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Maarten Naesens - One of the best experts on this subject based on the ideXlab platform.
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antibody mediated rejection with and without donor specific anti human leucocyte antigen antibodies performance of the peripheral blood 8 Gene Expression Assay
2020Co-Authors: Elisabet Van Loon, Evelyne Lerut, Henriette De Loor, Dirk Kuypers, Mariepaule Emonds, Dany Anglicheau, Wilfried Gwinner, Marie Essig, Pierre Marquet, Maarten NaesensAbstract:Background Recently a peripheral blood 8-Gene Expression Assay was developed for non-invasive detection of antibody-mediated rejection (ABMR) after kidney transplantation. Its value has not yet been evaluated in detail in clinical scenarios with different baseline disease probability [human leucocyte antigen donor-specific antibodies (HLA-DSA)-positive versus HLA-DSA-negative cases at the time of stable graft function versus graft dysfunction]. Methods Here we investigated the diagnostic accuracy of the 8-Gene Expression Assay for histology of ABMR (ABMRh) with or without HLA-DSA in a cross-sectional cohort study of 387 blood samples with a concomitant graft biopsy. Results In patients with HLA-DSA (n = 64), the 8-Gene Expression Assay discriminated DSA-positive ABMRh (DSAposABMRh) cases (n = 16) with good diagnostic performance {area under the receiver operating characteristic curve [AUROC] 83.1% [95% confidence interval (CI) 70.8-95.3]}. Also, in HLA-DSA-negative samples (n = 323), a clinically relevant diagnostic performance for DSAnegABMRh cases was found (n = 30) with an AUROC of 75.8% (95% CI 67.4-84.4). The 8-Gene Assay did not discriminate DSAposABMRh cases from DSAnegABMRh cases. There was a net benefit for clinical decision-making when adding the 8-Gene Expression Assay to a clinical model consisting of estimated glomerular filtration rate, proteinuria, HLA-DSA and age. Conclusion The 8-Gene Expression Assay shows great potential for implementation in the clinical follow-up of high-risk HLA-DSA-positive patients and clinical relevance in HLA-DSA-negative cases.
Neal D Shore - One of the best experts on this subject based on the ideXlab platform.
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a prospective adaptive utility trial to validate performance of a novel urine exosome Gene Expression Assay to predict high grade prostate cancer in patients with prostate specific antigen 2 10 ng ml at initial biopsy
2018Co-Authors: James M Mckiernan, Michael J Donovan, Mikkel Noerholm, Johan Skog, Alan W Partin, Eric Margolis, Ballentine Carter, Gordon D Brown, Phillipp Torkler, Neal D ShoreAbstract:Abstract Background Discriminating indolent from clinically significant prostate cancer (PCa) in the initial biopsy setting remains an important issue. Prospectively evaluated diagnostic Assays are necessary to ensure efficacy and clinical adoption. Objective Performance and utility assessment of ExoDx Prostate (IntelliScore) (EPI) urine exosome Gene Expression Assay versus standard clinical parameters for discriminating Grade Group (GG) ≥2 PCa from GG1 PCa and benign disease on initial biopsy. Design, setting, and participants A two-phase adaptive clinical utility study (NCT03031418) comparing EPI results with biopsy outcomes in men, with age ≥50 yr and prostate-specific antigen (PSA) 2–10ng/ml, scheduled for initial prostate biopsy. After EPI performance assessment during phase I, a clinical implementation document (ie, CarePath) was developed for utilizing the EPI test in phase II, where the biopsy decision is uncertain. Outcome measurements and statistical analysis Performance evaluation of the EPI test in patients enrolled in phase I and publication of a consensus CarePath for phase II. Results and limitations In a total of 503 patients, with median age of 64 yr, median PSA 5.4ng/ml, 14% African American, 70% Caucasian, 53% positive biopsy rate (22% GG1, 17% GG2, and 15% ≥ GG3), EPI was superior to an optimized model of standard clinical parameters with an area under the curve (AUC) 0.70 versus 0.62, respectively, comparable with previously published results (n=519 patients, EPI AUC 0.71). Validated cut-point 15.6 would avoid 26% of unnecessary prostate biopsies and 20% of total biopsies, with negative predictive value (NPV) 89% and missing 7% of ≥GG2 PCa. Alternative cut-point 20 would avoid 40% of unnecessary biopsies and 31% of total biopsies, with NPV 89% and missing 11% of ≥GG2 PCa. The clinical investigators reached consensus recommending use of the 15.6 cut-point for phase II. Outcome of the decision impact cohort in phase II will be reported separately. Conclusions EPI is a noninvasive, easy-to-use, Gene Expression urine Assay, which has now been successfully validated in over 1000 patients across two prospective validation trials to stratify risk of ≥GG2 from GG1 cancer and benign disease. The test improves identification of patients with higher grade disease and would reduce the total number of unnecessary biopsies. Patient summary It is challenging to predict which men are likely to have high-grade prostate cancer (PCa) at initial biopsy with prostate-specific antigen 2–10ng/ml. This study further demonstrates that the ExoDx Prostate (IntelliScore) test can predict ≥GG2 PCa at initial biopsy and defer unnecessary biopsies better than existing risk calculator's and standard clinical data.
