Christopher J Sweeney

Harvard Medical School, Boston, Massachusetts, United States

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Publications (184)1344.99 Total impact

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    ABSTRACT: Objectives: To investigate the association of host metabolic factors and the metabolic syndrome on prostate cancer specific death (PCSD) and overall survival (OS) in patients treated with androgen deprivation therapy (ADT) for biochemically recurrent disease. Patients and methods: The analysis included 273 prostate cancer patients treated with ADT for rising PSA after surgery or radiotherapy. Patients were assessed for the presence of diabetes, hypertension, dyslipidaemia, and obesity prior to the commencement of ADT and using ATPIII criteria for the presence of the composite diagnosis of metabolic syndrome (MS). Competing risks regression model assessed associations of time to PCSD with the metabolic conditions, while multivariable Cox regression model assessed associations of OS with MS and metabolic conditions. Results: During a median follow-up of 11.6 years, 157 (58%) patients died, of which 58 (21%) died of prostate cancer. At the start of ADT the median age was 74 (range=46, 92) years, the median PSA was 3.0 ng/mL. MS were observed in 31% patients; hypertension (68%) and dyslipidaemia (47%) were the most common metabolic conditions. No association of PCSD and MS status was observed. Patients with hypertension tended to have a higher cumulative incidence of PCSD compared to those without hypertension (sub-distribution hazards ratio HR=1.59 (95%CI 0.89, 2.84; p-value=0·11) though not statistically significant. Patients with MS had an increased risk of death from all causes (HR=1.56, 95%CI: 1.07, 2.29; p=0.02) when compared with patients without MS; as did patients with hypertension (HR=1·72, 95% CI: 1·18-2·49; p=0·004). Conclusions: No association of prostate cancer specific death and metabolic syndrome was observed in this cohort of men receiving ADT for biochemically recurrent prostate cancer. Patients with MS were associated with an increased risk of death from all causes and a similar effect was also observed for prostate cancer patients with hypertension alone. This article is protected by copyright. All rights reserved.
    No preview · Article · Jan 2016 · BJU International
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    ABSTRACT: Purpose: The International Germ Cell Cancer Collaborative Group (IGCCCG) criteria prognosticate survival outcomes in metastatic testicular germ cell tumor (MT-GCT), but how the initial risk changes over time for those who survived since curative treatment is unknown. Patients and methods: We assessed patients eligible for first-line therapy for MT-GCT at five tertiary cancer centers from 1990 to 2012 for 2-year conditional overall survival (COS) and conditional disease-free survival (CDFS), defined as the probability of surviving, or surviving and being disease free, respectively, for an additional 2 years at a given time point since the initial diagnosis. Results: For all patients (N = 942), 2-year COS increased from 92% (95% CI, 91% to 94%) at 0 months to 98% (95% CI, 97% to 99%), and 2-year CDFS increased from 83% (95% CI, 81% to 86%) at baseline to 98% (95% CI, 97% to 99%) at 24 months after diagnosis. Two-year COS improved by 2% (97% at 0 months, 99% at 24 months) in the IGCCCG favorable-risk group, by 5% (94% at 0 months, 99% at 24 months) in the intermediate-risk group, and by 22% (71% at 0 months to 93% at 24 months) in the poor-risk group. Two-year CDFS improved significantly at 12 months for each risk group (favorable, 91% baseline v 95% at 12 months; intermediate, 84% v 95%; poor, 55% v 85%). Baseline IGCCCG risk stratification was not associated with long-term COS or CDFS for patients who survived to greater than 2 years post therapy. No significant differences in COS and CDFS were noted between seminoma and nonseminoma; patients ≥ 40 years old had inferior 2-year COS from 0 to 12 months, but no differences were noted at 18 months. Conclusion: Our data suggest that the concept of conditional survival applies to patients with MT-GCT treated with curative therapy. Patients with MT-GCT who survived and remained disease free more than 2 years after the diagnosis had an excellent chance of staying alive and disease free in additional subsequent years, regardless of the initial IGCCCG risk stratification.
