Egfr - Epidermal growth factor receptor
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Publication
Journal: BMC cancer
December/5/2018
Abstract
Agarose encapsulated murine renal adenocarcinoma cells (RENCA macrobeads) are currently being investigated in clinical trials as a treatment for therapy-resistant metastatic colorectal cancer. We have previously demonstrated the capacity of RENCA macrobeads to produce diffusible substances that markedly inhibit the proliferation of epithelial-derived tumor cells outside the macrobead environment. This study examined the molecular mechanisms underlying the observed inhibition in targeted tumor cells exposed to RENCA macrobeads.We evaluated changes in transcription factor responses, participating intracellular signaling pathways and the involvement of specific cellular receptors in targeted tumor cells exposed to RENCA macrobeads.Factors secreted by RENCA macrobeads significantly up-regulated the activity of the MEF2 transcription factor as well as altered the transcription of MEF2b and MEF2d isoforms in targeted tumor cells. Suppression of individual or multiple MEF2 isoforms in target tumor cells markedly reduced the growth inhibitory effects of RENCA macrobeads. Furthermore, these effects were linked to the activation of the EGF receptor as attenuation of EGFR resulted in a substantial reduction of the cancer cell growth-inhibitory effect.Since interruption of the EGFR signaling cascade did not eliminate RENCA macrobead-induced growth control, our data suggests that RENCA macrobeads exert their full growth inhibitory effects through the simultaneous activation of multiple signaling pathways. In contrast to a precision medicine approach targeting single molecular abnormalities, the RENCA macrobead functions as a biological-systems therapy to re-establish regulation in a highly dysfunctional and dysregulated cancer system.
Publication
Journal: Pediatric transplantation
March/27/2019
Abstract
RTx of adult-size kidneys presents a size mismatch in small pediatric recipients, and there are potential surgical complications. This study reveals the outcomes of intra- and extraperitoneal RTx in low-weight (less than 15 kg) pediatric recipients. We studied 51 pediatric patients weighing less than 15 kg who received a living-related donor renal transplant between 2009 and 2017. The intraperitoneal (group A, n = 24) and extraperitoneal (group B, n = 27) approaches were compared. In group A, the mean age, Ht, and weight were 3.8 ± 1.6 years, 83.7 ± 6.5 cm, 10.5 ± 1.8 kg; in group B, 5.0 ± 1.9 years, 95.3 ± 7.3 cm, and 13.0 ± 1.4 kg. Single renal artery grafts (21 in group A and 16 in group B) and double renal artery grafts (three in group A and 11 in group B) were performed. Of the patients with double renal artery transplants, one in group A and six in group B underwent ex vivo arterial reconstruction. The eGFR (mL/min/1.73 m2 ) at 1-week post-transplant in group A was significantly higher than that in group B; the eGFRs at 4 weeks post-transplant did not differ. One graft was lost in group B because of vascular thrombosis. Post-transplant complications included ileus and transplant ureteral stenosis. There was no significant difference in 5-year graft survival rate (group A 100%, group B 91.7%). Both transplant approaches are feasible to adapt to a size mismatch between the adult-size donor kidney and low-weight pediatric recipients.
Publication
Journal: Nature reviews. Drug discovery
December/28/2018
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Publication
Journal: Biochemical and biophysical research communications
April/17/2006
Abstract
Exposure of MDA-MB-468 cells to ionizing radiation (IR) caused biphasic activation of ERK as indicated by its phosphorylation at Thr202/Tyr204. Specific epidermal growth factor receptor (EGFR) inhibitor AG1478 and specific Src inhibitor PP2 inhibited IR-induced ERK1/2 activation but phosphatidylinositol-3 kinase inhibitor wortmannin did not. IR caused EGFR tyrosine phosphorylation, whereas it did not induce EGFR autophosphorylation at Tyr992, Tyr1045, and Tyr1068 or Src-dependent EGFR phosphorylation at Tyr845. SHP-2, which positively regulates EGFR/Ras/ERK signaling cascade, became activated by IR as indicated by its phosphorylation at Tyr542. This activation was inhibited by PP2 not by AG1478, which suggests Src-dependent activation of SHP-2. Src and PTPalpha, which positively regulates Src, became activated as indicated by phosphorylation at Tyr416 and Tyr789, respectively. These data suggest that IR-induced ERK1/2 activation involves EGFR through a Src-dependent pathway that is distinct from EGFR ligand activation.
