bluuebunny/crossref_metadata_2025 huggingface dataset:
Prognostic outcome of gastric cancer patients with cancer stem cell SNPs in Asian versus western countries.
Authors: Labonte Melissa Janae , Wakatsuki Takeru , Zhang Wu , Yang Dongyun , Azuma Mizutomo , Gerger Armin , Stotz Michael , Ning Yan , Volz Nico Benjamin , Stintzing Sebastian , Li Joseph Ethan , El-Khoueiry Rita Elie , Wilson Peter M. D. , Koizumi Wasaburo , Watanabe Masahiko , Maus Martin K. H. , Barzi Afsaneh , Iqbal Syma , El-Khoueiry Anthony B. , Lenz Heinz-Josef
Published: March 2020

4110

Background: The clinical significance of cancer stem cells (CSC) has been well established; however, its prognostic role remains controversial. CD44 is recognized as a CSC marker in gastric cancer (GC) and, recently, the clinical impact of CD166 in GC was reported. Our group previously reported SNPs of CD44 and CD166 are associated with outcome in US patients (pts) with adjuvant GC and colorectal cancer, respectively. Since GC has regional differences in epidemiology and clinicopathology, we hypothesized that ethnicity and regional differences in GC could influence the prognostic role of CD44 and CD166. Methods: A total of 369 pts with histopathologically-confirmed localized (stage Ib to IV; AJCC-6th) GC were enrolled from Japan (n=169), the US (n=137), and Austria (n=63) between 2002 and 2010. CD44 rs187116 G>A and CD166 rs1157 G>A were analyzed. Genomic DNA was extracted from blood or tissue, and all samples were analyzed by PCR-based direct DNA-sequencing. Results: Pts homozygous for A/A CD44rs187116 (n=20) showed a median OS of 2.0 yrs vs not reached for patients harboring at least one-G allele (n=144) (HR: 2.87 [95%CI: 1.61-5.13], p<0.001) in Japanese cohort, while pts homozygous A/A (n=30) showed a median OS of 7.3 yrs vs 4.1 yrs for pts harboring at least one-G allele (n=94) (HR: 2.0 [95%CI: 0.90-4.55], p=0.079) in the US cohort. There were no significant differences in Austrian cohort alone or in combination with US cohort. In CD166 rs1157, pts harboring at least one-A allele (n=27) showed a median OS of 3.9 yrs vs not reached for pts homozygous G/G (n=142) (HR: 1.81 [95%CI: 1.05-3.12], p=0.033) in Japanese cohort., Although there were no significant differences in the US or Austrian cohort when analyzed separately, combining cohorts demonstrated that pts homozygous A/A (n=12) showed a median OS of not reached yrs vs 4.7 yrs for pts harboring at least one-G allele (n=179) (HR: 5.00 [95%CI: 0.70-35.95], p=0.073). Conclusions: SNP profiles in CSC markers predicted opposite prognostic outcomes in patients with GC among Asian and Western countries. This is the first report suggesting that the prognostic role of CSC markers in GC may differ based on ethnic groups or etiology differences.
Association of transcription factor 7-like 2 (TCF7L2) polymorphisms with worse survival in three independent cohorts from the United States, Austria, and Japan in patients with gastric cancer.
Authors: El-Khoueiry Rita Elie , Wakatsuki Takeru , Ning Yan , Zhang Wu , Yang Dongyun , Azuma Mizutomo , Gerger Armin , Stotz Michael , Labonte Melissa Janae , Wilson Peter M. D. , Volz Nico Benjamin , Stintzing Sebastian , Maus Martin K. H. , Sunakawa Yu , Koizumi Wasaburo , Watanabe Masahiko , Li Joseph Ethan , Barzi Afsaneh , El-Khoueiry Anthony B. , Lenz Heinz-Josef
Published: March 2020

