Matthew I Milowsky

University of North Carolina at Chapel Hill, North Carolina, United States

Are you Matthew I Milowsky?

Claim your profile

Publications (89)477.74 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Second-line treatment options for patients with advanced urothelial carcinoma (UC) are limited. Fibroblast growth factor receptor 3 (FGFR3) is dysregulated in UC by activating mutations or protein overexpression in non-mutant tumours. In this study, the efficacy, pharmacodynamics and safety of dovitinib-a broad-targeted inhibitor of tyrosine kinases, including FGFR3-were evaluated in patients with previously treated advanced UC with and without FGFR3 mutations. Forty-four adults with advanced UC who had progressed after one to three platinum-based and/or combination chemotherapy regimens were classified as having mutant (FGFR3(MUT); n=12), wild-type (FGFR3(WT); n=31), or unknown (n=1) FGFR3 status. Patients received 500mg dovitinib once daily on a 5-days-on/2-days-off schedule. The primary end-point of this two-stage study was the investigator-assessed overall response rate (ORR). Most of the patients were men (75%) and over half of the patients were aged ⩾65years (61%). All patients had received ⩾1 prior antineoplastic therapy for UC. The study was terminated at the end of stage 1, when it was determined by investigator review that the ORR of both the FGFR3(MUT) (0%; 95% confidence interval [CI], 0.0-26.5) and FGFR3(WT) (3.2%; 95% CI, 0.1-16.7) groups did not meet the criteria to continue to stage 2. The most common grade 3/4 adverse events, suspected to be study-drug related, included thrombocytopenia (9%), fatigue (9%), and asthenia (9%). Although generally well tolerated, dovitinib has very limited single-agent activity in patients with previously treated advanced UC, regardless of FGFR3 mutation status. clinicaltrials.gov NCT00790426. Copyright © 2014 Elsevier Ltd. All rights reserved.
    European journal of cancer (Oxford, England: 1990) 12/2014; 50(18):3145-52. · 4.12 Impact Factor
  • Angela B Smith, Matthew I Milowsky
    Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 11/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background The complete remission (CR) rate with salvage systemic therapy for urothelial carcinoma (UC) is unclear and its value as an intermediate endpoint and association with survival are unknown. Materials and methods Data from Phase II trials of salvage chemotherapy and/or biologic agents were pooled. Data regarding response, overall survival (OS), progression-free survival (PFS), time from prior chemotherapy (TFPC), hemoglobin (Hb), performance status (PS) and liver metastasis (LM) status were collected. Cox proportional hazards regression was used to evaluate the association of CR and other prognostic factors with outcomes. Results 789 of 818 patients enrolled in 12 phase II trials were evaluable. CR and partial response (PR) were seen in 14 (1.8%) and 109 (13.8%) patients. Median (95% CI) OS for those with a CR was 21.5 (14.2-34.3) months, compared with 6.7 (6.0-7.0) months in those without a CR (p<0.001). Median (95% CI) PFS for those with a CR was 15.7 (8.2-27.1) months, compared with 2.6 (2.4-2.8) months for those without a CR (p<0.001). Prior cisplatin and TFPC ≥3 months were associated with CR (p<0.05). The presence of poor prognostic factors and suboptimal response to prior therapy did not preclude CR. Conclusions CR occurs in 1.8% of patients receiving salvage therapy for advanced UC, and is strongly associated with durable OS and PFS. CR warrants validation as an intermediate endpoint and may help select agents for further investigation and tumors for molecular interrogation.
