bluuebunny/crossref_metadata_2025 huggingface dataset:
Pertuzumab plus trastuzumab for HER2-positive metastatic urothelial cancer (mUC): Preliminary data from MyPathway.
Authors: Bryce Alan Haruo , Kurzrock Razelle , Meric-Bernstam Funda , Hurwitz Herbert , Hainsworth John D. , Spigel David R. , Bose Ron , Swanton Charles , Burris Howard A. , Guo Shuangli , Yoo Bongin , Beattie Mary Stanley , Tayama Darren , Sweeney Christopher
Published: March 2017

348

Background: Patients (pts) with mUC have few treatment options beyond the second-line setting. HER2 gene amplification has been reported in a minority of pts with UC, but there have been anecdotal reports of the activity of HER2-targeted agents. MyPathway is a multi-basket study evaluating the efficacy and safety of targeted therapies in non-indicated tumor types harboring relevant molecular alterations. We present preliminary data for pts with HER2-positive mUC receiving HER2-targeted treatment with pertuzumab + trastuzumab. Methods: MyPathway (NCT02091141) is an open-label, multicenter, phase IIA study. Pts in this subset analysis had refractory mUC with HER2 amplification or putative activating mutations by gene sequencing, FISH, or IHC. Pts received standard doses of pertuzumab + trastuzumab without chemotherapy until disease progression or unacceptable toxicity. The primary endpoint is investigator-assessed overall response rate (RECIST v1.1). Results: As of July 31, 2016, 12 pts with platinum-resistant HER2-positive mUC (HER2-amplified, n=9; HER2-mutated, n=3) have been enrolled. At a median follow-up of 5.4 (range 0.9–14.5) mos, 1 pt had complete response (CR, ongoing at 12.5 mos), 2 had partial responses (PR; duration of response, 3.7 and 5.5 mos), and 2 had stable disease (SD) for >4 mos (Table). Safety was consistent with the product labels. Conclusions: Preliminary results indicate that the combination of pertuzumab + trastuzumab has activity in previously treated HER2-amplified mUC, including a durable CR in a pt with peritoneal metastases. Accrual to MyPathway is ongoing. Clinical trial information: NCT02091141. [Table: see text]
Targeting ERBB2 mutations in urothelial carcinoma.
Authors: Audenet Francois , Isharwal Sumit , Arcila Maria E. , Funt Samuel , Rosenberg Jonathan E. , Bajorin Dean F. , Bochner Bernard H. , Berger Michael F. , Al-Ahmadie Hikmat , Solit David B. , Iyer Gopa
Published: March 2017

354

Background: ERBB2 encodes human epidermal growth factor receptor 2 (HER2), a member of the EGFR family of receptor tyrosine kinases that signal through the pro-oncogenic MAP- and PI3K-kinase pathways. ERBB2 is altered by amplification and/or overexpression in various cancers, including urothelial carcinoma (UC). These alterations could confer sensitivity to ERBB2 kinase inhibitors in selected patients with UC. Methods: Patients diagnosed with UC were enrolled onto an institutional review board approved prospective sequencing protocol. Tumor and matched germline DNA were analyzed using the MSK-IMPACT assay that detects alterations in 410 oncogenes and tumor suppressor genes, including ERBB2. Results: Overall, 449 samples from 429 patients were sequenced from 2013 to August 2016. Genetic alterations in ERBB2 were found in 78 samples (17%). At the time of sample collection, 24 patients (31%) had non-muscle invasive bladder cancer (NMIBC), 30 patients (38%) had muscle-invasive bladder cancer (MIBC), 18 (23%) had metastatic disease and 7 (8%) had upper tract urothelial carcinoma (UTUC). Sixteen samples (21%) came from metastatic specimens. Of the observed 78 ERBB2 alterations, 20 samples had amplifications (26%) and 58 samples had mutations (74%). Seven samples (9%) had both. We identified 71 missense, 2 inframe and 1 fusion alteration, corresponding to a somatic mutation rate of 13.1%. Thirty-seven mutations (50%) were functionally characterized hot spots that are potentially actionable. Of note, the hot spot mutation S310F/Y was found in 29 samples (37%). Its mutation allele frequency varied significantly. There was a trend towards a higher mutant allele frequency of S310F/Y in higher stage disease without reaching statistical significance (Table). In our cohort, 3 patients were enrolled in clinical trials with ERBB2 kinase inhibitors based upon the presence of an ERBB2alteration. Conclusions: ERBB2is a frequent mutation at different stages of UC. In higher stage disease, clonal selection of the S310F/Y hot-spot mutation may occur and requires further study. [Table: see text]
Prognostic value of PD-1 and PD-L1 expression in patients with high-grade urothelial carcinoma of the upper urinary tract.
Authors: Krabbe Laura-Maria , Heitplatz Barbara , Hutchinson Ryan C , Woldu Solomon L , Preuss Sina , Wood Christopher G. , Karam Jose A. , Weizer Alon Z. , Raman Jay D. , Remzi Mesut , Rioux-Leclercq Nathalie , Haitel Andrea , Roscigno Marco , Bolenz Christian , Bensalah Karim , Sagalowsky Arthur I. , Shariat Shahrokh F. , Lotan Yair , Xylinas Evanguelos , Margulis Vitaly
Published: March 2017

