bluuebunny/crossref_metadata_2025 huggingface dataset:
Docetaxel with or without ramucirumab after immune checkpoint inhibition in platinum-refractory metastatic urothelial carcinoma (mUC): Prespecified subgroup analysis from the phase 3 RANGE trial.
Authors: Drakaki Alexandra , Kirby Conor J , Van Der Heijden Michiel Simon , Petrylak Daniel Peter , Powles Thomas , Chi Kim N. , Flechon Aude , Necchi Andrea , Geczi Lajos , Lee Jae-Lyun , Gakis Georgios , Bracarda Sergio , Chowdhury Simon , Lin Chia-Chi , Keizman Daniel , Vaishampayan Ulka N. , Liepa Astra M. , Zimmermann Annamaria , Bell-McGuinn Katherine M , Castellano Daniel E.
Published: February 2018

434

Background: Immune checkpoint inhibitors (ICI) targeting PD-1/PD-L1 have shown objective response rates (ORR) of 15-21% in PD-L1 unselected patients (pts) with platinum-refractory mUC. Overall results of RANGE, a randomized, double-blinded phase 3 trial comparing ramucirumab and docetaxel (R+D) to placebo and docetaxel (P+D) in pts with platinum-refractory mUC demonstrated an ORR of 24.5% to R+D and a statistically significant improvement in progression free survival (PFS; median 4.07 vs 2.76 mo; HR 0.757). Here we present a pre-specified subgroup analysis of pts who received a prior ICI. Methods: RANGE enrolled pts with progressive mUC during or after platinum-based chemotherapy. Additional prior treatment with one ICI was permitted. Pts were randomized (1:1) to receive D 75 mg/m2 up to 10 cycles with R 10 mg/kg or P on day 1 of a 21-day cycle until disease progression or other discontinuation criteria. Primary endpoint, investigator-assessed PFS, was analyzed in the first 437 randomized pts. Secondary endpoints included overall survival, objective response, and safety. Radiographic assessment occurred every 6 weeks. Results: Thirty three of the 437 pts (8%) in the PFS population received a prior ICI. The majority (91%) received the ICI immediately following platinum and immediately prior to RANGE. Most pts received atezolizumab (55%) or pembrolizumab (36%); ORR to prior ICI was 6% and the majority (67%) had progressive disease as best response. Median duration of the ICI was 3.5 mo (IQR 1.6-5.2). Disease sites at entry onto RANGE included lymph node (79%), lung (48%), liver (39%) and bone (18%). At data cutoff, responses were achieved by 5/14 (35.7%) on R+D, compared to 2/19 (10.5%) on P+D. Responses to R+D were independent of disease site. Of pts with liver metastases, 3/8 responded to R+D compared to 0/5 on P+D. Overall, median PFS was 5.29 mo on R+D and 2.76 mo on P+D (HR 0.920). The frequency of grade ≥3 adverse events was similar between arms. Conclusions: Acknowledging limitations of sample size, R+D showed higher ORR than P+D in pts who had progressed on platinum and ICI therapy, including those with liver metastases. Clinical trial information: NCT02426125.
Incidence and predictors of mortality following major urologic cancer surgery.
Authors: Mossanen Matthew , Krasnow Ross , Zlatev Dimitar V. , Chang Steven Lee
Published: February 2018

435

Background: Mortality following major urologic cancer surgery is a significant outcome to patients and providers. We utilized a population based cohort to test the hypothesis that the nature and number of perioperative complications impact the probability of mortality in major urologic surgery. Methods: Using the Premier Hospital Database we identified patients that underwent major urologic cancer surgery: radical prostatectomy (RP), radical nephrectomy (RN), or radical cystectomy (RC). Ninety-day complications were captured using ICD9 codes and complications were categorized according to the Agency for Healthcare Research and Quality Clinical Classification categories. The primary outcome was predicted probability of perioperative morality. Adjusted regression models were used and analyses were survey weighted. Models were adjusted for patient, hospital, and surgery characteristics, and we examined the predicted probability of mortality in three scenarios (no complication, index complication, or readmission complication). Results: From 2005-2013 we identified 630 828 RP, 306 532 RN, and 57 533 RC patients. At 90 days, 14.2% of RP patients had a complication, compared to 39% of RN patients and 68.3% of RC patients. Readmission rates at 90 days for RP were 1.9%, 5.9% for RN, and 19.9% for RC. For RN and RC the presence of a complication resulting in readmission compared to an index complication nearly doubled the predicted probability of mortality (RN 1.7% to 3.6%, and RC 3.9% to 6.8%). The number of complications during the index stay and on readmission compounded the impact on mortality. For RN and RC, 1 complication vs. 4 complications resulted in a nearly 3-fold increase in predicted probability of mortality. The nature of complications varied by incidence however, the three most common complications that resulted in the greatest increase in predicted probability of mortality across all three operations included pulmonary, cardiac, and renal complications. Conclusions: The number and nature of complications after major urologic cancer surgery impact the predicted probability of perioperative mortality and such data may be used to counsel patients when providing urologic cancer care.
C-reactive protein as a prognostic factor in advanced urothelial carcinoma receiving chemotherapy or immunotherapy.
Authors: Zhao Yan , Pond Gregory Russell , Naik Gurudatta , Wei Xiao X. , McGregor Bradley Alexander , Sonpavde Guru
Published: February 2018

