Use of plasma androgen receptor (AR) testing to optimize docetaxel chemotherapy in castration-resistant prostate cancer (CRPC): A multicenter biomarker study.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 5546-5546
Author(s):  
Vincenza Conteduca ◽  
Elena Castro ◽  
Daniel Wetterskog ◽  
Emanuela Scarpi ◽  
Nuria Romero-Laorden ◽  
...  
Keyword(s):  
Clinical Decision Making ◽  
Clinical Decision ◽  
Digital Pcr ◽  
Castration Resistant Prostate Cancer ◽  
Standard Regimen ◽  
Internal Validation ◽  
Castration Resistant ◽  
Potential Biomarker ◽  
Prospective Trials ◽  
Physician Patient

5546 Background: Plasma AR status has been identified as a potential biomarker of response in CRPC patients receiving docetaxel or the AR-targeted therapies abiraterone or enzalutamide. However, the relevance of plasma AR in the overall management of CRPC patients (pts) receiving docetaxel at different dose due to the toxicity profiles and physician-patient preferences is unknown. Methods: This was a multi-institution study of associations between baseline plasma AR-copy-number status assessed by droplet digital PCR and outcome in 325 CRPC pts. Between September 2011 and July 2019 pts started treatment with docetaxel administered at standard regimen 75mg/m2 every three weeks or adapted regimen (75-80% of standard recommended dose or 30mg/m2 weekly administration) at the discretion of the treating physician. Patients were assigned randomly into 2 sets with a ratio 2:1 to either training (n=217) and internal validation (n=108) cohorts. Results: In our study, adapted regimen of docetaxel was administered in 68 (31.3%) and 35 (32.4%) of training and validation cohorts, respectively. Based on plasma AR status, 67 (30.9%) and 39 (36.1%) validation and training set pts were classified as AR gain, respectively. In men treated with standard docetaxel regimen, no difference in progression-free/overall survival (PFS/OS) was seen between plasma AR normal and gain in both cohorts. In patients treated with adapted docetaxel regimen, we observed a significantly shorter median PFS (3.9 vs. 6.4 months, HR 4.77, 95%CI 1.48-3.80, p=0.0003) and median OS (11.2 vs . 20.4 months, HR 2.87, 95%CI 1.73-2.13, p=0.0008) in the training cohort. This finding was confirmed in the validation cohort (median PFS: 4.8 vs. 7.4 months, HR 2.54, 95%CI 1.40-4.58, p=0.005, and median OS: 11.8 vs. 26.4 months, HR 5.00, 95%CI 2.59-9.65, p<0.0001). In addition, AR-gained patients were less likely than AR normal to have a PSA decline when receiving an adapted regimen in both cohorts (p=0.010 e p=0.003, respectively). Conclusions: This study suggests that plasma AR may improve clinical decision making in choosing not only between AR-directed therapies and taxanes, but also between adapted and standard regimen of docetaxel in first- and subsequent-therapy lines, providing promising clinical implications to select the proper timing and dose of docetaxel. Prospective trials to validate these findings are warranted.

State-of-the-Art Management for the Patient with Castration-Resistant Prostate Cancer in 2012

2012 ◽  
pp. 289-291 ◽  
Author(s):  
Oliver Sartor
Keyword(s):  
Prostate Cancer ◽  
Clinical Decision Making ◽  
Clinical Decision ◽  
Phase Iii ◽  
Castration Resistant Prostate Cancer ◽  
Optimal Sequence ◽  
Molecular Stratification ◽  
Castration Resistant ◽  
Radium 223 ◽  
Phase Iii Trials

