bluuebunny/crossref_metadata_2025 huggingface dataset:
Cell-free tumor DNA and TERT promoter mutations in bladder cancer.
Authors: Huang Franklin W. , Rinne Mikael L. , Lundgren Kevin T. , Mullane Stephanie Anne , Moreno Irene , Reed Sarah , Gydush Greg , Adalsteinsson Viktor , Novak Jesse , Hahn William C. , Signoretti Sabina , Choueiri Toni K. , Garraway Levi A. , Bellmunt Joaquim
Published: March 2017

353

Background: Currently, there are no FDA-approved blood biomarkers for the prognosis or prediction of outcomes in urothelial carcinoma (UC). The telomerase reverse transcriptase ( TERT) promoter is recurrently mutated at high frequency in UC (50%). These mutations have been correlated with tumor recurrence and survival. Tumor cell-free DNA (cfDNA) with somatic genomic alterations can be found in the plasma of cancer patients and has the potential for use as a non-invasive cancer biomarker. Detection of TERT promoter mutations in cfDNA might be used as a prognostic tool to monitor disease outcome in UC patients. We set out to detect tumor cfDNA and TERT promoter mutations in cfDNA from patients with UC at different stages. Methods: UC patients receiving chemotherapy in the neoadjuvant, first or second-line metastatic setting had blood collected either before or during therapy. cfDNA was isolated from ~1ml plasma samples using the QIAmp (Qiagen) kit. Samples underwent ultra-low pass whole genome sequencing (ULP-WGS) to determine whether tumor cfDNA could be detected in these samples. TERT promoter mutations were detected using a sensitive qPCR assay. Results: 40 plasma samples from a total of 32 patients with urothelial carcinoma were analyzed. Sufficient amounts of plasma cfDNA were obtained for library construction and ULP-WGS in 11 patients. 6 of these 11 patients were determined to be positive for detectable tumor cfDNA and of these, all were metastatic and 50% (3/6) were positive for a TERT promoter mutation. In total, 8 out of 40 samples (20%) were positive for a TERT promoter mutation, including samples from two patients where total cfDNA yield was insufficient for library construction. A total of ~20% of patients with metastatic disease were positive for TERT promoter mutations in cfDNA. The low percentage of samples having sufficient cfDNA most likely reflects the low volume of plasma used. Conclusions: TERT promoter mutations were identified in cfDNA of UC patients. ULP-WGS showed tumor cfDNA in patients with a high tumor burden and metastatic disease. TERTpromoter mutations in cfDNA could potentially be used as a non-invasive method for detection of disease. These results have implications for the use of cfDNA in the evaluation of advanced UC.
Evaluation of monocytic myeloid-derived suppressor cell (M-MDSC) frequency in patients with metastatic urothelial carcinoma (mUC).
Authors: Funt Samuel , Mu Zhenyu , Cipolla Catharine Kline , Kania Brooke Elizabeth , Zheng Junting , Boyd Mariel Elena , Snyder Charen Alexandra , Callahan Margaret K. , Autio Karen A. , Regazzi Ashley Marie , Moran Meredith Maisie , Ostrovnaya Irina , Iyer Gopa , Wong Phillip , Lesokhin Alexander M. , Rosenberg Jonathan E. , Bajorin Dean F.
Published: March 2017

356

Background: M-MDSCs promote tumor progression through complex mechanisms, including immunosuppression and the production of mediators of angiogenesis and invasion. M-MDSCs are associated with poor outcomes in a number of malignancies. We conducted an exploratory analysis enumerating M-MDSCs (Lin-CD14+/HLA-DRlow/-) in the blood of pts with mUC and assessed for assay variability and correlation with clinical outcomes. Methods: Whole blood was collected at a single time point for each pt and stabilized in Cyto-Chex tubes. M-MDSC% was calculated by flow cytometric analysis of HLA-DR expression on CD14+ monocytes using an MSKCC developed computational algorithm-based approach (Kitano et al. 2014). Individual samples were run in quadruplicate at MSKCC. The mean MDSC% was used in subsequent analyses and the replicate standard deviation (SD) was considered a reflection of intra-assay variability. Clinical variables were collected and pts followed for OS, which was calculated from time of sample collection. Results: 21 pts with mUC who progressed after prior chemotherapy were included. At the time of collection, pts were on clinical trials with immune checkpoint blockade (n=13) or targeted therapy (n=1), receiving salvage chemotherapy (n=2), or awaiting treatment on clinical trials with immune checkpoint blockade (n=4) or targeted therapy (n=1). The median follow up from the time of collection in surviving patients (n=15) was 11.1 months (range: 10.5-11.5). Median OS was not reached. Mean (SD) M-MDSC% was 29.2 (4.92). The range of replicate SD was 0.13-1.05. M-MDSC% was not higher in pts with visceral mets (p=0.109). Pts with above median M-MDSC% had worse OS (p=0.01; 6 patients died during follow up, all with above median M-MDSC%). Conclusions: In a heterogeneous cohort of pts with mUC, the enumeration of M-MDSCs in stabilized whole blood was feasible and demonstrated marked inter-patient but not intra-assay variability. Pts with higher M-MDSC% values had worse OS. Additional characterization of M-MDSCs in larger cohorts and in pts receiving immunotherapy is ongoing and may have important prognostic and therapeutic implications in mUC.
Clinical and pathological outcomes for patients with T1HG bladder cancer managed with upfront cystectomy with or without neoadjuvant chemotherapy and the impact of the MDACC high-risk features.
Authors: Metcalfe Michael J. , Ferguson James Edward , Li Roger , Xiao Lianchun , Dinney Colin P.N. , Navai Neema , Shah Jay Bakul , Kamat Ashish M.
Published: March 2017