Publication
Journal: Journal of animal science and biotechnology
December/7/2018
Abstract
DNA methylation plays a vital role in reproduction. Entire genome DNA methylation changes during the oestrous phase (ES) and dioestrous phase (DS) in the ovaries of Guanzhong dairy goats were investigated using bisulphite sequencing to understand the molecular biological mechanisms of these goats' oestrous cycle.

Results
We discovered distinct genome-wide DNA methylation patterns in ES and DS ovaries. A total of 26,910 differentially methylated regions were upregulated and 21,453 differentially methylated regions were downregulated in the ES samples compared with the DS samples (P-values ≤0.05 and fold change of methylation ratios ≥2). Differentially methylated region analysis showed hypomethylation in the gene body regions and hypermethylation in the joining region between upstream regions and gene bodies. The methylation ratios of the STAR, FGF2, FGF12, BMP5 and SMAD6 genes in the ES samples were lower than those of the DS samples (P-values ≤0.05 and fold change of methylation ratios ≥2). Conversely, the methylation ratios of the EGFR, TGFBR2, IGF2BP1 and MMD2 genes increased in the ES samples compared with the DS samples. In addition, 223 differentially methylated genes were found in the GnRH signalling pathway (KO04912), ovarian steroidogenesis pathway (KO04913), oestrogen signalling pathway (KO04915), oxytocin signalling pathway (KO04921), insulin secretion pathway (KO04911) and MAPK signalling pathway (KO04010).

Conclusions
This study is the first large-scale comparison of the high-resolution DNA methylation landscapes of oestrous and dioestrous ovaries from dairy goats. Previous studies and our investigations have shown that the NR5A2, STAR, FGF2 and BMP5 genes might have potential application value in regulating caprine oestrus.

Publication
Journal: Clinical chemistry
December/7/2018
Abstract
The comeasurement of both genomic and transcriptomic signatures in single cells is of fundamental importance to accurately assess how the genetic information correlates with the transcriptomic phenotype. However, existing technologies have low throughput and laborious work flows.We developed a new method for concurrent sequencing of the transcriptome and targeted genomic regions (CORTAD-seq) within the same single cell on an automated microfluidic platform. The method was compatible with the downstream library preparation, allowing easy integration into existing next-generation sequencing work flows. We incorporated a single-cell bioinformatics pipeline for transcriptome and mutation analysis.

RESULTS
As proof of principle, we applied CORTAD-seq to lung cancer cell lines to dissect the cellular consequences of mutations that result in resistance to targeted therapy. We obtained a mean detection of 6000 expressed genes and an exonic rate of 50%. The targeted DNA-sequencing data achieved a 97.8% detection rate for mutations and allowed for the identification of copy number variations and haplotype construction. We detected expression signatures of tyrosine kinase inhibitor (TKI) resistance, epidermal growth factor receptor (EGFR) amplification, and expansion of the T790M mutation among resistant cells. We also identified characteristics for TKI resistance that were independent of EGFR T790M, indicating that other alterations are required for resistance in this context.

CORTAD-seq allows assessment of the interconnection between genetic and transcriptomic changes in single cells. It is operated on an automated, commercially available single-cell isolation platform, making its implementation straightforward.