Overview: Much progress has been made in metastatic castration-resistant prostate cancer (CRPC), and multiple new U.S. Food and Drug Administration (FDA)-approved survival-prolonging drugs are now available. In 2004, docetaxel/prednisone was the first therapy shown to prolong survival. In 2010 and 2011, sipuleucel-T, cabazitaxel/prednisone, and abiraterone/prednisone were FDA approved. Two new agents, radium-223 and MDV-3100, have recently reported large phase III trials prolonging overall survival and will be submitted for regulatory approval in 2012. One can now begin to ask, is there an optimal sequence for therapies in metastatic CRPC? Despite the recent progress, there is much we do not know and virtually no information on this important question. We know that abiraterone/prednisone and cabazitaxel/prednisone are appropriate choices for a patient after receiving docetaxel, but we do not know what, if anything, represents the optimal sequence for abiraterone and cabazitaxel. In fact we do not understand how one therapy may affect the response to a subsequent therapy. We are also aware that the pre- and postdocetaxel spaces represent regulatory rather than biologic divisions. In addition, despite the proven role of docetaxel/prednisone, many patients with CRPC are not considered to be suitable for chemotherapy, and worldwide many never receive any form of chemotherapy. What is the optimal management for these patients? Taken together it is reasonable to assess patient preferences, prior therapies and response/tolerance to prior therapies, burden of disease, comorbidities, current symptoms, drug toxicities, out-of-pocket costs, etc., in clinical decision making. Given the many factors we do not know, it is hard to be dogmatic in approaching the therapeutic options for the patient with CRPC. We will likely soon move beyond the current sequencing paradigm and begin to assess new combinations in a systematic and rational fashion. Perhaps one day, in the not too distant future, we will develop molecular “stratification systems” to better guide therapeutic choices in CRPC.

Clinical utility of CLIA-grade AR-V7 testing in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).

2017 ◽  
Vol 35 (6_suppl) ◽  
pp. 183-183 ◽  
Author(s):  
Mark Christopher Markowski ◽  
John Silberstein ◽  
James R. Eshleman ◽  
Jun Luo ◽  
Emmanuel S. Antonarakis
Keyword(s):  
Clinical Trial ◽  
Clinical Practice ◽  
Targeted Therapies ◽  
Clinical Decision Making ◽  
Clinical Decision ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Line Therapy ◽  
Improved Outcomes ◽  
Practice Methods

183 Background: The AR-V7 splice variant may confer resistance to AR-targeted therapies but not taxane chemotherapies. Since August 2015, a clinical-grade assay to detect AR-V7 mRNA expression in circulating tumors cells (CTC) has been available through a CLIA-certified lab at Johns Hopkins. In the first 12 months after launch, 195 AR-V7 tests were ordered for clinical purposes. We contacted the ordering providers of the first 100 tests using a questionnaire-based survey to determine how (and if) the results of AR-V7 testing were used in clinical practice. Methods: We identified 100 consecutive mCRPC pts who underwent AR-V7 testing in our CLIA lab. Ordering providers received a questionnaire for each test ordered, asking how (and if) the results of the assay affected their clinical decision-making, and whether a PSA50 response was obtained on next-line therapy after AR-V7 testing was performed. Results: 80 of 100 questionnaires were completed by 26 providers from 17 sites across 14 states. AR-V7 assay results were reported either as CTC negative (21/80: 26%), CTC+ AR-V7 negative (26/80: 33%), or CTC+ AR-V7 positive (33/80: 41%). Prevalence of AR-V7 detection increased with prior exposure to AR targeted drugs (Abi/Enza-naive 29%, post-Abi or Enza 39%, post-Abi and Enza 62%). Overall, management was impacted by AR-V7 testing in 54% of cases (43/80), and even more so with AR-V7+ results (see Table). AR-V7+ pts were commonly switched from AR targeted therapies to a taxane (10/19: 53%) or were offered a clinical trial (8/19: 42%). Pts who had a change in management based on AR-V7 testing were more likely to achieve a PSA50 response on next-line therapy than those not changing treatment (18/36: 50% vs 10/30: 33%). Conclusions: Providers used AR-V7 testing to influence clinical practice more often than not. AR-V7+ pts were most often treated with taxane-based therapy or offered a clinical trial, which may have improved outcomes. Clinical qualification of AR-V7 is ongoing. [Table: see text]

scholarly journals Molecular Testing in Patients With Castration-Resistant Prostate Cancer and Its Impact on Clinical Decision Making