366

Background: In muscle invasive bladder cancer there is an increased risk for systemic disease identified for patients with certain high risk features (HRF): pre-operative hydronephrosis (POH), lymphovascular invasion (LVI), abnormal exam under anesthesia (AbnEUA), and the presence of variant histology (VH). We sought to identify the effect of these high risk features in the T1HG population. Methods: With IRB approval, a single center retrospective review was performed on all patients at MDACC from 1995-2013 who underwent radical cystectomy (RC) for T1HG urothelial cancer. Patients were stratified according to the presence or absence of HRF defined by the presence of LVI, POH, VH, AbnEUA, prostatic ductal involvement (PDI), and the delivery of neoadjuvant chemotherapy (NAC). Primary outcome included pathologic T (pT) upstage and presence of lymph node positive disease (LN+) at time of RC, as well as survival outcomes. Results: 372 T1HG patients underwent RC, of these 196 (53%) have HRF including: VH (n=98, 25%), LVI (n=44, 12%), PDI (n=31, 8%), POH (n=38, 10%) and/or AbnEUA (n=34, 9%). pT upstage occurred in 43/176 (24.4%) of patients without HRF, in 45/151 (30%) of patients with 1 HRF, and in 38% (17/45) of patients with > 2 HRF (p=0.088). LN+ occurred in 18/176 (10.2%) of patients without HRF, 7.8% (15/151) of patients with 1 HRF and in 17.8% (8/45) of patients with > 2 HRF (p=0.0403). Presence of HRF were not significant for a decreased OS (p=0.076), DSS (0.425), and RFS (p=0.103). No patients without HRF got NAC, and 41/196 (21%) of patients with HRF received NAC. There was no effect of NAC on pT upstage (OR 1.184, 95% CI 0.355-3.954, p=0.7834) or rate of LN+ disease (OR 1.758, 95% CI 0.669-5.606, p=0.2525) on multivariate analysis. There was no effect of NAC on OS (p=0.122), DSS (0.437), or RFS (0.7483). Conclusions: Presence of certain high risk features in the T1HG setting does have increased risk of pT upstage and LN+ disease in patients treated with cystectomy. However, there is no effect seen on survival outcomes. Use of NAC did not significantly alter outcome in our cohort and should be reserved for the muscle invasive setting.
Lynch syndrome-associated upper tract urothelial cancer: Assessment of clinical screening criteria and tissue-based point of care testing.
Authors: Metcalfe Michael J. , Rao Priya , Mork Maureen E , Petros Firas G. , Xiao Lianchun , Broaddus Russell , Matin Surena F.
Published: March 2017

371

Background: Lynch syndrome (LS) is an inherited syndrome that places patients at risk for upper tract urothelial carcinoma (UTUC). Our goal was to identify the most reliable means of screening for LS in patients with UTUC at the point of care (POC). Methods: Patient information was retrospectively collected in an IRB-approved protocol on UTUC patients. LS screening was universally performed on all patients presenting from 1/2013-7/2016. We evaluated patient and family history (Amsterdam I and II criteria; AMS1 and AMS2, respectively), tumor immunohistochemistry (IHC) for 4 mismatch repair proteins (MMRP), tumor and normal tissue polymerase-chain reaction for microsatellite instability (MSI), and clinical genetic analysis and counseling (GAC), in those with undiagnosed LS. Patients who were AMS 2 positive, MSI positive, or IHC positive were considered as presumed Lynch syndrome (PLS) and were referred for GAC. Results: 101 UTUC patients without a history of LS were universally screened during clinical follow-up. A total of 15/101 (15%) patients were PLS. 7/101 (7%) patients met AMS2 criteria. 4 patients meeting AMS2 criteria had intact expression of MMRP and no MSI instability. 11 (11%) patients had either loss of one or more MMRP. There were two cases of MSI high instability, both in patients with MMRP loss. There were no cases of MSI-high instability and negative IHC. Insufficient tissue was found in 1/101 (1%) of IHC and 8/88 (9%) of MSI tests (p=0.0164). All patients with any positive screen were referred for GAC, 5 followed-up and all 5 patients had a confirmed germline mutation. The remaining did not follow through with GAC because of financial/insurance barriers. Conclusions: We identified 15% of universally screened UTUC as PLS at the POC using IHC and AMS2 criteria. IHC and AMS2 criteria appear to provide the most reliable screening. MSI is limited by requirement for normal tissue, a greater amount of tumor tissue, and can miss cases of MMRP loss. There are significant barriers to GAC. Our findings of a 15% rate of LS-related UTUC is consistent with prior laboratory tissue studies and has significant implications for universal POC testing of UTUC patients.
Prognostic classification of muscle-invasive bladder cancer (MIBC) following radical cystectomy (RC) alone or with perioperative chemotherapy: Analysis of the U.S. National Cancer Database (NCDB).
Authors: Sonpavde Guru , Nelson Rebecca A. , Pond Gregory Russell , Nix Jeffrey , Chennamsetty Avinash , Pal Sumanta K.
Published: March 2017