    No preview · Article · Jan 2016 · Journal of Clinical Oncology
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    ABSTRACT: Background: Results from large randomised controlled trials combining docetaxel or bisphosphonates with standard of care in hormone-sensitive prostate cancer have emerged. In order to investigate the effects of these therapies and to respond to emerging evidence, we aimed to systematically review all relevant trials using a framework for adaptive meta-analysis. Methods: For this systematic review and meta-analysis, we searched MEDLINE, Embase, LILACS, and the Cochrane Central Register of Controlled Trials, trial registers, conference proceedings, review articles, and reference lists of trial publications for all relevant randomised controlled trials (published, unpublished, and ongoing) comparing either standard of care with or without docetaxel or standard of care with or without bisphosphonates for men with high-risk localised or metastatic hormone-sensitive prostate cancer. For each trial, we extracted hazard ratios (HRs) of the effects of docetaxel or bisphosphonates on survival (time from randomisation until death from any cause) and failure-free survival (time from randomisation to biochemical or clinical failure or death from any cause) from published trial reports or presentations or obtained them directly from trial investigators. HRs were combined using the fixed-effect model (Mantel-Haenzsel). Findings: We identified five eligible randomised controlled trials of docetaxel in men with metastatic (M1) disease. Results from three (CHAARTED, GETUG-15, STAMPEDE) of these trials (2992 [93%] of 3206 men randomised) showed that the addition of docetaxel to standard of care improved survival. The HR of 0·77 (95% CI 0·68-0·87; p<0·0001) translates to an absolute improvement in 4-year survival of 9% (95% CI 5-14). Docetaxel in addition to standard of care also improved failure-free survival, with the HR of 0·64 (0·58-0·70; p<0·0001) translating into a reduction in absolute 4-year failure rates of 16% (95% CI 12-19). We identified 11 trials of docetaxel for men with locally advanced disease (M0). Survival results from three (GETUG-12, RTOG 0521, STAMPEDE) of these trials (2121 [53%] of 3978 men) showed no evidence of a benefit from the addition of docetaxel (HR 0·87 [95% CI 0·69-1·09]; p=0·218), whereas failure-free survival data from four (GETUG-12, RTOG 0521, STAMPEDE, TAX 3501) of these trials (2348 [59%] of 3978 men) showed that docetaxel improved failure-free survival (0·70 [0·61-0·81]; p<0·0001), which translates into a reduced absolute 4-year failure rate of 8% (5-10). We identified seven eligible randomised controlled trials of bisphosphonates for men with M1 disease. Survival results from three of these trials (2740 [88%] of 3109 men) showed that addition of bisphosphonates improved survival (0·88 [0·79-0·98]; p=0·025), which translates to 5% (1-8) absolute improvement, but this result was influenced by the positive result of one trial of sodium clodronate, and we found no evidence of a benefit from the addition of zoledronic acid (0·94 [0·83-1·07]; p=0·323), which translates to an absolute improvement in survival of 2% (-3 to 7). Of 17 trials of bisphosphonates for men with M0 disease, survival results from four trials (4079 [66%] of 6220 men) showed no evidence of benefit from the addition of bisphosphonates (1·03 [0·89-1·18]; p=0·724) or zoledronic acid (0·98 [0·82-1·16]; p=0·782). Failure-free survival definitions were too inconsistent for formal meta-analyses for the bisphosphonate trials. Interpretation: The addition of docetaxel to standard of care should be considered standard care for men with M1 hormone-sensitive prostate cancer who are starting treatment for the first time. More evidence on the effects of docetaxel on survival is needed in the M0 disease setting. No evidence exists to suggest that zoledronic acid improves survival in men with M1 or M0 disease, and any potential benefit is probably small. Funding: Medical Research Council UK.
