Halabi S.,Duke University |
Lin C.-Y.,Duke University |
Small E.J.,University of California at San Francisco |
Armstrong A.J.,Duke Prostate Center and the Duke Cancer Institute |
And 7 more authors.
Journal of the National Cancer Institute | Year: 2013
Background Several prognostic models for overall survival (OS) have been developed and validated in men with metastatic castration-resistant prostate cancer (mCRPC) who receive first-line chemotherapy. We sought to develop and validate a prognostic model to predict OS in men who had progressed after first-line chemotherapy and were selected to receive second-line chemotherapy. Methods Data from a phase III trial in men with mCRPC who had developed progressive disease after first-line chemotherapy (TROPIC trial) were used. The TROPIC was randomly split into training (n = 507) and testing (n = 248) sets. Another dataset consisting of 488 men previously treated with docetaxel (SPARC trial) was used for external validation. Adaptive least absolute shrinkage and selection operator selected nine prognostic factors of OS. A prognostic score was computed from the regression coefficients. The model was assessed on the testing and validation sets for its predictive accuracy using the time-dependent area under the curve (tAUC). Results The nine prognostic variables in the final model were Eastern Cooperative Oncology Group performance status, time since last docetaxel use, measurable disease, presence of visceral disease, pain, duration of hormonal use, hemoglobin, prostate specific antigen, and alkaline phosphatase. The tAUCs for this model were 0.73 (95% confidence interval [CI] = 0.72 to 0.74) and 0.70 (95% CI = 0.68 to 0.72) for the testing and validation sets, respectively. Conclusions A prognostic model of OS in the postdocetaxel, second-line chemotherapy, mCRPC setting was developed and externally validated. This model incorporates novel prognostic factors and can be used to provide predicted probabilities for individual patients and to select patients to participate in clinical trials on the basis of their prognosis. Prospective validation is needed. © The Author 2013.
Efficacy and safety of radium-223 dichloride in patients with castration-resistant prostate cancer and symptomatic bone metastases, with or without previous docetaxel use: A prespecified subgroup analysis from the randomised, double-blind, phase 3 ALSYMPCA trial
Hoskin P.,Mount Vernon Cancer Center |
Sartor O.,Tulane Cancer Center |
O'Sullivan J.M.,Queen's University of Belfast |
Johannessen D.C.,University of Oslo |
And 9 more authors.
The Lancet Oncology | Year: 2014
Background: Primary results from the phase 3 ALSYMPCA trial showed that radium-223 dichloride (radium-223), a targeted α-emitter, improved overall survival compared with placebo and was well tolerated in patients with castration-resistant prostate cancer and symptomatic bone metastases. We did a prespecified subgroup analysis from ALSYMPCA to assess the effect of previous docetaxel use on the efficacy and safety of radium-223. Methods: In the phase 3, randomised, double-blind ALSYMPCA trial, patients with symptomatic castration-resistant prostate cancer, at least two symptomatic bone metastases, no known visceral metastases, and who were receiving best standard of care were randomly assigned (2:1) via an interactive voice response system to receive six injections of radium-223 (50 kBq/kg intravenously) or matching placebo, with one injection given every 4 weeks. Patients had either received previous docetaxel treatment or were unsuitable for or declined docetaxel; previous docetaxel use (yes or no) was a trial stratification factor. We investigated the effect of previous docetaxel use on radium-223 treatment for the primary endpoint of overall survival, the main secondary efficacy endpoints, and safety. Efficacy analyses were done for the intention-to-treat population; safety analyses were done for the safety population. The trial has been completed and is registered with ClinicalTrials.gov, number NCT00699751. Findings: Randomisation took place between June 12, 2008, and Feb 1, 2011. 526 (57%) of 921 randomly assigned patients had received previous docetaxel treatment (352 in the radium-223 group and 174 in the placebo group) and 395 (43%) had not (262 in the radium-223 group and 133 in the placebo group). Radium-223 prolonged median overall survival compared with placebo, irrespective of previous docetaxel use (previous docetaxel use, hazard ratio [HR] 0·70, 95% CI 0·56-0·88; p=0·002; no previous docetaxel use, HR 0·69, 0·52-0·92; p=0·01). The benefit of radium-223 compared with placebo was seen in both docetaxel subgroups for most main secondary efficacy endpoints; risk for time to time to first symptomatic skeletal event was reduced with radium-223 versus placebo in patients with previous docetaxel use, but the difference was not significant in those with no previous docetaxel use. 322 (62%) of 518 patients previously treated with docetaxel had grade 3-4 adverse events, compared with 205 (54%) of 383 patients without docetaxel. Patients who had previously been treated with docetaxel had a higher incidence of grade 3-4 thrombocytopenia with radium-223 than with placebo (31 [9%] of 347 patients vs five [3%] of 171 patients), whereas the incidence was similar between treatment groups among patients with no previous docetaxel use (seven [3%] of 253 patients vs one [1%] of 130 patients). The incidences of grade 3-4 anaemia and neutropenia were similar between the radium-223 and placebo groups within both docetaxel subgroups. Interpretation: Radium-223 is effective and well tolerated in patients with castration-resistant prostate cancer and symptomatic bone metastases, irrespective of previous docetaxel use. Funding: Algeta ASA and Bayer HealthCare Pharmaceuticals. © 2014 Elsevier Ltd.