Publication
Journal: Frontiers in cell and developmental biology
February/19/2019
Publication
Journal: In vivo (Athens, Greece)
November/13/2018
Abstract
OBJECTIVE
The aim of this study was to evaluate the relationship between T790M status and the characteristics of non-small cell lung cancer (NSCLC) patients undergoing rebiopsy after initial epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy and whether the site of rebiopsy has an effect on the detection rate for T790M in these patients.
METHODS
We retrospectively reviewed the clinical data from stage IV or recurrent NSCLC patients who harbored EGFR mutations and who had initially received EGFR-TKI at our Center from January 2009 to December 2016.
RESULTS
Overall, 129 patients were included. The median age at EGFR-TKI therapy initiation was 73 years and 110 showed progressive disease. The presence of T790M mutation was associated with significantly longer progression-free survival (PFS) and EGFR mutation status. The participants' characteristics and rebiopsy site did not affect the T790M detection rate.
CONCLUSIONS
It is highly recommended that patients with exon 19 deletions and long PFS undergo screening for T790M.
Publication
Journal: Urology
December/31/2018
Abstract
To investigate the relationship between postoperative renal function and resected cortex margin volume calculated by a 3-dimensional reconstruction technique based on the resected specimen, and to determine predictors of renal function after robot-assisted partial nephrectomy.A total of 114 patients underwent robot-assisted partial nephrectomy from 2014 to 2018. Patients without a 1 mm slice computed tomography or renal scintigraphy were excluded. We identified the margins of the tumor from each resected specimen with 2 mm margin being added as the ischemic margin. The volume of the renal cortex was calculated automatically using 3-dimensional volume analyzer software. The total margin volume was excluded from the ipsilateral cortex volume to calculate the cortex volume split. Predicted estimated glomerular filtration rate (eGFR) was calculated using the change in cortex volume and then compared with the actual eGFR.Eighty-two patients were included in this retrospective study. Sixty-six patients (80%) were cT1a. A strong correlation was observed between renal scintigraphy split and pre- and postoperative cortex volume split (Pearson correlation coefficient r = 0.9330 and 0.8742, respectively). The predicted eGFR correlated strongly with post 1, 3, 6, and 12 months eGFR (r = 0.8929, 0.9294, 0.9320, and 0.8952, respectively). Preoperative relative renal function and total cortex margin volume were independent risk factors for decreasing postoperative renal function.This precise volumetric assessment that includes the resected margin is an alternative to renal scintigraphy for predicting postoperative relative renal function. The healthy cortex margin volume calculated by the reconstruction technique is an independent risk factor of decreasing postoperative renal function.
Publication
Journal: Journal of immunology research
December/31/2018
Abstract
Previously, we developed a novel EGFR-targeted antibody (denoted as Pan), which has superior antitumor activity against EGFR-overexpressed tumors. However, it shows marginal effect on the growth of esophageal cancers. Therefore, the variable region of Pan was fused to a fragment of Pseudomonas exotoxin A (PE38) to create the immunotoxin, denoted as Ptoxin (PT). Results indicated that PT shows more effective antitumor activity as compared with Pan both on EGFR-overexpressed KYSE-450 and KYSE-150 esophageal cancer cells, especially on KYSE-450 cells. Moreover, treatment of PT induces regression of KYSE-450 tumor xenografts in nude mice. Furthermore, we investigated the potential mechanism involved in the enhanced antitumor effects of PT. Data showed that PT was more potent in reducing the phosphorylation of EGFR and ERK1/2. More importantly, we for the first time found that PT was more effective than Pan in inducing ROS accumulation by suppression of the Nrf2-Keap1 antioxidant pathway, and then induced apoptosis in KYSE-450 esophageal cancer cells, which may partly explain the more sensitive response of KYSE-450 to PT treatment. To conclude, our study provides a promising therapeutic approach for immunotoxin-based esophageal cancer treatment.