    Clinical Genitourinary Cancer 10/2014; · 1.43 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Microsystem-based technologies are providing new opportunities in the area of in vitro diagnostics due to their ability to provide process automation enabling point-of-care operation. As an example, microsystems used for the isolation and analysis of circulating tumor cells (CTCs) from complex, heterogeneous samples in an automated fashion with improved recoveries and selectivity are providing new opportunities for this important biomarker. Unfortunately, many of the existing microfluidic systems lack the throughput capabilities and/or are too expensive to manufacture to warrant their widespread use in clinical testing scenarios. Here, we describe a disposable, all-polymer, microfluidic system for the high-throughput (HT) isolation of CTCs directly from whole blood inputs. The device employs an array of high aspect ratio (HAR), parallel, sinusoidal microchannels (25 × 150 μm; W × D; AR = 6.0) with walls covalently decorated with anti-EpCAM antibodies to provide affinity-based isolation of CTCs. Channel width, which is similar to an average CTC diameter (10–20 μm), plays a critical role in maximizing the probability of cell/wall interactions and allows for achieving high CTC recovery. The extended channel depth allows for increased throughput at the optimized flow velocity (2 mm/s in a microchannel); maximizes cell recovery, and prevents clogging of the microfluidic channels during blood processing. Fluidic addressing of the microchannel array with a minimal device footprint is provided by large cross-sectional area feed and exit channels poised orthogonal to the network of the sinusoidal capillary channels (so-called Z-geometry). Computational modeling was used to confirm uniform addressing of the channels in the isolation bed. Devices with various numbers of parallel microchannels ranging from 50 to 320 have been successfully constructed. Cyclic olefin copolymer (COC) was chosen as the substrate material due to its superior properties during UV-activation of the HAR microchannels surfaces prior to antibody attachment. Operation of the HT-CTC device has been validated by isolation of CTCs directly from blood secured from patients with metastatic prostate cancer. High CTC sample purities (low number of contaminating white blood cells) allowed for direct lysis and molecular profiling of isolated CTCs.
    Microsystem Technologies 10/2014; 20(10-11). · 0.83 Impact Factor
  • Arjun V. Balar, Matthew I. Milowsky
    [Show abstract] [Hide abstract]
    ABSTRACT: Urothelial cancer has long been known as a chemotherapy-sensitive disease. However, clinical trial data to date suggest a plateau to the magnitude of benefit from cytotoxic therapy alone. In spite of level 1 evidence supporting cisplatin-based chemotherapy for patients with muscle-invasive and metastatic urothelial cancer, underuse prevails among patients with localized disease and only a modest survival benefit exists in the metastatic setting, although trials have consistently demonstrated that there is a subset of patients who clearly benefit. Recent comprehensive genomic profiling has identified a high prevalence of actionable genomic alterations as well as other potential targets yet to be fully understood. Modern clinical trials must now focus on identifying predictive biomarkers to select those patients who will benefit most from cytotoxic chemotherapy, molecularly targeted therapy, or potentially both. Cancer 2014. © 2014 American Cancer Society.
    Cancer 08/2014; · 5.20 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: No guidelines exist for the management of micropapillary bladder cancer (MPBC) and most reports of this variant of urothelial carcinoma are case series comprising small numbers of patients. We sought to determine current practice patterns for MPBC using a survey sent to the Society of Urologic Oncology (SUO) and to present those results in the setting of a comprehensive review of the existing literature.
    Urologic oncology. 06/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: We sought to define whether there are intrinsic molecular subtypes of high-grade bladder cancer. Consensus clustering performed on gene expression data from a meta-dataset of high-grade, muscle-invasive bladder tumors identified two intrinsic, molecular subsets of high-grade bladder cancer, termed "luminal" and "basal-like," which have characteristics of different stages of urothelial differentiation, reflect the luminal and basal-like molecular subtypes of breast cancer, and have clinically meaningful differences in outcome. A gene set predictor, bladder cancer analysis of subtypes by gene expression (BASE47) was defined by prediction analysis of microarrays (PAM) and accurately classifies the subtypes. Our data demonstrate that there are at least two molecularly and clinically distinct subtypes of high-grade bladder cancer and validate the BASE47 as a subtype predictor. Future studies exploring the predictive value of the BASE47 subtypes for standard of care bladder cancer therapies, as well as novel subtype-specific therapies, will be of interest.