Sartor O.,Tulane Cancer Center |
Eisenberger M.,The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins |
Kattan M.W.,Cleveland Clinic |
Tombal B.,Catholic University of Louvain |
Lecouvet F.,Catholic University of Louvain
Oncologist | Year: 2013
The therapeutic landscape for the treatment of advanced prostate cancer is rapidly evolving, especially for those patients with metastatic castration-resistant prostate cancer (CPRC). Despite advances in therapy options, the diagnostic landscape has remained relatively static, with few guidelines or reviews addressing the optimal timing or methodology for the radiographic detectionofmetastaticdisease.Givenrecentreportsindicatinga substantial proportion of patients with CRPC thought to be nonmetastatic (M0) are in fact metastatic (M1), there is now a clear opportunity and need for improvement in detection practices. Herein, we discuss the current status of predicting the presence of metastatic disease, with a particular emphasis on the detection of the M0 to M1 transition. In addition, we review current data on newer imaging technologies that are changing the way metastases are detected. Whether earlier detection of metastatic disease will ultimately improve patient outcomes is unknown, but given that the therapeutic options for those with metastatic and nonmetastaticCPRCvary, there are considerable implications ofhowand when metastases are detected. ©AlphaMed Press 2013.
Sridhar S.S.,University of Toronto |
Freedland S.J.,Duke University |
Gleave M.E.,BC Cancer Agency |
Higano C.,Seattle Cancer Center Alliance |
And 4 more authors.
European Urology | Year: 2014
Context Until recently, the only approved agent for metastatic castration-resistant prostate cancer (mCRPC) was docetaxel chemotherapy. But over the last 5 years, significant advances in the field have led to the approval of five new agents, each with different mechanisms of action and demonstrating improved overall survival in separate randomized phase 3 trials. Many of these novel agents are now also being evaluated in earlier stages of the disease, which may ultimately lead to even better outcomes. Objective To summarize the current literature on the management of mCRPC with a particular focus on novel chemotherapy approaches, hormonal approaches, immunotherapy, and radiopharmaceuticals showing survival benefits in phase 3 clinical trials. Emerging therapies in late stages of development are also discussed briefly. Evidence acquisition A comprehensive search of PubMed, identified studies pertaining to novel therapies evaluated in mCRPC since the initial approval of docetaxel in 2004. Abstracts from major international meetings were hand searched to identify studies of novel agents in late stage development in mCRPC. The Clinical Trials.gov database was used to find ongoing clinical trials in the area of mCRPC. A detailed search of each new agent was also performed to ensure that additional trials of these agents in other stages of the disease were included where relevant. Evidence synthesis The main agents discussed are the androgen synthesis inhibitor abiraterone acetate, the androgen receptor inhibitor enzalutamide, the novel taxane chemotherapy cabazitaxel, the immunotherapy sipuleucel-T, and the radiopharmaceutical radium 223. Other emerging agents and a brief discussion of negative phase 3 results are also included. Conclusions It is a very exciting time in the field of mCRPC, where therapeutic advances have improved outcomes in this disease, although once metastatic overall median survival remains a dismal 2-3 years. The key now will be to understand how best to use these new agents, understand the mechanisms of resistance to them, continue to develop novel treatment strategies, and ultimately test these agents earlier in the disease when cure may be possible. © 2013 European Association of Urology.