436

Background: Clinical prognostic factors have been reported for patients receiving systemic chemotherapy. We hypothesized that markers of tissue damage and inflammation may be prognostic. We conducted a retrospective study to evaluate the prognostic impact of serum lactate dehydrogenase (LDH) and C-reactive protein (CRP) in patients with metastatic UC. Methods: We collected data for patients with metastatic UC receiving systemic therapy and measured serum LDH and CRP at baseline before initiating therapy. The variables collected were recognized clinical prognostic factors (performance status [PS], visceral metastasis, hemoglobin, albumin) and outcomes (time to failure [TTF], overall survival [OS]). TTF was defined as time from initiation of therapy to discontinuation of agent for any reason. LDH and CRP were evaluated on a log-continuous scale. The Kaplan-Meier method was used to estimate times to events. Cox proportional hazards regression and logistic regression were used to study the association of factors with TTF and OS. All tests were 2-sided and significance was defined as p≤0.05. Results: A total of 36 patients were available with a median age of 74 years. The systemic therapy was platinum-based chemotherapy in 18 patients (50%), PD1/PD-L1 inhibitor in 8 patients (22.2%) and the remaining received other agents (taxane or investigational). Twenty-nine (80.5%) had PS 0-1, 13 (36.1%) had visceral metastasis and 16 (44.4%) had received prior platinum-based chemotherapy. A total of 31 patients were evaluable for this analysis with 5 inevaluable due to missing data or inadequate follow-up. On multivariable analyses, only CRP was associated with TTF (HR 1.55 [95% CI: 1.10, 2.20], p = 0.013) and OS (HR 1.77 [95% CI1.10, 2.85], p = 0.018). The limitations of a small dataset and retrospective analysis apply. Conclusions: In patient with advanced UC receiving systemic chemotherapy or PD1/PD-L1 inhibitors as first-line or salvage therapy, CRP was significantly prognostic for both TTF and OS, while other factors were not. Given the potentially powerful prognostic impact of CRP, investigation in larger datasets is warranted to enable better prognostic stratification.
Correlation of MTOR protein expression in the tumor and its microenvironment with more aggressive pathology at cystectomy.
Authors: Winters Brian , Vakar-Lopez, MD Funda , Brown, BS Lisha , Montgomery Robert B. , Seiler Roland , Hsieh Andrew Caleb , Wright Jonathan L. , Lam Hung-Ming
Published: February 2018

438

Background: The mechanistic target of rapamycin (mTOR) has been implicated in driving tumor biology in multiple malignancies, including urothelial carcinoma (UC). We investigate how mTOR and phosphorylated mTOR (pmTOR) protein expression in both the tumor, and the tumor microenvironment, correlate with final pathologic stage at cystectomy after neoadjuvant chemotherapy (NAC). Methods: A single-institution retrospective analysis was performed on 62 patients with cT2-4Nany UC undergoing NAC followed by radical cystectomy. Diagnostic (transurethral resection specimens, TURBT) and post-NAC radical cystectomy specimens were evaluated for mTOR and pmTOR protein expression using immunohistochemistry of the tumor, peritumoral stroma, and normal surrounding tissue. Protein expression levels were compared between TURBT and cystectomy samples. Whole transcriptome analysis was performed to evaluate mRNA expression relative to mTOR pathway activation. Results: Baseline levels of mTOR and pmTOR within TURBT specimens were not associated with clinical stage or response to NAC overall. Non-responder patients, defined as pT2-T4/pTanyN+, had significantly elevated mTOR tumor staining (p = 0.006) and sustained mTOR and pmTOR staining in the peritumoral and surrounding normal stroma of cystectomy specimens compared with baseline TURBT samples (NS). In contrast, complete responders (pT0), had significant decreases in tumoral mTOR and pmTOR protein expression at cystectomy (p = 0.01-0.03). Several genes relevant to mTOR activity were found to be overexpressed in post-NAC cystectomy samples (compared with TURBT) of non-responder patients (THBS1, FN1, FOS, CNN1, COL1A2). Conclusions: Our results suggest that mTOR pathway activity is increased in the tumor and sustained the tumor microenvironment of patients with adverse pathologic findings at cystectomy after NAC. These findings suggest the relevance of targeting the mTOR pathway in bladder cancer.
The impact of tertiary Gleason pattern 5 in the grade group system on recurrence following radical prostatectomy in patients with prostate cancer.
Authors: Kato Masashi , Tsuzuki Toyonori , Ishida Ryo , Kimura Tohru , Kamihira Osamu , Sassa Naoto , Gotoh Momokazu
Published: February 2018

44

Background: The current ISUP/WHO grade group system classified the Gleason grade into five groups. Although presence of tertiary Gleason pattern 5 (tG5) reported to be related with unfavorable tumor characteristic, only a few data is available about influences on the grade group system of tG5 so far. In this study, we evaluated the effect of tG5 on recurrence following radical prostatectomy in patients with prostate cancer. Methods: We retrospectively evaluated 1,020 patients with prostate cancer who underwent radical prostatectomy without neoadjuvant therapy at the hospitals that the authors were affiliated with between 2005 and 2013. After excluding the patients with missing data or slides, 1000 patients were enrolled in this study. All prostatectomy specimen slides were reviewed by a single genitourinary pathologist according to ISUP 2014. Recurrence following radical prostatectomy was defined according to European Association of Urology guidelines. The endpoint was defined as an increase in PSA level. Results: Patient median age was 67 years (range 49–77 years). The median serum PSA was 6.9 ng/mL (range 0.4–82 ng/mL). The median follow-up period was 69 months (range 0.7–134 months). All the patients showed Group1:163 cases (16.3%), Group2: 436 (43.6%), Group 2 with tG5: 54 (5.4%), Group 3:121 (12.1%), Group 3 with tG5: 89 (8.9%), Group 4: 39 (3.9%), and Group 5: 98 (9.8%). PSA progression-free survival was significantly different among the five groups (Group1-5) (p = 0.0001). As concerning tG5, it showed significant difference between Group 2 and Group 2 with tG5 by using log rank test (p < 0.0001). Similarly, there was significant difference between Group 3 and Group 3 with tG5 (p = 0.001). On the other hand, there was no difference between Group 2 with tG5 and Group 3 (p = 0.916), and in the same way, no difference between Group 3 with tG5 and Group 4 (p = 0.854). Conclusions: The Presence of tG5 on the grade group system increase PSA progression following radical prostatectomy in patients with prostate cancer. Especially, Group 2 and 3 showed upgrade by presence of tG5. Integrating tG5 into the grade group system will improve the accuracy of patient outcome predictions.
Heat targeted drug delivery (COMBAT) in superficial TCC : First midterm results in a cohort of high-risk patients scheduled for cystectomy.
Authors: Voegeli Thomas Alexander , Frank Eric , Bach Christian , Nzeh Catejan
Published: February 2018