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clinical utility of a biopsy based cell cycle Gene Expression Assay in localized prostate cancer
2014Co-Authors: Neal D Shore, Raoul S Concepcion, Daniel Saltzstein, Scott M Lucia, Arletta Van Breda, William Welbourn, Nicolas Lewine, Gary Gustavsen, Kristin Pothier, Michael K BrawerAbstract:AbstractObjective:The CCP signature test (Prolaris) quantifies a patient’s risk of disease progression and prostate cancer specific mortality using a Gene-Expression-based cell cycle progression (CCP) score. This study evaluated the potential clinical utility of the CCP test in a US-based clinical setting.Methods:Urologists who participated in a prospective clinical study were sent a retrospective questionnaire to assess the value of the CCP test result. Fifteen board-certified urologists participated in the study, representing 15 distinct community urology group practices. Questionnaires were received for 294 evaluable patients. All patients had localized prostate cancer (T1–T3b, N0, M0).Results:Physicians found the CCP score valuable and indicated that 55% of tests Generated a mortality risk that was either higher or lower than expected. Physicians also indicated that 32% of test results would lead to a definite or possible change in treatment. The data suggest that the test would have the net effect of...
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original article clinical utility of a biopsy based cell cycle Gene Expression Assay in localized prostate cancer
2014Co-Authors: Neal D Shore, Raoul S Concepcion, Daniel Saltzstein, Scott M Lucia, Arletta Van BredaAbstract:Objective: The CCP signature test (Prolaris) quantifies a patient’s risk of disease progression and prostate cancer specific mortality using a Gene-Expression-based cell cycle progression (CCP) score. This study evaluated the potential clinical utility of the CCP test in a US-based clinical setting. Methods: Urologists who participated in a prospective clinical study were sent a retrospective questionnaire to assess the value of the CCP test result. Fifteen board-certified urologists participated in the study, representing 15 distinct community urology group practices. Questionnaires were received for 294 evaluable patients. All patients had localized prostate cancer (T1–T3b, N0, M0). Results: Physicians found the CCP score valuable and indicated that 55% of tests Generated a mortality risk that was either higher or lower than expected. Physicians also indicated that 32% of test results would lead to a definite or possible change in treatment. The data suggest that the test would have the net effect of shifting patients from more aggressive treatment to more conservative treatment. This was evidenced by the significant association between change in treatment and lower CCP scores (p50.002) and by the fact that 62% of tests likely to lead to a definite or possible change in treatment had mortality risks lower than the physician expected versus only 10% with risks higher than expected.
Joseph A Sparano - One of the best experts on this subject based on the ideXlab platform.
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simulation modeling to extend clinical trials of adjuvant chemotherapy guided by a 21 Gene Expression Assay in early breast cancer
2019Co-Authors: Jinani Jayasekera, Joseph A Sparano, Robert Gray, Claudine Isaacs, Allison W Kurian, Suzanne C Oneill, Clyde B Schechter, Jeanne S MandelblattAbstract:Purpose The Trial Assigning Individualized Options for Treatment (TAILORx) found chemotherapy could be omitted in many women with hormone receptor-positive, HER2-negative, node-negative breast cancer and 21-Gene recurrence scores (RS) 11-25, but left unanswered questions. We used simulation modeling to fill these gaps. Methods We simulated women eligible for TAILORx using joint distributions of patient and tumor characteristics and RS from TAILORx data; treatment effects by RS from other trials; and competing mortality from the Surveillance, Epidemiology, and End Results program database. The model simulations replicated TAILORx design, and then tested treatment effects on 9-year distant recurrence-free survival (DRFS) in 14 new scenarios: eight subgroups defined by age (≤50 and >50 years) and 21-Gene RS (11-25/16-25/16-20/21-25); six different RS cut points among women ages 18-75 years (16-25, 16-20, 21-25, 26-30, 26-100); and 20-year follow-up. Mean hazard ratios SD, and DRFS rates are reported from 1000 simulations. Results The simulation results closely replicated TAILORx findings, with 75% of simulated trials showing noninferiority for chemotherapy omission. There was a mean DRFS hazard ratio of 1.79 (0.94) for endocrine vs chemoendocrine therapy among women ages 50 years and younger with RS 16-25; the DFRS rates were 91.6% (0.04) for endocrine and 94.8% (0.01) for chemoendocrine therapy. When treatment was randomly assigned among women ages 18-75 years with RS 26-30, the mean DRFS hazard ratio for endocrine vs chemoendocrine therapy was 1.60 (0.83). The conclusions were unchanged at 20-year follow-up. Conclusions Our results confirmed a small benefit in chemotherapy among women aged 50 years and younger with RS 16-25. Simulation modeling is useful to extend clinical trials, indicate how uncertainty might affect results, and power decision tools to support broader practice discussions.
