News Article | April 18, 2017
Philadelphia, PA, April 18, 2017 - In the past, all forms of metastatic prostate cancer have been considered incurable. In recent years, the FDA has approved six drugs for men with metastatic disease, all of which can increase survival. In a study published in Urology®, researchers demonstrate for the first time that an aggressive combination of systemic therapy (drug treatment) with local therapy (surgery and radiation) directed at both the primary tumor and metastasis can eliminate all detectable disease in selected patients with metastatic prostate cancer. While the study is only a first step, one-fifth of the patients treated had no detectable disease, with an undetectable prostate-specific-androgen (PSA) and normal blood testosterone, after 20 months. The results suggest that some men who have previously been considered incurable can possibly be cured; investigators also establish a new paradigm for testing various drug combinations in conjunction with local treatment of the prostate to determine which is the best approach (ie, has the highest undetectable disease rate). Such results could not have been achieved with any single therapy alone. According to lead investigator Howard I. Scher, MD, Chief of the Genitourinary Oncology Service at Memorial Sloan Kettering Cancer Center in New York City, "The sequential use of the three different modalities helped illustrate the role and importance of each in achieving the undetectable PSA with normal testosterone level end point, which represents a 'no-evidence of disease' status." Longer follow-up is needed to determine whether these patients were in fact cured. Twenty men with metastatic prostate cancer, five with extra-pelvic lymph nodal disease and 15 with bone with or without nodal disease, were treated with androgen deprivation therapy (ADT), radical surgery that included a retroperitoneal lymph node dissection as needed, and radiation therapy to visible metastatic lesions in bone. ADT was stopped after a minimum of six months if an undetectable PSA was achieved after combined modality therapy. Other patients were treated continuously. The combined treatment regimen including surgery was well tolerated. Matthew J. O'Shaughnessy, MD, PhD, Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, commented "While the role of local therapy in metastatic prostate cancer is still under investigation, aggressive resection of visible disease performed by experienced surgeons was critical to the outcome." Of the five patients with extra-pelvic lymph node involvement, four achieved an undetectable PSA after ADT and surgery, while the fifth needed radiation to reach this milestone. However, none achieved the primary end point of undetectable PSA with testosterone recovery at 20 months after initiation of therapy with ADT alone, although one patient had a PSA of Of the 15 patients with bone metastases, 14 (93%) reached an undetectable PSA when ADT, surgery, and radiation were used. Ultimately, four (27%) achieved the proposed end point, a PSA of 150 ng/dL at 20 months after the start of ADT, which remained undetectable in two patients for 27 and 46 months, respectively. Commenting on the study, Oliver Sartor, MD, Cancer Research, Department of Medicine and Urology, Tulane University School of Medicine, New Orleans, LA, stated, "The end point deserves special mention, as the end point of undetectable PSA after testosterone recovery has been previously discussed but rarely studied. The authors proposed that this end point may serve as a first step toward establishing a curative paradigm. Many in the field agree, but note that the longevity of effect is essential to prove the point of curability. Regardless, the movement toward a curative paradigm is much needed and the investigators are to be congratulated for setting forth a paradigm that can be used to assess the possibility of cure in a reasonable period of time." "A multimodal treatment strategy for patients who present with disease that is beyond the limits of curability by any single modality enables the evaluation of new approaches in order to prioritize large-scale testing in early stages of advanced disease. The end point also shifts the paradigm from palliation to cure," remarked Dr. Scher. It is expected that an upcoming Phase 2 trial will further test this endpoint and combined modality approach.
Figueroa J.D.,U.S. National Cancer Institute |
Figueroa J.D.,University of Edinburgh |
Middlebrooks C.D.,U.S. National Cancer Institute |
Banday A.R.,U.S. National Cancer Institute |
And 151 more authors.