    Proceedings of the National Academy of Sciences 02/2014; · 9.81 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Upper tract urothelial carcinoma (UTUC) is a rare disease in Western countries and garners little focused attention in urologic and oncologic circles. We report highlights from the first symposium on UTUC. All participants were asked to provide a summary of their presentation to be included as part of these proceedings. Submitted summaries were synthesized into this document. All contributors reviewed and provided input on the final draft. Five highlights are included in this report, including landmark research that not only reveals the likely cause of Balkan endemic nephropathy and associated UTUC but also links it directly to UTUC in Taiwan. Because of the ubiquitous use of Aristolochia plants in these herbal remedies, a public health problem of considerable magnitude is anticipated in Asian countries. Gene expression signatures reveal some differential expression in bladder carcinoma, such as CLCA2 and GABRE. Few urinary markers have proven utility for the diagnosis and follow-up of UTUC, and no tissue or blood-based markers are currently undergoing clinical application. Novel endoscopic therapies provide some hope of improving tissue sampling, diagnosis, and kidney-sparing therapeutics, but the greatest potential lies in improving clinical (preoperative) risk stratification, which is critically limited in this disease. Biomarkers, currently untested, hold promise in identifying patients most likely to benefit from perioperative chemotherapy and at high risk from cisplatin-induced nephrotoxicity. Despite its rarity in the West, UTUC is reaching potentially epidemic proportions in the East because of exposure to carcinogenic herbal remedies. Critical trials are needed to improve our understanding and treatment of UTUC. Because of the broad range of comorbid conditions in patients suffering from this disease, it is the consensus of the participants that future clinical trials should be practical in design and applicable to a broad range of patients, diverging from the current dogma of narrow patient selection criteria in clinical trials. Practical designs would maximize accrual for a still uncommon disease, and their findings would be applicable to a larger proportion of patients than current narrowly selected designs.
    Urologic Oncology 01/2014; · 3.65 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Salvage systemic therapy for advanced urothelial carcinoma has substantial unmet needs. Small phase II trials have been conducted with varying eligibility criteria, which render cross-trials comparisons difficult. Moreover, accrual to trials is hampered by comorbidities, elderly age and poor performance status. Therefore, improvements in clinical trial design may facilitate further advances. This commentary summarizes recent data regarding prognostic factors, which allow us to recommend inclusive, yet rational, eligibility criteria and stratification factors to enhance accrual and improve interpretability of data from phase II trials: 1) allowing either prior perioperative platinum-based chemotherapy within 1 year or prior platinum-based chemotherapy for metastatic disease, 2) allowing ≤2 prior lines of therapy, 3) allow patients regardless of quality of response to prior therapy, 4) allow all sites of primary urothelial malignancy, and 5) a preplanned analysis of outcomes controlled for baseline prognostic factors.
    Clinical Genitourinary Cancer 01/2014; · 1.43 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Objectives No guidelines exist for the management of micropapillary bladder cancer (MPBC) and most reports of this variant of urothelial carcinoma are case series comprising small numbers of patients. We sought to determine current practice patterns for MPBC using a survey sent to the Society of Urologic Oncology (SUO) and to present those results in the setting of a comprehensive review of the existing literature. Materials and methods A survey developed by the Translational Science Working Group of the Bladder Cancer Advocacy Network–sponsored Think Tank meeting was distributed to members of the SUO. The results from 118 respondents were analyzed and presented with a literature review. Results Most survey respondents were urologists, with 80% considering bladder cancer their primary area of interest. Although 78% of the respondents reported a dedicated genitourinary pathologist at their institution, there were discrepant opinions on how a pathologic diagnosis of MPBC is determined as well as variability on the proportion of MPBC that is clinically significant. Among them, 78% treat MPBC differently than conventional urothelial carcinoma, with 81% reporting that they would treat cT1 MPBC with upfront radical cystectomy. However, the respondents had split opinions regarding the sensitivity of MPBC to cisplatin-based chemotherapy, which affected utilization of neoadjuvant chemotherapy in muscle-invasive disease. Conclusions The management of MPBC is diverse among members of the SUO. Although most favors early cystectomy for cT1 MPBC, there is no consensus on the use of neoadjuvant chemotherapy for muscle-invasive MPBC.
