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VEGF-Related Germinal Polymorphisms May Identify a Subgroup of Breast Cancer Patients with Favorable Outcome under Bevacizumab-Based Therapy-A Message from COMET, a French Unicancer Multicentric Study.

ABSTRACT: The prospective multicenter COMET trial followed a cohort of 306 consecutive metastatic breast cancer patients receiving bevacizumab and paclitaxel as first-line chemotherapy. This study was intended to identify and validate reliable biomarkers to better predict bevacizumab treatment outcomes and allow for a more personalized use of this antiangiogenic agent. To that end, we aimed to establish risk scores for survival prognosis dichotomization based on classic clinico-pathological criteria combined or not with single nucleotide polymorphisms (SNPs). The genomic DNA of 306 patients was extracted and a panel of 13 SNPs, covering seven genes previously documented to be potentially involved in drug response, were analyzed by means of high-throughput genotyping. In receiver operating characteristic (ROC) analyses, the hazard model based on a triple-negative cancer phenotype variable, combined with specific SNPs in VEGFA (rs833061), VEGFR1 (rs9582036) and VEGFR2 (rs1870377), had the highest predictive value. The overall survival hazard ratio of patients assigned to the poor prognosis group based on this model was 3.21 (95% CI (2.33-4.42); p < 0.001). We propose that combining this pharmacogenetic approach with classical clinico-pathological characteristics could markedly improve clinical decision-making for breast cancer patients receiving bevacizumab-based therapy.

SUBMITTER: Gal J

PROVIDER: S-EPMC7700430 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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VEGF-Related Germinal Polymorphisms May Identify a Subgroup of Breast Cancer Patients with Favorable Outcome under Bevacizumab-Based Therapy-A Message from COMET, a French Unicancer Multicentric Study.

Gal Jocelyn J Milano Gérard G Brest Patrick P Ebran Nathalie N Gilhodes Julia J Llorca Laurence L Dubot Coraline C Romieu Gilles G Desmoulins Isabelle I Brain Etienne E Goncalves Anthony A Ferrero Jean-Marc JM Cottu Paul-Henri PH Debled Marc M Tredan Olivier O Chamorey Emmanuel E Merlano Marco Carlo MC Lemonnier Jérôme J Etienne-Grimaldi Marie-Christine MC Pierga Jean-Yves JY

Pharmaceuticals (Basel, Switzerland) 20201123 11

The prospective multicenter COMET trial followed a cohort of 306 consecutive metastatic breast cancer patients receiving bevacizumab and paclitaxel as first-line chemotherapy. This study was intended to identify and validate reliable biomarkers to better predict bevacizumab treatment outcomes and allow for a more personalized use of this antiangiogenic agent. To that end, we aimed to establish risk scores for survival prognosis dichotomization based on classic clinico-pathological criteria combi ...[more]

PMID: 33238394

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Project description:ImportanceSecond-line treatment with chemotherapy plus bevacizumab or cetuximab is a valid option for metastatic colorectal cancer.ObjectiveTo evaluate the progression-free survival (PFS) rate at 4 months with chemotherapy plus bevacizumab vs cetuximab for patients with progression of metastatic colorectal cancer after bevacizumab plus chemotherapy.Design, setting, and participantsA prospective, open-label, multicenter, randomized phase 2 trial was conducted from December 14, 2010, to May 5, 2015. The main eligibility criterion was disease progression after bevacizumab plus fluorouracil with irinotecan or oxaliplatin in patients with wild-type KRAS exon 2 metastatic colorectal cancer. All analyses were performed on the modified intent-to-treat population.InterventionsPatients were randomized to arm A (FOLFIRI [fluorouracil and folinic acid combined with irinotecan] or modified FOLFOX6 [fluorouracil and folinic acid combined with oxaliplatin] plus bevacizumab) or arm B (FOLFIRI or modified FOLFOX6 plus cetuximab); the second-line chemotherapy regimen was chosen according to first-line treatment (crossover).Main outcomes and measuresThe primary end point was the 4-month PFS rate. Secondary end points included safety, objective response rate, overall survival, and PFS.ResultsA total of 132 patients (47 women and 85 men; median age, 63.0 years [range, 33.0-84.0 years]; 74 patients with an Eastern Cooperative Oncology Group performance status of 0, 54 patients with a performance status of 1, and 4 patients with unknown performance status) were included at 25 sites. The 4-month PFS rate was 80.3% (95% CI, 68.0%-88.3%) in arm A and 66.7% (95% CI, 53.6%-76.8%) in arm B. The median PFS was 7.1 months (95% CI, 5.7-8.2 months) in arm A and 5.6 months (95% CI, 4.2-6.5 months) in arm B (hazard ratio, 0.71; 95% CI, 0.50-1.02; P = .06), and the median overall survival was 15.8 months (95% CI, 9.5-22.3 months) in arm A and 10.4 months (95% CI, 7.0-16.2 months) in arm B (hazard ratio, 0.69; 95% CI, 0.46-1.04; P = .08). A central analysis of KRAS (exons 2, 3, and 4), NRAS (exons 2, 3, and 4), and BRAF (V600) was performed for 95 tumor samples. Eighty-one patients had wild-type KRAS and wild-type NRAS tumors.Conclusions and relevanceThe results of the PRODIGE18 (Partenariat de Recherche en Oncologie DIGEstive) study showed a nonsignificant difference but favored continuation of bevacizumab with chemotherapy crossover for patients with wild-type RAS metastatic colorectal cancer that progressed with first-line bevacizumab plus chemotherapy.Trial registrationClinicalTrials.gov identifier: NCT01442649 and clinicaltrialsregister.eu identifier: EUDRACT 2009-012942-22.