Publication
Journal: Journal of clinical pharmacy and therapeutics
December/22/2018
Abstract
The use of cisplatin in the treatment of lung carcinoma is limited by nephrotoxicity. The aim of this study was to determine whether the incidence of nephrotoxicity in patients with lung carcinoma is affected by the infusion rate of cisplatin (rapid infusion of cisplatin in 1 hour compared to regular infusion in 3 hours).This observational, retrospective study was performed on patients diagnosed with non-small-cell lung carcinoma (NSCLC), small-cell lung carcinoma (SCLC) or mesothelioma receiving a cisplatin-containing chemotherapy regimen. Patients were divided into two cohorts (infusion of cisplatin in 1 hour vs 3 hours) based on the starting date of the chemotherapy regimen. The primary objectives were the difference in renal function after three cycles of chemotherapy and the incidence of nephrotoxicity. To assess nephrotoxicity, both the incidence of acute kidney injury (AKI) grade 1 and the maximum decrease in estimated glomerular filtration rate (eGFR) were determined.A total of 230 lung carcinoma patients with a cisplatin-containing chemotherapy regimen were included. Baseline characteristics were similar for the rapid and regular infusion cohorts, except for type of lung carcinoma, chemotherapy regimen and prevalence of hypertension. There was no significant difference in renal function between rapid infusion of cisplatin and regular infusion of cisplatin (eGFR 86.1 mL/min [71.0-96.3] vs 87.9 mL/min [71.6-97.3]; P = 0.938). The incidence of AKI grade 1 was not significantly different between rapid and regular infusion of cisplatin (29.3% vs 29.8%; P = 0.932). The maximum decrease in eGFR was 14.8 mL/min in the rapid infusion cohort and 17.7 mL/min in the regular infusion cohort (P = 0.364).The incidence of nephrotoxicity after repeated infusion of cisplatin was not affected by the infusion rate of cisplatin. Therefore, a 1-hour infusion of cisplatin is a safe and feasible method, which may potentially shorten duration of hospital admittance and enable treating patients in the outpatient setting.
Publication
Journal: Journal of the National Comprehensive Cancer Network : JNCCN
December/14/2018
Publication
Journal: Journal of developmental biology
December/14/2018
Abstract
EGF, emitted by the Anchor Cell, patterns six equipotent C. elegans vulval precursor cells to assume a precise array of three cell fates with high fidelity. A group of core and modulatory signaling cascades forms a signaling network that demonstrates plasticity during the transition from naïve to terminally differentiated cells. In this review, we summarize the history of classical developmental manipulations and molecular genetics experiments that led to our understanding of the signals governing this process, and discuss principles of signal transduction and developmental biology that have emerged from these studies.
Publication
Journal: Acta biochimica et biophysica Sinica
August/19/2018
Abstract
Filamin A (FLNa) is a ubiquitously expressed cytoplasmic protein, which composes of an N-terminal actin binding domain (ABD) followed by 24 Ig-like repeats. FLNa functions as a cytoskeletal protein that links transmembrane receptors, including integrins, to F-actin and serves as a signaling intermediate. Recent studies have identified FLNa as a scaffold protein that interacts with over 90 proteins and plays vital roles in cellular signaling transduction. Mutations or defects in human FLNa gene have been shown to cause numerous developmental defects. Moreover, aberrant expression of FLNa has been observed in many cancers, such as parathyroid tumor, cervical cancer, and breast cancer. However, its role in lung adenocarcinoma has seldom been discussed. In the present study, our in vitro and in vivo studies demonstrated that silencing FLNa expression in lung cancer cell line A549 cells promoted proliferation, migration, and invasiveness of A549 cells by enhancing the activation of epidermal growth factor receptor and ERK signaling pathway. These results shed light on novel functions of FLNa in lung cancer and uncovered novel mechanisms, these results provided possible targets for the prediction and treatment for lung adenocarcinoma.