    Urologic Oncology: Seminars and Original Investigations. 01/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background Outcomes with concurrent chemoradiation for penile squamous cell carcinoma (PSCC) are unclear and only anecdotal reports have been published. We performed a retrospective analysis of patients who received concurrent chemotherapy and radiotherapy for PSCC. Patients and methods Individual patient level data were obtained from 5 institutions for outcomes with concurrent chemoradiation for PSCC. Descriptive statistics were calculated and univariable Cox proportional hazards regression analysis was conducted to examine the prognostic impact of candidate factors on progression-free survival (PFS) and overall survival (OS). Results A total of 26 men were evaluable. The mean age was 60.3 years. The clinical stage was ≤3 in 9 patients (36%) and stage 4 in the rest. Soft tissue and visceral metastasis were present in 35% and 20% of patients, respectively. The chemotherapy was cisplatin-based in 92.3% of patients and the median (range) of external beam radiotherapy administered was 4900 cGy (1800-7000). The median OS was 6.9 months (95% CI: 5, 14) and the median PFS was 5.1 months (95% CI: 2.5, 7.0). When excluding patients with M1 disease, the remaining patients (N=21) had a median OS and PFS of 10.0 months (95% CI: 5, 14) and 6.0 months (95% CI: 2.0, 7.0), respectively. Baseline neutrophil by lymphocyte ratio (NLR) was significantly associated with survival and visceral metastasis showed a trend for association with OS. Conclusions Concurrent chemoradiation demonstrated poor outcomes for locally advanced PSCC. Better understanding of tumor biology and study of novel combinations of biologic agents with radiation are warranted.
    Clinical Genitourinary Cancer 01/2014; · 1.43 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background The differential impact of number of prior lines of therapy and setting of prior therapy (perioperative, metastatic) is unclear in advanced urothelial carcinoma (UC). Patients and methods Ten phase II trials of salvage chemotherapy and/or biologic agent therapy enrolling 731 patients were available. Data on the number of prior lines of therapy and setting of prior therapy were required in addition to known previously recognized prognostic factors: time from prior chemotherapy, hemoglobin, performance status and liver metastasis status. Cox proportional hazards regression was used to evaluate the association of number of prior lines and prior perioperative therapy with overall survival (OS) as the primary clinical endpoint. Trial was a stratification factor. Results 711 patients were evaluable. The overall median PFS and OS were 2.7 and 6.8 months, respectively. The number of prior lines were 1 in 559 (78.6%), 2 in 111 (15.6%), 3 in 29 (4.1%), 4 in 10 (1.4%) and 5 in 2 (0.3%) patients. Prior perioperative chemotherapy was given to 277 (39.1%) and chemotherapy for metastatic disease to 454 (64.1%). The number of prior lines was not independently associated with OS (HR 0.99 [95% CI: 0.86-1.14]). Prior peri-operative chemotherapy was a favorable factor for OS on univariable but not multivariable analysis. Conclusions The number of prior lines of therapy and prior perioperative chemotherapy were not independently prognostic in UC patients receiving salvage therapy. Adoption of these data in salvage therapy trials should enhance accrual, the interpretability of results and drug development.
    Clinical Genitourinary Cancer 01/2014; · 1.43 Impact Factor
  • Matthew I Milowsky, William Y Kim
    [Show abstract] [Hide abstract]
    ABSTRACT: Bladder cancer is a disease of older patients who often have multiple comorbidities. Although cisplatin-based combination chemotherapy is the standard of care in the neoadjuvant and metastatic settings, outcomes remain poor, and approximately half of patients are ineligible for cisplatin where treatment options are severely limited. Recent comprehensive genome sequencing studies have defined the mutational spectra of high-grade urothelial carcinoma of the bladder. Although there is a high prevalence of potentially actionable genomic alterations, whether these events represent true oncogenic vulnerabilities has yet to be confirmed. Given the demographics and genetics, we propose that bladder cancer represents an ideal model to study the potential of targeted therapy in older patients who are too often unable to receive cisplatin-based therapy and where novel treatment strategies are desperately needed.
    American Society of Clinical Oncology educational book / ASCO. American Society of Clinical Oncology. Meeting. 01/2014; 34:e192-5.