Human Molecular Genetics | Year: 2015
Candidate gene and genome-wide association studies (GWAS) have identified 15 independent genomic regions associated with bladder cancer risk. In search for additional susceptibility variants, we followed up on four promising single-nucleotide polymorphisms (SNPs) that had not achieved genome-wide significance in 6911 cases and 11 814 controls (rs6104690, rs4510656, rs5003154 and rs4907479, P < 1 × 10-6), using additional data from existing GWAS datasets and targeted genotyping for studies that did not have GWAS data. In a combined analysis, which included data on up to 15 058 cases and 286 270 controls, two SNPs achieved genome-wide statistical significance: Rs6104690 in a gene desert at 20p12.2 (P = 2.19 × 10-11) and rs4907479 within the MCF2L gene at 13q34 (P = 3.3 × 10-10). Imputation and fine-mapping analyses were performed in these two regions for a subset of 5551 bladder cancer cases and 10 242 controls. Analyses at the 13q34 region suggest a single signal marked by rs4907479. In contrast, we detected two signals in the 20p12.2 region-the first signal is marked by rs6104690, and the second signal is marked by two moderately correlated SNPs (r2 = 0.53), rs6108803 and the previously reported rs62185668. The second 20p12.2 signal is more strongly associated with the risk of muscle-invasive (T2-T4 stage) compared with non-muscle-invasive (Ta, T1 stage) bladder cancer (case-case P ≤ 0.02 for both rs62185668 and rs6108803). Functional analyses are needed to explore the biological mechanisms underlying these novel genetic associations with risk for bladder cancer. Published by Oxford University Press 2016. This work is written by (a) US Government employee(s) and is in the public domain in the US.
Scher H.I.,Genitourinary Oncology Service |
Anand A.,Genitourinary Oncology Service |
Rathkopf D.,Genitourinary Oncology Service |
Shelkey J.,Genitourinary Oncology Service |
And 15 more authors.
The Lancet | Year: 2010
Background MDV3100 is an androgen-receptor antagonist that blocks androgens from binding to the androgen receptor and prevents nuclear translocation and co-activator recruitment of the ligand-receptor complex. It also induces tumour cell apoptosis, and has no agonist activity. Because growth of castration-resistant prostate cancer is dependent on continued androgen-receptor signalling, we assessed the antitumour activity and safety of MDV3100 in men with this disease. Methods This phase 1-2 study was undertaken in fi ve US centres in 140 patients. Patients with progressive, metastatic, castration-resistant prostate cancer were enrolled in dose-escalation cohorts of three to six patients and given an oral daily starting dose of MDV3100 30 mg. The fi nal daily doses studied were 30 mg (n=3), 60 mg (27), 150 mg (28), 240 mg (29), 360 mg (28), 480 mg (22), and 600 mg (3). The primary objective was to identify the safety and tolerability profi le of MDV3100 and to establish the maximum tolerated dose. The trial is registered with ClinicalTrials.gov, number NCT00510718. Findings We noted antitumour eff ects at all doses, including decreases in serum prostate-specifi c antigen of 50% or more in 78 (56%) patients, responses in soft tissue in 13 (22%) of 59 patients, stabilised bone disease in 61 (56%) of 109 patients, and conversion from unfavourable to favourable circulating tumour cell counts in 25 (49%) of the 51 patients. PET imaging of 22 patients to assess androgen-receptor blockade showed decreased18F-fl uoro-5α-dihydrotestosterone binding at doses from 60 mg to 480 mg per day (range 20-100%). The median time to progression was 47 weeks (95% CI 34-not reached) for radiological progression. The maximum tolerated dose for sustained treatment (>28 days) was 240 mg. The most common grade 3-4 adverse event was dose-dependent fatigue (16 [11%] patients), which generally resolved after dose reduction. Interpretation We recorded encouraging antitumour activity with MDV3100 in patients with castration-resistant prostate cancer. The results of this phase 1-2 trial validate in man preclinical studies implicating sustained androgenreceptor signalling as a driver in this disease. Funding Medivation, the Prostate Cancer Foundation, National Cancer Institute, the Howard Hughes Medical Institute, Doris Duke Charitable Foundation, and Department of Defense Prostate Cancer Clinical Trials Consortium.
PubMed | Karolinska Institutet, Danish Cancer Society, Finnish National Institute for Health and Welfare, International Agency for Research on Cancer IARC and 57 more.
Type: Journal Article | Journal: Human molecular genetics | Year: 2016
Candidate gene and genome-wide association studies (GWAS) have identified 15 independent genomic regions associated with bladder cancer risk. In search for additional susceptibility variants, we followed up on four promising single-nucleotide polymorphisms (SNPs) that had not achieved genome-wide significance in 6911 cases and 11 814 controls (rs6104690, rs4510656, rs5003154 and rs4907479, P < 1 10(-6)), using additional data from existing GWAS datasets and targeted genotyping for studies that did not have GWAS data. In a combined analysis, which included data on up to 15 058 cases and 286 270 controls, two SNPs achieved genome-wide statistical significance: rs6104690 in a gene desert at 20p12.2 (P = 2.19 10(-11)) and rs4907479 within the MCF2L gene at 13q34 (P = 3.3 10(-10)). Imputation and fine-mapping analyses were performed in these two regions for a subset of 5551 bladder cancer cases and 10 242 controls. Analyses at the 13q34 region suggest a single signal marked by rs4907479. In contrast, we detected two signals in the 20p12.2 region-the first signal is marked by rs6104690, and the second signal is marked by two moderately correlated SNPs (r(2) = 0.53), rs6108803 and the previously reported rs62185668. The second 20p12.2 signal is more strongly associated with the risk of muscle-invasive (T2-T4 stage) compared with non-muscle-invasive (Ta, T1 stage) bladder cancer (case-case P 0.02 for both rs62185668 and rs6108803). Functional analyses are needed to explore the biological mechanisms underlying these novel genetic associations with risk for bladder cancer.