442

Background: Due to the suboptimal outcomes in recurrent superficial TCC over the last 30 years the search for new treatments continues. We report the first mid term results of a high risk cohort of heavily pretreated patients by a circulating device for intravesical thermochemotherapy.It is known that the effect of mitomycin increases at a temperature over 40 C. Methods: 58 patients with different failed methods of former intravesical therapy and recurrent TCC (21 intermediate risk and 37 high risk patients) were treated with the COMBAT device which facilitates irrigation of the bladder with mitomycin 40 mg at exactly 43 degree Celsius for 1 hour/6 courses weekly.Side effects were monitored prospectively and success of the treatment was controlled by ReTUR whenever possible and afterwards by 3 monthly cystoscopy and cytology. Results: 22 patients had dysuria during treatment and 9/58 suffered from hematuria but without intervention. In 6 cases urinary tract infection occured and 3 patients had allergic reaction. In one patient thermochemotherapy must be terminated due to pain and discomfort, no long term morbidity was recorded over the whole period. The FU was 14 month (3-29) for the entire cohort, 17 patients had a FU of over 2 years. One Patient had recurrent pTaGIII Tumor managed successfully by TUR. 2 patients underwent cystectomy because of invasive recurrence early after intravesical therapy, one patient developed bone metastasis 2 years after therapy without intravesical tumor. Conclusions: Thermochemotherapy with heated mitomycin is a well tolerated new option for patients with superficial TCC who are at high risk of recurrence or progression.The toxicity is acceptable and no long term morbidity was obeserved. The rate of cystectomies in this heavily pretreated group of patients including 18 BCG failures was very low with N= 2 respective 1,9%. Intravesical thermochemotherapy seems to be a new therapeutic bladder preserving option in high risk patients with superficial TCC. It is of note that thermochemotherapy has now been included in the European Guidelines.
Evaluation of the timing of adjuvant mitomycin C following nephroureterectomy for urothelial carcinoma of the upper urinary tract.
Authors: Noennig Blake , Bozorgmehri Shahab , Terry Russell , Otto Brandon , Blute Mike , Su Li-Ming , Crispen Paul
Published: February 2018

444

Background: Results of randomized trials support a single dose of intravesical chemotherapy (IVC) following radical nephroureterectomy (RNU) for urothelial carcinoma. Our goal was to evaluate the impact of the timing of intravesical mitomycin C (MMC) administration on the rate of bladder tumor recurrence (BTR) following RNU. Methods: After obtaining IRB approval, we performed a retrospective review of patients who underwent RNU for upper tract urothelial carcinoma (UTUC) and received intravesical MMC between 2008 and 2016 at our institution. Patients were categorized into two separate groups based on the timing of MMC administration: (1) patients who received MMC on the day of surgery (POD0) and (2) patients who received MMC on post-operative day 1 or later (POD1). Our primary endpoint was BTR rate within the first year after surgery. Our secondary endpoint was overall BTR rate. Results: Fifty-one patients met our inclusion criteria: (POD0: n = 30; POD1: n = 21). Mean length of follow-up for each group was 22.1 and 12.5 months, respectively (p = 0.02). There were no statistically significant differences in baseline characteristics of age, gender, race, surgical approach, tumor grade, tumor stage, surgical margins, nodal status, concomitant CIS, or history of bladder cancer. BTR rates at 1 year for the POD0 and POD1 groups were 16% and 33%, respectively (p = 0.17). Overall BTR rates were 23% and 33%, respectively (p = 0.43). Multivariate analysis noted that the POD0 patients had a significantly lower rate of BTR in the first year postoperatively (HR = 0.082, 95% CI = 0.01-0.56, p = 0.01). Other factors that were associated with a higher rate of BTR within the first year were open surgery (HR = 7.9, 95% CI = 1.18-53.88, p = 0.03), positive surgical margins (HR = 37.9, 95% CI = 1.74-825.35, p = 0.02), and concomitant CIS (HR = 10.8, 95% CI = 1.08-108.72). Conclusions: Our results suggest that the timing of intravesical MMC administration may impact the rate of BTR following RNU for urothelial carcinoma. This is the first study of its kind to attempt to identify the importance of timing of MMC administration relative to BTR following RNU. Further prospective studies are warranted to validate our current findings.
Response to platinum-based therapy (PBT) and immune checkpoint inhibitors (ICI) in metastatic urothelial carcinoma (mUC) patients (pts) with genomic alterations (GA) in homologous recombination repair (HRR) genes.
Authors: Mendiratta Prateek , Loehr Andrea , Simmons Andrew , Barata Pedro C. , Klek Stefan , Pritchard Amy , Emamekhoo Hamid , Funchain Pauline , Sohal Davendra , Ali Siraj Mahamed , Gilligan Timothy D. , Ornstein Moshe Chaim , Garcia Jorge A. , Rini Brian I. , Grivas Petros
Published: February 2018