4111

Background: The Wnt/β-catenin signaling pathwaycontrols cell proliferation and differentiation. Disruption of this pathway has been shown in the majority of colorectal (CRC) and gastric cancer (GC). The TCF7L2 complex plays a critical role in this pathway. Interaction of TCF7L2 and β-catenin results in translocation to the nucleus and leads to up-regulation of target genes, including c-myc and cyclin D1. Previous reports have shown that TCF7L2 polymorphism rs7903146 C/T is associated with CRC risk and outcome; however, the prognostic role of this polymorphism in GC is unknown. Therefore, we tested the hypothesis of whether this polymorphism could predict outcome in GC in three independent cohorts. Methods: A total of 369 patients (pts) with histopathologically-confirmed localized GC were enrolled from Japan (n=169), the US (n=137), and Austria (n=63) between 2002 and 2010. Results: In the US cohort, pts with at least one-T allele ((T/T or C/T; n=46) showed a median TTR of 1.7 yrs vs. 4.4 yrs compared to pts homozygous C/C (n=76) (HR: 2.09 95%CI: 1.21- 3.59, p=0.0053). A similar trend was shown in the Austrian cohort, where pts harboring at least one-T allele (n=25) showed a median DFS of 2.08 yrs vs. 5.42 yrs for pts homozygous C/C (n=38) (HR: 1.79 [95%CI: 0.90-3.55], p=0.092). Moreover, in the Japanese cohort, pts homozygous for T/T demonstrated (n=2) a median DFS of 0.15 yrs vs. 4.82 yrs for pts harboring at least one-C allele (n=165) (HR: 10.5 [95%CI: 2.46-45.5], p=0.001). These results were confirmed in the OS in the US and Japanese cohorts. Pts at least one-T allele (n=46) showed a median OS of 3.3 yrs vs. 5.5 yrs for pts homozygous C/C (n=76) (HR: 2.41 95%CI: 1.28-4.53, p=0.0043) in the US cohort, while pts homozygous T/T showed (n=2) a median OS of 0.22 yrs vs 5.76 yrs for pts harboring at least one-C allele (n=165) (HR: 15.2 [95%CI: 3.50-66.7], p<0.001). Conclusions: TCF7L2 polymorphism was associated with worse prognosis in recurrence in pts with GC in three independently global cohorts. This polymorphism may be negative prognostic factor in GC regardless of ethnicity and etiology, suggesting the importance role of Wnt/β-Catenin signaling in GC.
Randomized dose comparison phase II study of the oral transforming growth factor-beta (TGF-ß) receptor I kinase inhibitor LY2157299 monohydrate (LY) in patients with advanced hepatocellular carcinoma (HCC).
Authors: Faivre Sandrine J. , Santoro Armando , Kelley Robin Katie , Merle Philippe , Gane Ed , Douillard Jean-Yves , Waldschmidt Dirk , Mulcahy Mary Frances , Costentin Charlotte , Minguez Beatriz , Papappicco Pasqua , Gueorguieva Ivelina , Cleverly Ann , Desaiah Durisala , Lahn Michael M. F. , Murray Nicola , Benhadji Karim A. , Raymond Eric , Giannelli Gianluigi
Published: March 2020