Project description:OBJECTIVES:To evaluate the accuracy of diagnoses of COVID-19 based on chest CT as well as inter-observer agreement between teleradiologists during on-call duty and senior radiologists in suspected COVID-19 patients. MATERIALS AND METHODS:From March 13, 2020, to April 14, 2020, consecutive suspected COVID-19 adult patients who underwent both an RT-PCR test and chest CT from 15 hospitals were included in this prospective study. Chest CTs were immediately interpreted by the on-call teleradiologist and were systematically blind reviewed by a senior radiologist. Readings were categorised using a five-point scale: (1) normal; (2) non-infectious findings; (3) infectious findings but not consistent with COVID-19 infection; (4) consistent with COVID-19 infection; and (5) typical appearance of COVID-19 infection. The diagnostic accuracy of chest CT and inter-observer agreement using the kappa coefficient were evaluated over the study period. RESULTS:In total, 513 patients were enrolled, of whom 244/513 (47.6%) tested positive for RT-PCR. First readings were scored 4 or 5 in 225/244 (92%) RT-PCR+ patients, and between 1 and 3 in 201/269 (74.7%) RT-PCR- patients. The data were highly consistent (weighted kappa = 0.87) and correlated with RT-PCR (p < 0.001, AUC1st-reading = 0.89, AUC2nd-reading = 0.93). The negative predictive value for scores of 4 or 5 was 0.91-0.92, and the PPV for a score of 5 was 0.89-0.96 at the first and second readings, respectively. Diagnostic accuracy was consistent over the study period, irrespective of a variable prevalence rate. CONCLUSION:Chest CT demonstrated high diagnostic accuracy with strong inter-observer agreement between on-call teleradiologists with varying degrees of experience and senior radiologists over the study period. KEY POINTS:• The accuracy of readings by on-call teleradiologists, relative to second readings by senior radiologists, demonstrated a sensitivity of 0.75-0.79, specificity of 0.92-0.97, NPV of 0.80-0.83, and PPV of 0.89-0.96, based on "typical appearance," as predictive of RT-PCR+. • Inter-observer agreement between the first reading in the emergency setting and the second reading by the senior emergency teleradiologist was excellent (weighted kappa = 0.87).

Project description:BACKGROUND:It is well known that the standard doses of a given drug may not have equivalent effects in all patients. To date, the management of depression remains mainly empirical and often poorly evaluated. The development of a personalized medicine in psychiatry may reduce treatment failure, intolerance or resistance, and hence the burden and costs of mood depressive disorders. The Geneva Cocktail Phenotypic approach presents several advantages including the "in vivo" measure of different cytochromes and transporter P-gp activities, their simultaneous determination in a single test, avoiding the influence of variability over time on phenotyping results, the administration of low dose substrates, a limited sampling strategy with an analytical method developed on DBS analysis. The goal of this project is to explore the relationship between the activity of drug-metabolizing enzymes (DME), assessed by a phenotypic approach, and the concentrations of Venlafaxine (VLX) + O-demethyl-venlafaxine (ODV), the efficacy and tolerance of VLX. METHODS/DESIGN:This study is a multicentre prospective non-randomized open trial. Eligible patients present a major depressive episode, MADRS over or equal to 20, treatment with VLX regardless of the dose during at least 4 weeks. The Phenotype Visit includes VLX and ODV concentration measurement. Following the oral absorption of low doses of omeprazole, midazolam, dextromethorphan, and fexofenadine, drug metabolizing enzymes activity is assessed by specific metabolite/probe concentration ratios from a sample taken 2 h after cocktail administration for CYP2C19, CYP3A4, CYP2D6; and by the determination of the limited area under the curve from the capillary blood samples taken 2-3 and 6 h after cocktail administration for CYP2C19 and P-gp. Two follow-up visits will take place between 25 and 40 days and 50-70 days after inclusion. They include assessment of efficacy, tolerance and observance. Eleven french centres are involved in recruitment, expected to be completed within approximately 2 years with 205 patients. Metabolic ratios are determined in Geneva, Switzerland. DISCUSSION:By showing an association between drug metabolism and VLX concentrations, efficacy and tolerance, there is a hope that testing drug metabolism pathways with a phenotypical approach would help physicians in selecting and dosing antidepressants. The MARVEL study will provide an important contribution to increasing the knowledge of VLX variability and in optimizing the use of methods of personalized therapy in psychiatric settings. TRIAL REGISTRATION:ClinicalTrials.gov NCT02590185 (10/27/2015). This study is currently recruiting participants.

Dataset Information

VEGF-Related Germinal Polymorphisms May Identify a Subgroup of Breast Cancer Patients with Favorable Outcome under Bevacizumab-Based Therapy-A Message from COMET, a French Unicancer Multicentric Study.

Publications

VEGF-Related Germinal Polymorphisms May Identify a Subgroup of Breast Cancer Patients with Favorable Outcome under Bevacizumab-Based Therapy-A Message from COMET, a French Unicancer Multicentric Study.

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