447

Background: Deleterious GA in genes of the HRR pathway and tumor mutational load (TML; mutations/Mb) were shown to predict response to PBT and ICI; further validation can be informative. We assessed the predictive role of such GA in mUC. Methods: Tissue from mUC pts treated with PBT or ICI in the 1st line setting underwent genomic profiling (GP) via FoundationOne. Pts were analyzed in 2 groups based on the presence of potentially function-impairing GA (using classification criteria) in any of 15 pre-selected HRR genes. Exploratory assessment of overall response rate (ORR; RECIST v1.1), progression-free and overall survival (PFS, OS) based on presence of relevant GA was performed using Cox proportional hazards model, Kaplan Meier estimates, and Fisher’s exact test. Results: GA were noted in 22% of 88 identified mUC pts with available GP from 2012 to 2017. The most common deleterious GA were BRCA1/2 (n=6), ATM (n=6), CDK12 (n=2), BRIP1 (n=2), BARD1 (n=1), RAD51 (n=1), and CHEK2 (n=1). Of 88 pts, 62 were treated in the 1st line setting (median age 69; 27% women; 42% never smokers). Of these 62 pts, 42 received PBT and 20 ICI. Deleterious GAs were noted in ≥1 HR gene in 24% and 10% of pts in each group, respectively. The ORR was 40% and 43% in PBT pts with and without GA in any HRR gene, respectively. Analysis showed a median OS (10.6 vs 14.3 months, p=0.11), median PFS (6.1 vs 7.9 months, p=0.05), and no difference in the rate of responders vs non-responders (p=0.53) to PBT in pts with vs without GA in HRR genes. Analysis of ICI treated pts was not feasible (only 2 had GA in HRR genes). Median TML was 8 and 10 in pts with available data treated with PBT and ICI, respectively. There was no correlation between TML and response to either 1st line therapy (analysis underpowered). Of pts with GA in HR genes, the one with the longest OS had 2 GA (CDK12; FANCA). Conclusions: Deleterious GAs in genes of HRR pathway are frequent in mUC supporting TCGA and other datasets but did not confer sensitivity to 1st line PBT in our relatively small cohort. Further biomarker validation combined with LOH assessment can inform decision making and clinical trial designs.
Nivolumab demonstrates benefit over nomogram-predicted 12-month survival as salvage therapy for metastatic urothelial carcinoma.
Authors: Pond Gregory Russell , Sonpavde Guru , Galsky Matt D. , Sharma Padmanee , Rosenberg Jonathan E. , Choueiri Toni K. , Bellmunt Joaquim , Lee Jae-Lyun , Lee Soon Il , Azrilevich Alex , Yang Shuo , Gooden Kyna McCullough , Bajorin Dean F.
Published: February 2018

451

Background: Intermediate endpoints of benefit in metastatic urothelial carcinoma (mUC) nonrandomized trials are necessary to identify promising drugs, particularly for checkpoint inhibitors, where response and progression-free survival remain suboptimal. We previously reported a nomogram (Pond GR et al, 2017 GU Cancers Symposium) using 5 prognostic factors (hemoglobin < 10 g/dL, Eastern Cooperative Oncology Group performance status ≥1, presence of liver metastasis, time from last treatment ≤3 months, and albumin < lower limit of normal) from phase 2 trials of historical agents (eg, taxanes) to estimate 12-month overall survival (OS), against which observed survival could be compared. Nivolumab was granted approval as salvage therapy for patients with mUC, based on the CheckMate (CM) 275 trial; it is thus of interest to compare the nivolumab observed survival versus nomogram-predicted survival results. Methods: Data were obtained from CM 275, including survival and all 5 prognostic factors. Nomogram points were calculated and the expected 12-month OS was estimated. Bootstrap analyses based on 2000 replications were used to estimate 95% confidence intervals (CIs) for the median expected, observed, and difference between the expected and observed 12-month OS values. All tests were 2-sided, with statistical significance defined as P≤0.05. Results: Data were available from 270 patients from CM 275. Fifteen patients did not have albumin recorded and were excluded. Among the 255 evaluable patients, 46 (18.0%) patients had 0 adverse prognostic factors, 85 (33.3%) had 1, and 124 (48.6%) had 2 or more. The observed nivolumab 12-month OS from CM 275 (43.3% [95% CI, 37.0%-50.5%]) was 19.8% higher (95% CI, 13.6%-26.4%) when compared with the nomogram-predicted 12-month OS (23.5%; [95% CI, 22.5%-25.5%]) if patients received historical chemotherapy. Across all 2000 bootstrap samples, the observed nivolumab 12-month OS exceeded the nomogram-predicted 12-month OS. Conclusions: Nivolumab was associated with a significantly improved 12-month OS compared with historical chemotherapy based on the value predicted by the validated nomogram incorporating baseline prognostic factors. Clinical trial information: NCT02387996.
Prognostic value of CD56, ASCL1, and other biomarkers in small cell bladder cancer (SCBC).
Authors: Koshkin Vadim S. , Reynolds Jordan , Elson Paul , McKenney Jesse , Isse Kumiko , Saunders Laura R. , Hu Ming , Stephenson Andrew J. , Fergany Amr Farouk , Lee Byron , Rini Brian I. , Garcia Jorge A. , Mian Omar Y. , Grivas Petros
Published: February 2018