4118

Background: TGF-ß signaling is associated with HCC progression in moderate to poorly differentiated tumors overexpressing alpha-fetoprotein (AFP) levels. We report here the safety and antitumor activity of LY in HCC patients with elevated AFP in this ongoing study. Methods: Patients with advanced HCC who progressed on sorafenib (SF) or are ineligible to receive SF, advanced Child-Pugh A/B7 HCC, AFP ≥1.5x ULN, ECOG PS ≤1, measurable disease (RECIST 1.1), and ≤1 prior systemic regimen were eligible. LY was administered as intermittent dosing of 14 days on/14 days off (28 days =1 cycle). Patients were randomized to either 160 mg/day (Arm A) or 300 mg/day (Arm B) LY. Primary endpoints were time-to-progression (TTP) and biomarker changes (serum AFP, TGF-ß and E-cadherin) for each dose. Secondary endpoints included toxicity (CTCAE, V 4.0) and pharmacokinetics (PK). Results: 106 patients were enrolled (Arm A=37; B=69), including 92% non-Asians. Baseline characteristics were (Arm A/B): median age 61/66 years; PS=0 60/51%; Child-Pugh A 97/86%; etiology: hepatitis C 30/33%, hepatitis B 24/25%, alcohol 22/22%. Overall, 78/83% of patients had received prior SF; 64/58% of patients had AFP ≥400 ng/mL. Median TTP was 12.0 weeks (90% CI: 7.1, 12.6) in the overall population (Arm A, 12.6 weeks; Arm B, 10.9 weeks). In SF-naïve patients, TTP was 18.3 weeks (90% CI: 6.3-non-estimable). TTP was higher in the non-alcohol compared to alcohol-only etiology group (median 12.1 vs. 6.1 weeks). Median baseline serum TGF-ß1 was 3.4 ng/mL (range: 1.4-3.7) and E-cadherin was 6.1 mg/mL (range: 1.9-17.3). AFP decline of >25% occurred in 21/106 patients (20%). Four patients discontinued treatment due to a drug-related AE. Most common grade 3/4 related AEs in patients were: neutropenia (n=3), GI bleeding (n=2), fatigue (n=2), and anemia (n=2). Preliminary PK analysis (51 patients) demonstrated moderate interpatient exposure variability (42%). Conclusions: Based on the manageable toxicity profile, the evidence for biomarker/TTP responses, and an analysis of the aggregate PK/PD data, the 300 mg/day dose was chosen for future studies in HCC. Clinical trial information: NCT01246986.
Prognostic delineation of papillary cholangiocarcinoma based on the invasive proportion.
Authors: Onoe Shunsuke , Shimoyama Yoshie , Ebata Tomoki , Yokoyama Yukihiro , Igami Tsuyoshi , Sugawara Gen , Nakamura Shigeo , Nagino Masato
Published: March 2020

4119

Background: Intraductal papillary neoplasm of the bile duct (IPNB) is a presumed precursor lesion in biliary carcinogenesis, clinicopathologically overlapping with papillary cholangiocarcinoma (PCC); however, as IPNB has no standardized definition, this relationship remains equivocal. Here, we aimed to develop a new PCC prognostic model, focusing on the invasive proportion. Methods: Among 605 patients with surgically resected cholangiocarcinoma in Nagoya University Hospital between 2000 and 2011, 173 (29%) had intraductal exophytic papillary lesions. These were divided into four subsets based on the invasive component: non-invasive (PCC-1, n = 13), ≤10% (PCC-2, n = 30), 11-50% (PCC-3, n = 55), and >50% (PCC-4, n = 75). Results: Invasion beyond the ductal wall was observed in 83% of PCCs and 99% of non-papillary cholangiocarcinomas (NPCC, n = 432; P < 0.001). Regional lymph node metastases were more frequent in NPCC (48%) than PCC (32%; P < 0.001). Five-year survival was better for PCC (52%) than NPCC (37%; P < 0.001), indicating the papillary component to be a significant independent prognosticator. PCC-4 and NPCC had similar clinicopathological features and overlapping survival curves: 32% and 37% at 5 years (P = 0.877), both lower than those of PCC-1, PCC-2, and PCC-3 (respectively, 91%, 71%, and 60% at 5 years; P < 0.01 in all combinations). Multivariate analysis in PCC showed >50% invasive component, nodal metastasis, and positive surgical margin as independent predictors. Conclusions: The presence of an intraductal papillary component was an important determinant of better survival in cholangiocarcinoma. PCC exhibited a more aggressive histologic character and worse survival with progression of the invasive component. PCC with >50% invasive component was morphologically and prognostically similar to NPCC. Therefore, we propose that IPNB should be nosologically applied only for PCC cases with ≤50% invasive component.
Correlation between VEGF and VEGF-R polymorphisms, toxicity, and clinical outcome in HCC patients receiving sorafenib.
Authors: Faloppi Luca , Scartozzi Mario , Bianconi Maristella , Loretelli Cristian , Svegliati Baroni Gianluca , De Minicis Samuele , Mandolesi Alessandra , Giampieri Riccardo , Bittoni Alessandro , Del Prete Michela , Maccaroni Elena , Cecchini Luca , Bearzi Italo , Benedetti Antonio , Cascinu Stefano
Published: March 2020