Publication
Journal: Turk patoloji dergisi
December/31/2018
Abstract
The purpose of our study was to assess trophoblastic and uterine sufficiency in miscarriage pathogenesis with immunohistochemical methods and to determine if they could be used as a screening tool for the risk of miscarriage in the future.Placental tissue specimens that were comprised of 20 spontaneous abortions, 23 voluntarily terminated (induced) abortions, and 12 tubal pregnancies were included in this study. Trophoblastic cells and implantation area were evaluated for staining with EGFR-1, MMP-3, and MMP-9 by immunohistochemistry.EGFR-1 expression was more intense and diffuse in decidual cells in the placental bed of spontaneous abortion specimens; this difference was statistically significant (P=0.004). MMP-3 expression was markedly increased in villous and extravillous trophoblastic cells in induced abortions; the difference between the groups was found to be statistically significant (P values ranged from < 0.01 to 0.005). MMP-9 expression tended to be higher in spontaneous abortion and tubal pregnancy specimens, and the results were statistically significant as P values were lower than 0.01.Higher EGFR-1 expression in the decidual tissue of spontaneous abortion specimens suggests that EGFR-1 triggers the migration of extravillous trophoblasts, leading to their destructive invasion. Similarly, MMP-9 immunopositivity might be indicative of aggressive invasion contributing to spontaneous abortion pathogenesis. Relatively high levels of MMP-3 expression in induced abortion specimens used as a control group might be a predictor of successful implantation, whereas its decreased expression might be indicative of risk for pregnancy loss.
Publication
Journal: The Lancet. Oncology
September/16/2019
Publication
Journal: Therapeutic apheresis and dialysis : official peer-reviewed journal of the International Society for Apheresis, the Japanese Society for Apheresis, the Japanese Society for Dialysis Therapy
October/1/2019
Abstract
High body mass index (BMI) is the most common parameter to assess excess adiposity, and has been linked to glomerular hyperfiltration (GH). However, BMI may be misleading in the estimation of body fat content due to its inability to discriminate between body fat and lean mass. In recent years, the convenient biological impedance analysis (BIA) has made prediction of certain diseases somewhat feasible and accessible using body composition (BC). Accordingly, we conducted a cross-sectional study to explore the association between BC and GH among Chinese adult population. A total of 6902 adults (aged 38.6 ± 8.3 years, 70.1% males) who consecutively visited the Health Checkup Clinic were enrolled. BC including fat mass and lean body mass (LBM) was evaluated by BIA. The upper quartile of eGFR which exceeded 117.3 mL/min/1.73 m2 was defined as GH, in comparison with the lower three quartiles (control group). As a categorical outcome, GH subjects had higher fat/LBM than the control group, which was 34.7 ± 10.9 (%) vs. 34.0 ± 10.5 (%), P = 0.01; however, the BMI in GH group was lower than in the control group, which was 24.5 ± 3.7 (%) vs. 24.9 ± 3.6 (%), P<0.001. Fat/height and Fat/BSA were not significantly different between the two groups. Moreover, after adjusted for potential confounders, fat/LBM significantly correlated with GH (OR = 2.09, 95% CI, 1.11 to 3.93). The study revealed that fat/LBM significantly correlated with GH among Chinese adult population, which highlights that adiposity might be an important and potentially modifiable determinant of GH. This article is protected by copyright. All rights reserved.