452

Background: Increased DLL3 expression (exp) and small cell % (SC%) were found in prior analyses to predict worse outcomes in SCBC. Assessment of gene and protein exp of other Notch pathway and neuroendocrine (NE) markers, such as ASCL1 and CD56, can help with prognostication and treatment target identification in SCBC. Methods: Among 63 patients (pts) with biopsy-confirmed SCBC seen at Cleveland Clinic (1993-2015), 52 had tissue available for IHC analysis of tumor biomarkers: DLL3, PD-L1, ASCL1 and CD56. All pts had clinical and outcomes data, and had SC% quantified by central path review. A subset of 39 pts had gene exp analysis using HTG EdgeSeq OBP assay. Correlations among biomarkers, between biomarkers and pt characteristics as well as gene exp were assessed. Multivariate analyses (MVA) were used to identify predictors of overall (OS) and progression-free survival (PFS). Results: In the 52 pt cohort, median age was 71, 83% were men, 39% had LN+ disease, and 79% had SC% > 50%. Protein exp ( > 1% of tumor cells) of DLL3, PD-L1, ASCL1 and CD56 was noted in 68%, 30%, 52% and 81% of pts, respectively. ASCL1 protein exp correlated with protein exp of DLL3 (r = 0.73, p < .0001), CD56 (r = 0.35, p = .01), and SC% (r = 0.34, p = .01) and correlated with gene exp of several Notch genes and NE markers: DLL3, DLL4, Notch1, CHGA (p < .05 for all). CD56/NCAM1 protein exp correlated with DLL3 protein exp (r = 0.32, p = .02) and with SC% (r = 0.26, p = .06) and with gene exp of DLL4, Notch1, SYP and NCAM1 (p < .05 for all). In MVA, increased CD56 protein exp ( > 30%) was associated with shorter OS (HR: 2.23; 95%CI 1.06-4.70, p = .03) and PFS (HR: 2.07; 95%CI 1.02-4.20, p = .04). Pts with low protein exp of both CD56 (≤30%) and DLL3 (≤10%) had longer median OS (103.4 vs 18.4 months, p = .01) and PFS (92.2 vs 11.4 months, p = .02) relative to pts with high protein exp of either biomarker. Conclusions: Most SCBC tumors expressed CD56, and increased exp predicted shorter OS and PFS, findings similar to those reported for DLL3. Low concurrent exp of both CD56 and DLL3 proteins was associated with better outcomes. Strong correlation of CD56/NCAM1 gene and protein exp suggests that its regulation may be at the transcriptional level. Gene exp signature prognostic of outcomes is currently being pursued in SCBC.
Correlation of circulating tumor DNA (ctDNA) assessment with tissue-based comprehensive genomic profiling (CGP) in metastatic urothelial cancer (mUC).
Authors: McGregor Bradley Alexander , Chung Jon , Bergerot Paulo Gustavo , Forcier Brady , Grivas Petros , Choueiri Toni K. , Ross Jeffrey S. , Ali Siraj Mahamed , Stephens Philip J. , Miller Vincent A. , Gregg Jeffrey P. , MacVicar Gary R. , Bauer Todd Michael , Pal Sumanta K.
Published: February 2018

453

Background: Emerging data suggest a role for targeted therapy in patients (pts) with mUC whose tumors contain actionable genomic alterations (GA). Liquid biopsy of ctDNA from blood provides an attractive alternative for CGP in pts in whom tissue-based testing is not feasible. Methods: Hybrid capture-based genomic profiling was performed using FoundationACT assay in a CLIA-certified, CAP-accredited, NY State-approved laboratory. Cell free DNA was extracted from plasma using 20 ml whole blood and underwent CGP of 62 genes. Sequencing was performed to a median unique coverage of 6756× using the Illumina HiSeq 2500/4000 platform. Barcode-based error correction enabled analysis of GA at low allele frequency (AF), including base substitutions and short in/dels (AF≥0.1% for both), rearrangements, and copy number amplification. For several pts, non-temporally matched tissue-based CGP data was available. Comparisons to other CGP datasets of UC ctDNA and tissue were performed. Results: 66 pts with median age 68 (range 29-86) underwent ctDNA assessment as clinical test. There was evidence for ctDNA in 56 pts (85%), and ≥1 GA was noted in 48 pts (73%). The estimated median ctDNA fraction in plasma was 1.9%. In cases with detectable ctDNA, the most frequently altered genes were TP53 (68%), TERT-promoter (38%), PIK3CA (13%), FGFR3 (13%), KRAS (11%), NF1 (6%), ERBB2 (6%). Observed GA frequencies were comparable to prior studies of ctDNA and tissue. Both tissue and ctDNA-based CGP data with clinical correlation was available for several pts. A pt with FGFR3 GA in baseline tumor tissue had disappearance of FGFR3 GA and detection of new TP53 GA in ctDNA after targeted treatment with FGFR3 inhibitor. In a pt with ERBB2 and TP53 GAs in baseline tumor tissue, ctDNA at time of resistance to cisplatin-based therapy showed persistence of ERBB2 and TP53 GAs and new NF1 GA. Conclusions: Most pts with mUC had detectable ctDNA, and frequencies were comparable to prior data sets Detection of potentially targetable GA support further clinical utility assessment. Concordance between tissue and ctDNA in temporally matched samples with clinical annotation warrants further investigation.
Impact of neoadjuvant chemotherapy on pathologic outcomes in patients with upper tract urothelial carcinoma undergoing extirpative surgery.
Authors: Almassi Nima , Gao Tianming , Lee Byron , Stein Robert , Haber Georges-Pascal , Ornstein Moshe Chaim , Rini Brian I. , Gilligan Timothy D. , Garcia Jorge A. , Stephenson Andrew J. , Grivas Petros
Published: February 2018

