Edmund C.P. Chedgy

Impact of Therapy on Genomics and Transcriptomics in High-Risk Prostate Cancer Treated with Neoadjuvant Docetaxel and Androgen Deprivation Therapy

Purpose: The combination of docetaxel chemotherapy and androgen deprivation therapy (ADT) has become a standard treatment for patients with metastatic prostate cancer. The recently accrued phase III CALGB 90203 trial was designed to investigate the clinical effectiveness of this treatment approach earlier in the disease. Specimens from this trial offer a unique opportunity to interrogate the acute molecular response to docetaxel and ADT and identify potential biomarkers. Experimental Design: We evaluated baseline clinical data, needle biopsies, and radical prostatectomy (RP) specimens from 52 (of 788) patients enrolled on CALGB 90203 at one high volume center. Pathology review, tumor and germline-targeted DNA sequencing (n = 72 genes), and expression profiling using NanoString platform (n = 163 genes) were performed to explore changes in critical prostate cancer pathways linked to aggression and resistance. Results: Three of 52 patients had only microfocal residual cancer at prostatectomy. The most common alterations included TMPRSS2-ERG fusion (n = 32), TP53 mutation or deletion (n = 11), PTEN deletion (n = 6), FOXA1 (n = 6), and SPOP (n = 4) mutation, with no significant enrichment in posttreated specimens. We did not observe AR amplification or mutations. The degree of AR signaling suppression varied among treated tumors and there was upregulation of both AR and AR-V7 expression as well as a subset of neuroendocrine and plasticity genes. Conclusions: These data support the feasibility of targeted and temporal genomic and transcriptome profiling of neoadjuvant-treated prostate cancer with limited formalin-fixed paraffin embedded tissue requirement. Characterization of the heterogeneity of treatment response and molecular outliers that arise posttreatment provides new insight into potential early markers of resistance. Clin Cancer Res; 23(22); 6802–11. ©2017 AACR.

Using the neoadjuvant chemotherapy paradigm to develop precision therapy for muscle-invasive bladder cancer

BACKGROUND Bladder cancer is a leading cause of morbidity and mortality. Despite recent advances in understanding its molecular biology, the 5-year survival for muscle-invasive disease (muscle-invasive bladder cancer [MIBC]) remains approximately 50%. Although neoadjuvant chemotherapy (NAC) offers an established 5% absolute survival benefit at 5 years, only the 40% of patients with a major tumor response appear to benefit. There remains, therefore, a critical unmet need for predictive markers to determine which patients are best managed with NAC, as well as for novel targeted therapies to overcome resistance to NAC. METHODS The NAC paradigm offers the optimal clinical context for developing precision therapy for MIBC. Abundant tissue is available for analysis before NAC in all patients and after NAC in patients with residual MIBC. Technologic advances have enabled next-generation sequencing and gene expression microarray analysis of routinely collected and even archived tissue specimens. These technologies provide a foundation for the identification of markers of chemoresistance and for the development of rational cotargeting strategies. RESULTS Modern computational methods allow for some measure of target validation, which can be enhanced by the use of patient-derived primary xenografts (PDX). These PDX can be established at the time of radical cystectomy after NAC if there is residual MIBC. By the time a patient recurs clinically, candidate drugs targeting specific molecular changes in the patient tumor and corresponding PDX would have been tested in the PDX model, and only the most efficacious drug(s) would be administered to the patient. Liquid biopsies in the form of circulating tumor DNA and circulating tumor cells allow noninvasive longitudinal monitoring of the molecular landscape of an advanced tumor as it is being treated with successive courses of systemic therapy. CONCLUSIONS These tools combined form the foundation of an evidence-based precision oncology strategy for MIBC.

Radical Cystectomy and the Multidisciplinary Management of Muscle-Invasive Bladder Cancer