372

Background: While the role of adjuvant therapy for MIBC is being evaluated in randomized trials of patients (pts) following RC with or without neoadjuvant chemotherapy (NC), pts receiving adjuvant chemotherapy (AC) have been excluded. Understanding the prognosis of a broad spectrum of pts undergoing RC with or without perioperative chemotherapy may aid patient selection, stratification and interpretation of nonrandomized data. We conducted a retrospective analysis of the NCDB to construct a comprehensive prognostic nomogram in this broad population. Methods: Data from NCDB was obtained for all patients diagnosed with clinical (c)-T2-T4aN0M0 urothelial carcinoma of bladder who underwent RC in the US from 2004-2013. Those who underwent RC > 6 months (mo) after initiating NC, received AC > 4 mo after RC were excluded to allow only those receiving optimal therapy. Pts with unknown race and number of lymph nodes (LNs) examined were also excluded. Multivariate analyses were conducted to determine the impact on survival of: clinical stage, pathologic (p)-stage, treatment group (RC alone, NC, AC), age, year of diagnosis, Charlson Comorbidity Index (CCI), race, number of examined LNs examined and sex. Results: A total of 10,256 pts were evaluable for analysis: 6864 in the RC group, 1380 in the AC group and 2012 in the NC group. On multivariate analysis, the following variables were significantly (p < 0.001) associated with survival: treatment group, age ( < 65 vs. ≥ 65 years), CCI, p-stage and number of examined LNs. Calibration was performed and the c-index was 0.79 (95% CI: 0.76-0.81). Limitations of a retrospective analysis apply. Conclusions: A comprehensive prognostic nomogram to predict the survival of pts with MIBC undergoing RC with or without NC or AC was proposed. The estimation of residual risk of mortality after RC alone or with AC or NC aids optimal stratification of pts in more inclusive randomized trials of subsequent adjuvant therapy. The nomogram also highlights the impact of comorbidities and age, and helps interpret non-randomized data evaluating perioperative regimens.
Comprehensive genomic characterization of upper tract urothelial carcinoma (UTUC).
Authors: Moss Tyler J. , Qi Yuan , Xi Liu , Peng Bo , Mosqueda Maribel E , Guo Charles , Ittman Michael , Wheeler David A. , Lerner Seth P. , Matin Surena F.
Published: March 2017

375

Background: Integrated analysis of UTUC was performed to characterize the genomic landscape of UTUC and provide insights into biology. Methods: 31 untreated samples underwent WES, RNAseq, and RPPA. Consensus mutation calls from independent pipelines of 2 centers identified gene expression clusters using unsupervised consensus hierarchical clustering (UCHC). Results: Clinical data are shown in the Table. WES identified mutations in FGFR3 (74.1%; 92% low grade, 60% high grade), KMT2D (44.4%), PIK3CA (25.9%), TP53 (22.2%). APOBEC and CpG signatures were identified. Expressed marker genes from bladder TCGA were not associated with molecular subtypes in this study. UCHC of RNAseq segregated samples into 4 molecular subtypes. Cluster 1: no PIK3CA mutations; enriched for nonsmokers, high grade non-muscle invasive tumors, high recurrence rates and favorable survival. Cluster 2: 100% FGFR3 mutations; enriched for low grade, noninvasive disease, no bladder recurrences. Cluster 3: 100% FGFR3 mutations, 71% PIK3CA, no TP53 mutations; high tobacco use and bladder recurrence (62.5%); tumors all non-muscle invasive. Cluster 4: KMT2D (62.5%), FGFR3 (50%), TP53 (50%) mutations, no PIK3CA mutations; enriched for high grade, muscle-invasive disease, tobacco use, CIS, reduced survival; novel fusion of SH3KBP1-CNTNAP5 was identified, with high expression levels in the sample. Conclusions: We show mutations in UTUC occurring at differing frequencies and subtypes than bladder cancer. Novel fusion SH3KBP1 regulates RTK signaling and acts to recycle TGFβ receptors. Further studies are needed to validate the described subtypes, explore their responses to therapy, and better define the novel fusion mutation. [Table: see text]
High responses to chemotherapy in patients with metastatic urothelial cancer (MUC) after frontline immunotherapy.
Authors: Szabados Bernadett , Wimalasingham Akhila Ganeshi , Tang Yen Zhi , Sahdev Anju , Gomez De Liano Lista Alfonso , Lim Louise , Hopkins Thomas , Berner Alison , Powles Thomas
Published: March 2017

377

Background: The effect of prior immune checkpoint inhibition therapy (CI) on the efficacy of subsequent chemotherapy is largely unknown in MUB. The identification of the optimal sequence of chemotherapy and IO is yet to be determined, but may influence outcomes. Methods: A retrospective audit and comparison of patients who progressed after first and second line CI and received subsequent standard chemotherapy was performed. Date was collected across a broad spectrum of CI. We report on patient’s characteristics and response rates of 20 sequential patients collected from one institution who received chemotherapy after CI. Patients were separated into 2 groups. Group A had not previously received chemotherapy (n=10), group B had previously received at least 1 chemotherapy regimen (n=10). Central radiology review was performed. We assessed objective response rate by RECIST v 1.1. Kaplan Meier method was used. Results: Median age for the whole cohort was 64 yrs (45-80). The commonest chemotherapy regimen in group A and B were cisplatin-gemcitabine (80%) and carboplatin paclitaxel (70%) respectively. Results are summarised in the table. The median change in target lesions in the front line immunotherapy cohort was -49% (-81 to +8%). Only two patients (20%) in group B responded to chemotherapy and both presented a long interval between first and 2ndline chemotherapy (9-12 months); compared to 56% responding in group A. Conclusions: Chemotherapy maintains its efficacy after front line CI with deep responses. Although numbers are modest, results strongly suggest patients should be offered chemotherapy in this setting. [Table: see text]
Relationships between an androgen receptor output signature (ARoS), AR expression, and poor prostate cancer prognosis in RP tissues.
Authors: Alshalalfa Mohammed , Santiago-Jimenez Maria , Erho Nicholas , Fishbane Nicholas , Yousefi Kasra , Ashab Hussam Al-Deen , Davicioni Elai , Ross Ashley , Schaeffer Edward M.
Published: March 2017