News Article | December 14, 2016
SAN FRANCISCO--(BUSINESS WIRE)--Invitae Corporation (NYSE:NVTA), one of the fastest growing genetic information companies, has seen a significant increase in genetic testing for prostate cancer since the publication of landmark data showing testing may be underutilized when screening for and treating the second most common cancer in men. The company’s panel is the most comprehensive and affordable genetic test available to urologists and oncologists who treat men with prostate cancer, establishing the company as a new leader in prostate cancer testing. According to a study in the New England Journal of Medicine (NEJM), the incidence of germline mutations in men with metastatic prostate cancer is over 11% – higher than the historical rate for BRCA1 and BRCA2 mutations in high-risk breast cancer patients. Additionally, the study suggests that family history alone may be insufficient for gauging risk of prostate cancer and making treatment decisions. The study showed mutations in multiple DNA repair genes, including BRCA1, BRCA2, ATM, CHEK2, RAD51D, and PALB2, are significantly increased in metastatic prostate cancer patients. Related findings further support offering all men with metastatic prostate cancer germline genetic testing. “I believe the NEJM study showing inherited DNA-repair gene defects are more common in prostate cancer patients than expected is among the most important data published this year,” said Oliver Sartor, MD, Laborde Professor of Cancer Research, Tulane Cancer Center in New Orleans. “The results add to the growing body of evidence regarding hereditary mutations associated with prostate cancer and confirm and extend the importance of the germline mutations. My research showed at least 1 in 8 men meeting recommended criteria for BRCA testing carried an identifiable and actionable germline mutation. Just as we see in inherited breast cancer, analyzing only BRCA1 or BRCA2 would fail to identify more than 50 percent of men with relevant germline mutations." Invitae has more experience with hereditary cancer testing in prostate cancer than most other laboratories due to its broad, comprehensive menu and flexible ordering approach. The Invitae Prostate Cancer Panel analyzes up to 14 genes that are associated with a hereditary predisposition to prostate cancer. This panel may be considered for individuals with prostate cancer, especially early onset, aggressive or metastatic tumors. Other candidates for testing include patients whose history is suggestive of a hereditary cancer syndrome, such as a personal and/or family history of: Research published in the Journal of Clinical Oncology has shown BRCA1 and BRCA2 mutations are both known to increase the lifetime risk of prostate cancer by about 20%. HOXB13 mutations are associated with an up to 60% lifetime risk of prostate cancer, according to another study. In addition, African American men with prostate cancer may be more likely to have germline mutations in the BRCA1 and BRCA2 genes than Caucasian men with prostate cancer, as presented during the 111th Annual Scientific Meeting of the American Urological Association this year. According to the American Cancer Society, nearly three million men have been diagnosed with prostate cancer in the United States. “We are now beginning to truly understand how mutations in the BRCA genes could impact a man’s risk of developing prostate cancer and aggressive disease, just as we do with breast cancer in women,” said Brian Helfand, MD, PhD, clinical associate professor at the University of Chicago and a clinician at NorthShore University HealthSystem in Chicago. “Invitae’s testing provides us with information on clinically significant genes, allowing clinicians to use the information to identify men with prostate cancer at earlier stages and provide personalized therapies to those with potentially lethal disease.” Rapid results and genetic counseling support available for clinicians and patients Invitae provides results in as few as 10 calendar days (14 days on average). To help support clinicians and their patients, Invitae offers its clinicians access to its Clinical Consult Service, where Invitae’s expert team of medical geneticists and genetic counselors provide support through the entire testing process to select the right test, clarify results, and review individual patient cases at no additional charge. Invitae also makes genetic counseling services available as needed. “Use of Invitae’s prostate cancer panels increased throughout the year, and the trend intensified with the publication of data confirming the role of gene mutations in patients with aggressive prostate cancer. It’s clear the prostate cancer community is responding to research showing the value of genetic information that has long benefitted the breast and ovarian cancer communities,” said Robert Nussbaum, MD, chief medical officer of Invitae. “Invitae has gained extensive experience in hereditary prostate cancer throughout 2016, which ultimately positions us as the strongest partner for clinicians who treat prostate cancer, as well as the biopharma companies pursuing targeted therapeutic approaches,” said Sean George, PhD, president and chief operating officer of Invitae. Invitae is a Medicare provider, and is in contract with major national and regional commercial payers. The company is committed to driving down the cost of genetic testing with simple and transparent pricing, including a $475 up-front, patient-pay price for any test within a single clinical area. Invitae Corporation's (NYSE: NVTA) mission is to bring comprehensive genetic information into mainstream medical practice to improve the quality of healthcare for billions of people. Invitae’s goal is to aggregate most of the world’s genetic tests into a single service with higher quality, faster turnaround time, and lower price than many single-gene and panel tests today. The company currently provides a diagnostic service comprising hundreds of genes for a variety of genetic disorders associated with oncology, cardiology, neurology, pediatrics, and other rare disease areas. For more information, visit our website at invitae.com. This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, including statements relating to Invitae’s panel establishing the company as a new leader in prostate cancer testing; that genetic testing will allow clinicians to identify men with prostate cancer at earlier stages and provide personalized therapies; that the prostate cancer community is responding to research showing the value of genetic information; and Invitae being positioned as the strongest partner for clinicians who treat prostate cancer, as well as biopharma companies pursuing targeted therapeutic approaches. Forward-looking statements are subject to risks and uncertainties that could cause actual results to differ materially, and reported results should not be considered as an indication of future performance. These risks and uncertainties include, but are not limited to: risks associated with the company’s ability to use rapidly changing genetic data to interpret test results accurately, consistently, and quickly; the company’s history of losses; the company’s need to scale its infrastructure in advance of demand for its tests and to increase demand for its tests; the company’s ability to develop and commercialize new tests and expand into new markets; the risk that the company may not obtain or maintain sufficient levels of reimbursement for its tests; laws and regulations applicable to the company’s business, including state licensing requirements and potential regulation by the Food and Drug Administration; and the other risks set forth in the company’s filings with the Securities and Exchange Commission, including the risks set forth in the company’s Quarterly Report on Form 10-Q for the quarter ended September 30, 2016. These forward-looking statements speak only as of the date hereof, and Invitae Corporation disclaims any obligation to update these forward-looking statements. NOTE: Invitae and the Invitae logo are trademarks of Invitae Corporation. All other trademarks and service marks are the property of their respective owners.