  • [Show abstract] [Hide abstract]
    ABSTRACT: To evaluate the association between patterns of care and patient survival for the treatment of muscle-invasive bladder cancer (MIBC) using a large, national database. We identified a cohort of 36,469 patients with MIBC (Stage II) from 1998 to 2010 from the National Cancer Data Base. Patients were stratified into four treatment groups: radical cystectomy, chemo-radiation, other therapy, or no treatment. Overall survival (OS) between groups was evaluated using the Kaplan Meier (KM) method and Log Rank test. A multivariable Cox proportional hazards model was fit to evaluate the association between treatment groups with OS. Among treatment groups, 27% received radical cystectomy, 10% chemo-radiation, 61% other therapy, and 2% no treatment. Unadjusted KM analysis showed significant differences by group, with cystectomy having the greatest median OS (48 months) followed by chemo-radiation (28 months), other therapy (20 months), and no treatment (5 months). When controlling for multiple covariates, OS for cystectomy was similar to chemo-radiation (HR 1.05, 95% CI 0.98, 1.12), but superior to other therapy (HR 1.42; 95% CI 1.35, 1.48), and no treatment (HR 2.40; 95% CI 2.12, 2.72). OS for chemo-radiation was superior to other therapy and no treatment. Radical cystectomy and chemo-radiation are significantly underutilized despite a substantial survival benefit compared to other therapies or no treatment. Future studies are needed to optimize care delivery and improve outcomes for patients with MIBC.
    BJU International 12/2013; · 3.05 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Prognostic factors in men with penile squamous cell carcinoma (PSCC) receiving systemic therapy are unknown. A prognostic classification system in this disease may facilitate interpretation of outcomes and guide rational drug development. We performed a retrospective analysis to identify prognostic factors in men with PSCC receiving first-line systemic therapy for advanced disease. Individual patient level data were obtained from 13 institutions to study prognostic factors in the context of first-line systemic therapy for advanced PSCC. Cox proportional hazards regression analysis was conducted to examine the prognostic effect of these candidate factors on progression-free survival (PFS) and overall survival (OS): age, stage, hemoglobin, neutrophil count, lymphocyte count, albumin, site of metastasis (visceral or nonvisceral), smoking, circumcision, regimen, ECOG performance status (PS), lymphovascular invasion, precancerous lesion, and surgery following chemotherapy. The effect of different treatments was then evaluated adjusting for factors in the prognostic model. The study included 140 eligible men. Mean age across all men was 57.0 years. Among them, 8.6%, 21.4%, and 70.0% of patients had stage 2, 3, and 4 diseases, respectively; 40.7% had ECOG PS≥1, 47.4% had visceral metastases, and 73.6% received cisplatin-based chemotherapy. The multivariate model of poor prognostic factors included visceral metastases (P<0.001) and ECOG PS≥1 (P<0.001) for both PFS and OS. A risk stratification model constructed with 0, 1, and both poor prognostic factors was internally validated and demonstrated moderate discriminatory ability (c-statistic of 0.657 and 0.677 for OS and PFS, respectively). The median OS for the entire population was 9 months. Median OS was not reached, 8, and 7 months for those with 0, 1, and both risk factors, respectively. Cisplatin-based regimens were associated with better OS (P = 0.017) but not PFS (P = 0.37) compared with noncisplatin-based regimens after adjusting for the 2 prognostic factors. In men with advanced PSCC receiving first-line systemic therapy, visceral metastases and ECOG PS≥1 were poor prognostic factors. A prognostic model including these factors exhibited moderate discriminatory ability for outcomes and warrants external validation. Patients receiving cisplatin-based regimens exhibited better outcomes compared with noncisplatin-based regimens after adjusting for prognostic factors.