38

Background: The Androgen-receptor (AR) signaling plays a pivotal role in prostate cancer initiation and progression. AR amplification and overexpression have been associated with lethal PCa and CRPC; however, much of the impact of these events on cancer progression is poorly understood with an unclear prognostic significance of down-stream targets of AR. Methods: A total of 2,555 RP expression profiles were extracted from the Decipher GRID database; 262 of which were from retrospective natural history cohort with known metastasic outcomes and the remaining from anonymized prospective cases with basic demographic and pathological data available. We built a 9 gene AR-output signature (ARoS) score based on canonical androgen regulated genes to represent AR-output activity in RP tissues. The 9 genes were weighted based on their distribution skewness in the prospective data (n = 2,293) and then scores were calculating by summing the weighted expression of the 9 genes. Results: AR expression and ARoS score were not strongly correlated with approximately 50% of samples with low ARoS have relatively high AR expression. In a prospective cohort of 2,293 patients, low ARoS was associated with higher Decipher metastasis risk scores (OR: 3.1, p < 0.001), higher Gleason grade (OR: 2.4, p < 0.001), ERG-fusion negative (OR: 1.8, p < 0.001) and SVI (OR: 2.1, p < 0.001). Additionally, low ARoS was associated with higher expression of neuroendocrine biomarkers (NCAM1, ENO2). In a large retrospective cohort with long term clinical follow-up, patients with low ARoS score had a higher probability of 10-year metastasis rate (p = 0.002). In 55 patients from this cohort who received ADT post metastasis, the ARoS signature derived from primary tissue was lower in patients who developed CRPC (p < 0.001). Furthermore, ARoS was significantly lower in mCRPC samples (p < 0.001) compared to primary PCa tissues. Conclusions: ARoS derived from primary prostate cancer tissue is correlated with metastatic outcomes and progression to CRPC. With further validation, such a signature may better predict those patients which require early intensification of systemic therapy.
Characterization of POLE-mutated (POLE+) urothelial carcinoma of the bladder and urinary tract (UC).
Authors: Teo MinYuen , Al-Ahmadie Hikmat , Cha Eugene K. , Dalbagni Guido , Bochner Bernard H. , Solit David B. , Berger Michael F. , Taylor Barry S. , Bajorin Dean F. , Iyer Gopa , Rosenberg Jonathan E.
Published: March 2017

387

Background: The POLE gene encodes for the catalytic and proofreading unit of DNA polymerase epsilon. Mutations in POLE gene, recently observed in endometrial and colorectal cancers, are associated with unique clinical features and an ultramutated phenotype. We sought to quantify and characterize POLE+ in UC. Methods: POLE+ cases were identified from a database of 532 UC tumors sequenced with the MSK-IMPACT assay (Cheng et al J Mol Diagn 2015). Tumors were classified based on total mutation: hypermutated (20 - 149 mutations) and ultramutated ( ≥ 150 mutations) as previously described in colon cancer (Stadler et al J Clin Oncol 2016). An institutional cohort of patients with metastatic UC was used as historical POLE- control (n = 94). Results: Thirty two POLE+ patients (6%) and 42 mutations were identified. Median age of diagnosis was 65 years (range: 31 - 94) and 81% were male. Seven patients were found to have Lynch’s syndrome, 8 with ERCC2 mutations which were hotspots or within the helicase domains and 1 with germline NBN mutation. These were excluded from further analysis. Of the remaining 16 patients (3%) and 22 mutations, four were found within the proofreading domain (positions 268 – 471), one was a previously reported hotspot (P286R) and one was a truncating mutation (R114*). Four cases were considered hypermutated and two ultramutated based on mutation counts. Clinically, four had non-invasive disease and 4 had metastatic disease at diagnosis. Eight patients had muscle-invasive disease, five of whom received neoadjuvant chemotherapy. All 8 patients developed metastatic disease with a median time interval of 10.3 months (range: 3.3 – 29.6). Nine of the 12 metastatic patients had nodal metastases while only one had visceral metastasis. With median follow-up of 25.4 months, median overall survival from metastatic diagnosis was not reached and 83% remained alive at 2 years, which was superior to survival for POLE- metastatic patients (HR 0.36, p = 0.04) and POLE- nonvisceral, node only metastatic patients (HR 0.33, p = 0.03). Conclusions: POLE+ prevalence is low in UC but might exhibit superior overall survival. It remains to be investigated if this is strictly the effect of POLE+ or other as yet unidentified genomic events.
The impact of peri-operative chemotherapy for patients with lymph node-positive urothelial cancer.
Authors: Kaiser Jeenan , Li Haocheng , Lee-Ying Richard M. , Heng Daniel Yick Chin , Alimohamed Nimira S.
Published: March 2017

388

Background: Patients with locally advanced urothelial cancer with regional lymph node involvement (LN+) have a poor prognosis. Surgical management of these patients is controversial and practice patterns vary. We evaluated the outcomes of patients with LN+ disease treated with pre-operative chemotherapy and cystectomy, cystectomy and post-operative chemotherapy, and chemotherapy alone. Methods: Patients with urothelial cancer with TxN1-3M0 disease treated with chemotherapy in Alberta from 2005 to 2015 were evaluated. Progression-free survival (PFS) and overall survival (OS) were evaluated using Kaplan-Meier analysis. Cox regression analysis was performed to evaluate the impact of age, gender, T stage, and N stage on survival. Results: 184 patients with LN+ disease treated with chemotherapy were evaluable for outcomes; 42 underwent pre-operative chemotherapy (Group A), 92 underwent post-operative chemotherapy (Group B), and 50 received chemotherapy alone (Group C). The median age at diagnosis was 65 years (range 31-89) and most patients (83%) were male. The median follow-up time was 23.2 months. A higher T stage was seen in patients in Group A, while patients in Group C had a higher N stage. The median number of chemotherapy cycles delivered was equal in all arms at 4. Patients in Group A or B had significantly better PFS and OS compared with patients in Group C (Table). When adjusting for age, gender, T stage, and N stage, patients in Group C had significantly lower OS compared with those patients in Group A (HR 1.87, 95% CI 1.09 – 3.18, p=0.02). Conclusions: In this real-world analysis of patients with LN+ urothelial cancer, patient outcomes were improved with surgical resection of disease in combination with pre-operative chemotherapy. After chemotherapy in fit patients with LN+ disease, surgical management is a reasonable consideration. [Table: see text]
Difference in risk factors associated with biochemical recurrence after salvage RT compared to post-prostatectomy patients with negative margins.
Authors: Hopper Austin B , Sandhu Ajay Pal , Einck John Paul
Published: March 2017