2017 ◽  
pp. 1-11 ◽  
Author(s):  
Derrick L. Tao ◽  
Shawna Bailey ◽  
Tomasz M. Beer ◽  
Erik Foss ◽  
Brooke Beckett ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Decision Making ◽  
Clinical Decision Making ◽  
Clinical Decision ◽  
Pten Expression ◽  
Molecular Testing ◽  
Castration Resistant Prostate Cancer ◽  
Molecular Abnormalities ◽  
Castration Resistant ◽  
Guided Therapy

Purpose Metastatic castration-resistant prostate cancer (CRPC) is the lethal form of the disease. Many groups have performed mutational or immunohistochemistry (IHC) testing in metastatic CRPC to identify treatment targets. However, the frequency with which mutational or IHC data have an impact on clinical decision making and the outcomes of molecularly guided therapy in CRPC are largely unknown. We report our institution’s experience with mutational and IHC testing in patients with metastatic CRPC and its impact on clinical decision making and patient outcomes. Methods Between 2012 and 2015, 59 patients with CRPC underwent metastatic tissue biopsies and were genotyped with a 37–cancer gene panel in a Clinical Laboratory Improvement Amendments–certified laboratory. PTEN expression by IHC testing was also measured in 35 of these samples. A retrospective chart review was performed to determine whether the genomic information was acted upon and the outcome of patients whose treatment was guided by molecular testing. Results Forty-six of 59 patients with CRPC (78.0%) had biopsies with adequate tumor for mutational testing. Thirty-one of 46 subjects (67.4%) had mutations identified by sequencing. Of the 35 patients with CRPC whose biopsies were evaluated for PTEN expression by IHC testing, 13 had PTEN loss. Two patients had treatment on the basis of molecular testing, and one of these subjects had greater tumor control with molecularly guided therapy than his immediate prior therapy. Conclusion Targeted sequencing and IHC can identify clinically informative molecular abnormalities in CRPC. Despite this, a small minority of patients in our series underwent therapies guided by mutational or IHC testing. Actionability of abnormalities identified in metastatic CRPC may be improved with access to clinical trials, insurance approval for unapproved uses of existing anticancer drugs, and larger gene sequencing panels that include more frequently mutated genes.

scholarly journals Clinical Utility of CLIA-Grade AR-V7 Testing in Patients With Metastatic Castration-Resistant Prostate Cancer

2017 ◽  
pp. 1-9 ◽  
Author(s):  
Mark C. Markowski ◽  
John L. Silberstein ◽  
James R. Eshleman ◽  
Mario A. Eisenberger ◽  
Jun Luo ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Trial ◽  
Messenger Rna ◽  
Clinical Decision Making ◽  
Clinical Laboratory ◽  
Specific Antigen ◽  
Clinical Decision ◽  
The United States ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant

Purpose A splice variant of the androgen receptor, AR-V7, confers resistance to AR-targeted therapies (ATTs) but not taxane chemotherapies in patients with metastatic castration-resistant prostate cancer. Since August 2015, a clinical-grade assay to detect AR-V7 messenger RNA expression in circulating tumors cells (CTCs) has been available to providers through a Clinical Laboratory Improvement Amendments–certified laboratory at Johns Hopkins University. Methods We contacted ordering providers of the first 150 consecutive tests by using a questionnaire-based survey to determine how the results of AR-V7 testing were used to influence clinical practice. Results In all, 142 (95%) of 150 questionnaires were completed by 38 providers from 29 sites across the United States and Canada. AR-V7 test results were reported either as CTC– (28%), CTC+/AR-V7– (30%), or CTC+/AR-V7+ (42%). Prevalence of AR-V7 detection increased with prior exposure to ATTs (abiraterone and enzalutamide naïve, 22%; after abiraterone or enzalutamide, 35%; after abiraterone and enzalutamide, 43%). Overall, management was affected by AR-V7 testing in 53% of the patients and even more often with CTC+/AR-V7+ results. AR-V7+ patients were commonly switched from ATT to taxane chemotherapy (43%) or were offered a clinical trial (43%); management remained unchanged in only 14% of these patients. Overall, patients who had a change in management on the basis of AR-V7 testing were significantly more likely to achieve a physician-reported 50% decline in prostate-specific antigen response on next-line therapy than those who did not change treatment (54% v 31%; P = .015). Conclusion Providers used AR-V7 testing to influence clinical decision making more often than not. Physicians reported that men with AR-V7+ results had the most treatment changes, and such men were preferentially managed with taxane therapy or offered a clinical trial, which may have improved outcomes.