    Full-text · Article · Dec 2015 · The Lancet Oncology
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    ABSTRACT: Background: Cancer survivors express anxiety that chemotherapy exposure may lead to transmissible genetic damage in post-treatment children. Preclinical models suggest chemotherapy exposure may result in considerable genomic alterations in post-exposure progeny. Epidemiological studies have not demonstrated a significant increase in congenital abnormalities in post-treatment children of cancer survivors, but the inherited genome-wide effect of chemotherapy exposure in humans is unknown. Methods: Two testicular cancer survivors cured with chemotherapy who had children pre- and post-exposure without sperm banking were identified. Familial germline whole genome sequencing (WGS) was performed for these families, and analytical methods were utilized to identify de novo alterations, including mutations, recombinations, and structural rearrangements in the pre- and post-exposure offspring. Results: No increase in de novo germline mutations in post-exposure children compared to their pre-exposure siblings. Furthermore, there was no increased short insertion/deletions, recombination frequency or structural rearrangements in these post-exposure children. Conclusions: In two families of male cancer survivors, there was no transmissible genomic impact of significant mutagenic exposure in post-exposure children. This study may provide possible reassuring evidence for patients undergoing chemotherapy who are unable to have pre-treatment sperm cryopreservation. Expanded cohorts that utilize WGS to identify environmental exposure effects on the inherited genome may inform the generalizability of these results.
    Preview · Article · Dec 2015 · Clinical Cancer Research
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    ABSTRACT: Introduction: We evaluated the incidence and predictors of the use of long-term (2-3 years) versus shorter term androgen deprivation therapy (ADT) in radiation-managed men with high-risk prostate cancer. Patients and methods: We identified 302 patients from the Dana-Farber Cancer Institute patient registry who had been diagnosed with high-risk prostate cancer (T3a or prostate-specific antigen [PSA] > 20 ng/mL or Gleason score 8-10) from 1993 to 2015. We assessed the intended duration of ADT and used multivariable Cox regression to evaluate the predictors of receiving a shorter course of ADT than recommended by the guidelines (< 2 years). Results: The course of ADT intended by physicians increased after the 2008/2009 publication of trials showing the superiority of long-term versus short-term ADT, with 43.5% intending ≥ 2 years before versus 61.4% after (P = .014). Starting in 2010, 49.4% of patients actually received < 2 years of ADT. The most common reasons for receipt of shorter course ADT were intolerance of ADT side effects, patient comorbidity/age, the presence of T3a on magnetic resonance imaging only as the sole high-risk feature, or participation in a clinical trial. Moderate to severe comorbidity assessed using the Adult Comorbidity Evaluation-27 (adjusted hazard ratio [AHR] = 2.94), Gleason score < 8 (AHR = 5.66), and PSA < 20 ng/mL (AHR = 4.19) all predicted for receipt of shorter course ADT (P < .05 for all). Conclusion: In a tertiary-care setting, the rates of long-course ADT for high-risk disease have increased since the 2008/2009 trials supporting its use. However, approximately one half of patients continued to receive shorter course ADT, often because of intolerance of side effects, underlying comorbidity, or physician judgment about the aggressiveness of the disease.
    No preview · Article · Dec 2015 · Clinical Genitourinary Cancer
  • Srikala S. Sridhar · Christopher J. Sweeney

    No preview · Article · Dec 2015 · European Urology
  • Brandon Bernard · Christopher J. Sweeney
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    ABSTRACT: Testicular germ cell tumors (GCTs) include seminoma and nonseminoma. Chance of cure is excellent for clinical stage I disease regardless of whether adjuvant treatment or a surveillance strategy with treatment only for those who relapse is used. Risk of recurrence is greater in nonseminoma with evidence of lymphovascular invasion, but most can be salvaged with chemotherapy and survival rates remain high. This article outlines key pathologic and clinical considerations in clinical stage I seminoma, nonseminoma, advanced disease, and assessment of cancer of unknown primary as a potential GCT.
