of the US across lung, CRC and pancreatic cancer types, was carried out using Diaceutics’ proprietary Global Diagnostics Index (GDI), a real-world data diagnostic database, to determine market readiness for companion diagnostic (CDx) and follow-on testing in the dawn of transformative therapies. Potential barriers to test adoption were explored including reimbursement analysis. Results: Genomic analysis shows CRC tumors change after treatment with first-line therapies rendering the primary tumor profile result less reliable. This highlights a distinct need for repeated testing post-treatment for continued efficacy in therapeutics. Patients with pancreatic cancer would benefit the most from increased testing for G12C particularly earlier testing as KRAS mutants occur before neoplastic transformation. Although the market appears ready, reimbursement for KRAS G12C remains a challenge for pancreatic cancer compared to either lung or CRC. Conclusions: This study provides genomic evidence of the necessity for more frequent tumor testing post-treatment with chemotherapy, and earlier testing in pancreatic cancer to enhance efficacy of targeted therapies. The market is ready for increased testing volumes, yet problems surrounding reimbursement and stage of testing remain. Earlier testing may increase survival and decrease cost of patient care, suggesting more frequent testing is imperative across cancer types.
Early carcinoembryonic antigen (CEA) dynamics to predict fruquintinib efficacy in FRESCO, a 3+ line metastatic colorectal carcinoma (mCRC) phase III trial.
Authors: Bai Yuxian , Qin Shukui , Li Jin , Deng Yanhong , Yang Lei , Xu Rui-hua , Chen Zhendong , Zhong Haijun , Pan Hongming , Guo Weijian , Shu Yongqian , Yuan Ying , Xu Jianming , Shen Lin , Wang Ning , Zhang Bin , Zhang Qiang , Fan Songhua , Guo Xiaojun , Peng Mengye 
Published: May 2020

e16001 Background: The FRESCO phase 3 trial demonstrated a significant survival benefit with fruquintinib vs. placebo in the third-line or later therapy of mCRC patients. CEA levels are widely used in conjunction with imaging to monitor response to systemic therapy in patients with mCRC. Herein, we undertook post-hoc analyses of FRESCO patient data to investigate the early changes in CEA during treatment, as well as potential relationships with efficacy parameters. Methods: Patients were included if baseline CEA was abnormal according to local lab reference range. Serum CEA levels were measured at baseline and Day 1 of each cycle (except for Cycle 1). Early CEA change was analyzed at first radiological evaluation (C3D1, Week 8), CEA response was defined as ≥ 50% decrease from baseline, and CEA progression was defined as ≥ 100% increase from baseline. Overall survival (OS) and progression-free survival (PFS) were evaluated by Kaplan-Meier method; hazard ratio (HR) was estimated through Cox proportional hazards model; p-value was generated from log rank test. Results: 88.4% (245/277) and 94.9% (130/137) of patients had an abnormal baseline CEA in the fruquintinib group and placebo group, respectively. Median baseline CEA values were similar between treatment groups. After 2 cycles of treatment, the proportion of patients had CEA response was significantly higher in the fruquintinib group than placebo group (30.0% vs. 1.3%, p < 0.001). In the fruquintinib group, patients with early CEA response (n = 63) had longer median OS (12.8 vs. 7.8 months, HR = 0.45, p < 0.001) and median PFS (5.6 vs. 3.7 months, HR = 0.49, p < 0.001) than patients without (n = 147). 66.7% (140/210) of patients in fruquintinib group had stable disease (SD), and fruquintinib in those patients with concomitant CEA response exhibited a significantly greater OS benefit than with CEA progression (14.4 vs. 8.7 months, HR = 0.38, p = 0.004). Conclusions: Fruquintinib increased early CEA response. CEA response at first radiological evaluation after cycle 2 could be considered as a predictor for better OS and PFS. Among patients with SD at first evaluation, those with CEA response seems benefit more from fruquintinib. Clinical trial information: NCT02314819 .
Correlation of existence and number of mutations in DDR signaling pathway genes with poor survival after resection of colorectal liver metastases.
Authors: Wang Kun , Wang Hongwei , Jin Kemin , Zhang Xiaoyu , Yang Chunhe , Xing Baocai 
Published: May 2020