358

Background: To investigate the prognostic value of PD-1 and PD-L1 expression in patients with high-grade upper tract urothelial carcinoma (UTUC). Methods: Tissue microarrays were created using 448 patients from the International UTUC collaboration who underwent extirpative surgery for high-grade UTUC and stained for PD-1 (antibody (AB): NAT105, diluted 1:250 from Ventana) and PD-L1 (AB: E1L3N prediluted from Cell Signaling). PD-1 and PD-L1 expression was assessed in a semi-quantitative fashion and any percentage of staining of the tumor cells (PD-L1) and tumor-infiltrating lymphocytes (PD-1) was considered positive. Univariate (UVA) and multivariate analyses (MVA) were performed to assess independent prognosticators of oncological outcomes. No funding was received. Results: Median age of the cohort was 69.2 years and 56.5% of patients were male. PD-L1 and PD-1 were positive in 24.1% and 37.5% of patients. PD-L1 positivity was associated with favorable pathological stage, where as PD-1 positivity was significantly associated with pelvicalyceal location, lymph node metastases, non-organ confined disease, presence of lymphovascular invasion, sessile architecture, necrosis, concomitant CIS, and history of non-muscle invasive bladder cancer. PD-L1 positivity was not significantly associated with survival outcomes. In Cox regression UVA, PD-1 positivity was associated with worse recurrence-free survival (RFS) (HR 1.5 (95%CI 1.08-2.14, p=0.016)), cancer-specific survival (CSS) (HR 1.5 (95%CI 1.07-2.19, p=0.021)), and overall survival (OS) (HR 1.5 (95%CI 1.10-1.97, p=0.009)). However in MVA, PD-1 positivity was not found to be an independent predictor of RFS, CSS or OS. Conclusions: PD-1 positivity of tumor-infiltrating lymphocytes was associated with adverse pathological criteria and was a significant prognosticator for RFS, CSS and OS on UVA in patients treated with extirpative surgery for high-grade UTUC in a large, multi-institutional cohort. In MVA, the independent prognostic value of PD-1 was not confirmed. PD-L1 positivity was associated with lower tumor stage, but not with other pathological characteristics or survival outcomes.
Glucose metabolism and bladder cancer.
Authors: Lee Eugene K. , Pirani Karim , Holzbeierlein Jeffrey M. , Martin Paige , Rangarajan Parthasarathy , Hamilton-Reeves Jill , Anant Shrikant
Published: March 2017

359

Background: To understand and evaluate the role of glucose metabolism in bladder cancer growth, in the identification of disease, and development of potential treatment strategies. Methods: UMUC3, T24 and 253JBV cells were grown in varying glucose concentrations (25, 100 and 200mg/dl) and cell proliferation assay with Vi-Cell was performed. Next, we used Qiagen PCR array of glucose metabolic pathway of the UMUC3 cell line under different glucose concentrations. PKM2 is a driver of glycolysis and exists in an inactive dimer or active tetramer. Dimer PKM2 also known as Tumor M2-PK was measured in urine samples of bladder cancer patients using a commercially available ELISA kit (ScheBo Biotech AG). Lastly, Shikonin, a PKM2 inhibitor was evaluated as an inhibitor of bladder cancer cell proliferation using Vi-Cell. Results: Increased glucose concentration 200mg/dl leads to increased proliferation in bladder cancer cells while decreased concentration of glucose; 25mg/dl reduces proliferation compared to control (100). PCR array demonstrates genes in the glycolytic pathway genes are upregulated in cells that are grown in 200mg/dl glucose media and the TCA cycle genes are upregulated in cells that are subjected to the 25mg/dl glucose media when compared to control (100mg/dl). The enzyme pyruvate kinase M2 (PKM2) controls the transition from the glycolytic pathway to TCA cycle. We have found that 9/10 (90%) of bladder cancer urine samples show elevated levels of tumor M2-PK (>104) compared to urine from two normal subjects (~30 units ) using a commercially available ELISA kit. Conclusions: Increased glucose concentration 200mg/dl leads to increased proliferation in bladder cancer cells while decreased concentration of glucose; 25mg/dl reduces proliferation compared to control (100).
Prescribing preferences of U.S. oncologists for patients (Pts) with metastatic urothelial carcinoma (mUC) at first recurrence: Impact of novel agents.
Authors: Lankford Maria L. , Willey Joanne P. , Buettner Arden , Britton Susan Lynne , Scharf Mitch , Dreicer Robert
Published: March 2017

365

Background: In May 2016 atezolizumab (A) was approved for the treatment of pts with locally advanced or mUC who have disease progression during or following platinum-containing chemotherapy (PCCT), or within 12 months (mos) of neoadjuvant or adjuvant treatment with PCCT. We evaluated prescribing preferences (PPrefs) of 248 U.S-based oncologists for 1strecurrence treatment across a range of clinical scenarios prior to and following A approval. Methods: PPrefs were assessed through a validated, case-based market research tool (Challenging Cases). Assessment dates were 3/5 and 4/30 (PRE-) and 8/6 (POST-approval). Data were acquired using blinded, audience-response technology. A core scenario (CS) and 5 variant scenarios (V1, 2, 3, 4, 5) were utilized. CS: 69-year-old pt with muscle invasive bladder cancer, with a CrCl 62 ml/min, Hgb 12.5, and PS 1, recurs in the liver and bone 18 months after receiving neoadjuvant gemcitabine/cisplatin and a radical cystectomy. V1: Same as CS but with reduced CrCl 48 ml/min. V2: Same as CS but recurrence at 6 months. V3: Same as V2 but multiple comorbidities and PS 2. V4: Same as CS but age 79. V5: Same as V4 but multiple comorbidities. The same query was posed in each setting: What therapy would you choose? Results: See Table. Conclusions: Following the approval of A, overall PPref of most regimens offered decreased across nearly all 1st recurrence scenarios in favor of A. This is particularly stark in platinum unfit (older, comorbid, poor PS) pts. This highlights the previously unmet medical need in the PCCT pre-treated mUC pts. [Table: see text]
Increased utilization of advanced imaging technology and its economic impact for patients diagnosed with bladder cancer in the United States.
Authors: Kosarek Christopher David , Huo Jinhai , Baillargeon Jacques G. , Kuo Yong-Fang , Fang Justin Edwin , Ghaffary Cameron , Kerr Preston , Kim Simon P. , Orihuela Eduardo , Tyler Douglas S. , Giordano Sharon Hermes , Freedland Stephen J. , Kamat Ashish M. , Williams Stephen Bentley
Published: March 2017