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tailorx phase iii trial of chemoendocrine therapy versus endocrine therapy alone in hormone receptor positive her2 negative node negative breast cancer and an intermediate prognosis 21 Gene recurrence score
2018Co-Authors: Joseph A Sparano, Robert Gray, Della Makower, William C Wood, Tracy Lively, Thomas James Saphner, Maccon M Keane, Henry L Gomez, Pavan Reddy, Timothy F GogginsAbstract:LBA1Background: In hormone receptor (HR)-positive, HER2-negative, axillary node (AN)-negative breast cancer, the 21-Gene Expression Assay (Oncotype DX Recurrence Score [RS]) is prognostic for distant recurrence, prognostic for low recurrence with endocrine therapy alone if low (0-10), and predictive of chemotherapy benefit if high (26 or higher). We performed a prospective, randomized trial of endocrine therapy (ET) versus chemoendocrine therapy (CET) in women with a mid-range RS of 11-25. Methods: Eligibility criteria included women 18-75 years of age with HR-positive, HER2-negative, axillary node (AN)-negative breast cancer and tumors 1.1-5.0 cm in size (or 0.6-1.0 cm and int/high grade) and agreed to have chemotherapy assigned or randomized based on the RS. Women with a mid-range RS (11-25) were randomized to receive ET or CET. The primary endpoint was invasive disease-free survival (iDFS), and the trial was designed to show non-inferiority for ET alone by not rejecting equality (hazard ratio [HR] marg...
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adjuvant chemotherapy guided by a 21 Gene Expression Assay in breast cancer
2018Co-Authors: Joseph A Sparano, Robert Gray, Della Makower, Kathleen I Pritchard, Kathy S Albain, Daniel F Hayes, Charles E Geyer, E C Dees, Matthew P GoetzAbstract:Abstract Background The recurrence score based on the 21-Gene breast cancer Assay predicts chemotherapy benefit if it is high and a low risk of recurrence in the absence of chemotherapy if it is low; however, there is uncertainty about the benefit of chemotherapy for most patients, who have a midrange score. Methods We performed a prospective trial involving 10,273 women with hormone-receptor–positive, human epidermal growth factor receptor 2 (HER2)–negative, axillary node–negative breast cancer. Of the 9719 eligible patients with follow-up information, 6711 (69%) had a midrange recurrence score of 11 to 25 and were randomly assigned to receive either chemoendocrine therapy or endocrine therapy alone. The trial was designed to show noninferiority of endocrine therapy alone for invasive disease–free survival (defined as freedom from invasive disease recurrence, second primary cancer, or death). Results Endocrine therapy was noninferior to chemoendocrine therapy in the analysis of invasive disease–free surv...
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prospective study of magnetic resonance imaging mri and multiparameter Gene Expression Assay in ductal carcinoma in situ dcis a trial of the ecog acrin cancer research group e4112
2017Co-Authors: Seema A Khan, Joseph A Sparano, Constance D Lehman, Constantine Gatsonis, Lawrence J Solin, Sunil Badve, Ralph L Corsetti, Habib Rahbar, Brad Snyder, Derrick W SpellAbstract:534Background: Prior retrospective studies have evaluated breast MRI in DCIS, and prospective-retrospective biomarker studies have shown that the DCIS Score is prognostic for recurrence after BCS alone. E4112 is a prospective cohort study designed to assess the combined impact of breast MRI and DCIS Score on surgical and RT management. Methods: Women diagnosed with screen-detected DCIS on core biopsy, if BCS eligible, underwent breast MRI. Those remaining so following MRI and related biopsies, with no invasive disease, underwent BCS. If final surgical margins were ≥2 mm, the DCIS lesion was submitted for DCIS Score Assay. Women with low DCIS Score (≤39, LS) were advised that RT could be avoided; RT was recommended to those with high/intermediate (H/I) scores. The primary objective was to estimate the fraction converting to mastectomy (Mx) following MRI. Secondary objectives included estimation of re-operation rates after first BCS, and DCIS Score distribution.A sample size of 333 evaluable women would all...