Publication
Journal: Medicine
October/25/2019
Abstract
The aim of this meta-analysis is to investigate the impact of Osimertinib on treatment efficacy in advanced nonsmall cell lung cancer (NSCLC).Trials comparing Osimertinib against epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs)/chemotherapy in patients with NSCLC with an epidermal growth factor receptor (EGFR) mutation were included, and the pooled data for progression-free survival (PFS), overall survival (OS), overall response rate (ORR), disease control rate (DCR), and adverse events (AEs) were analyzed.Analysis results based on 6 eligible trials showed that Osimertinib significantly improved the overall PFS (hazard ratio [HR] = 0.38, 95% confidence interval [CI] = 0.29-0.50), improved the OS (HR = 0.66, 95% CI = 0.48-0.89), increased the ORR (odds ratio [OR] = 1.76, 95% CI = 1.14-2.72), increased the overall DCR (OR = 1.18, 95% CI = 1.02-1.37), and reduced the grade 3 or greater AEs (relative ratio [RR] = 0.50, 95% CI = 0.33-0.75) in all subgroups except in the ORR in the Exon 19 deletion (Ex19del) and/or L858R subgroup. Compared to patients with Ex19del and/or L858R mutation, patients with the T790M mutation had the benefits of a greater PFS (41.7%), a greater ORR (80.0%), a greater DCR (71.2%), and fewer grade 3 or greater AEs (70.7%) (each P < .05). Race, sex, age, EGFR mutation, and smoking history may significantly predict additional benefits from Osimertinib, but there were no significant differences between subgroups stratified by these clinical characteristics.Osimertinib showed greater treatment benefit for patients with NSCLC with EGFR mutation than EGFR-TKIs/chemotherapy, especially for T790M mutation-positive patients.
Publication
Journal: The Journal of clinical investigation
October/29/2019
Abstract
Immunotherapy targeting programmed cell death-1 (PD-1) induces durable antitumor efficacy in many types of cancer. However, such clinical benefit is limited because of the insufficient reinvigoration of antitumor immunity with the drug alone; therefore, rational therapeutic combinations are required to improve its efficacy. In our preclinical study, we evaluated the antitumor effect of U3-1402, a human epidermal growth factor receptor 3 (HER3)-targeting antibody-drug conjugate, and its potential synergism with PD-1 inhibition. Using a syngeneic mouse tumor model that is refractory to anti-PD-1 therapy, treatment with U3-1402 exhibited an obvious antitumor effect via direct lysis of tumor cells. Disruption of tumor cells by U3-1402 enhanced the infiltration of innate and adaptive immune cells. Chemotherapy with exatecan derivative (Dxd: the drug payload of U3-1402) revealed that the enhanced antitumor immunity produced by U3-1402 was associated with the induction of alarmins including HMGB-1 via tumor-specific cytotoxicity. Notably, U3-1402 significantly sensitized the tumor to PD-1 blockade, as a combination of U3-1402 and the PD-1 inhibitor significantly enhanced antitumor immunity. Further, clinical analyses indicated that tumor-specific HER3 expression was frequently observed in patients with PD-1 inhibitor-resistant solid tumors. Overall, U3-1402 is a promising candidate as a partner of immunotherapy for such patients.
Publication
Journal: Journal of cellular and molecular medicine
November/6/2019
Abstract
The antitumour effect of melittin (MEL) has recently attracted considerable attention. Nonetheless, information regarding the functional role of MEL in bladder cancer (BC) is currently limited. Herein, we investigated the effect of MEL on critical module genes identified in BC. In total, 2015 and 4679 differentially expressed genes (DEGs) associated with BC were identified from the GSE31189 set and The Cancer Genome Atlas database, respectively. GSE-identified DEGs were mapped and analysed using Gene Ontology and Kyoto Encyclopaedia of Genes and Genomes analyses to determine BC-involved crucial genes and signal pathways. Coupled with protein-protein interaction network and Molecular Complex Detection analyses, Modules 2 and 4 were highlighted in the progression of BC. In in-vitro experiments, MEL inhibited the proliferation, migration, and invasion of UM-UC-3 and 5637 cells. The expression of NRAS, PAK2, EGFR and PAK1 in Module 4-enriched in the MAPK signalling pathway-was significantly reduced after treatment with MEL at concentrations of 4 or 6 μg/mL. Finally, quantitative reverse transcription-polymerase chain reaction and Western blotting analyses revealed MEL inhibited the expression of genes at the mRNA (ERK1/2, ERK5, JNK and MEK5), protein (ERK5, MEK5, JNK and ERK1/2) and phosphorylation (p-ERK1/2, p-JNK, and p-38) levels. This novel evidence indicates MEL exerts effects on the ERK5-MAK pathway-a branch of MAPK signalling pathway. Collectively, these findings provide a theoretical basis for MEL application in BC treatment.