368

Background: This study examined utilization patterns and predictors for use of positron emission tomography-computed tomography (PET/CT), magnetic resonance imaging (MRI), and computed tomography (CT) among Medicare beneficiaries diagnosed with bladder cancer. Methods: We used the Surveillance, Epidemiology and End Results (SEER)-Medicare linked databases to analyze claims data for 36,855 patients aged 60-90 years diagnosed with bladder cancer from 2004 to 2011. The Cochran-Armitage test for trend was used to determine whether significant changes in the proportion of patients receiving advanced imaging after cancer diagnosis occurred during the time interval; trends in the usage of the imaging modality types were assessed. Multivariable logistic regression modeling was conducted to analyze potential demographic and clinical predictors associated with receipt of advanced imaging. The costs of imaging were measured using Medicare payments. Results: While the overall trend of imaging use remained essentially unchanged over the study period, there was a significant decrease in the proportion of patients who received conventional imaging modalities (MRI and CT; P < .05) and a significant increase in the proportion of patients receiving the more advanced imaging modality (PET/CT; P < .0001). On multivariable analysis, receipt of PET/CT was significantly higher in female patients, Non-Hispanics, residents in West Census region, patients with higher grade tumors, those diagnosed with advanced stage disease, hydronephrosis, and those that received radical cystectomy and chemotherapy. In the cost analysis, the estimated national excess medical spending for advanced imaging was $6.1 million. Conclusions: The sharp increase of advanced imaging (PET/CT) and substantial costs associated with this rapid adoption as we have documented suggests that further efforts should be made to evaluate the clinical and economic benefits of PET/CT imaging and to elucidate its appropriateness of use among bladder cancer patients.
Dissecting the genomic landscape of metastatic bladder cancer using circulating tumor DNA.
Authors: Struss Werner J. , Vandekerkhove Gillian , Annala Matti , Todenhoefer Tilman , Beja Kevin , Eigl Bernhard J. , Wyatt Alexander William , Black Peter C.
Published: March 2017

378

Background: To date, only limited data are available on genomic alterations present in metastatic lesions of patients with metastatic urothelial carcinoma (mUC). The constant release of cell free DNA (cfDNA) from tumor cells into the peripheral blood stream may provide a valuable source for detection of cancer associated somatic copy number variations and mutations. The aim of this project was to evaluate the feasibility of detecting clinically relevant genomic alterations in mUC by next-generation sequencing (NGS) of circulating cfDNA. Methods: Peripheral blood (20ml) was collected from 15 patients with mUC before chemotherapy. Plasma cfDNA was isolated using the QIAAmp Circulating Nucleic Acid Kit. Germline control DNA was extracted from peripheral blood mononuclear cells (PBMCs) using the DNEasy Kit (Qiagen). We performed deep (>500X) targeted DNA sequencing on cfDNA and germline DNA using a custom NimbleGen SeqCap EZ Choice Library and Illumina sequencers. Our custom panel included 50 bladder cancer-relevant genes, including key tumor suppressors (e.g. TP53, RB1, CDKN2A), cell cycle drivers (e.g. CCND1, CCNE1), DNA repair genes (e.g. ATM, BAP1, ERCC2), PI3K pathway genes (e.g. PIK3CA, PTEN, AKT1), and other oncogenic pathways (e.g. RAS/RAF, EGFR, ERBB2, PPARG, FGFR3). Results: Somatic mutations and/or copy number changes were detected in 14/15 samples, with a median variant allele frequency >5%. The overall mutational landscape was highly consistent with bladder cancer, including mutations in TP53 and ARID1A (and other chromatin modifiers), as well as hotspot activating mutations in PIK3CA. Typical copy number changes, including focal amplifications of ERBB2, KRAS, and CCNE1 were detected. We identified complex gene rearrangements, including an activating FGFR3 fusion in one case. Extended analyses with a larger patient population are currently pending. Conclusions: Non-invasive characterization of genomic changes in peripheral blood of patients with mUC using NGS of plasma cfDNA is feasible in a high proportion of patients. Analysis of cfDNA might therefore provide an improved understanding of genomic changes in mUC and could be developed as a biomarker to help guide the use of targeted therapies.
Comprehensive genomic sequencing of urothelial tumors to identify rare driver genomic alterations in SMARCB1 in a subset of patients.
Authors: Gupta Sumati , Albertson Daniel Joseph , Gaston David , Heilbrun Marta Elise , Agarwal Neeraj , Liu Ting , Miller Vincent A. , Ross Jeffrey S. , Millis Sherri Z. , Ali Siraj Mahamed
Published: March 2017