39

Background: Previous research has also shown that higher pathologic stage, higher Gleason score (GS) and positive margins are associated with increased rates of disease recurrence after prostatectomy and may be indicators for early intervention with adjuvant or salvage radiotherapy (SRT). Conversely, a negative surgical margin is a negative prognostic factor for the success of SRT. We sought to investigate the relative significance of prognostic factors in patients grouped by margin status and differences in their response to treatment. Methods: 227 patients were treated with SRT at our institution between Jan 2005 and Dec 2013. Patients with positive lymph nodes at surgery, those treated with adjuvant radiation and patients with metastases prior to SRT were excluded, leaving 196 for analysis. Biochemical recurrence (BCR) was defined as post-SRT PSA nadir + 0.2 ng/mL. Median follow-up was 48 mo. Covariates evaluated were factors found to be significant in previous studies on SRT (pre-SRT PSA, pathologic stage, GS) as well as treatment to the pelvis vs fossa. Patients were grouped by margins and evaluated using Kaplan-Meier and multivariate Cox regression. Results: In univariate analysis of patients with positive margins significant factors for increased rates of recurrence were pre-SRT PSA (p = 0.016), GS (p < 0.001), and pathologic stage (p < 0.001). Treatment to the pelvis was not significant. Conversely, in patients with negative margins, pre-SRT PSA and GS no longer significantly affected BCR and pathologic stage only approached significance (p = 0.061). In these patients treatment to the pelvis was significantly associated with decreased BCR (p = 0.005). On multivariate analysis these trends in significance were maintained. Conclusions: In post-prostatectomy patients with negative margins treatment to the pelvis is associated with improved bPFS, while traditional factors associated with recurrence such as pathologic stage, GS and pre-treatment PSA were not significant. Patients with negative margins and PSA recurrence after prostatectomy should be considered for treatment to the pelvic nodes, even in the absence of nodal involvement on imaging.
Dacomitinib (Daco) induction therapy for locally advanced (LA) or metastatic penile squamous cell carcinoma (PSCC): An open label, single-arm, phase II study.
Authors: Necchi Andrea , Lo Vullo Salvatore , Raggi Daniele , Giannatempo Patrizia , Nicolai Nicola , Piva Luigi , Biasoni Davide , Catanzaro Mario , Torelli Tullio , Stagni Silvia , Calareso Giuseppina , Togliardi Elena , Colecchia Maurizio , Busico Adele , Perrone Federica , Gloghini Annunziata , Sonpavde Guru , Mariani Luigi , Salvioni Roberto
Published: March 2017

399

Background: The prognosis of patients (pts) with PSCC is primarily depending on the involvement of regional lymph nodes (LN). Owing to the limited efficacy of chemotherapy (ChT), new drugs are warranted. Daco is a potent, irreversible TKI of human EGFR/HER1, HER2 and HER4. Methods: In a phase 2 study (NCT01728233), pts received Daco 45 mg/d orally continuously. Inclusion criteria were SCC histology, and clinical stage N2-3 or M1; no prior ChT was allowed. Computed tomography (CT) and PET/CT scans were repeated q8 wks. Responding pts with LA-PSCC were offered radical surgery. The primary endpoint was the objective response-rate (ORR = CR+PR according to RECIST v1.1). The study was conducted according to a Bayesian design, based on predictive probability; the target was to demonstrate that the ORR exceeded 20%. Translational analyses on pre-Daco tumor samples included: EGFR and HER2 amplification (ampl), in-situ hybridization for HPV, and next generation sequencing. Results: From 06/13 to 09/16, 26 pts were treated. 7 (26.9%) had visceral metastases. 50% had pelvic and 57.7% clinically-involved bilateral LN. 1 CR + 7 PR were obtained (ORR = 30.4%, 95% credibility interval 14.9-48.6%). Median follow up = 16.6 months; 12-m PFS = 24.1% (95%CI: 11.1-52.3); 12-m OS = 50.7% (95%CI: 31.7-80.9). The current Bayesian posterior probability of exceeding the 20% ORR target is 89%. Tissue samples from 23 pts were analyzed. Only 2 pts were HPV+ (1SD, 1PD). EGFR ampl was found in 4 pts (1 CR, 1 PR, 2 SD) and it was confirmed in all post-Daco samples. TERT mutations (60%) were found in responders (R) only. Mutations in genes potentially associated with resistance to EGFR inhibitors ( HRAS, BRAF, PIK3CA, PTEN, STK11) were found in 47% non responders (NR) vs 25% R. HRAS and BRAF mutations segregated with NR (20%). Additional unfrequent mutations of druggable targets were found: RAC1, TSC1 and mTOR in R, FGFR2, RAD50, PDGFRB and FLT4 in NR, IGF2R in both. Conclusions: Dacomitinib was active in HPV-negative, advanced PSCC. Among multiple altered pathways, we were able to delineate the possible molecular profile of responders. An expansion cohort to confirm the translational findings is planned. Clinical trial information: NCT01728233.
Prostate cancer outcomes for African American and caucasian patients undergoing radical prostatectomy.
Authors: Cullen Jennifer , Kuo Huai-Ching , Chen Yongmei , Hurwitz Lauren , Rosner Inger L. , Porter Christopher , Brand Timothy C. , Sterbis Joseph , Stroup Sean , Rebbeck Timothy , D'Amico Anthony Victor , Lu-Yao Grace L.
Published: March 2017