scholarly journals Early Identification of Patients with Acute Gastrointestinal Bleeding using Electronic Health Record Phenotyping

2020 ◽  
Author(s):  
Dennis Shung ◽  
Cynthia Tsay ◽  
Loren Laine ◽  
Prem Thomas ◽  
Caitlin Partridge ◽  
...  
Keyword(s):  
Risk Stratification ◽  
Gastrointestinal Bleeding ◽  
Real Time ◽  
Decision Rule ◽  
Language Processing ◽  
Clinical Decision Making ◽  
External Validation ◽  
Clinical Decision ◽  
Internal Validation ◽  
Electronic Health

Background and AimGuidelines recommend risk stratification scores in patients presenting with gastrointestinal bleeding (GIB), but such scores are uncommonly employed in practice. Automation and deployment of risk stratification scores in real time within electronic health records (EHRs) would overcome a major impediment. This requires an automated mechanism to accurately identify (“phenotype”) patients with GIB at the time of presentation. The goal is to identify patients with acute GIB by developing and evaluating EHR-based phenotyping algorithms for emergency department (ED) patients.MethodsWe specified criteria using structured data elements to create rules for identifying patients, and also developed a natural-language-processing (NLP)-based algorithm for automated phenotyping of patients, tested them with tenfold cross-validation (n=7144) and external validation (n=2988), and compared them with the standard method for encoding patient conditions in the EHR, Systematized Nomenclature of Medicine (SNOMED). The gold standard for GIB diagnosis was independent dual manual review of medical records. The primary outcome was positive predictive value (PPV).ResultsA decision rule using GIB-specific terms from ED triage and from ED review-of-systems assessment performed better than SNOMED on internal validation (PPV=91% [90%-93%] vs. 74% [71%-76%], P<0.001) and external validation (PPV=85% [84%-87%] vs. 69% [67%-71%], P<0.001). The NLP algorithm (external validation PPV=80% [79-82%]) was not superior to the structured-datafields decision rule.ConclusionsAn automated decision rule employing GIB-specific triage and review-of-systems terms can be used to trigger EHR-based deployment of risk stratification models to guide clinical decision-making in real time for patients with acute GIB presenting to the ED.

scholarly journals Clinical utility of targeted SARS-CoV-2 serology testing to aid the diagnosis and management of suspected missed, late or post-COVID-19 infection syndromes: Results from a pilot service implemented during the first pandemic wave

PLoS ONE ◽  
2021 ◽  
Vol 16 (4) ◽  
pp. e0249791
Author(s):  
Nicola Sweeney ◽  
Blair Merrick ◽  
Rui Pedro Galão ◽  
Suzanne Pickering ◽  
Alina Botgros ◽  
...  
Keyword(s):  
Clinical Utility ◽  
Clinical Decision Making ◽  
Clinical Decision ◽  
Performance Characteristics ◽  
Direct Care ◽  
Serological Testing ◽  
Internal Validation ◽  
Assay Performance ◽  
Adults And Children ◽  
Test Probability