385

Background: Multiple genomic alterations leading to overlapping dysregulation of cell cycle, kinase and phosphotidyl \inositol-3-OHkinase signaling and chromatin remodeling are the hallmark of urothelial carcinoma (UC). ARID1A and SMARCA2 loss are frequently altered leading to SWI/SNF nucleosome-remodeling complex dysregulation in urothelial cancers. Mutations affecting components of the SWI/SNF complex lead to aggressive de-differentiated neoplasms. SMARCB1 loss has been implicated in malignant rhabdoid tumors, epithelioid sarcoma and renal medullary carcinoma. Upper tract UC patients with SMARCB1 loss may represent a novel, rare subset. Methods: Tissue from UC patients (n=1099) was assayed by hybrid-capture based comprehensive genomic profiling (CGP) in the course of clinical care to evaluate genomic alterations (GA: base substitutions, indels, amplifications, copy number alterations, fusions/rearrangements) and targeted therapy opportunities; 315 genes frequently altered in cancer were assayed. One patient had an advanced poorly differentiated neoplasm and received conventional chemotherapy. Results: CGP identified 10 (1%) patients with SMARCB1 alterations and different patterns overall in GAs. Three patients (1 kidney, 1 ureter, and 1 bladder) had bi-allelic loss of SMARCB1, and 7 others had a loss of function alteration with loss of heterozygosity. These patients with SMARCB1 bi-allelic loss had few or no additional alterations, notably no alterations in TP53, CDKN2A/B, or TERT, which are observed in greater than 50% of urothelial tumors, or RB1 alterations observed in ~22% of UC. The patient treated with cisplatin based chemotherapy achieved a pathologic CR. Conclusions: Genomic profiles of tumors from patients with UC revealed a rare population of patients with alterations impacting chromatin regulation and tumor suppression, specifically through loss of SMARCB1. Tumors with SMARCB1 loss have a very low burden of genetic alterations and SMARCB1 loss or deletion may be the sole driving mutation. Conventional chemotherapy may be effective. Inhibitors of EZH2, HDAC and CDK4 may be potential treatment strategies to target this subset of tumors.
Impact of histologic subtype on bladder cancer outcome.
Authors: Washington Samuel L , Sanford Thomas , Leapman Michael S. , Meng Maxwell V. , Porten Sima P.
Published: March 2017

391

Background: Variant histology is increasingly recognized but its impact on outcomes is less well known compared to urothelial carcinoma (UC). We aim to evaluate the impact of variant histology on bladder cancer outcomes using the National Cancer Database (NCDB), a U.S. population-based cohort capturing approximately 70% of newly diagnosed cancer cases. Methods: We identified patients with bladder cancer from 2004 to 2013 treated with radical cystectomy. We compared clinical and pathologic characteristics between those with UC and those with variant histology. Chi-square test was utilized for categorical variables and Independent Samples t-test for continuous variables. Multivariable Cox regression was used with hazard ratios (HR) and 95% confidence intervals (CI) to identify independent predictors of overall survival. Results: A total of 40,918 patients were identified with mean age 67 years, with male (75%) and Caucasian (90.9%) predominance. Median follow-up was 36.9 months (IQR 16.1-67.5). Squamous cell carcinoma (4.4%), small cell carcinoma (1.6%) and micropapillary (0.9%) were the most common variant histologies. Variant histology was found more commonly in women (35.6% vs 23.4%, p < 0.05), black (8.8% vs 5.6%, p < 0.05), stage pT3 or T4 (67% vs 50.2%, p < 0.05) and node positive (30.8% vs 26.9%, p < 0.05). In adjusted models squamous cell carcinoma (HR 1.3, 95% CI 1.2-1.4), small cell carcinoma (HR 1.6, 95% CI 1.5-1.8) and black ethnicity (HR 1.2, 95% CI 1.1-1.2) were independent predictors of increased mortality risk while micropapillary was associated with decreased risk (HR 0.8, 95% CI 0.7-1.0) after controlling for age, gender, surgical margin status, pathologic T stage, pathologic N stage and history of chemotherapy. All associations remained statistically significant (p < 0.05). Conclusions: Non-urothelial histology was associated with worse overall survival in patients with bladder cancer treated with radical cystectomy; however, contrary to some previous reports, micropapillary variant was associated with lower risk of death. In addition, black ethnicity was associated with worse survival. Further investigation is needed to explore the impact of variant histology as well as other socioeconomic factors on survival after cystectomy.
Preoperative risk factors predicting postoperative complications in radical cystectomy for bladder cancer.
Authors: Jensen Derek , Graw Stefan , Niu Sida , Glazyrine Vassili , Koestler Devin , Lee Eugene K.
Published: March 2017

395

Background: Radical cystectomy is an extensive operation with complications reported in up to 30.5% of patients. High complication rates contribute to increased costs, patient morbidity and mortality. Accurate prospective predictions of patients’ risk for post−surgical complications have the potential to identify at risk patients. Risk estimators have been developed but often involve an extensive number of factors or produce expansive results that are not clinically useful. Methods: 330 patients who underwent radical cystectomy for bladder cancer from January 2008 to July 2014 were included in this study. Potential preoperative risk predictors were collected from medical history, TURBT pathology, preoperative labs, proposed procedure type, and prior treatments. Postoperative complications were graded using the Clavien−Dindo scale. Multivariate logistic regression models were used to predict post−operative complications. Accuracy of prediction models was assessed using the area under the receiver operating characteristic curve. Results: Of the potential preoperative risk factors, 5, 10 and 16 unique predictors along with two way interactions were determined to have strong association with 90 day postoperative complications, yielding an AUC of 0.69, 0.79 and 0.91 respectively. Conclusions: Our findings suggest routinely collected preoperative patient−level clinical variables may be useful for determining patient risk for short−term postoperative complications. The flexibility in our prediction model for the number of predictor inputs allow users to tailor the degree of risk assessment based on a patient’s baseline heath status. A simple and accessible prediction model with selective predictors may help identify at risk patients for patient education, counseling and development of risk reduction strategies.
Combination checkpoint immunotherapy and cytotoxic chemotherapy: Pembrolizumab (Pembro) plus either docetaxel or gemcitabine in patients with advanced or metastatic urothelial cancer.
Authors: Lara Primo , Beckett Laurel , Li Yueju , Parikh Mamta , Robles Daniel , Aujla Pawandeep , Pan Chong-xian
Published: March 2017

