Showing papers by "Lawrence D. True published in 2014"

The Androgen-Regulated Protease TMPRSS2 Activates a Proteolytic Cascade Involving Components of the Tumor Microenvironment and Promotes Prostate Cancer Metastasis

Abstract: TMPRSS2 is an androgen-regulated cell-surface serine protease expressed predominantly in prostate epithelium. TMPRSS2 is expressed highly in localized high-grade prostate cancers and in the majority of human prostate cancer metastases. Through the generation of mouse models with a targeted deletion of Tmprss2 , we demonstrate that the activity of this protease regulates cancer cell invasion and metastasis to distant organs. By screening combinatorial peptide libraries, we identified a spectrum of TMPRSS2 substrates that include pro-hepatocyte growth factor (HGF). HGF activated by TMPRSS2 promoted c-MET receptor tyrosine kinase signaling, and initiated a proinvasive epithelial-to-mesenchymal transition phenotype. Chemical library screens identified a potent bioavailable TMPRSS2 inhibitor that suppressed prostate cancer metastasis in vivo . Together, these findings provide a mechanistic link between androgen-regulated signaling programs and prostate cancer metastasis that operate via context-dependent interactions with extracellular constituents of the tumor microenvironment. Significance: The vast majority of prostate cancer deaths are due to metastasis. Loss of TMPRSS2 activity dramatically attenuated the metastatic phenotype through mechanisms involving the HGF–c-MET axis. Therapeutic approaches directed toward inhibiting TMPRSS2 may reduce the incidence or progression of metastasis in patients with prostate cancer. Cancer Discov; 4(11); 1310–25. ©2014 AACR . See related commentary by Rubin, [p. 1262][1] This article is highlighted in the In This Issue feature, [p. 1243][2] [1]: /lookup/volpage/4/1262?iss=11 [2]: /lookup/volpage/4/1243?iss=11

Aggressive Variants of Castration-Resistant Prostate Cancer

Abstract: A subset of patients with advanced castration-resistant prostate cancer may eventually evolve into an androgen receptor (AR)-independent phenotype, with a clinical picture associated with the development of rapidly progressive disease involving visceral sites and hormone refractoriness, often in the setting of a low or modestly rising serum prostate-specific antigen level. Biopsies performed in such patients may vary, ranging from poorly differentiated carcinomas to mixed adenocarcinoma-small cell carcinomas to pure small cell carcinomas. These aggressive tumors often demonstrate low or absent AR protein expression and, in some cases, express markers of neuroendocrine differentiation. Because tumor morphology is not always predicted by clinical behavior, the terms "anaplastic prostate cancer" or "neuroendocrine prostate cancer" have been used descriptively to describe these rapidly growing clinical features. Patients meeting clinical criteria of anaplastic prostate cancer have been shown to predict for poor prognosis, and these patients may be considered for platinum-based chemotherapy treatment regimens. Therefore, understanding variants within the spectrum of advanced prostate cancer has important diagnostic and treatment implications.

Intense Androgen-Deprivation Therapy With Abiraterone Acetate Plus Leuprolide Acetate in Patients With Localized High-Risk Prostate Cancer: Results of a Randomized Phase II Neoadjuvant Study

Abstract: Purpose Cure rates for localized high-risk prostate cancers (PCa) and some intermediate-risk PCa are frequently suboptimal with local therapy. Outcomes are improved by concomitant androgen-deprivation therapy (ADT) with radiation therapy, but not by concomitant ADT with surgery. Luteinizing hormone–releasing hormone agonist (LHRHa; leuprolide acetate) does not reduce serum androgens as effectively as abiraterone acetate (AA), a prodrug of abiraterone, a CYP17 inhibitor that lowers serum testosterone (< 1 ng/dL) and improves survival in metastatic PCa. The possibility that greater androgen suppression in patients with localized high-risk PCa will result in improved clinical outcomes makes paramount the reassessment of neoadjuvant ADT with more robust androgen suppression. Patients and Methods A neoadjuvant randomized phase II trial of LHRHa with AA was conducted in patients with localized high-risk PCa (N = 58). For the first 12 weeks, patients were randomly assigned to LHRHa versus LHRHa plus AA. After a ...