    No preview · Article · Dec 2015 · Surgical Pathology Clinics

  • No preview · Article · Nov 2015 · International journal of radiation oncology, biology, physics

  • No preview · Article · Nov 2015 · International journal of radiation oncology, biology, physics
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    ABSTRACT: Purpose: Recent data suggest that neuroendocrine signaling may influence progression in some cancers. We aimed to determine whether genes within the five major stress-related signaling pathways are differentially expressed in tumor tissue when comparing prostate cancer patients with lethal and non-lethal disease. Experimental design: We measured mRNA expression of 51 selected genes involved in predetermined stress-related signaling pathways (adrenergic, glucocorticoid, dopaminergic, serotoninergic, and muscarinic systems) in tumor tissue and normal prostate tissue collected from prostate cancer patients in the Physicians' Health Study (n=150; n=82 with normal) and the Health Professionals Follow-Up Study (n=254; n=120 with normal). We assessed differences in pathway expression in relation to prostate cancer lethality as the primary outcome, and to biomarkers as secondary outcomes. Results: Differential mRNA expression of genes within the adrenergic (p=0.001), glucocorticoid (p<0.0001), serotoninergic (p=0.0019), and muscarinic (p=0.0045) pathways in tumor tissue was associated with the risk of lethality. The adrenergic pathway was also statistically significant (p=0.001) when comparing against differential expression of genes not involved in the pathways. In adjacent normal prostate tissue, none of the pathways was clearly differentially expressed between lethal and non-lethal prostate cancer. The glucocorticoid and adrenergic pathways were associated with cell proliferation, while the glucocorticoid pathway was additionally associated with angiogenesis and perineural invasion. Conclusions: Our study suggests that stress-related signaling pathways, particularly the adrenergic and glucocorticoid, may be dysregulated in the tumors of men whose prostate cancer proves to be lethal, and motivates further investigation of these pathways in functional studies.
    No preview · Article · Oct 2015 · Clinical Cancer Research
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    ABSTRACT: Purpose: We aimed to describe changes in treatment patterns for clinical T3 prostate cancer (PCa) from 1998 to 2012, specifically investigating what factors influence receipt of prostatectomy or radiation. Materials and methods: Using the Surveillance, Epidemiology, and End Results database, we studied 11,604 men with clinical T3N0M0 PCa from 1998 to 2012, with treatment categorized as radiation, radical prostatectomy (RP), or no curative therapy. We calculated rate of treatment type by year of diagnosis to investigate trends in treatment patterns, further stratifying by clinical T3a, defined as unilateral and bilateral extracapsular extension (n = 3,842), vs. T3b (defined as extension to seminal vesicles (n = 3,665). Finally, a multivariable logistic regression analysis measured association of demographic and clinical variables with type of treatment received for years 2010 to 2011. Results: Rates of prostatectomy increased significantly from 1998 to 2012 (12.5% vs. 44.4%), radiation decreased significantly (55.8% vs. 38.4%), and receipt of no treatment also decreased (31.7% vs. 17.2%, all P<0.001). These trends were similar for clinical T3a and T3b. Rates of prostatectomy surpassed radiation by 2008 in clinical T3a, reaching 49.8% vs. 37.1%, respectively, in 2012 (P = 0.002), and were statistically similar to radiation in 2012 for clinical T3b, reaching 41.6% vs. 42.1% (P = 0.92). Multivariable logistic regression analysis demonstrated that patients were less likely to receive prostatectomy than radiation if biopsy Gleason scores of 8 to 10 (adjusted odds ratio [AOR] = 0.41, 0.32-0.53), higher initial prostate-specific antigen (AOR = 0.97, 0.97-0.98), and older age (AOR = 0.92, 0.90-0.03, all P<0.01). The likelihood of RP was similar among cT3b vs. cT3a (AOR = 0.95, 0.71-1.26, P = 0.74). Conclusions: Since 1998, there has been a significant increase in the use of RP for clinical T3 PCa and a significant decrease in the use of radiation such that in 2012, the use of prostatectomy exceeded the use of radiation.