457

Background: Neoadjuvant chemotherapy (NAC) is infrequently administered to patients with upper tract urothelial carcinoma (UTUC) undergoing radical nephroureterectomy or segmental ureterectomy and its impact on pathologic outcomes unclear. We examine pathologic outcomes in patients with UTUC receiving NAC before extirpative surgery using a population-based cancer registry. Methods: Patients who underwent extirpative surgery for UTUC from 2006-2014 were identified from the National Cancer Database. Among patients with available clinicopathologic data, the incidence of pathologic down-staging, defined as a lesser pathologic compared to clinical stage, was compared between patients who did and did not receive NAC. A multivariable model was developed to identify predictors of pathologic down-staging. Results: 7,244 patients were identified with non-metastatic UTUC who underwent extirpative surgery in the study period. 260 patients (3.6%) received NAC, with the use of NAC increasing over time from 2.0% patients in 2006 to 7.1% of patients in 2014 (linear trend p < 0.001). Clinical and pathologic staging data were available for 119 and 2904 patients who did and did not receive NAC, respectively. Thirty patients (25.2%) who received NAC experienced pathologic down-staging, compared to 52 patients (1.8%) who did not receive NAC (p < 0.0001). On multivariable analysis, NAC was associated with a higher likelihood of pathologic down-staging (OR 10.2, 95% CI 5.4-19.3). Additional predictors of pathologic down-staging include a higher clinical T stage (p = 0.001) and African-American race (OR 2.7, 95% CI 1.1-6.6). Compared to renal pelvis UTUC, ureteral UTUC was associated with a similar likelihood of pathologic down-staging (OR 1.5, 95% CI 0.9-2.5). Conclusions: NAC is infrequently used among patients with UTUC undergoing extirpative surgery. A higher incidence of pathologic down-staging was observed among patients receiving NAC. These findings suggest clinical benefit of NAC with respect to pathologic outcomes in patients with UTUC and may help guide selection of patients for NAC prior to radical surgery until data from prospective studies becomes available.
Novel transgenic knockout model of basal-squamous bladder cancer.
Authors: Osei Amponsa Vasty , Zheng Zongyu , Walter Vonn , Warrick Joshua , Mendelsohn Cathy , Kaestner Klaus , Wu Xue-Ru , Raman Jay , DeGraff David
Published: February 2018

459

Background: The recent description of the highly aggressive Basal-Squamous molecular subtype of bladder cancer (BLCa) requires the development of new in vivo models for the study of this clinical entity. Although loss of the transcription factor Forkhead box A1 ( FOXA1) is significantly associated with the Basal-Squamous subtype, cooperating genetic alterations are unknown. Herein, we identify genetic alterations that potentially cooperate with FOXA1 loss to drive tumorigenesis and/or the Basal-Squamous phenotype and develop a novel transgenic model for the study of Basal-Squamous BLCa. Methods: We interrogated The Cancer Genome Atlas (TCGA) BLCa study to identify common genetic alterations associated with FOXA1 copy number (CN) loss. Based on our results, we utilized a bladder-specific Cre-LoxP ( Uroplakin II-Cre) to constitutively knock-out (KO) Foxa1 and/or Pten in mouse urothelium. Two cohorts of mice were aged for 6 and 12 months, and a third cohort was exposed to the bladder-specific carcinogen N-butyl-(4-hydroxybutyl)-nitrosamine (BBN; 0.05%) for 12 weeks. Following all experiments, the bladder tissue was isolated and characterized. Results: The TCGA data revealed that combined CN loss of both FOXA1 and PTEN occurs in 17% of MI BLCa patients. At 6 months of age, our mice developed urothelial hyperplasia, whereas at 12 months of age, double KO ( Foxa1-/-/Pten-/-) mice developed carcinoma in situ (CIS) with SqD, enriched for basal (Krt5/6 and 14) and reduced in luminal (Gata3 and Pparγ) markers. Increased tumor stage was significantly associated with combined KO of at least one allele of Foxa1 and Pten following BBN exposure. Moreover, upregulation of apoptosis related genes was observed by RNA-sequencing data. Conclusions: In advanced BLCa, CN loss of FOXA1 and PTEN is common. Genetic ablation of Foxa1 and Pten results in CIS with SqD and a pathologic profile consistent with the Basal-Squamous subtype and accelerated tumor onset following carcinogen exposure. Therefore, we describe the development of a novel model for the study of Basal-Squamous BLCa potentially useful for preclinical studies.
Minimizing prostate cancer admissions via enhanced outpatient care: A model for savings.
Authors: Parikh Anish , Sanderson Mark , Isola Luis M. , Ennis Ronald D.
Published: February 2018

46

Background: Hospitalization is a major contributor to cost in oncology. Minimizing avoidable admissions can lead to substantial savings. Methods: We studied Medicare claims data from 160 admissions for prostate cancer (PCa) patients from 1/2012 to 5/2015. Admissions with the lowest 50th percentile of charges were assessed for being potentially avoidable by 2 independent chart reviews; remaining admissions were assumed to be unavoidable due to medical complexity. Common admitting diagnoses were targeted by theoretical care pathways designed to minimize avoidable admissions via expedited outpatient follow-up. We compared the cost of the avoidable admissions to that of implementing 3 such pathways then estimated the financial impact. Results: Total cost for all 160 admissions was $1,979,200. 25% of these admissions, accounting for $494,800, were deemed potentially avoidable. Our model exchanged each of these admissions for a routine clinic visit which led to an estimated $464,800 in savings, or a 23% improvement in total cost. The most common admitting diagnoses were fever (18%), pain (12%), and dehydration (8%). On review, 3/9 fever admissions in this set were deemed avoidable with 1 extra clinic visit, 3 with 3 visits, and 3 were unavoidable, yielding a 53% reduction in cost for this diagnosis. Similar analyses led to cost reductions of 75% and 66% for pain and dehydration admissions, respectively. Combining just these 3 theoretical interventions led to an estimated savings of $146,955, or a 7.4% improvement in total cost. Conclusions: A sizable portion of PCa admissions can be avoided, with ample savings, if a system is in place to provide the additional care that often exceeds the capabilities of a busy practice. [Table: see text]
Overall survival and treatment patterns among real-world patients with locally advanced or metastatic urothelial carcinoma treated with first-line therapy.
Authors: Simeone Jason C , Nordstrom Beth L , Patel Ketan , Klein Alyssa B , Horne Laura
Published: February 2018