398

Background: Metastatic urothelial cancer (mUC) is only modestly responsive to checkpoint inhibitor immunotherapy; e.g., the PDL1 inhibitor atezolizumab confers only a 16% tumor response rate (RR) in platinum-treated mUC. Chemotherapy is hypothesized to enhance tumoral neoantigen expression thus priming response to PD1-directed immunotherapy. Here we report results from the initial cohort of an investigator-initiated trial of Pembro plus either docetaxel or gemcitabine in platinum-treated mUC patients (pts). Methods: Primary endpoint was safety; secondary endpoints were overall RR and progression-free survival (PFS). Eligible pts had Zubrod PS 0-1, adequate end-organ function, and up to 2 prior lines of chemo (at least 1 platinum-based). Dose limiting toxicity (DLT) was any grade (Gr) 3+ non-heme toxicity, Gr3+ neutropenia w/ fever or infection, or Gr4 platelets (plts), or Gr3 plts with bleeding. In dose level (DL) 1, treatment consisted of Pembro 200 mg IV on D1 q3 weeks plus either docetaxel 75 mg/m2 on D1 (Arm 1) or gemcitabine 1000 mg/m2 on D1&D8 (Arm 2). Results: Overall 12 pts were enrolled in DL1, six in each arm. Median age was 69 years (range 45-84), 8 (67%) male, & 10 (83%) of white race. One pt in each arm had DLT: Gr3 hypophosphatemia in Arm 1, Gr3 diarrhea in Arm 2. Attributable Gr3+ toxicities were seen in 7 (54%). Most common Gr3+ AEs were anemia (5, 38%), fatigue (4, 31%), & neutropenia (4, 31%). There were no treatment related deaths; 3 died from tumor progression (PD). As of 10/2016, 4 pts remain on active therapy. In total 4 pts had confirmed response (1 CR, 3 PR), 2 had stable disease (SD), and 6 had PD for an overall RR of 33% and Disease Control Rate (DCR) of 50%. Arm 1 had an overall RR of 50% (1CR, 2PR, 1SD) and DCR of 67%. Arm 2 had an overall RR of 17% (1PR, 1SD) and DCR of 33%. Median PFS (overall, Arm 1 & 2) were 4.8, 5.7, and 3.7 months. Conclusions: Pembro 200 mg IV q3 weeks plus either full-dose docetaxel or gemcitabine is feasible in platinum-treated mUC pts. Encouraging anti-tumor activity for chemo-immunotherapy was seen in this ongoing study, particularly with Pembro+docetaxel. Further investigation of this approach is warranted. Clinical trial information: NCT02437370.
Evaluation of the Decipher prostate cancer classifier to predict metastasis and disease-specific mortality from genomic analysis of diagnostic prostate needle biopsy specimens.
Authors: Nguyen Paul L. , Haddad Zaid , Lam Lucia L.C. , Ong Kaye , Buerki Christine , Deheshi Samineh , Yousefi Kasra , Davicioni Elai , Tosoian Jeffrey J. , Lotan Tamara L. , Feng Felix Yi-Chung , Trock Bruce J. , Ross Ashley , Klein Eric A.
Published: March 2017

4

Background: Accurate risk stratification after diagnosis of prostate cancer (PCa) is key to optimal treatment decision-making. Decipher RP is an extensively validated genomic classifier used to determine biological potential for metastasis. Here, in a multi-institutional cohort, we aimed to evaluate its ability to predict metastasis and prostate cancer-specific mortality from analysis of PCa needle biopsy tumor tissue specimens. Methods: We identified 175 patients treated with either first-line RP or first-line radiation therapy (RT) + androgen deprivation therapy (ADT) with available genomic expression profiles generated from diagnostic biopsy specimens obtained from three tertiary referral centers: Cleveland Clinic, Brigham and Women’s Hospital and Johns Hopkins. The core with the highest grade was sampled and Decipher was calculated based on a locked random forest model. Cox univariable and multivariable (MVA) proportional hazards model and survival c-index were used to evaluate the performance of Decipher. Results: Overall, 85% of patients had NCCN intermediate and high-risk disease. Of the 175 patients, 43% and 57% were treated with first-line RP and RT+ADT, respectively. With a median follow-up of 6 years, 32 patients developed metastases and 11 of these patients died of PCa. For prediction of metastasis 5 years post biopsy, Decipher had a c-index of 0.74 (95% confidence interval [CI] 0.63-0.84) compared to 0.66 (95% CI 0.53-0.77) for CAPRA and 0.66 (95% CI 0.55-0.77) for NCCN risk group. On MVA, when modeled with CAPRA, Bx Decipher remained a significant predictor of metastasis (Decipher Bx hazard ratio [HR] 1.33 per 10% increase in score, 95% CI 1.06–1.69, P = 0.01). Decipher Bx was also a significant predictor of PCSM (Decipher Bx HR 1.57 per 10%, 95% CI 1.07–2.40, P = 0.02) Conclusions: Decipher Bx was able to predict metastasis and PCSM from diagnostic biopsy specimens in a cohort of primarily intermediate and high-risk men regardless of first line treatment. This additional genomic information provides important risk stratification to help guide therapy for men with intermediate- and high-risk disease.
Development of a novel immunotherapy for muscle invasive bladder cancer (MIBC).
Authors: Tcherepanova Irina Y. , Leibovich Bradley C. , Slagter-Jager Jacoba , Dillon Patrick , Leland Shawn Michael , Mynderse Lance A , Costello Brian Addis , Nicolette Charles A.
Published: March 2017