40

Background: A disproportionate burden of prostate cancer (CaP) incidence and mortality is observed for African American (AA) versus Caucasian (CA) patients in the US. Potential underlying reasons for racial disparity include biology, comorbidity profiles, access to health care, adherence to follow-up care and/or treatment aggressiveness. This study examined CaP progression and overall survival (OS) among AA and CA patients undergoing radical prostatectomy (RP). Methods: This retrospective cohort study examined men enrolled in the Center for Prostate Disease Research (CPDR) Multi-Center National Database between January 1, 1990 and December 31, 2014. Patients with biopsy-detected CaP without metastasis and treated with RP within 12 months of CaP diagnosis were eligible. Biochemical recurrence (BCR) was defined as a PSA value of > = 0.4 ng/mL followed by a subsequent increase. PSADT was categorized as < 3, 3-8.99, 9-14.99, and > = 15 months. Kaplan-Meier estimation curves and multivariable Cox proportional hazards analysis were used to examine BCR and OS. Results: A total of 6,785 patients were eligible; 21.5% self-reported as AA and 78.5% self-reported as CA. Median follow-up time was 6.1 years. Comparable distributions of pathologic features at RP and adjuvant treatment over time were observed across race but several comorbid conditions were more common in AA patients including cardiovascular disease, hypertension, diabetes, and other cancer types. In race-specific unadjusted Kaplan Meier analyses, PSADT was an important predictor of BCR and OS for both AA and CA patients (Log rank p < 0.0001 for all KM models). In multivariable analysis, a greater odds of BCR over time was observed for AA versus CA patients (HR = 1.28, CI = 1.11, 1.48, p = 0.0009) after adjustment for D’Amico risk stratum, comorbidity, pathological features, and PSADT. PSADT was a critical predictor of BCR, with worst outcomes at extreme comparison of PSADT categories: HR < 3 vs. > = 15 months= 41.5, CI = 33.6, 51.3, p < 0.0001). Conclusions: In a large racially diverse, longitudinal cohort with equal health care access, there was a striking relationship between PSADT and time to BCR for each racial group and poorer outcomes for AA versus CA patients.
Liver metastases in germ cell tumors.
Authors: Boulos Suliman , Shamash Jonathan , Wong Han Hsi , Rudman Sarah Maria , Doherty Gary , Ansell Wendy , Berney Daniel , Reinius Marika , Wilson Peter , Shephard Linda , Mazhar Danish
Published: March 2017

403

Background: Metastatic germ cell tumour (GCT) to the liver is considered rare and usually caries adverse outcomes. We aimed to determine the outcome of patients with metastatic GCT to the liver. Methods: We identified retrospectively 36 patients with metastatic germ cell tumour to the liver between the years 2001 and 2015, from which 34 were non-seminomatous germ cell tumours (NSGCT) and two seminomas. 35 patients had other sites of metastases including lungs, bones and brain. Elevated tumour markers were seen in the vast majority of patients (97.2%). 15 patients received treatment with dose intense regime including actinomycin-D, high-dose methotrexate, etoposide and cisplatin (GAMEC) every 14 days, 20 patients received the standard protocol of bleomycin, etoposide and cisplatin (BEP) every 21 days and one patient received POMB/ACE chemotherapy. 20 patients had an induction cycle of cisplatin, vincristine and bleomycin (Baby-BOP) prior to initial treatment. Results: 12 patients had radiological complete response (CR) and 19 patients had radiological partial response (PR) in the liver, with five patients having a CR in all sites with negative markers. Five patients underwent liver resection with no viable tumour seen. Three patients that underwent liver resection also had retroperitoneal lymph node dissection (RPLND) the histology from which was viable seminoma in one case, mature teratoma in one case and necrosis in the final patient.16 patients had marker negative PR, 10 patients had marker positive PR and 5 patients had a marker negative CR. 15 patients eventually relapsed and 10 died with only one liver relapse. Median Overall survival for patients that received BEP was 35.38 months (not reached for GAMEC) (p = 0.0147). The median progression free survival (PFS) for the BEP group was 24.45 months (not reached for GAMEC) (p = 0.22) and the 2-years PFS for the GAMEC and BEP groups were 73% and 55% respectively. Conclusions: Within this cohort, liver metastasis from germ-cell tumour had a good response to chemotherapy, with progression occurring mainly in extra-hepatic sites. There was also a suggestion that dose dense GAMEC regime may offer superior efficacy compared with BEP.These results also question the role of liver metastectomy after initial response to chemotherapy.
Predictors for malignant tissue (MT) in residual masses (RM) of non-seminomatous germ cell tumors (NSGCT) treated by chemotherapy (CT) before surgery.
Authors: Stern Natacha , Bompas Emmanuelle , Bogart Emilie , Laestadius Fredrik , Mouillet Guillaume , Schlurmann Friederike , Leblanc Eric , Penel Nicolas , Lotz Jean-Pierre , Amela Eric
Published: March 2017

405

Background: About half of the patients operated for RM after CT for a NSGCT doesn’t benefit from surgery because RM contain only necrosis. We develop and validate a predictive score for identifying MT (teratoma and/or viable cancer cells) after primary CT for disseminated NSGCT. Methods: We have conducted a retrospective study. The development cohort (cohort 1) consists in 193 pts treated with CT and surgery of RM at the Oscar Lambret Cancer Center between 1997 and 2014. The validation cohort (cohort 2) consists in 98 pts treated in 5 other French sites. Size of RM, modification in size after CT, pre- and post-CT AFP levels, pre- and post-CT HCG levels, pre- and post-CT LDH levels were collected. The predictive factors have been first identified using univariate logistic regression analysis and then selected using step-by-step (forward) logistic regression. Discrimination has been assessed using Akaike Information Criterion (AIC) and ROC curve. Results: The rates of MT in the RM were 52% and 68%, in the cohort 1 and 2, respectively. The 1-, 2- and 5-y OS in the development cohort were 99, 97 and 95%, respectively. The 1-, 2 and 5-y relapse-free survival in the development cohort were 96, 92 and 91%, respectively. In univariate analysis, the predictive factors for MT were: size of RM > 15 mm (OR=3.32 [95%-CI: 1.6-6.2], p=0.001), stable RM versus diminution in size of RM (OR=3.0 [1.5-5.9] p=0.001) or increase in size versus diminution in size of RM (OR=8.6 [1.7-41.9] p=0.008) and pre-CT AFP level > ULN (OR=2.9 [1.4-6.3], p=0.006). The multivariate analysis had retained 2 predictors for MT: size of RM and pre-CT AFP level > ULN. The ROC was 0.71 [0.61-0.80] with an AIC=143 in the development cohort, and was 0.59 [IC95% 0.46-0.72] in the validation cohort. The model showed adequate calibration with a Hosmer-Lemeshow test p=0.69. Conclusions: Surgery of RM is part of standard of care of disseminated NSGCT. However, this surgery is morbid and at the end about 50% of pts are free of MT. We have developed and validated a predictive score for identifying pts benefiting of surgery.
Nonguideline concordant treatment of testicular cancer.
Authors: Paffenholz Pia , Pfister David , Heidenreich Axel
Published: March 2017