Brown M.S.,Center for Computer Vision and Imaging Biomarkers |
Chu G.H.,Center for Computer Vision and Imaging Biomarkers |
Kim H.J.,Center for Computer Vision and Imaging Biomarkers |
Allen-Auerbach M.,University of California at Los Angeles |
And 13 more authors.
Nuclear Medicine Communications | Year: 2012
OBJECTIVE: The development and evaluation of a computer-aided bone scan analysis technique to quantify changes in tumor burden and assess treatment effects in prostate cancer clinical trials. METHODS: We have developed and report on a commercial fully automated computer-aided detection (CAD) system. Using this system, scan images were intensity normalized, and then lesions were identified and segmented by anatomic region-specific intensity thresholding. Detected lesions were compared against expert markings to assess the accuracy of the CAD system. The metrics Bone Scan Lesion Area, Bone Scan Lesion Intensity, and Bone Scan Lesion Count were calculated from identified lesions, and their utility in assessing treatment effects was evaluated by analyzing before and after scans from metastatic castration-resistant prostate cancer patients: 10 treated and 10 untreated. In this study, patients were treated with cabozantinib, a MET/vascular endothelial growth factor inhibitor resulting in high rates of resolution of bone scan abnormalities. RESULTS: Our automated CAD system identified bone lesion pixels with 94% sensitivity, 89% specificity, and 89% accuracy. Significant differences in changes from baseline were found between treated and untreated groups in all assessed measurements derived by our system. The most significant measure, Bone Scan Lesion Area, showed a median (interquartile range) change from baseline at week 6 of 7.13% (27.61) in the untreated group compared with -73.76% (45.38) in the cabozantinib-treated group (P=0.0003). CONCLUSION: Our system accurately and objectively identified and quantified metastases in bone scans, allowing for interpatient and intrapatient comparison. It demonstrates potential as an objective measurement of treatment effects, laying the foundation for validation against other clinically relevant outcome measures. Copyright © Lippincott Williams & Wilkins.
Molina A.M.,Genitourinary Oncology Service |
Molina A.M.,Cornell University |
Tickoo S.K.,Sloan Kettering Cancer Center |
Ishill N.,Sloan Kettering Cancer Center |
And 9 more authors.
American Journal of Clinical Oncology: Cancer Clinical Trials | Year: 2011
OBJECTIVES: Sarcomatoid variant is a spindle cell phenotype of renal cell carcinoma (RCC), which is associated with a poor prognosis. We reviewed outcomes of systemic therapy for metastatic, sarcomatoid-variant RCC. METHODS: Clinical features, treatment outcome, and survival were evaluated in 63 patients with sarcomatoid-variant metastatic RCC (47 clear cell, 16 nonclear cell). Initial systemic treatment included antiangiogenesis-targeted therapy (n=34), cytokines (n=20), and chemotherapy (n=9). RESULTS: Five of 63 patients (8%) achieved an objective response to the first systemic treatment: 1 (5%) to cytokine and 4 (12%) to sunitinib-targeted therapy. Median progression-free survival for 63 patients was 3 months (95% confidence interval), and median overall survival was 10 months (95% confidence interval). The median progression-free survival for patients treated with sunitinib versus all others was 4.4 months versus 2 months (P=0.03), and 3 months for patients with clear-cell histology versus 1.6 months for nonclear-cell histology (P=0.004). CONCLUSIONS: Metastatic sarcomatoid-variant RCC was associated with a poor response to systemic therapy. Sunitinib treatment resulted in a modest response rate, but studies to characterize the underlying tumor biology of sarcomatoid-variant RCC, to assess outcome to targeted agents, and to develop novel treatment strategies are warranted. Copyright © 2011 by Lippincott Williams & Wilkins.