402

Background: AGS-003 is an autologous tumor RNA-loaded dendritic cell-based immunotherapy being tested in advanced renal cell carcinoma (RCC) patients. The immunologic specificity for the patient’s own tumor is achieved using amplified tumor RNA electroporated into monocyte derived dendritic cells. To produce AGS-003 for RCC patients the RNA is amplified from a 100 mg primary tumor sample obtained via nephrectomy. In this non treatment study we evaluated the feasibility of RNA amplification from MIBC tissue acquired by transurethral resection of bladder tumor (TURBT). Methods: MIBC tissue was obtained via TURBT. Following draining of the irrigant used during the TURBT procedure, tissue was placed into an RNA preservative solution to prevent RNA degradation until processing. Methods developed for the amplification of RCC tumor RNA and RNA quality testing were applied to the RNA extracted from the MIBC specimens. Results: This work demonstrated that the methods developed for the amplification and testing of RNA from RCC can be successfully employed for the amplification of RNA from MIBC specimens collected by TURBT. Results demonstrated that the total RNA yields obtained from bladder tissue exceed that of similar masses of primary RCC tumors. This finding enabled the reduction in the amount of starting material from 100 mg to 50 mg of bladder tissue. The amount of amplified RNA produced from the lower bladder cancer masses were sufficient to support the production of immunotherapy at full scale (17 doses average). Conclusions: These data demonstrate the feasibility of RNA extraction and amplification from muscle invasive bladder cancer tissue and supports our planned phase II clinical study. [Table: see text]
Post-orchiectomy adjuvant therapy versus surveillance for stage IS testicular cancer.
Authors: Kamran Sophia C. , Seisen Thomas , Markt Sarah C. , Preston Mark A , Frazier A. Lindsay , Sweeney Christopher , Beard Clair
Published: March 2017

406

Background: To assess contemporary treatment patterns and survival for stage IS testicular cancer. Methods: Using the National Cancer Data Base, we identified 1,362 patients with AJCC stage IS testicular cancer (seminoma or non-seminoma) treated between 2004-2012 with either adjuvant therapy (AT) or initial surveillance. AT was defined as the receipt of chemotherapy, radiotherapy (RT), or retroperitoneal lymph node dissection (RPLND) as part of first line treatment after orchiectomy. Annual percent change (APC) in the use of AT was calculated and multivariable logistic regression analysis was performed to identify predictors of receiving AT. Inverse probability of treatment weighting (IPTW)-adjusted Kaplan-Meier curves and Cox regression analyses were used to compare overall survival (OS) between AT and initial surveillance groups. All analyses were stratified according to histologic type. Results: Overall, there were 581 (43%) and 781 (57%) men with seminoma and non-seminoma, respectively. Among men with seminoma, 61% received AT (RT = 45%, chemo = 16%) while 39% received initial surveillance. The use of AT decreased over the study period (APC = -2.7; 95%CI: -4.4, 1.1; P = 0.001). Predictors of receiving AT included low income (OR = 1.63; 95%CI: 1.03, 2.56; P = 0.04), while year of diagnosis (OR = 0.89; 95%CI: 0.83, 0.96; P = 0.003) predicted the opposite. The 5-year IPTW-adjusted rates of OS were 99% and 97% in the AT and initial surveillance groups, respectively (HR = 0.36; 95%CI: 0.12, 1.14; P = 0.08). Among men with non-seminoma, 47% received AT (chemo = 38%, RPLND = 9%) while 53% received initial surveillance. The use of AT remained stable over the study period (APC = +0.8; 95%CI: -0.7, +2.2; P = 0.29). Predictors of receiving AT included stage ≥ pT2 (OR = 1.78; 95%CI: 1.06, 3.00; P = 0.03), and lymphovascular invasion (OR = 2.68; 95%CI: 1.88, 3.83; P < 0.001). The 5-year IPTW-adjusted rates of OS were 97% and 95% in the AT and initial surveillance groups, respectively (HR = 0.66; 95%CI: 0.27, 1.61; P = 0.36). Conclusions: Trends in the use of AT for stage IS testicular cancer differed according to histologic type. Nonetheless, we report 5-year OS rates of ≥ 95% for seminoma and non-seminoma without any significant benefit with the use of AT.
Evaluation of patient (Pt), treatment, and prognostic factors in urinary tract adenocarcinoma.
Authors: Sadaps Meena , Zahoor Haris , Elson Paul , Emamekhoo Hamid , Schach Kim , Brey Nicole DiBiase , Kaouk Jihad , Haber Georges-Pascal , Gong Michael C. , Berglund Ryan Kent , Krishnamurthi Venkatesh , Ulchaker James , Gilligan Timothy D. , Rini Brian I. , Garcia Jorge A. , Grivas Petros
Published: March 2017

408

Background: Adenocarcinoma is a rare histological subtype of urinary tract cancer with limited data regarding risk factors, effectiveness of treatment, and prognostic factors. Methods: To identify prognostic features, we evaluated demographics, treatment, and progression-free and overall survival (PFS, OS) in a retrospective review of 49 pts with adenocarcinoma of the bladder (n=35), ureter (n=1), or urethra (n=13) evaluated at Cleveland Clinic from January 2000 to April 2016. Uni- and multi- variable analyses (UVA, MVA) were used to identify prognostic factors. OS was measured from diagnosis to death and PFS from diagnosis to first of recurrence/progression or death. Results: 25 (51%) pts were women, median age at diagnosis was 62 (33-82), 30 pts (61%) presented with hematuria, and 13/36 (36%) had hydronephrosis. Treatment included cystectomy in 43 pts (88%), neoadjuvant chemotherapy in 3 pts (MVAC, gemcitabine/cisplatin, paclitaxel/cisplatin), adjuvant chemotherapy in 2 pts (gemcitabine), and systemic therapy for advanced or recurrent disease in 6 pts. Overall, 23 pts (47%) recurred/progressed and 31 (63%) died [12 without recurrence/progression]. Estimated median OS and PFS from diagnosis were 38.1 and 24.5 months, respectively. Pts with hydronephrosis at time of diagnosis had shorter PFS (p=0.06) and OS (p=0.007). Among the cystectomy pts, MVA identified pN stage and presence of signet-ring cells or papillary component as the only independent predictors of OS, while pN stage was the only independent predictor of PFS. Combining these factors, 3 prognostic groups for OS were identified (Table). Conclusions: pN stage and morphology are independent predictors of OS in pts with urinary tract adenocarcinoma after radical surgery and can stratify pts into distinct prognostic groups. If validated in larger cohorts, these factors could be used for prognostication, clinical decision making, and trial stratification. [Table: see text]
Validation of a 17-Gene Genomic Prostate Score (GPS) as a predictor of biochemical recurrence (BCR) in men with prostate cancer treated with radical prostatectomy (RP) in a community setting.
Authors: VanDenEeden Stephen K. , Zhang Nan , Quesenberry Charles P , Han Jeong S , Leimpeter Amethyst D , Shan Jun , Tsiatis Athanasios C. , Lawrence H. Jeffrey , Febbo Phillip G. , Presti Joseph C
Published: March 2017