407

Background: The management of testicular cancer requires a complex multimodal therapeutic approach. Despite the availability of regularly updated national and international guidelines on testicular cancer, treatment still differs between the institutions probably affecting the patients’ outcome. Our study aims to investigate frequently occurring errors regarding the diagnosis and therapy of testicular cancer in consideration of the current EAU guidelines. Methods: We performed a retrospective analysis including 129 patients diagnosed with testicular cancer that were referred to our department between 09/2015 and 10/2016. Patients’ age, histology, clinical stage, IGCCCG risk classification, treatment (surveillance, chemotherapy, radiotherapy, surgery) and follow-up were investigated and compared to the EAU guidelines’ recommendations. Results: Of the eligible 129 patients, 34 (26%) patients displayed a non-guideline concordant care. The most common error was undertreatment (47%), mostly due to missing chemotherapy cycles. Modified treatment and overtreatment occurred in 20% and 16% respectively, while inappropriate treatment (9%) and misdiagnosis (6%) were rarely seen. In secondary treated patients, non-guideline concordant therapy was observed more frequently compared to those patients receiving primary therapy (59% vs. 41 %). Almost all patients (93%) receiving a non-guideline concordant therapy suffered a relapse in contrast to 67% of patients that were treated according to the EAU guidelines. Conclusions: Non-adherence to the current EAU guidelines on testicular cancer appears to be a major problem in various testicular cancer treating institutions. In our study, the most frequent error was undertreatment, followed by modified treatment and overtreatment. Inappropriate therapy leads to a higher relapse rate and morbidity associated with a worse curative outcome.
Treatment patterns and impact of race in patients receiving first-line therapy for advanced penile squamous cell carcinoma (PSCC).
Authors: Morgan Charity , Diorio Gregory , Spiess Philippe E. , Sonpavde Guru
Published: March 2017

413

Background: Treatment patterns and outcomes with first-line therapy for PSCC are unclear. We conducted a retrospective analysis of the NCDB to study this issue and evaluate prognostic factors in treated patients (pts). Methods: Data from the NCDB was obtained for pts diagnosed with clinical stage 4 PSCC from 1998-2011. The following variables were evaluated: age, Charlson Comorbidity Index (CCI), race, survival, socioeconomic status (SES) based on median income of area of residence and therapy. Treatment patterns were described. Multivariate analyses (MVA) were conducted to assess the impact of factors on survival of pts receiving therapy. Results: Of 14,395 pts with PSCC, 614 pts with stage 4 PSCC were evaluable with complete data. The mean age was 61.9 (range 22-90), 498 (81.1%) were white and 91 (14.8%) were black. 300 (48.7%) pts received no anti-cancer therapy, 245 (39.9%) received chemotherapy (+/- other therapy) and 69 (11.24%) received radiation (+/- non-chemotherapy agents). Pts in the chemotherapy group were significantly younger (mean age 58.8 years) than those in the radiation (63.5 years) or no therapy (64.1 years) group (p < 0.001), but there were no significant differences in other variables between the 3 groups. The median survival from date of therapy of those in the chemotherapy and radiation groups were 9.75 and 8.65 months, respectively. MVA of pts who received therapy showed that non-white race (p = 0.006) and shorter time from diagnosis to therapy (p = 0.005) were significantly associated with poor survival, while chemotherapy, SES, age and CCI did not impact survival. Additionally, non-white race showed a trend for association with poor survival (p = 0.089) in those not receiving anti-cancer therapy. Conclusions: A minority of pts (39.9%) with stage 4 PSCC received chemotherapy in this large NCDB cohort, who were younger than those who received radiation or no therapy. The association of non-white race with poor survival suggests the impact of germline factors and disparities in therapy. The absence of significant impact of chemotherapy on survival in this real world PSCC cohort highlights unmet needs in this orphan disease and the need for discovery of effective agents.
Pazopanib (PZP) in germ cell tumors (GCT) after chemotherapy (CT) failure: Final results of the open label, single-group, phase II Pazotest trial.
Authors: Necchi Andrea , Lo Vullo Salvatore , Giannatempo Patrizia , Raggi Daniele , Calareso Giuseppina , Togliardi Elena , Crippa Flavio , Pennati Marzia , Zaffaroni Nadia , Perrone Federica , Colecchia Maurizio , Nicolai Nicola , Mariani Luigi , Salvioni Roberto
Published: March 2017