    No preview · Article · Oct 2015 · Urologic Oncology
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    ABSTRACT: Purpose: To define characteristics, treatment response, and outcomes of men with brain metastases (BM) from germ cell tumors (GCT). Patients and methods: Data from 523 men with BM from GCT were collected retrospectively from 46 centers in 13 countries by using standardized questionnaires. Clinical features were correlated with overall survival (OS) as the primary end point. Results: BM were present at initial diagnosis in 228 men (group A) and at relapse in 295 men (group B). OS at 3 years (3-year OS) was superior in group A versus group B (48% v 27%; P < .001). Multiple BM and the presence of liver or bone metastasis were independent adverse prognostic factors in both groups; primary mediastinal nonseminoma (group A) and elevations of α-fetoprotein of 100 ng/mL or greater or of human chorionic gonadotropin of 5,000 U/L or greater (group B) were additional independent adverse prognostic factors. Depending on these factors, the 3-year OS ranged from 0% to 70% in group A and from 6% to 52% in group B. In group A, 99% of patients received chemotherapy; multimodality treatment or high-dose chemotherapy was not associated with statistically improved survival in multivariable analysis. In group B, only 54% of patients received chemotherapy; multimodality treatment was associated with improved survival compared with single-modality therapy (hazard ratio, 0.51; 95% CI, 0.36 to 0.73; P < .001), as was high-dose compared with conventional-dose chemotherapy (hazard ratio, 0.41; 95% CI, 0.24 to 0.70; P = .001). Conclusion: Men with BM from GCT have poor OS, particularly if additional risk factors are present. High-dose chemotherapy and multimodality treatment seemed to improve survival probabilities in men with BM at relapse.
    Full-text · Article · Oct 2015 · Journal of Clinical Oncology
  • Elizabeth A Guancial · Jonathan E Rosenberg · Christopher J Sweeney
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    ABSTRACT: Urothelial carcinoma (UC) is a chemosensitive disease with high response rates to platinum-based combination chemotherapy in locally advanced or advanced disease. However, de novo or emergence of cisplatin-resistance limits the duration of response, patients are frequently ineligible for cisplatin, and therapies tested thus far have minimal activity as second-line therapy. The first wave of clinical trials of novel agents and targeted therapy have modestly advanced the field and laid the foundations for future studies. These trials include the deployment of monoclonal antibodies and tyrosine kinase inhibitors that target mediators of angiogenesis and growth receptors. Novel cytotoxic agents have also been tested as single-agents in the second-line setting and together with the first-line combination of gemcitabine with cisplatin. To date, these novel agents have yet to demonstrate the ability to substantially improve the overall survival of patients with bladder cancer. Comparative trials of chemotherapy with or without a novel agent are ongoing and have the potential to improve upon current standard therapy. Moreover, state-of-the-art technologies have been developed that will likely identify the molecular alterations which drive both UC and platinum-resistance and in turn provide opportunities for drug development. The latter includes an interrogation of microRNAs and the integrated study of genetic mutations in extreme phenotypes of the disease. In essence, this ongoing work paired with physician and patient commitments to clinical trial participation will ultimately lead to advances in the care of patients with urothelial cancer.
    No preview · Article · Oct 2015
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    ABSTRACT: Objectives: To investigate the relationship between microliths and germ cell tumor histologic subtypes and determine whether microliths correlate with tumor stage at diagnosis. Methods: A total of 1249 patients with testicular cancer seen between 1999 and 2013 were evaluated; 346 of 1249 patients (28%) with primary testicular tumors and sonographic imaging of unaffected testicular tissue formed the analytic cohort. Age, ethnicity, tumor histologic subtype, and stage at diagnosis were extracted from the medical record. Two examiners concurrently recorded the highest number of microliths per image of unaffected testicular tissue. Results: A total of 175 of 346 patients (51%) had 1 or more microliths; 69 of 346 (20%) had more than 5 microliths per image. The histologic percentage of seminomas positively correlated with the microlith count (rs = 0.12; P = .036); the histologic percentage of embryonal components negatively correlated with the microlith count (rs = -0.15; P = .007). A higher microlith count was associated with a lower stage at diagnosis (P = .0243). Subgroup analysis of pure seminomas suggested a trend toward a higher microlith count in patients with lower-stage disease at diagnosis (P= .07). No association was found between the tumor stage at diagnosis and microlith count in patients with greater than 50% embryonal components of tumors (P = .55). No association was found between microliths and age, tumor size, and presence of lymphovascular/rete testis invasion (P = .120, .500, .629, and .155, respectively). Conclusions: Patients with testicular cancer who have microliths may be more likely to have a higher percentage of seminomas and a lower percentage of embryonal components in their primary tumors. Microliths also showed an association with earlier stages of disease at diagnosis.