41

Background: Validated biomarkers can improve risk stratification for men with prostate cancer (PCa). A biopsy-based RT-PCR assay that provides a GPS (scale 0-100) has been validated as an independent predictor of adverse surgical pathology and BCR after RP in men with low-risk and low-volume intermediate-risk PCa. We sought to confirm that GPS is a predictor of BCR across the full spectrum of clinical risk (low, intermediate and high) in a large cohort of men with long term follow up within Kaiser Permanente Northern California (KPNC). Methods: From the KPNC clinical database of 6,184 RP treated men diagnosed with NCCN very low, low, intermediate and high-risk PCa between 1995- 2010, we performed a retrospective cohort study using stratified cohort sampling. BCR was defined as either 2 successive post-RP PSAs ≥ 0.2, or initiation of salvage therapy after a rising PSA ≥ 0.1. Archival biopsy tissue was assayed to yield a GPS. Univariable and multivariable Cox proportional hazards models were used to estimate the association, accounting for sampling weights and covariates. Results: Tissue was retrieved for 334 patients. 279 met all eligibility criteria and 259 (93%) generated a valid GPS. The cohort consisted of 117 BCR and 142 non-BCR events. GPS was strongly associated with BCR - HR/20 GPS units = 2.5; p < 0.0001 in univariable analysis, and after adjusting for PSA, clinical T stage and central biopsy Gleason Score (HR/20 units = 2.1; p = 0.002). The association between GPS and BCR was similar within different racial groups. Each of the 4 gene groups in GPS contributed to the prediction of BCR. Conclusions: GPS was associated with BCR independently of other clinical factors in surgically treated men with PCa, and may provide improved risk stratification beyond clinical risk assessment.
Laparoscopic retroperitoneal lymph node dissection (L-RPLND) as therapeutic in stage I nonseminomatous germ cell testicular tumors: Findings from a referral center.
Authors: Nicolai Nicola , Gasperoni Francesca , Biasoni Davide , Tarabelloni Nicholas , Catanzaro Mario , Stagni Silvia , Torelli Tullio , Piva Luigi , Kungulli Afrovita , Tesone Antonio , Giannatempo Patrizia , Raggi Daniele , Necchi Andrea , Salvioni Roberto , Pizzocaro Giorgio
Published: March 2017

411

Background: Active surveillance or one course of BEP are the usual policies in stage I NSGTT. RPLND has been progressively abandoned due to morbidity and, mostly, to its low reproducibility. L-RPLND was introduced aiming at reducing morbidity, but few systematic data are available concerning its therapeutic efficacy. A long-term accrual in a referral center is presented. Methods: Analysis includes patients undergoing primary L-RPLND between 2000 and 2014, performed by 4 different surgeons. Patients underwent unilateral dissection according to a template in use since 1980. Adjuvant chemotherapy was provided in cases with a positive nodal ratio ≥ 25%. Regular follow-up was provided. Performance, safety and effectiveness measures have been analyzed. Results: Out of 225 patients, full data including clinico-pathologic variables and follow-up are available in 188 cases. Mean age is 31 yrs, vascular invasion is present in 37.2%. Left dissections are 52%. Fifteen (8%) cases have been converted to open RPLND. Median duration of RPLND is 200 min. Median number of removed nodes is 15 (IQR: 11-20). Complications of Clavien Dindo grade ≥ 3 are 9. Twenty-six patients have metastatic nodes (pN+) and 6 received adjuvant chemotherapy. After a median follow-up of 40 months (range: 24, 71), 11 relapses occurred: 6 (3.7%) of 162 pN0 and 5 of 20 pN+ not undergoing adjuvant chemotherapy. Infield recurrences are not reported. All relapsed patients have been rescued by first line chemotherapy. Presence of vascular invasion (p .073) and node ratio as continuous variable (p .097) are not associated with recurrence considering all cases, while conversion to open RPLND is significant (p .019), considering patients operated by the two surgeons with homogeneous variables. Conclusions: L-RPLND in a referral centre is a safe procedure and is apparently effective as open surgery, as there is no an excess of relapses in pN0 cases (3.6%), and the proportion of relapses in pN1 (25%) compares with the traditional figures of open surgery. Conversion to open surgery may be a marker predicting recurrence in a mature phase of experience.
Distress screening in patients with urogenital malignancies.
Authors: Paffenholz Pia , Angerer-Shpilenya Maria , Salem Johannes , Pfister David , Heidenreich Axel
Published: March 2017