464

Background: Although platinum-based chemotherapy has been the standard of care for the treatment of locally advanced or metastatic urothelial carcinoma (UC), overall survival (OS) remains poor. Real world data on the treatment patterns for UC and effectiveness of these treatments are limited. Methods: Patients with locally advanced or metastatic UC who received first line therapy were identified from the Flatiron Oncology electronic medical record database from 2011–2016; patients who previously received immunotherapy treatment were excluded. Treatment characteristics included the most frequently administered first-line regimens in the study cohort and the time from advanced/metastatic diagnosis to start of first-line therapy. Median OS from the start of first-line therapy was calculated using Kaplan-Meier curves and 95% confidence intervals (CI) are presented. Results: Of 1,811 included patients who met study inclusion and exclusion criteria, the mean age was 70.4 ± 9.5 years, and 73.2% were male. Fewer than 3% of patients were tested for PD-L1 during follow-up. Platinum-based chemotherapy was the most commonly prescribed first-line treatment and immunotherapy was used in 1.3% of first-line regimens (Table 1); patients received a median of one treatment line during follow-up. The median OS was 12.7 months (95% CI: 11.8–13.5) from initiation of first-line therapy. Conclusions: Overall survival among locally advanced/metastatic UC patients who received first-line therapy in a real-world setting was approximately one year. As immunotherapy treatment for UC becomes more common, the impact on OS in the real world setting remains to be seen. [Table: see text]
FGFR3-TACC3 fusion in bladder cancer: Enrichment in the young, never-smokers, and Asians.
Authors: Nassar Amin , Lundgren Kevin , Pomerantz Mark , Van Allen Eliezer Mendel , Choudhury Atish Dipankar , Harshman Lauren Christine , Preston Mark A. , Mouw Kent William , Wei Xiao X. , McGregor Bradley A , Choueiri Toni K. , Bellmunt Joaquim , Kwiatkowski David J. , Sonpavde Guru
Published: February 2018

465

Background: Bladder cancer patients (pts) are typically elderly with median age ~70 years. We hypothesized that younger pts (≤age 50) with muscle-invasive bladder cancer (MIBC) have distinct molecular features, including potential driver mutations that could serve as therapeutic targets. Methods: We used the MIBC TCGA cohort (n = 412, Cell 2017) analyzed by whole exome sequencing as a discovery cohort, and then confirmed observations using 356 pts with MIBC and high grade (HG) non-MIBC analyzed at Dana Farber Cancer Institute (DFCI) by the Oncopanel assay. Oncopanel assesses 447 somatic cancer genes and 191 regions across 60 genes for rearrangement detection by massively parallel sequencing. We examined associations between age (≤50, 51-65, and > 65) and molecular features, using the χ2 test for discrete data, and the Wilcoxon Rank Sum Test for quantitative data. Nominal p values were obtained, and the FDR correction was employed to obtain q values. Results: The following DNA alterations were significantly enriched in the TCGA in ≤50 vs 51-65 vs > 65 age groups respectively: focal deletion in CREBBP (3/25 [12%] vs 2/137 [1.5%] vs 1/250 [0.4%], p < 0.0001, q = 0.0126); microRNA Cluster III (13/25 [52%] vs 53/137 [38.7%] vs 55/250 [22%], p = 0.0005, q = 0.0252); fusion in FGFR3-TACC3 (3/25 [12%] vs 2/137 [1.5%] vs 5/250 [2%], p = 0.0055, q = 0.1386). Given that FGFR3-TACC3 fusions are potential therapeutic targets, we examined the association between FGFR3-TACC3 fusions and clinical features in a pooled analysis combining the TCGA and DFCI cohorts totaling 768 pts. FGFR3-TACC3 fusions were enriched in: ≤50 age group vs 51-65 vs > 65 (4/33 [12.1%] vs 7/232 [3%] vs 6/503 [1.2%] respectively, p = 0.0001). Fusions were also significantly more common in Asians vs. Blacks vs. Whites (6/47 [12.8%] vs 1/28 [3.6%] vs 10/666 [1.5%] respectively, p < 0.0001) and in never-smokers vs. ever smokers (12/194 [6.2%] vs 5/545 [0.9%] respectively, p < 0.0001). Conclusions: FGFR3-TACC3 fusion, a known potentially actionable genomic alteration in MIBC, is significantly enriched in young pts, never-smokers and those of Asian ethnicity. Clinical testing to detect FGFR3-TACC3 fusion should be prioritized for MIBC and HG-non-MIBC pts meeting these criteria.
Ten year treatment outcomes of radical prostatectomy vs external beam radiation therapy vs. brachytherapy for 1,503 patients with intermediate risk prostate cancer.
Authors: Goy Barry W. , Soper Margaret S. , Burchette Raoul J. , Chang Tangel C. , Cosmatos Harry A.
Published: February 2018