Should radical cystectomy be considered an alternative treatment to bladder preservation trimodality therapy in patients with muscle-invasive bladder cancer?—No. Radical cystectomy should not be considered an alternative treatment to trimodal therapy. Instead, it should be considered the gold-standard treatment for patients with muscle-invasive bladder cancer (MIBC). According to the European Association of Urology guidelines, radical cystectomy (RC) is given a grade A recommendation for treating T2-T4aN0M0 and high-risk nonmuscle-invasive bladder cancer. Radical cystectomy is given a grade A based on clinical studies of good quality and consistency and involving at least 1 randomized clinical trial. Multimodality bladder–sparing therapy, on the other hand, should only be considered an alternative option for selected pT2N0M0 tumors and is not the standard of care. The European Society of Medical Oncology guidelines similarly recommend radical cystectomy with extended lymphadenectomy as the standard of care in MIBC, as do the guidelines of the National Comprehensive Cancer Network. There is a wealth of published literature regarding the evidence for the effectiveness of RC for MIBC. One of the largest, mature series,1 published nearly a decade ago, based on a retrospectively and prospectively collected database of 888 patients undergoing open RC and pelvic lymphadenectomy, demonstrated bladder cancer–specific survival rates (SD) of 66% (2%) for all stages of disease. This survival rate (SD) improved to 78% (4%) at 10 years for stage pT2N0 or less tumors. In a more contemporary, international series2 analyzing the long-term outcomes of 742 patients undergoing robot-assisted RC, a 75% 5-year cancer-specific survival for all stages of disease was demonstrated. The published literature on trimodality therapy (TMT) is much more limited, and TMT has not been applied in nearly as many patients. Patient cohorts are smaller, and there is potential bias in patient selection. There is likely a bias toward lower disease burden for TMT, but there may be a bias toward younger and healthier patients undergoing RC. Furthermore, the most prominent reports on TMT are derived from prospective clinical trials that can also be biased toward better outcomes. An additional confounder in comparing outcomes between modalities is the dependence of TMT on clinical staging only (which often underestimates disease burden) vs pathologic staging for RC. According to a prospective, randomized clinical trial,3 in the most experienced centers offering TMT for MIBC the 5-year disease-specific survival has only reached 64% for all stages of disease, improving to 74% for clinical T2 disease. Adding to this evidence of inferior survival, almost one-third of patients treated with TMT may end up requiring a salvage cystectomy as definitive treatment for their bladder cancer.4 Patients need to be carefully counselled that cystectomy following TMT failure is technically challenging and is associated with a higher complication rate. Most surgeons would be unwilling to create a neobladder after failed radiation. On the other hand, there is little evidence in the literature to support the widely held bias that bladderfunctional outcomes are poor after TMT, provided that patients are selected appropriately. One of the putative aims of TMT is to preserve the bladder and potentially avoid the morbidity and perceived negative effects on quality of life (QoL) associated with cystectomy. It is reported that up to 66% of patients undergoing RC will suffer from a grade 2 to 5 perioperative complication.5 Given that a systematic review of TMT has demonstrated acute toxic effects to be in the region of 10% to 36% with late rates of toxic effects in the region of 39%, TMT compares favorably with RC. However, an analysis on the effect of cystectomy on QoL has found no statistically significant differences between preoperative and postoperative QoL scores for patients undergoing either open or robotic RC with either an ileal conduit or neobladder.5 A recent systematic review4 reported there was insufficiently robust data to fully evaluate the QoL outcomes following TMT in comparison with RC. Therefore, it would seem that despite a higher rate of morbidity with RC there appears to be no significant evidence to suggest that patients undergoing TMT have a better QoL than those undergoing RC. The discussion around RC and TMT should not pit one against the other but should instead focus on the complementary use of both to maximize patient benefit. Urologists must overcome their inherent bias against radiation-based therapy and embrace its use for appropriate patients. Approximately half of patients with MIBC in the United States are receiving any treatment with curative intent.6 Advanced age and comorbid status increase the risks of treatment, but many patients considered ineligible for RC may be suitable for TMT, especially when 5-fluorouracil and mitomycin are used instead of cisplatin for radiosensitization. Efforts therefore need to be directed to improving access to optimal delivery of both modalities of curative treatment. Optimal delivery of RC includes more than just removing the bladder safely. If RC is truly optimized, the comparison with TMT could favor RC even more. Urologists have a poor track record for following therapeutic guidelines; yet, if we were more rigorous in this regard, we could enhance the outcomes of RC. We continue to discuss the merits of neoadjuvant VIEWPOINT

Case ‒ Uretero-internal iliac artery fistula presenting with multiple negative angiographic studies

We report a rare case of a patient presenting with visible, unexplained hematuria and share the diagnostic challenges faced in the setting of multiple angiographic studies that failed to demonstrate an uretero-internal iliac artery fistula. Uretero-arterial fistulas (UAF) are rare, but well-recognized, with increasingly common risk factors (Table 1). 1 Due to its rarity, delay to diagnosis is common, when investigating recurrent hematuria with multiple negative investigations. 1,2

You Pays Your Money, You Takes Your Choice: Functional Outcomes Following Curative Treatment for Clinically Localized Prostate Cancer

Daniel A. Barocas, MD, MPH; JoAnn Alvarez, MA; Matthew J. Resnick, MD, MPH; Tatsuki Koyama, PhD; Karen E. Hoffman, MD, MHSc, MPH; Mark D. Tyson, MD; Ralph Conwill, BS; Dan McCollum, BS; Matthew R. Cooperberg, MD, MPH; Michael Goodman, MD, MPH; Sheldon Greenfield, MD; Ann S. Hamilton, PhD, MA; Mia Hashibe, PhD, MPH; Sherrie H. Kaplan, PhD, MS, MPH; Lisa E. Paddock, PhD, MPH; Antoinette M. Stroup, PhD; Xiao-Cheng Wu, MD, MPH; David F. Penson, MD, MPH

Impact of therapy on gene expression in high-risk prostate cancer (PCA) treated with neoadjuvant docetaxel and androgen deprivation therapy.

8 Background: Molecular analyses of neoadjuvant post-treatment radical prostatectomy (RP) specimens has been challenging as often times only microscopic foci remain present at time of RP precluding RNA-seq. DNA analysis alone in the absence of expression may be suboptimal in elucidating complex mechanisms of resistance and/or prognostic risk stratification. We therefore set out to develop an assay that could quantify mRNA expression in treated and untreated PCA using formalin fixed paraffin embedded (FFPE) tissues. Methods: We evaluated 40 untreated and post-treatment FFPE specimens as well as patient-matched pre-treated needle biopsies and baseline clinical data from patients enrolled on CALGB 90203: a randomized phase 3 trial comparing noeadjuvant docetaxel and ADT followed by RP vs RP alone for men with high risk localized PCA. High-density tumor areas were selected for RNA extraction (min 50ng RNA). We used NanoString nCounter to quantify gene expression of a custom panel of 75 genes including AR and ...