Ehrlich M.,Tulane Cancer Center |
Lacey M.,Tulane University
Epigenomics | Year: 2013
Differentiation-related DNA methylation is receiving increasing attention, partly owing to new, whole-genome analyses. These revealed that cell type-specific differential methylation in gene bodies is more frequent than in promoters. We review new insights into the functionality of DNA methylation during differentiation, with emphasis on the methylomes of myoblasts, myotubes and skeletal muscle versus non-muscle samples. Biostatistical analyses of data from reduced representation bisulfite sequencing are discussed. Lastly, a model is presented for how promoter and intragenic DNA hypermethylation affect gene expression, including increasing the efficiency of polycomb silencing at some promoters, downmodulating other promoters rather than silencing them, counteracting enhancers with heterologous specificity, altering chromatin conformation by inhibiting the binding of CTCF, modulating mRNA transcript levels by inhibiting overlapping promoters of noncoding RNA genes or by regulating the use of alternative mRNA promoters, modulating transcription termination, regulating alternative splicing and acting as barriers to the spread of activating chromatin. © 2013 Future Medicine Ltd.
Deininger P.,Tulane Cancer Center
Genome Biology | Year: 2011
Alu elements are primate-specific repeats and comprise 11% of the human genome. They have wide-ranging influences on gene expression. Their contribution to genome evolution, gene regulation and disease is reviewed. © 2011 BioMed Central Ltd.
Deininger P.,Tulane Cancer Center
Genome biology | Year: 2011
Alu elements are primate-specific repeats and comprise 11% of the human genome. They have wide-ranging influences on gene expression. Their contribution to genome evolution, gene regulation and disease is reviewed.
Lewis B.,Tulane Cancer Center |
Sartor O.,Tulane Cancer Center
Current Opinion in Urology | Year: 2012
PURPOSE OF REVIEW: Randomized clinical trials of palliative radiation therapy and radiopharmaceuticals are emphasized, and new concepts in targeted alpha-emitter therapy are introduced. RECENT FINDINGS: Radiation therapy has a proven palliative role in the treatment of patients with advanced prostate cancer. Findings from radium clinical trials emphasize the importance of alpha particles as a new therapeutic modality in patients with bone metastatic castrate-resistant prostate cancer. We introduce the concept of alpha-emitting particles from both a basic and clinical perspective in the realm of bone-targeted radiopharmaceuticals and discuss how these agents compare and contrast with conventional beta-emitting radioisotopes. The physics, radiobiology, and survival data with radium are unique compared with previously used radiopharmaceuticals. SUMMARY: Targeted alpha-emitting therapies such as radium have the capacity to change the way we treat patients with bone-metastatic prostate cancer. © 2012 Lippincott Williams & Wilkins, Inc.
Belancio V.P.,Tulane Cancer Center
Analytical Biochemistry | Year: 2011
Reporter gene assays have proven to be an important tool in analyzing cis and trans factors that influence gene expression. However, they have sometimes been adapted for studies in which they are not totally reliable. Modifications that change the RNA expressed from the reporter gene may result in regulation of reporter gene expression at multiple levels simultaneously. The data provided here illustrate the difficulties that may arise from posttranscription regulation in various reporter gene formats. This serves as a warning that further RNA studies may be necessary, if comparisons are to be made between reporter constructs whose RNA is not identical. © 2011 Elsevier Inc. All rights reserved.