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prospective validation of a 21 Gene Expression Assay in breast cancer
2015Co-Authors: Joseph A Sparano, Robert Gray, Della Makower, Kathleen I Pritchard, Kathy S Albain, Daniel F Hayes, Charles E Geyer, E C Dees, E A Perez, John A OlsonAbstract:BackgroundPrior studies with the use of a prospective–retrospective design including archival tumor samples have shown that Gene-Expression Assays provide clinically useful prognostic information. However, a prospectively conducted study in a uniformly treated population provides the highest level of evidence supporting the clinical validity and usefulness of a biomarker. MethodsWe performed a prospective trial involving women with hormone-receptor–positive, human epidermal growth factor receptor type 2 (HER2)–negative, axillary node–negative breast cancer with tumors of 1.1 to 5.0 cm in the greatest dimension (or 0.6 to 1.0 cm in the greatest dimension and intermediate or high tumor grade) who met established guidelines for the consideration of adjuvant chemotherapy on the basis of clinicopathologic features. A reverse-transcriptase–polymerase-chain-reaction Assay of 21 Genes was performed on the paraffin-embedded tumor tissue, and the results were used to calculate a score indicating the risk of breast-...
Torsten O Nielsen - One of the best experts on this subject based on the ideXlab platform.
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a rapid and cost effective Gene Expression Assay for the diagnosis of well differentiated and dedifferentiated liposarcomas
2021Co-Authors: Xiu Qing Wang, Xue Qi Wang, Anika Terra Ye Way Hsu, Angela Goytain, Torsten O NielsenAbstract:Histologic examination neither reliably distinguishes benign lipomas from atypical lipomatous tumor/well-differentiated liposarcoma, nor dedifferentiated liposarcoma from other pleomorphic sarcomas, entities with different prognoses and management. Molecular confirmation of pathognomonic 12q13-15 amplifications leading to MDM2 overExpression is a diagnostic gold standard. Currently the most commonly used Assay for this purpose is fluorescence in situ hybridization (FISH), but this is labor intensive. This study assessed whether newer NanoString-based technology could allow for more rapid and cost-efficient diagnosis of liposarcomas on standard formalin-fixed tissues through Gene Expression. Leveraging large-scale transcriptome data from The Cancer Genome Atlas, 20 Genes were identified, most from the 12q13-15 amplicon, that distinguish dedifferentiated liposarcoma from other sarcomas and can be measured within a single NanoString Assay. Using 21 cases of histologically ambiguous low-grade adipocytic tumors with available MDM2 amplification status, a machine learning–based analytical pipeline was built that assigns a given sample as negative or positive for liposarcoma based on quantitative Gene Expression. The effectiveness of the Assay was validated on an independent set of 100 sarcoma samples (including 40 incident prospective cases), where histologic examination was considered insufficient for clinical diagnosis. The NanoString Assay had a 93% technical success rate, and an accuracy of 97.8% versus an MDM2 amplification FISH gold standard. NanoString had a considerably faster turnaround time and was cheaper than FISH.