414

Background: Therapeutic options for patients (pts) with chemoresistant GCT are limited and prognosis is poor. PZP is a potent and selective tyrosine kinase inhibitor (TKI) with distinct antiangiogenic activity. Methods: In Pazotest trial (NCT01743482), pts were given PZP 800 mg/day until disease progression (PD) or unacceptable toxicity. Eligibility included failure of ≥ 2 platinum-based CT, including high-dose (HD)-CT. Baseline serum tumor markers (STM), computed tomography and FDG-PET were repeated after 4 wks and q8 weeks thereafter. The primary endpoint was PFS (H0: 3-m PFS ≤ 10%, H1: ≥ 25%, α = 5%/β = 20%). PD was defined as rising STM, increasing size of nonteratomatous masses (RECIST v1.1), or the appearance of new lesions. Translational analyses included circulating IL8 levels and next generation sequencing of pre-PZP tissue from extreme responders. Results: 43 pts were enrolled from 05/2013 to 07/2016. 35 pts (81.4%) had nonseminoma, 6 (14%) primary mediastinal GCT. The number of failed CT regimen was: 2 (11.6%), 3 (51.2%), > 3 (37.2%). 53.5% had failed HDCT. 39 pts had elevated STM: 56.4% AFP, 43.6% HCG. Grade 3-4 adverse events were seen in 4 pts (increased AST/ALT). 26/39 pts (66.7%) had STM reduction (38.5% > 50% from baseline) after 4 wks. RECIST results: 1 partial response, 20 stable disease, 16 PD (6 not evaluable). 12 (27.9%) had a decreased FDG uptake. Median follow-up was 29.6 months. 3-m PFS was 12.8% (95%CI: 5.7-28.9), median PFS was 2.5 m (IQR: 1.0-3.0). 24-m OS was 14.2% (95%CI: 6.0-33.7). In pts with > 50% STM decline, 24-m OS was 24.1% (95%CI: 8.3-69.6). Univariably, STM was associated with OS (HCG vs AFP: HR: 2.73, 95%CI: 1.24-6.02, p = 0.042). Baseline and +4wks IL8 levels did not predict for PFS/OS. In 2 responding pts, new mutations were found ( FLT3, G846V and RAD50 E448Q classified as damaging; TSC2, R197M and TNF A16V classified as benign). Conclusions: PZP was well tolerated and showed predictable activity, with early but short-living STM decline. Long term survival was obtained in a significant proportion of pts. Based on the present results, PZP may be investigated in earlier disease stages as an optimal bridging therapy preceding salvage curative treatment. Clinical trial information: NCT01743482.
A new HSP90 inhibitor as therapeutic agent for bladder cancer.
Authors: Liu Weiya , Lee Eugene K. , Pirani Karim , Blagg Brian S. J. , Holzbeierlein Jeffrey M.
Published: March 2017

416

Background: Hsp90 represents one of the most promising biological targets for the treatment of cancer, including bladder cancer. A number of Hsp90 inhibitors that target the N-terminal ATP-binding pocket have demonstrated potent antiproliferative effects. However, a major drawback is that they induce a prosurvival heat shock response (HSR). We demonstrate the effects of a novel Hsp90 beta selective inhibitor on bladder cancer cells, which shows potent antiproliferative effects without inducing HSR. Methods: Cell Titer-Glo luminescent anti-proliferative assay was used to determine the IC50 numbers in UC3 cells. Trypan Blue Cytotoxicity assay was performed for 24h treatment with increasing concentrations of the inhibitor. Effects of the cmpound on Hsp90’s client protein degradation were investigated by Western Blot. Results: This new compound exhibits potent anti-proliferative in bladder cancer cells. IC50 number is determined as 0.30 µM for UC3 cancer cells. The toxicity assay was also performed over UC3 cells at 24h.1uM KU new compound has the similar effects on UC3 cells as 10 uM 17AAG: inhibit the cancer cells growth to half, but maintain over 60% viability of the cells. The western blot were also performed over UC3 cells, and some new target proteins such as FGFR3 and PKM2 were investigated. The data showed that, this new compound would not induce the heat shock response like 17AAG (Hsp27), and did cause some Hsp90β related protein degradation (CXCR4). FGFR3, PKM2, Her2, Hsf-1and B-raf all show degradation to different extent. Conclusions: A novel Hsp90 inhibitor, exhibits potent anti-proliferative and cytotoxic activity along with client protein degradation, without induction of HSR in bladder cancer cell lines. The reduction of Hsp90 beta related client protein caused by this compound suggests the potential to develop isoform specific inhibitors of Hsp90 for better antitumor therapies.
Outcomes for patients with advanced N3 penile cancer undergoing flap reconstruction and adjuvant chemo/radiotherapy.
Authors: Muneer Asif , MacAskill Findlay , Christodoulidou Michelle , Akers Clare , Mosahebi Ash , Younis Ibby , Nigam Raj , Malone Peter
Published: March 2017

419

Background: Patients presenting with advanced penile cancer with significant inguinal disease requiring extensive resection. Reconstruction is required to cover the defect and protect underlying vascular structures when undergoingl adjuvant treatment. Often the performance status or the extent of the disease makes neoadjuvant chemo/radiotherapy difficult. Although this group of patients undoubtedly have a poor prognosis, palliative resection reduces the tumour burden and allows improved wound management and quality of life. The aim of this study was to present the techniques and report the outcomes for patients with N3 disease undergoing flap reconstruction. Methods: Medical records were reviewed for penile cancer patients with fixed inguinal nodal disease either at presentation or recurrence. Resection was performed by a team comprising urological and plastic surgeons. Cancer specific survival and the impact of adjuvant chemo/radiotherapy was recorded. Results: Seventeen patients were included; mean age 62 (range 37–85) years. Nine (53%) patients had a first presentation with penile cancer and advanced nodal disease, with 8 (47%) presenting with inguinal disease recurrence. The majority (n = 13) underwent a vertical rectus abdominis musculocutaneous (VRAM) flap. Of these, 3 required femoral vein reconstruction. Where defects were smaller, a tensor fascia latae (n = 2) or a scrotal advancement flap was used (n = 1). The average length of stay was 23 days (10-45 days) regardless of type of flap. Ten patients had adjuvant radiotherapy, 5 underwent neoadjuvant chemotherapy with a 4 undergoing adjuvant chemotherapy. The disease specific survival was 595 days (range 24-3881). Complications were related to wound healing and managed conservatively. Post operative lower limb lymphoedema occurred in the majority of patients. There were no flap failures and all but one patient was discharged home. Conclusions: Aggressive surgical management for patients with extensive nodal disease and flap reconstruction is feasible. This aids wound management and improves the quality of life for patients. Survival rates can extend to over 12 months following adjuvant treatment.