The Critical Role of the Pathologist in Determining Eligibility for Active Surveillance as a Management Option in Patients With Prostate Cancer: Consensus Statement With Recommendations Supported by the College of American Pathologists, International Society of Urological Pathology, Association of Directors of Anatomic and Surgical Pathology, the New Zealand Society of Pathologists, and the Prostate Cancer Foundation

Abstract: Context.—Prostate cancer remains a significant public health problem. Recent publications of randomized trials and the US Preventive Services Task Force recommendations have drawn attention to over...

Targeted Androgen Pathway Suppression in Localized Prostate Cancer: A Pilot Study

Abstract: Purpose Ligand-mediated activation of the androgen receptor (AR) is critical for prostate cancer (PCa) survival and proliferation. The failure to completely ablate tissue androgens may limit suppression of PCa growth. We evaluated combinations of CYP17A and 5-α-reductase inhibitors for reducing prostate androgen levels, AR signaling, and PCa volumes. Patients and Methods Thirty-five men with intermediate/high-risk clinically localized PCa were randomly assigned to goserelin combined with dutasteride (ZD), bicalutamide and dutasteride (ZBD), or bicalutamide, dutasteride, and ketoconazole (ZBDK) for 3 months before prostatectomy. Controls included patients receiving combined androgen blockade with luteinizing hormone-releasing hormone agonist and bicalutamide. The primary outcome measure was tissue dihydrotestosterone (DHT) concentration. Results Prostate DHT levels were substantially lower in all experimental arms (0.02 to 0.04 ng/g v 0.92 ng/g in controls; P < .001). The ZBDK group demonstrated the greate...

Consensus statement with recommendations on active surveillance inclusion criteria and definition of progression in men with localized prostate cancer: the critical role of the pathologist.

Abstract: Active surveillance (AS) is an important management option for men with low-risk, clinically localized prostate cancer. The clinical parameters for patient selection and definition of progression for AS protocols are evolving as data from several large cohorts matures. Vital to this process is the critical role pathologic parameters play in identifying appropriate candidates for AS. These findings need to be reproducible and consistently reported by surgical pathologists. This report highlights the importance of accurate pathology reporting as a critical component of these protocols.

Chemotherapy-induced monoamine oxidase expression in prostate carcinoma functions as a cytoprotective resistance enzyme and associates with clinical outcomes.

Abstract: To identify molecular alterations in prostate cancers associating with relapse following neoadjuvant chemotherapy and radical prostatectomy patients with high-risk localized prostate cancer were enrolled into a phase I-II clinical trial of neoadjuvant chemotherapy with docetaxel and mitoxantrone followed by prostatectomy. Pre-treatment prostate tissue was acquired by needle biopsy and post-treatment tissue was acquired by prostatectomy. Prostate cancer gene expression measurements were determined in 31 patients who completed 4 cycles of neoadjuvant chemotherapy. We identified 141 genes with significant transcript level alterations following chemotherapy that associated with subsequent biochemical relapse. This group included the transcript encoding monoamine oxidase A (MAOA). In vitro, cytotoxic chemotherapy induced the expression of MAOA and elevated MAOA levels enhanced cell survival following docetaxel exposure. MAOA activity increased the levels of reactive oxygen species and increased the expression and nuclear translocation of HIF1α. The suppression of MAOA activity using the irreversible inhibitor clorgyline augmented the apoptotic responses induced by docetaxel. In summary, we determined that the expression of MAOA is induced by exposure to cytotoxic chemotherapy, increases HIF1α, and contributes to docetaxel resistance. As MAOA inhibitors have been approved for human use, regimens combining MAOA inhibitors with docetaxel may improve clinical outcomes.

Novel Neoadjuvant Therapy Paradigms for Bladder Cancer: Results from the National Cancer Center Institute Forum

Abstract: Objective To bridge gaps in translational science and develop the concepts for 2 novel biomarker-driven clinical trials: one in the presurgical setting and the other in the setting of bladder preservation with chemoradiation. Methods and materials The National Cancer Institute sponsored a forum, “Novel Neoadjuvant Therapy for Bladder Cancer,” which brought leading clinical and laboratory-based scientists together with the advocacy community. Results The group designed a neoadjuvant clinical trial to compare the clinical efficacy of the two frontline chemotherapy regimens (gemcitabine plus cisplatin versus MVAC) and the ability of a gene expression profiling-based algorithm (CoXEN) to predict complete pathological response. The trial was recently opened under the leadership of the Southwest Oncology Group (SWOG, S1314), receiving support for the biomarker studies from the NCI’s BISQFP resource. A second clinical trial was planned that will examine the relationship between expression of the DNA repair protein MRE11 and complete response in patients treated with concurrent 5-flurouracil/mitomycin C plus radiation. Conclusion The meeting provided a unique opportunity to launch a collective effort to establish molecular-based therapies for muscle-invasive urothelial cancer. The goal is to use this framework to develop comparable trials with immunotherapy in non-muscle invasive cancers and to exploit the neoadjuvant platform to develop targeted therapy in muscle-invasive disease.