Publication
Journal: Journal of cancer research and clinical oncology
November/2/2019
Abstract
Partial nephrectomy has been persuaded as a widely accepted surgical procedure for T1a (≤ 4 cm) renal tumors. However, when treating T1b (4-7 cm) renal cell carcinoma (RCC), the "optimal" method of surgery is still debatable. The aim of the research is to evaluate the long-term oncological and renal functional outcomes of laparoscopic radical nephrectomy (LRN) versus laparoscopic partial nephrectomy (LPN) for patients with T1b RCC.From March 1, 2003 to July 1, 2016, 331 patients were included in the current study. Patients presented with unilateral T1b RCC and underwent either LPN (n = 177) or LRN (n = 154). Relevant clinical data including follow-ups were acquired from patients.The operation time of the LPN group patients was longer than that of LRN group (94.3 min vs 88.3 min, p = 0.021) and LPN group patients required shorter stays in hospital (11.5 days vs. 13.4 days, p = 0.009). Contrast to LRN, level of eGFR was superior in LPN at the postoperative time of 1 day, 3 months, 6 months, 12 months and 24 months (all p < 0.001). Kaplan-Meier plots and log-rank tests showed that patients undergoing LPN had a much higher overall survival (OS) (p = 0.007), cancer-specific survival (CSS) (p = 0.006) and metastasis-free survival (MFS) (p = 0.008) than those receiving LRN. In comparison with the LRN group, multivariable Cox analysis indicated that patients of the LPN group had a 1.9-fold OS, 2.9-fold CSS and 2.3-fold MFS.For patients with T1b RCC, our findings revealed that OS, CSS and MFS are superior in patients receiving LPN than those treated with LRN. With the benefit of preserving renal function of LPN, which leads a less incidence risk of other systematic diseases, LPN may be the preferred option when condition permits for cases involving T1b RCC.
Publication
Journal: European journal of cancer (Oxford, England : 1990)
October/21/2019
Abstract
We conducted a double-randomised phase III trial to evaluate a concomitant taxane-anthracycline regimen in node-positive breast cancer and the efficacy of trastuzumab in the human epidermal growth factor receptor 2 (HER2)-positive subpopulation.

METHODS
A total of 3010 patients with node-positive breast cancer were randomly assigned to receive 6 cycles of 500 mg/m2 of fluorouracil, 100 mg/m2 of epirubicin and 500 mg/m2 of cyclophosphamide (FEC) or 75 mg/m2 of epirubicin and 75 mg/m2 of docetaxel (ED). Patients with HER2-positive tumours were secondary randomly assigned to either trastuzumab or observation. The primary end-point was disease-free survival (DFS) in the two chemotherapy arms.

After a 115-month median follow-up, DFS was not significantly better in the ED arm (DFS: 70%, 95% confidence interval [CI]: 67-72) than in the FEC arm (DFS: 68%, 95% CI: 65-70; hazard ratio [HR] = 0.88, 95% CI: 0.77-1.01; p = 0.064). The OS was not different between FEC (OS: 80%, 95% CI: 78-83) and ED (OS: 81%, 95% CI: 79-83); HR = 0.97, 95% CI: 0.81-1.16; p = 0.729). ED appeared more toxic. In the 528 HER2-positive subset, there was trend for a higher DFS, in the intention-to-treat population, in the trastuzumab arm (DFS: 68%, 95% CI: 61-74) than in the observation arm (DFS: 60%, 95% CI: 54-66; HR = 0.77, 95% CI: 0.57-1.03; p = 0.079). In the per-protocol population, DFS was significantly higher in the trastuzumab arm (DFS: 70%, 95% CI: 63-76) than in the observation arm (DFS: 59%, 95% CI: 53-65; HR = 0.69, 95% CI: 0.51-0.94; p = 0.0156). The OS was not different between these 2 arms.This study did not show superiority of the concomitant anthracycline-taxane arm which was more toxic in high-risk node-positive breast cancer patients. Long-term results of the HER2-positive subpopulation are in line with those of the other adjuvant trastuzumab trials but quantitatively less pronounced mostly because of lack of power.