During the first wave of the global COVID-19 pandemic the clinical utility and indications for SARS-CoV-2 serological testing were not clearly defined. The urgency to deploy serological assays required rapid evaluation of their performance characteristics. We undertook an internal validation of a CE marked lateral flow immunoassay (LFIA) (SureScreen Diagnostics) using serum from SARS-CoV-2 RNA positive individuals and pre-pandemic samples. This was followed by the delivery of a same-day named patient SARS-CoV-2 serology service using LFIA on vetted referrals at central London teaching hospital with clinical interpretation of result provided to the direct care team. Assay performance, source and nature of referrals, feasibility and clinical utility of the service, particularly benefit in clinical decision-making, were recorded. Sensitivity and specificity of LFIA were 96.1% and 99.3% respectively. 113 tests were performed on 108 participants during three-week pilot. 44% participants (n = 48) had detectable antibodies. Three main indications were identified for serological testing; new acute presentations potentially triggered by recent COVID-19 e.g. pulmonary embolism (n = 5), potential missed diagnoses in context of a recent COVID-19 compatible illness (n = 40), and making infection control or immunosuppression management decisions in persistently SARS-CoV-2 RNA PCR positive individuals (n = 6). We demonstrate acceptable performance characteristics, feasibility and clinical utility of using a LFIA that detects anti-spike antibodies to deliver SARS-CoV-2 serology service in adults and children. Greatest benefit was seen where there is reasonable pre-test probability and results can be linked with clinical advice or intervention. Experience from this pilot can help inform practicalities and benefits of rapidly implementing new tests such as LFIAs into clinical service as the pandemic evolves.

scholarly journals A CT-based radiomics nomogram for predicting prognosis of coronavirus disease 2019 (COVID-19) radiomics nomogram predicting COVID-19

2021 ◽  
Vol 94 (1117) ◽  
pp. 20200634
Author(s):  
Hang Chen ◽  
Ming Zeng ◽  
Xinglan Wang ◽  
Liping Su ◽  
Yuwei Xia ◽  
...  
Keyword(s):  
Clinical Decision Making ◽  
Predictive Performance ◽  
Clinical Decision ◽  
Ct Images ◽  
Prediction Performance ◽  
Clinical Factors ◽  
Training Set ◽  
Clinical Model ◽  
Potential Biomarker ◽  
Validation Set

Objectives: To identify the value of radiomics method derived from CT images to predict prognosis in patients with COVID-19. Methods: A total of 40 patients with COVID-19 were enrolled in the study. Baseline clinical data, CT images, and laboratory testing results were collected from all patients. We defined that ROIs in the absorption group decreased in the density and scope in GGO, and ROIs in the progress group progressed to consolidation. A total of 180 ROIs from absorption group (n = 118) and consolidation group (n = 62) were randomly divided into a training set (n = 145) and a validation set (n = 35) (8:2). Radiomics features were extracted from CT images, and the radiomics-based models were built with three classifiers. A radiomics score (Rad-score) was calculated by a linear combination of selected features. The Rad-score and clinical factors were incorporated into the radiomics nomogram construction. The prediction performance of the clinical factors model and the radiomics nomogram for prognosis was estimated. Results: A total of 15 radiomics features with respective coefficients were calculated. The AUC values of radiomics models (kNN, SVM, and LR) were 0.88, 0.88, and 0.84, respectively, showing a good performance. The C-index of the clinical factors model was 0.82 [95% CI (0.75–0.88)] in the training set and 0.77 [95% CI (0.59–0.90)] in the validation set. The radiomics nomogram showed optimal prediction performance. In the training set, the C-index was 0.91 [95% CI (0.85–0.95)], and in the validation set, the C-index was 0.85 [95% CI (0.69–0.95)]. For the training set, the C-index of the radiomics nomogram was significantly higher than the clinical factors model (p = 0.0021). Decision curve analysis showed that radiomics nomogram outperformed the clinical model in terms of clinical usefulness. Conclusions: The radiomics nomogram based on CT images showed favorable prediction performance in the prognosis of COVID-19. The radiomics nomogram could be used as a potential biomarker for more accurate categorization of patients into different stages for clinical decision-making process. Advances in knowledge: Radiomics features based on chest CT images help clinicians to categorize the patients of COVID-19 into different stages. Radiomics nomogram based on CT images has favorable predictive performance in the prognosis of COVID-19. Radiomics act as a potential modality to supplement conventional medical examinations.

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