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the prosigna Gene Expression Assay and responsiveness to adjuvant cyclophosphamide based chemotherapy in premenopausal high risk patients with breast cancer
2018Co-Authors: Maj-britt Jensen, Sean Ferree, Torsten O Nielsen, Anne-vibeke Lænkholm, Jens Ole Eriksen, Pernille Wehn, Tressa Hood, Namratha Ram, Wesley Buckingham, Bent EjlertsenAbstract:The PAM50-based (Prosigna) risk of recurrence (ROR) score and intrinsic subtypes are prognostic for women with high-risk breast cancer. We investigate the predictive ability of Prosigna regarding the effectiveness of cyclophosphamide-based adjuvant chemotherapy in premenopausal patients with high-risk breast cancer. Prosigna Assays were performed on the NanoString platform in tumors from participants in Danish Breast Cancer Group (DBCG) 77B, a four-arm trial that randomized premenopausal women with high-risk early breast cancer to no systemic treatment, levamisole, oral cyclophosphamide (C) or cyclophosphamide, methotrexate and fluorouracil (CMF). In total, this retrospective analysis included 460 women (40% of the 1146 randomized patients). The continuous Prosigna ROR score was prognostic in the no systemic treatment group (unadjusted P < 0.001 for disease-free survival (DFS), P = 0.001 for overall survival (OS)). No statistically significant interaction of continuous ROR score and treatment on DFS and OS was found. A highly significant association was observed between intrinsic subtypes and C/CMF treatment for DFS (Pinteraction = 0.003 unadjusted, P = 0.001 adjusted) and OS (Pinteraction = 0.04). In the adjusted analysis treatment with C/CMF was associated with a reduced risk of DFS events in patients with basal-like (hazard ratio (HR) 0.14; 95% CI 0.06; 0.32) and luminal B (HR 0.48; 95% CI 0.27; 0.84) subtypes but not in patients with Human epidermal growth factor receptor-enriched (HR 1.05; 95% CI 0.56; 1.95) or luminal A (HR 0.61; 95% CI 0.32; 1.16) subtypes. The Prosigna ROR score and intrinsic subtypes were prognostic in high-risk premenopausal patients with breast cancer, and intrinsic subtypes identify high-risk patients with or without major benefit from adjuvant C/CMF treatment.
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The Prosigna Gene Expression Assay and responsiveness to adjuvant cyclophosphamide-based chemotherapy in premenopausal high-risk patients with breast cancer
2018Co-Authors: Maj-britt Jensen, Sean Ferree, Torsten O Nielsen, Anne-vibeke Lænkholm, Jens Ole Eriksen, Pernille Wehn, Tressa Hood, Namratha Ram, Wesley Buckingham, Bent EjlertsenAbstract:Abstract Background The PAM50-based (Prosigna) risk of recurrence (ROR) score and intrinsic subtypes are prognostic for women with high-risk breast cancer. We investigate the predictive ability of Prosigna regarding the effectiveness of cyclophosphamide-based adjuvant chemotherapy in premenopausal patients with high-risk breast cancer. Methods Prosigna Assays were performed on the NanoString platform in tumors from participants in Danish Breast Cancer Group (DBCG) 77B, a four-arm trial that randomized premenopausal women with high-risk early breast cancer to no systemic treatment, levamisole, oral cyclophosphamide (C) or cyclophosphamide, methotrexate and fluorouracil (CMF). Results In total, this retrospective analysis included 460 women (40% of the 1146 randomized patients). The continuous Prosigna ROR score was prognostic in the no systemic treatment group (unadjusted P
Elisabet Van Loon - One of the best experts on this subject based on the ideXlab platform.
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antibody mediated rejection with and without donor specific anti human leucocyte antigen antibodies performance of the peripheral blood 8 Gene Expression Assay
2020Co-Authors: Elisabet Van Loon, Evelyne Lerut, Henriette De Loor, Dirk Kuypers, Mariepaule Emonds, Dany Anglicheau, Wilfried Gwinner, Marie Essig, Pierre Marquet, Maarten NaesensAbstract:Background Recently a peripheral blood 8-Gene Expression Assay was developed for non-invasive detection of antibody-mediated rejection (ABMR) after kidney transplantation. Its value has not yet been evaluated in detail in clinical scenarios with different baseline disease probability [human leucocyte antigen donor-specific antibodies (HLA-DSA)-positive versus HLA-DSA-negative cases at the time of stable graft function versus graft dysfunction]. Methods Here we investigated the diagnostic accuracy of the 8-Gene Expression Assay for histology of ABMR (ABMRh) with or without HLA-DSA in a cross-sectional cohort study of 387 blood samples with a concomitant graft biopsy. Results In patients with HLA-DSA (n = 64), the 8-Gene Expression Assay discriminated DSA-positive ABMRh (DSAposABMRh) cases (n = 16) with good diagnostic performance {area under the receiver operating characteristic curve [AUROC] 83.1% [95% confidence interval (CI) 70.8-95.3]}. Also, in HLA-DSA-negative samples (n = 323), a clinically relevant diagnostic performance for DSAnegABMRh cases was found (n = 30) with an AUROC of 75.8% (95% CI 67.4-84.4). The 8-Gene Assay did not discriminate DSAposABMRh cases from DSAnegABMRh cases. There was a net benefit for clinical decision-making when adding the 8-Gene Expression Assay to a clinical model consisting of estimated glomerular filtration rate, proteinuria, HLA-DSA and age. Conclusion The 8-Gene Expression Assay shows great potential for implementation in the clinical follow-up of high-risk HLA-DSA-positive patients and clinical relevance in HLA-DSA-negative cases.