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Background: Malignant tumors do not only have a somatic but also a psychological impact on patients. To date, only a few studies are available which evaluated the potential psychological burden of patients suffering from urogenital cancers. In this prospective, longitudinal study we examine the baseline psychological distress of patients treated for urogenital malignancies focussing on testicular cancer (TC) and prostate cancer (PCA). Methods: Psychological distress of 192 inpatients treated for urogenital malignancies was evaluated using the distress thermometer (DT), an established tool for the detection of distress, prior to any surgical or systemic therapy. The DT consists of a visual analogue scale ranging from 0 to 10 resulting in a low (0-3), moderate (4-6) or high (7-10) stress level. Furthermore, it contains a 36-item list of problems subdivided into 5 categories (practical, family, emotional, spiritual/religious, physical). Results: The mean DT score was 5 (interquartile range (IQR) 3-7) with the most common stressors being of emotional origin, namely fear (50%), worry (44%), nervousness (42%), sleep disorders (39%) and fatigue (32%). DT analysis did not reveal any difference between the tumor entities but 64% of all patients displayed a moderate to high stress level requiring psycho-oncological support. The comparison of PCA and TC demonstrated a higher distress level in PCA patients in the subgroups of metastatic disease (median 5.5, IQR 4-8 vs. median 4, IQR 2-6; p = 0.018), secondary therapy (median 6, IQR 5-8 vs. median 4.5, IQR 2.75-6; p = 0.023) and salvage treatment (median 7, IQR 4.5-9 vs. 5, IQR 2.75-6; p = 0.021). PCA patients receiving salvage treatment displayed significantly higher distress levels compared to non-salvage treated patients (median 7, IQR 4.5-9 vs. median 5, IQR 2-7; p 0.028). Conclusions: Our study shows that 64% of urological tumor patients should be offered psycho-oncological support. Especially patients suffering from advanced stage PCA seem to have a high stress level. Thus, physicians in the field of urologic oncology should be aware of their patients’ psychological distress in order to identify high-risk patients and provide them with an appropriate psycho-oncological support.
Current patterns of care for patients with stage I testicular seminoma: Survey of U.S. radiation oncologists on treatment recommendations.
Authors: Mitin Timur , Jain Aditya , Degnin Catherine , Chen Yiyi , Hung Arthur , Jaboin Jerry Jeff , Thomas Charles R.
Published: March 2017

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Background: Most men with Stage I testicular seminoma are cured with surgery alone, now a preferred strategy per national guidelines. The current pattern of practice among US radiation oncologists (RO) is unknown. Methods: We have surveyed practicing US RO via a short online questionnaire. Respondents’ characteristics, self-rated knowledge, perceived patient (pt) compliance rates with observation protocols and expected rate of infertility with and without adjuvant treatments were analyzed for association with treatment recommendations. Results: We received 353 responses from practicing US RO, of whom 23% consider themselves experts. Recommendations are summarized in the table. 34% believe that survival is jeopardized in case of recurrence on observation, but this belief does not impact the recommendation. Over 70% of respondents rate non-compliance with observation at > = 30%. Responders with a higher perceived non-compliance rate are more likely to recommend adjuvant therapy (Fisher’s exact p < 0.01). 52% routinely advise fertility assessment and/or sperm banking for pts who elect observation or chemotherapy, and 74% advise for pts undergoing RT. Respondents are more likely to recommend fertility assessment if they perceive a higher rate of infertility (Mantel-Haenszel Chi-square p < 0.01). 45% administer adjuvant RT in pts with elevated pre-orchiectomy alpha-fetoprotein levels. Conclusions: There is a dramatic uptake of observation as the recommended approach to pts with Stage I seminoma in US RO practices, despite a significant concern among practitioners about pt compliance. Further clinical work must establish best practices to minimize the effect on fertility, as well as guidelines for pts with Stage IS testicular seminoma. [Table: see text]
A predictive model to identify patients at risk of local recurrence following glansectomy for penile squamous cell cancer (SCC).
Authors: Albersen Maarten , Parnham Arie , Freeman Alex , Nigam Raj , Malone Peter , Muneer Asif
Published: March 2017

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Background: Penile preserving surgery for penile cancer is associated with a higher risk of local recurrence (LR). This study developed a predictive model for LR following glansectomy and split skin graft reconstruction . Methods: Retrospective review performed of 177 patients undergoing glansectomy over a 10 year period. The clinicopathological features, LR patterns and cancer-specific survival (CSS) were recorded. Univariate and multivariate logistic regression was used to identify prognostic indicators for LR. The hazard ratio (HR) for LR was estimated using a KM analysis and based on these data we designed a postoperative model for the prediction of LR. Results: The median follow-up period following surgery was 41.4 (1.9-155) months. In total, 9.3 % of the patients developed a LR. Univariate, but not multivariate logistic regression identified perineural invasion (PNI), carcinoma in situ and high grade disease, but not basaloid variant, T stage, lymphovascular invasion and positive resection margins on the specimen to be predictors of LR. A risk model was designed using PNI, CIS and high grade disease in the resected specimen. KM analysis and log rank test revealed no significant differences in LR-free survival between patients with 0 vs 1 or 2 vs 3 risk factors whereas the chance of having local recurrence with 2 risk factors was significantly higher (HR = 5,75; 95% CI 1,43 to 23,15) than with 1 risk factor. A risk stratification model based on a cut-off score of > 1 out of 3 risk factors discriminated well between patients with a high vs low chance of recurrence in a Kaplan-Meier analysis (HR 9.18, 95% CI 3.29 to 25.65 P < 0.001). Indeed, ROC-curve analysis showed an optimal cut-off point of > 1 risk factors with an AUC of 0.77 (P < 0.001, specificity 63%, specificity of 85%) for prediction of LR. Conclusions: Although,LR after glansectomy does not affect the CSS, patients at risk of local recurrence can be identified when > 1 of the factors PNI, CIS and high grade are found on histopathological analysis of the glans. These findings can define the frequency of follow-up and -if validated on pre-op biopsy- potentially be helpful in planning the margins of surgical resection in patients with penile SCC.