Methodological requirements for valid tissue-based biomarker studies that can be used in clinical practice

Abstract: Paralleling the growth of ever more cost efficient methods to sequence the whole genome in minute fragments of tissue has been the identification of increasingly numerous molecular abnormalities in cancers—mutations, amplifications, insertions and deletions of genes, and patterns of differential gene expression, i.e., overexpression of growth factors and underexpression of tumor suppressor genes. These abnormalities can be translated into assays to be used in clinical decision making. In general terms, the result of such an assay is subject to a large number of variables regarding the characteristics of the available sample, particularities of the used assay, and the interpretation of the results. This review discusses the effects of these variables on assays of tissue-based biomarkers, classified by macromolecule—DNA, RNA (including micro RNA, messenger RNA, long noncoding RNA, protein, and phosphoprotein). Since the majority of clinically applicable biomarkers are immunohistochemically detectable proteins this review focuses on protein biomarkers. However, the principles outlined are mostly applicable to any other analyte. A variety of preanalytical variables impacts on the results obtained, including analyte stability (which is different for different analytes, i.e., DNA, RNA, or protein), period of warm and of cold ischemia, fixation time, tissue processing, sample storage time, and storage conditions. In addition, assay variables play an important role, including reagent specificity (notably but not uniquely an issue concerning antibodies used in immunohistochemistry), technical components of the assay, quantitation, and assay interpretation. Finally, appropriateness of an assay for clinical application is an important issue. Reference is made to publicly available guidelines to improve on biomarker development in general and requirements for clinical use in particular. Strategic goals are formulated in order to improve on the quality of biomarker reporting, including issues of analyte quality, experimental detail, assay efficiency and precision, and assay appropriateness.

Prostate cancer that is within 0.1 mm of the surgical margin of a radical prostatectomy predicts greater likelihood of recurrence.

Abstract: Surgical margin status at prostatectomy is an important predictor of biochemical recurrence (BCR). The current convention is to categorize a margin as negative if tumor cells are not at the inked margin, even if they are within a few cells of the margin. We hypothesized that cancer within 0.1 mm of the margin conferred an increased risk for BCR. We determined the risk for BCR on the bass of surgical margin status in a cohort of 1588 patients who underwent radical prostatectomy for prostate cancer (PCa) between 1998 and 2011. Surgical margins were categorized as positive, close (<0.1 mm from tumor cells), or negative. Multivariate hazard ratios (HRs) for BCR were determined by margin status. We identified 1588 patients, of whom 193 had PCa recurrence. The margin status was negative in 1058 (67%), close in 232 (15%), and positive in 298 (19%). Cancer that was close to the margin was a significant and independent predictor of BCR (HR 1.53; 95% confidence interval, 1.00-2.32) and was not statistically different than a positive surgical margin (HR 2.10; 95% confidence interval, 1.48-2.99). Cancer that is within 0.1 mm of the surgical margin of a prostatectomy is associated with an increased risk for PCa recurrence. Patients with that margin status may be reasonable candidates for adjuvant local therapy.

Readability of urologic pathology reports: the need for patient-centered approaches.