    Urologic Oncology 12/2013; · 3.65 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: To determine whether neoadjuvant chemotherapy (NAC) is a predictor of post-operative complications, length of stay, or operative time after radical cystectomy (RC) for bladder cancer. A retrospective review of the American College of Surgeons National Surgical Quality Improvement Program (NSQIP) database was performed to identify patients receiving NAC prior to RC from 2005-2011. Bivariable and multivariable analyses were performed to determine whether NAC was associated with 30-day peri-operative outcomes such as complications, length of stay, and operative time. Of the 878 patients who underwent RC for bladder cancer in our study, 78 (8.9%) received NAC. Excluding those patients who were ineligible for NAC due to renal insufficiency, 78/642 (12.1%) received NAC. 457 of the 878 patients (52.1%) undergoing RC had at least 1 complication within 30 days, including 43 of 78 patients (55.1%) who received NAC and 414 of 800 patients (51.8%) who did not (p = 0.58). On multivariable logistic regression, NAC was not a predictor of complications (p=0.87), reoperation (p=0.16), wound infection (p=0.32), or wound dehiscence(p=0.32). Using multiple linear regression, NAC was not a predictor of increased operative time (p=0.24), and patients undergoing NAC had decreased hospital length of stay (p=0.02). Our study is the first large multi-institutional analysis specifically comparing complications after RC with and without NAC. Using a nationally validated, prospectively maintained database specifically designed to measure perioperative outcomes, we found no increase in perioperative complications or surgical morbidity with NAC. In light of these findings and the well-established overall survival benefit over surgery alone, efforts are needed to improve the uptake of NAC.
    BJU International 11/2013; · 3.05 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: To examine the association of hospital volume and 90-day mortality after cystectomy, conditional on survival to 30 days SUBJECTS AND METHODS: The National Cancer Database was used to evaluate 30- and 90-day mortality for 35,055 bladder cancer cases that received cystectomy at 1,118 hospitals. Patient data were aggregated into hospital volume categories based on average annual number of procedures [<10 low volume hospital (LVH), 10-19, ≥20 high volume (HVH)]. Associations between mortality and clinical, demographic and hospital characteristics were analyzed using hierarchical logistic regression models. To assess the association between hospital volume and 90-day mortality independent from shorter-term mortality, 90-day mortality conditional on 30-day survival was assessed in the multivariate modeling. Unadjusted 30- and 90-day mortality rates were 2.7% and 7.2% overall, 1.9% and 5.7% among HVH, and 3.2% and 8.0% among LVH, respectively. Compared to HVH, the adjusted risks among LVH [OR (95% CI)] of 30- and 90-day mortality conditional on having survived through 30 days from the hierarchical models were 1.5 (1.3-1.9), and 1.2 (1.0-1.4), respectively. Low hospital volume was associated with increased 30- and 90-day mortality. These data support the need for further research to better understand the relatively high mortality rates seen between 30-90 days, which are high and less variable across hospital volume strata. The stronger association between volume and 30-day mortality suggests that quality-reporting efforts should focus on shorter term outcomes.
    BJU International 11/2013; · 3.05 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Bladder cancer is notable for a striking heterogeneity of disease-specific risks. Among the approximately 75% of incident cases found to be superficial to the muscularis propria at the time of presentation (non-muscle-invasive bladder cancer), the risk of progression to the lethal phenotype of muscle-invasive disease is strongly associated with stage and grade of disease. Given the suggestion of an increasing percentage of low-risk cases in hospital-based registry data in recent years, the authors hypothesized that population-based data may reveal changes in the stage distribution of early-stage cases. Surveillance, Epidemiology, and End Results (SEER) data were used to examine trends for the stage-specific incidence of bladder cancer between 1988 and 2006, adjusted for age, race, and sex, using Joinpoint and nonparametric tests. The adjusted incidence rate of papillary noninvasive (Ta) predominantly low grade (77%) disease was found to increase from 5.52 to 9.09 per 100,000 population (P < .0001), with an average annual percentage change of +3.3. Over the same period, concomitant, albeit smaller, decreases were observed for flat in situ (Tis) and lamina propria-invasive (T1) disease (2.57 to 1.19 and 6.65 to 4.61 per 100,000 population [both P < .0001]; average annual percent change of -5.0 and -1.6, respectively). The trend was most dramatic among patients in the oldest age strata, suggesting a previously unappreciated cohort phenomenon. The findings of the current study should motivate further epidemiological investigations of differential associations of genetic and environmental factors with different bladder cancer phenotypes as well as further scrutiny of clinical practice guideline recommendations for the growing subgroup of predominantly older patients with lower-risk disease. Cancer 2013. © 2013 American Cancer Society.