47

Background: To compare 10-year treatment outcomes of RP (radical prostatectomy) vs EBRT (external beam radiation therapy) vs BT (brachytherapy) for patients with IRPC (intermediate risk prostate cancer). Methods: A retrospective analysis using propensity score matching was performed on 1,503 IRPC patients who underwent treatment from 2004 to 2007. 819 underwent RP, 574 underwent EBRT to a median dose of 75.3 Gray, and 110 underwent BT using iodine-125. Biochemical failure was defined by the AUA (American Urological Association) definition of PSA (prostate specific antigen) failure for RP patients, and the ASTRO-Phoenix definition (American Society of Therapeutic Radiology and Oncology) for the EBRT and BT patients. Results: Median follow up was 10 years for RP, 9.6 for EBRT, and 9.8 for BT (range 1-13.4 years). With RP 76.3% had Gleason score 7 vs 72.8% for EBRT vs 57.3% for BT, p = 0.0001. Median initial PSA was 7.4 for RP, 9.4 for EBRT, and 8.3 for BT, p < 0.0001. Neoadjuvant androgen deprivation therapy was given in 58.9% of EBRT patients vs 12.7% of BT vs 0.6% for RP, p < 0.0001. Only 14% of BT received supplemental external radiation. The 10-year FFBF (freedom from biochemical failure) was 82.0% for BT vs 58.0% for RP vs 58.8% for EBRT, p < 0.0001. Subset analysis of unfavorable IRPC patients showed a 10 year FFBF of 81.6% for BT vs 55.8% for RP vs 51.0% for EBRT, p < 0.0001. The 10-year freedom from salvage therapy was 89.5% for BT vs 64.0% for RP vs 73.4% for EBRT, p < 0.0001. There were no significant differences in distant metastases-free survival, prostate cancer-specific survival, or overall survival after adjusting for age. Multivariate analysis between pairwise groups with BT balanced by stabilized inverse probability of treatment weights showed that BT remained an independent predictor for improved FFBF, p = 0.049 for BT vs EBRT, and p < 0.0001 for BT vs RP. Conclusions: Brachytherapy using iodine-125 is a reasonable treatment option for IRPC patients. Although BT showed improved FFBF after propensity score matching, this did not impact overall survival.
Perioperative hypogonadism in men undergoing radical cystoprostatectomy for bladder cancer.
Authors: Smelser Woodson , Lee Eugene , Nangia Ajay , Glavin Katherine , Holzbeierlein Jeffrey M.
Published: February 2018

470

Background: Radical cystectomy (RC) is associated with significant morbidity, and loss of body weight is a common after RC, even in patients without significant nutritional deficiencies. Prior studies have demonstrated a high prevalence of hypogonadism (HG) in men with cancer and who undergo anesthesia/major surgery. The suppression of testosterone persists up to seven days following surgery. We hypothesize that hypogonadism is prevalent in male patients undergoing RC for bladder cancer (BC), and that it persists in the post-operative period. Methods: We implemented a prospective, IRB-approved trial (Clinical trials.gov # NCT03063125) to prospectively enroll 25 men with no prior history of treatment for HG or other hormonal disorders with a new diagnosis of non-metastatic bladder cancer undergoing RC. Pre-operative total, free testosterone and luteinizing hormone (LH) were obtained. These labs were then repeated on post-operative days 2, 3, 30, and 90. The threshold for normal total testosterone was defined as > 250 ng/dl. Demographic data were recorded. Results: Between March and September 2017, 9 patients have been enrolled into the study. Mean patient age is 68.5 years (52-85). The mean pre-operative total testosterone was 247 ng/dl (range 50-496 ng/dl) and 6/9 (66.7%) patients had HG. Two patients had abnormal pre-operative LH levels (range 21-57 mIU/L). Testosterone decreased by a mean of 99 ng/dl between pre-op assessment and post-operative day 2 [95% CI 66.2, 131.8]; all 6 men who initially had HG remained below 250 ng/dl. Two men moved from eugonadal (347 ng/dl, 316 ng/dl) to hypogonadal (213 ng/dl,192 ng/dl, respectively) by post-operative day 2. At 30 days post-op, the mean T level was 206 ng/dl. No patients had returned to levels at or above their pre-operative baseline and 8/9 (88.9%) had HG (range 40-356 ng/dl). Conclusions: Hypogonadism is prevalent in men undergoing RC; our trial demonstrates a pre- and 30 day post-operative prevalence of 66.7% and 88.9%%. Furthermore, HG persisted beyond the immediate post-operative period. Treatment of peri-operative HG with correction to a eugonadal state may represent a therapeutic intervention to reduce the morbidity associated with radical cystectomy. Clinical trial information: NCT03063125.
Cost-effectiveness of pembrolizumab in second-line advanced bladder cancer.
Authors: Sarfaty Michal , Hall Peter , Chan Kelvin K. , Virik Kiran , Leshno Moshe , Gordon Noa , Moore Assaf , Neiman Victoria , Rosenbaum Eli , Goldstein Daniel A.
Published: February 2018

472

Background: Recently, immune-modulating drugs have been introduced to the second line setting of advanced bladder cancer. Pembrolizumab increases overall survival and is associated with less toxicity compared to chemotherapy in this setting based on the Keynote-045 study. The high cost of immunotherapy necessitates an assessment of its value by considering both efficacy and cost. The objective of this study is to estimate the cost-effectiveness of pembrolizumab for the second-line treatment of advanced bladder cancer from the perspective of payers in multiple countries. Methods: We developed a Markov model to compare the costs and effectiveness of pembrolizumab with those of chemotherapy in the second-line treatment of advanced bladder cancer. Health outcomes were measured in life-years (LYs) and quality-adjusted life-years (QALYs). Drug costs were acquired for the following countries: U.S., U.K., Canada and Australia. Model robustness was addressed in univariate and probabilistic sensitivity analyses. Results: Pembrolizumab generated a gain of 0.36 QALYs compared to chemotherapy. Our analysis established the following incremental cost-effectiveness ratios (ICERs) for pembrolizumab versus chemotherapy in second-line advanced bladder cancer treatment - U.S. $122,557/QALY, U.K. $91,995/QALY, Canada $93,648/QALY, and Australia $99,966/QALY. The willingness-to-pay (WTP) thresholds per QALY are considered to be around 100,000-150,000 US dollars for the U.S., 20,000-50,000 pounds for the U.K. [25,000-65,000 US $], 20,000-100,000 CAD for Canada [16,000-80,000 US $] and 40,000-75,000 AUD for Australia [32,000-60,000 US $]. Conclusions: Cost-effectiveness and WTP thresholds vary between countries. Compared to the other countries examined, U.S. drug prices were found to be highest, leading to the highest ICER. With standard willingness-to-pay thresholds, pembrolizumab may be considered cost-effective in the U.S., but not in the other countries examined.