Publication
Journal: Nederlands tijdschrift voor geneeskunde
December/20/2018
Abstract
The objective of this study is to determine at a national level whether patients with metastatic non-small cell lung cancer (NSCLC) are adequately tested for EGFR mutations and ALK rearrangement, because targeted therapy is tailored to the results of molecular diagnostics.Retrospective cohort study.Data from all patients with metastatic non-squamous NSCLC diagnosed in 2013 or 2015 were identified from the Netherlands Cancer Registry, and coupled with data from the Netherlands national pathology registry (PALGA). Using information extracted from PALGA we determined what percentage of the tumours were tested for EGFR or KRAS mutations and ALK rearrangement, identified the variables that were associated with the performance of molecular diagnostics and investigated the differences between 48 laboratories.A total of 6,619 patients were included (2013: n = 3,195; 2015: n = 3,424). In 2013, EGFR or KRAS testing was performed on 73.1% of the tumours (variation between laboratories 30.6-91.7%); in 2015 this was 78.9% (variation 40.0-91.0%). In 2013 49.5% of the tumours without EGFR or KRAS mutations underwent ALK testing (variation between laboratories 6.3-100%) and in 2015 ALK testing was performed on 77.4% (32.5-100%). In 2015, 6 and 7 laboratories tested significantly fewer EGFR and ALK tests, respectively, than the national average.In 2013, molecular testing for EGFR and KRAS mutations and, in particular, for ALK rearrangement was suboptimal. EGFR and ALK testing was performed significantly more often in 2015. Despite this increase, there is room for improvement in a number of laboratories and hospitals, considering that some patients were possibly wrongly not eligible for targeted therapy.
Publication
Journal: BMC cancer
June/29/2019
Abstract
In the management of patients with RAS wild-type metastatic colorectal cancer (mCRC), anti-epidermal growth factor receptor (EGFR) therapies have demonstrated a clinical benefit, with longer survival. However, the correlation between the emergence of circulating RAS mutations and secondary resistance to anti-EGFR therapies requires further elucidation. In this study, we aim to examine evolutionary changes in RAS mutations through liquid biopsy in patients with mCRC during and after anti-EGFR therapy.A total of 120 patients diagnosed with RAS wild-type mCRC will be enrolled in this study. Patients will receive a cetuximab-based infusional 5-fluorouracil regimen as first-line treatment. Cetuximab-based treatment is expected to continue until disease progression, intolerable toxic effects, or withdrawal of consent. Blood samples from enrolled patients will be collected before and then every 3 months during cetuximab-based treatment and also at disease progression. These blood samples will be evaluated for RAS resistance mutations by using the MassARRAY platform. The primary endpoint is the percentage of RAS mutations detected in circulating DNA from patients during cetuximab treatment. The correlation between the tumor response and survival outcomes of these patients and the emergence of circulating RAS mutations will be further analyzed.Liquid biopsy is a powerful technology that can represent tumor heterogeneity in a relatively noninvasive manner. Because RAS mutations play a major role in resistance to anti-EGFR therapy for mCRC, examining evolutionary changes in these mutations during such treatment through liquid biopsy would be useful. After comprehensively analyzing the emergence of circulating RAS mutations and its clinical relevance in this study, our results should provide practical guidance on anti-EGFR therapy for mCRC.The date of trial registration ( NCT03401957 ) in this study was January 17, 2018.
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