    No preview · Article · Sep 2015 · Journal of ultrasound in medicine: official journal of the American Institute of Ultrasound in Medicine
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    ABSTRACT: Objective: To identify contemporary, clinically low-risk patients with ≥50% cores positive and compare the risk of upgrading at prostatectomy to other low- or intermediate-risk patients. Methods: We studied 14,902 patients with prostate cancer in the Surveillance, Epidemiology, and End Results database in 2010-2011 with prostatectomy. Patients were categorized by NCCN clinical risk-groups, separating low-risk patients by percent positive biopsy cores (PBC). We measured incidence of pathologic high-risk disease, defined as pT3a-T4 or Gleason 8-10, and multivariable logistic regression (MVA) was used to determine if patients with clinical low-risk disease and ≥50% PBC were similar to other low- or intermediate-risk patients. This analysis was repeated with favorable- and unfavorable-intermediate risk. Results: At prostatectomy, 9.2% of clinically low-risk and <50%PBC, 18.6% of clinically low-risk and ≥50%PBC, and 27.6% of clinically intermediate-risk patients had occult, high-risk disease (p<0.001). On MVA low-risk with ≥50%PBC were more likely than low-risk with <50%PBC to have pathologic high-risk disease (Adjusted odds ratio [AOR] 2.28, 95%CI 1.90-2.73, p<0.001), had similar risk to favorable-intermediate disease overall (AOR 1.09, 0.91-1.31, p=0.33), and had higher risk than favorable-intermediate among men over 60 (AOR 1.28, 1.00-1.64, p=0.04). Low-risk and ≥50%PBC had a mean tumor size similar to unfavorable-intermediate risk (21.3 vs. 21.0mm, p=0.82). Conclusion: Nearly one in five clinically low-risk prostate cancer patients with ≥50% positive biopsy cores harbor occult pT3a-T4 or Gleason 8-10, suggesting that national guidelines should not classify low-risk with ≥50% cores positive as "low-risk" and patients should be made aware of this excess risk if considering active surveillance.
    No preview · Article · Sep 2015 · Urology

  • No preview · Article · Sep 2015

  • No preview · Article · Sep 2015
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    ABSTRACT: During the past 35 years, survival rates for children with extracranial malignant germ cell tumors (GCTs) have increased significantly. Success has been achieved primarily through the application of platinum-based chemotherapy regimens; however, clinical challenges in GCTs remain. Excellent outcomes are not distributed uniformly across the heterogeneous distribution of age, histologic features, and primary tumor site. Despite good outcomes overall, the likelihood of a cure for certain sites and histologic conditions is less than 50%. In addition, there are considerable long-term treatment-related effects for survivors. Even modest cisplatin dosing can cause significant long-term morbidities. A particular challenge in designing new therapies for GCT is that a variety of specialists use different risk stratifications, staging systems, and treatment approaches for three distinct age groups (childhood, adolescence, and young adulthood). Traditionally, pediatric cancer patients younger than 15 years have been treated by pediatric oncologists in collaboration with their surgical specialty colleagues. Adolescents and young adults with GCTs often are treated by medical oncologists, urologists, or gynecologic oncologists. The therapeutic dilemma for all is how to best define disease risk so that therapy and toxicity can be appropriately reduced for some patients and intensified for others. Further clinical and biologic insights can only be achieved through collaborations that do not set limitations by age, sex, and primary tumor site. Therefore, international collaborations, spanning different cooperative groups and disciplines, have been developed to address these challenges. © 2015 by American Society of Clinical Oncology.
    No preview · Article · Aug 2015 · Journal of Clinical Oncology
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    ABSTRACT: Abiraterone improves the overall survival of men with metastatic castration resistance prostate cancer. However, de novo or adaptive resistance to abiraterone limits its activity. Rational combinations of drugs with different mechanisms of action that overcome resistance mechanisms may improve the efficacy of therapy. To that end, we studied the molecular and phenotypic effects of the combination of cabozantinib plus abiraterone. Three prostate cancer cell lines were used to interrogate the in vitro molecular and anti-proliferative effects of the single agents and combination of cabozantinib and abiraterone. The in vivo impact of the combination was assessed using the LAPC4-CR xenograft mouse model. In vitro proliferation studies demonstrated single agent doses between 2 and 10 μM for abiraterone and cabozantinib inhibit prostate cancer cell proliferation in a dose-dependent manner and the anti-cancer activity of abiraterone is enhanced when combined with cabozantinib. In vivo LAPC4-CR xenograft mouse studies also showed that cabozantinib can improve the anti-tumor activity of abiraterone. Cabozantinib, a multiple receptor tyrosine kinase inhibitor, enhances the ability of abiraterone to inhibit AR activity in a cell line dependent manner. In addition our cell line studies demonstrate abiraterone stimulated IGF-1R phosphorylation with downstream activation of MEK1/2 and ERK1/2, and that this potential adaptive resistance mechanism was inhibited by cabozantinib. Cabozantinib can enhance the efficacy of abiraterone by blocking multiple compensatory survival mechanisms including IGF-1R activation and supports the assessment of the combination in a clinical trial. Copyright © 2015, American Association for Cancer Research.