e16004 Background: Patients of colorectal cancer with liver metastatic (CRLM) show various in recurrence and prognosis. Previous researches have revealed that the disfunction of DNA damage repair (DDR) signaling pathways was correlative with oncogenesis and poor prognosis. Here we aimed to determine the impact of DDR gene mutations on survival in patients undergoing CRLM resection. Methods: Tumor tissues from 164 patients with CRLM were collected for next generation sequencing (NGS). Single nucleotide variants, indels, and copy number variations were obtained from a 620-gene panel, including 68 genes in 7 DDR signaling pathways. Correlations of mutations in DDR genes with overall survival (OS) and recurrence-free survival (RFS) were determined by using Kaplan-Meier analysis. Results: 152/164 of patients carried at least one of DDR gene alternations. The most frequently mutated gene was TP53 (132/164), followed by CHEK2 (21/164), BRCA2 (10/164), ATM (9/164), PRKDC (8/164), FANCM (8/164), ATR (7/164), POLE (5/164), BRCA1 (4/164), POLD (3/164). Survival analysis indicated that TP53 mutations were not correlated with OS and RFS (P = 0.38 and 0.21). Further analysis in the TP53mut subgroup showed that the patients with other DDR gene mutations (64/132, 48.48%) exhibited a significantly worse OS than the wild type ones (P = 0.04). Especially, gene alternations involving in the Fanconi anemia (FA) pathway were significantly associated with worse OS and RFS (P = 0.0014 and 0.006). Interestingly, besides the TP53 mutation, patients carrying more than 2 other DDR gene mutations (10/64, 15.63%) also showed worse OS and RFS than patients with single mutation and wild type in DDR genes. (OS: 19 vs 35 months, P = 0.053; RFS: 3 vs 11 months, P = 0.084). Conclusions: Mutations in DDR signaling pathways predicted worse survival in TP53-mutated CRLM patients after surgery. These findings may be useful for clinical decision making in patients with tumor characteristics associated with poor prognosis and for risk stratification of patients in future clinical studies.
Relationship of KIAA1199 on neutrophil recruitment and promotion of colorectal cancer liver metastasis via TGF-β signaling.
Authors: Wang Haihong , Lin Zhenyu , Zhang Tao , Ren Jinghua 
Published: May 2020

e16005 Background: Metastasis is the main cause of cancer-related death governed by both cancer cell-intrinsic properties and extrinsic immune contexture. Our previous reports have suggested critical roles of KIAA1199 in tumor invasion and metastasis in colorectal cancer (CRC). In the present study, we explored the potential effects of KIAA1199 on pre-metastatic niche formation. Methods: The CIBERSORT algorithm analysis for 241 patients with colorectal cancer from the Cancer Genome Atlas was performed to investigate the relationship between KIAA1199 expression and neutrophil accumulation. Neutrophils and T cells were isolated, stimulated and/or cultured for in vitro function assays. Proteins were knocked down in MC38 and HCT116 colorectal cancer cell lines, which were analyzed by immunoblotting and chemotaxis assays. Results: We demonstrate that patients with high KIAA1199 showed an increased level of liver-infıltrating neutrophils, which is further validated using flow cytometry analyses in mouse metastasis model. The increased influx of neutrophils is associated with KIAA1199-driven CRC liver metastasis. Neutrophils isolated from pre-metastatic niche decreased CD8+ T cells infiltration and IFN-r+ CD8+ T cells proportion in vivo. Moreover, they showed a N2-like phenotype and expressed higher level immunosuppressive molecules when exposed to the supernatant of normal CRC cell compared to KIAA1199-knock down cell. In CRC cells, we also found a positive correlation between expression of KIAA1199 and genes that ELR+ chemotaxis of neutrophil (CXCL1/CXCL3/CXCL5), which recruited neutrophils to CRC tumor via CXCR2. Importantly, LY2109761, a TGF-β receptor inhibitor, is sufficient to reduce the mRNA levels of these genes. Furthermore, there is a positive correlation between expression of KIAA1199 and expression of Transforming Growth Factor beta pathway genes (TGFBR1, TGFBR2, and pSMAD3), and further co-immunoprecipitation analysis suggests that KIAA1199 may activate the TGF-β signaling pathway via interacting with the TGFBR1 or TGFBR2. Conclusions: Our data indicate that the upregulation of KIAA1199 may increase the expression of cytokines mediated by TGF-β signaling, which can recruit metastasis-supporting neutrophils to promote colorectal cancer liver metastasis. Blockade of the TGF-β signaling could be a novel therapeutic approach against KIAA1199-high expression CRC.