    Cancer 10/2013; · 5.20 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: PURPOSEWe sought to define the prevalence and co-occurrence of actionable genomic alterations in patients with high-grade bladder cancer to serve as a platform for therapeutic drug discovery. PATIENTS AND METHODS An integrative analysis of 97 high-grade bladder tumors was conducted to identify actionable drug targets, which are defined as genomic alterations that have been clinically validated in another cancer type (eg, BRAF mutation) or alterations for which a selective inhibitor of the target or pathway is under clinical investigation. DNA copy number alterations (CNAs) were defined by using array comparative genomic hybridization. Mutation profiling was performed by using both mass spectroscopy-based genotyping and Sanger sequencing.ResultsSixty-one percent of tumors harbored potentially actionable genomic alterations. A core pathway analysis of the integrated data set revealed a nonoverlapping pattern of mutations in the RTK-RAS-RAF and phosphoinositide 3-kinase/AKT/mammalian target of rapamycin pathways and regulators of G1-S cell cycle progression. Unsupervised clustering of CNAs defined two distinct classes of bladder tumors that differed in the degree of their CNA burden. Integration of mutation and copy number analyses revealed that mutations in TP53 and RB1 were significantly more common in tumors with a high CNA burden (P < .001 and P < .003, respectively). CONCLUSION High-grade bladder cancer possesses substantial genomic heterogeneity. The majority of tumors harbor potentially tractable genomic alterations that may predict for response to target-selective agents. Given the genomic diversity of bladder cancers, optimal development of target-specific agents will require pretreatment genomic characterization.
    Journal of Clinical Oncology 07/2013; · 18.04 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Variations in urothelial carcinoma (UC) response to platinum chemotherapy are common and frequently attributed to genetic and epigenetic variations of somatic DNA. We hypothesized that variations in germline DNA may contribute to UC chemosensitivity. DNA from 210 UC patients treated with platinum-based chemotherapy was genotyped for 80 single nucleotide polymorphisms (SNPs). Logistic regression was used to examine the association between SNPs and response, and a multivariable predictive model was created. Significant SNPs were combined to form a SNP score predicting response. Eleven UC cell lines were genotyped as validation. Six SNPs were significantly associated with 101 complete or partial responses (48%). Four SNPs retained independence association and were incorporated into a response prediction model. Each additional risk allele was associated with a nearly 50% decrease in odds of response [odds ratio (OR) = 0.51, 95% confidence interval 0.39-0.65, P = 1.05 × 10(-7)). The bootstrap-adjusted area under the curves of this model was greater than clinical prognostic factors alone (0.78 versus 0.64). The SNP score showed a positive trend with chemosensitivity in cell lines (P = 0.115). Genetic variants associated with response of UC to platinum-based therapy were identified in germline DNA. A model using these genetic variants may predict response to chemotherapy better than clinical factors alone.
    Annals of Oncology 07/2013; · 7.38 Impact Factor

Publication Stats

2k Citations
477.74 Total Impact Points

Institutions

  • 2012–2014
    • University of North Carolina at Chapel Hill
      • Department of Medicine
      North Carolina, United States
    • University of Texas Medical Branch at Galveston
      Galveston, Texas, United States
    • Vanderbilt University
      • Department of Neurology
      Nashville, MI, United States
  • 2002–2013
    • Weill Cornell Medical College
      • • Division of Hematology/Medical Oncology
      • • Department of Pathology and Laboratory Medicine
      • • Division of Hospital Medicine
      • • Department of Urology
      New York City, NY, United States
  • 2008–2012
    • Memorial Sloan-Kettering Cancer Center
      • • Genitourinary Oncology Service
      • • Department of Surgery
      New York City, New York, United States
  • 2011
    • American College of Surgeons
      Chicago, Illinois, United States
  • 2009
    • New York Presbyterian Hospital
      • Department of Pain Medicine
      New York City, New York, United States
  • 2001–2009
    • Cornell University
      • • Department of Medicine
      • • Department of Urology
      Ithaca, NY, United States