    No preview · Article · Aug 2015 · Clinical Cancer Research
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    ABSTRACT: Background: Androgen-deprivation therapy (ADT) has been the backbone of treatment for metastatic prostate cancer since the 1940s. We assessed whether concomitant treatment with ADT plus docetaxel would result in longer overall survival than that with ADT alone. Methods: We assigned men with metastatic, hormone-sensitive prostate cancer to receive either ADT plus docetaxel (at a dose of 75 mg per square meter of body-surface area every 3 weeks for six cycles) or ADT alone. The primary objective was to test the hypothesis that the median overall survival would be 33.3% longer among patients receiving docetaxel added to ADT early during therapy than among patients receiving ADT alone. Results: A total of 790 patients (median age, 63 years) underwent randomization. After a median follow-up of 28.9 months, the median overall survival was 13.6 months longer with ADT plus docetaxel (combination therapy) than with ADT alone (57.6 months vs. 44.0 months; hazard ratio for death in the combination group, 0.61; 95% confidence interval [CI], 0.47 to 0.80; P<0.001). The median time to biochemical, symptomatic, or radiographic progression was 20.2 months in the combination group, as compared with 11.7 months in the ADT-alone group (hazard ratio, 0.61; 95% CI, 0.51 to 0.72; P<0.001). The rate of a prostate-specific antigen level of less than 0.2 ng per milliliter at 12 months was 27.7% in the combination group versus 16.8% in the ADT-alone group (P<0.001). In the combination group, the rate of grade 3 or 4 febrile neutropenia was 6.2%, the rate of grade 3 or 4 infection with neutropenia was 2.3%, and the rate of grade 3 sensory neuropathy and of grade 3 motor neuropathy was 0.5%. Conclusions: Six cycles of docetaxel at the beginning of ADT for metastatic prostate cancer resulted in significantly longer overall survival than that with ADT alone. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00309985.).
    Full-text · Article · Aug 2015 · New England Journal of Medicine

Publication Stats

5k Citations
1,344.99 Total Impact Points

Institutions

  • 2013-2016
    • Harvard Medical School
      • Department of Radiation Oncology
      Boston, Massachusetts, United States
  • 2010-2015
    • Harvard University
      Cambridge, Massachusetts, United States
    • Dana-Farber Cancer Institute
      • • Lank Center for Genitourinary Oncology
      • • Department of Medical Oncology
      Boston, Massachusetts, United States
  • 2014
    • Fox Chase Cancer Center
      Filadelfia, Pennsylvania, United States
    • Massachusetts General Hospital
      Boston, Massachusetts, United States
  • 2013-2014
    • Brigham and Women's Hospital
      Boston, Massachusetts, United States
  • 1999-2011
    • Indiana University-Purdue University Indianapolis
      • • Department of Medicine
      • • Department of Surgery
      • • Division of Hematology/Oncology
      Indianapolis, Indiana, United States
  • 2009-2010
    • University of Adelaide
      • Faculty of Health Sciences
      Tarndarnya, South Australia, Australia
  • 2008
    • Indiana University-Purdue University School of Medicine
      • Department of Medicine
      Indianapolis, Indiana, United States
  • 1998-2006
    • Indiana University Bloomington
      Bloomington, Indiana, United States
  • 2004
    • Beth Israel Deaconess Medical Center
      Boston, Massachusetts, United States