Abstract: Introduction The pathology report informs a patient׳s prognosis and treatment options. However, pathology reports are written using complex medical vocabulary. We evaluated the readability of pathology reports for common urologic cancers (prostate, bladder kidney, and testicular) to identify sources of confusion that could be addressed through modified patient-centered pathology reports. Methods Pathology reports from 5 cases of each of the following procedures were analyzed: partial nephrectomy, radical nephrectomy, radical prostatectomy, ultrasound-guided prostate needle biopsy (PNBx), radical cystectomy, transurethral resection of bladder tumor, radical orchiectomy, and retroperitoneal lymph node dissection. Reports were edited for grammar and syntax, and the Flesch-Kincaid readability software calculated the reading level. Modifications were performed to identify sources of obstruction to readability. We compared modified and base reports using independent samples t tests. Results Bladder cancer pathology had the highest readability index; radical prostatectomy and PNBx pathology reports had the lowest average readability indices. Modified reports that both omitted gross pathologic and immunohistochemistry content and also replaced oncologic and histology terms with lay terminology had significantly lower reading levels than base reports (P Conclusions Pathology reports are written at reading levels above the average reading capability of most Americans. Deleting descriptive pathologic terms and replacing complex medical terminology with lay terms resulted in improved readability for some urologic oncology reports but complicated readability for others. Our findings may guide the development of patient-centered pathology reports.

Prognostic biomarkers: an introduction

Abstract: When we started postgraduate training in pathology, over 40 years ago, life was relatively simple. The final goal of a diagnostic pathologist evaluating cases was to make diagnoses. Disease classification using morphological criteria was the name of the game. The toolbox was growing from simplicity—for 100 years, basic histological techniques had not changed—to a more sophisticated level. Enzyme histochemistry was a new star on the horizon, and electron microscopy was a promising addition to the available technical arsenal. Immunofluorescence had been invented some years before, and enzyme-labeled antibody methods for immunostaining using transmission light microscopy, a tool without which today’s pathologist would feel decapitated, was quietly moving from the research lab into diagnostic use. There were few guidelines. Standardized synoptic reporting did not exist. The pathologist’s report could still almost be “the most individualistic expression of the most individualistic emotion”, to cite words from Willem Kloos, a much admired Dutch poet from the late nineteenth century. Things have changed. Disease classifications have become muchmore canonized with the AFIP tumor atlas series and the WHO classification “blue books.”Guidelines, imposing common structure and content to histopathological evaluation of biopsies and surgical specimens, have become indispensable in today’s pathology practice. Global standardization through synoptic reporting using evidence-based data sets, as is pioneered by the ICCR initiative (http://www.rcpa.edu.au/ Library/Practising-Pathology/ICCR/Cancer-Datasets), should lead to a universally high quality of pathology reporting. The background of much of this evolution is advancing quality of care, along with the spectacular development of medical technology and the therapeutic armamentarium that bedside clinicians use. As members of the team of specialists caring for a patient, pathologists have to respond to the questions their clinicians ask. And these are no longer “just a diagnosis.” The likelihood that a patient is cured by the initial therapeutic approach, in terms of resection margins and prognostic factors, has led to standardized tumor staging (TNM) and attempts to standardized grading of tumors. Molecular technology now allows the pathologist for a limited but expanding group of tumors an assessment of the likelihood of response to new forms of (targeted) treatment, the dawn of the era of “personalized medicine” along with “companion diagnostics” based on biomarkers [1]. What then do clinicians need? A simple graphical presentation of the issues at stake is given in Fig. 1. Predictive pathology has become the fancy of the day, not in the least since the pharmaceutical industry has come to grips with the realization that public acceptance of effective but expensive therapeutic options depends on the likelihood that a given patient will respond to their new drug. Many pharmaceutical companies have incorporated the development of “companion diagnostics” in their drug development approaches [2, 3], a field to which our friends of the Journal of Pathology have dedicated a whole review issue (http:// onlinelibrary.wiley.com/doi/10.1002/path.2014.232.issue-2/ issuetoc). The “predictive” hype has almost overtaken “prognostic” as focus of interest at the frontline of the development of diagnostic pathology. And yet, the question “will this patient need additional (systemic) treatment” after F. T. Bosman Institute of Pathology, University of Lausanne Medical Center, 1011 Lausanne, Switzerland e-mail: Fred.bosman@chuv.ch

More accurate ways to measure tumor cellularity.

Abstract: To the Editor Portier et al1 compared the accuracy of two molecular assays of allele frequency as metrics of tumor cellularity of cancer tissue specimens. They reported that both assays were imprecise, correlating poorly with their “standard” of tumor cellularity, which was based on the consensus visual estimates by two pathologists of the percentage of nuclei that were tumor nuclei. Their approach raises questions and concerns. Visual estimates are not accurate estimates of cellularity. Interobserver variability in estimating cellularity has been shown to be too high to be reliable. Smits et al2 reported markedly high differences in estimates of lung cancer cellularity …