4123

Background: The introduction of sorafenib for the treatment of advanced HCC radically changed patients’ clinical outcome. However response to treatment as well as toxicity are still largely unpredictable in the single patient. We previously reported that VEGF and VEGFR polymorphisms may have a predictive and prognostic role in this setting, but little is known about the possible correlation with toxicity. The aim of our study was to evaluate whether VEGF and VEGFR genotyping was able to correlate with toxicity in HCC patients receiving sorafenib. Methods: 73 histological samples of HCC patients receiving sorafenib were tested for VEGF-A, VEGF-C and VEGFR-1,2,3 single nucleotide polymorphisms (SNPs). Patients time to progression (TTP), overall survival (OS) and toxicities were analysed. Results: VEGF-A rs833061 T>C, rs699947 C>A and rs2010963 C>G polymorphisms were statistically significant associated with any grade global (respectively: p=0.031; p=0.018; p=0.003) and cutaneous toxicities (respectively: p=0.043; p=0.019; p=0.025). Furthermore patients with any grade global and cutaneous toxicities showed a better progression free survival and overall survival (global toxicity PFS: 7.0 vs 5.0 months, p=0.016; OS: 26.8 vs 13.0 months, p=0.023) (cutaneous toxicity PFS: 7.6 vs 5.1 months, p=0.033; OS: 22.7 vs 13.3 months, p=0.014) Conclusions: In our analysis patients with polymorphism T at rs833061, C at rs699947 and C at rs2010963 showed a higher rate of toxicities and, accordingly to our previous report, this correlates with a better PFS and OS. Analysis of VEGF and its receptor genes polymorphisms represents a clinical tool to identify patients with favourable response to sorafenib presumably related to a more efficient control of tumour growth. The occurrence of toxicity could be an interesting clinical surrogate during sorafenib treatment and may help clinicians in a more cautious and aware management of HCC patients.
Postoperative nomogram for predicting survival after resection for intrahepatic cholangiocarcinoma.
Authors: Ribero Dario , Rosso Stefano , Pinna Antonio Daniele , Nuzzo Gennaro , Guglielmi Alfredo , Aldrighetti Luca , Leone Francesco , Aglietta Massimo , Giulini Stefano Maria , Gerunda Giorgio Enrico , Tomatis Mariano , Berloco Pasquale , Calise Fulvio , Opocher Enrico , Gruttadauria Salvatore , Torzilli Guido , Capussotti Lorenzo
Published: March 2020

4129

Background: Conventional staging systems have limited value for survival estimation in individual patients because of the multiple predictors of outcome. Nomograms may overcome these limitations. Thus we developed and internally validated a postoperative nomogram to predict survival after resection of intrahepatic cholangiocarcinoma (IHC) and compared its predictions to those obtained using the 7th Ed. AJCC/UICC stage groupings. Methods: Prospective clinicopathologic data from 574 patients who underwent hepatic resection at 12 tertiary hepatobiliary centres (1995-2011) were used. After inputting missing values with regression imputation, the nomogram was developed from a Cox regression model with overall survival (OS) as the primary end-point. Calibration and internal validation were performed calculating the agreement between observed and predicted outcomes in terms of percentage of predicted errors (PE). Discrimination was quantified with the concordance index (CI). Both CI and PE were then corrected for over-optimism using bootstrapping with 100-fold cross-validation sampling. Credibility intervals around 3- and 5-year predicted survival were estimated from an empirical Bayesian model. Results: At last follow-up (median duration 27.6 months) 243 patients had died. Three and five-years OS were 52% and 39%. The predictive accuracy of the nomogram (CI: 66.5), which includes 7 variables (tumour size and number, lymph-node metastases, vascular invasion, perineural invasion, CA19.9 level, and radicality of resection), was good and superior to that of the current AJCC/UICC staging system (CI: 58.4). Percentage of PE for the AJCC/UICC staging system were 24%, while the studied model offered a PE slightly under 20%. Heterogeneity was observed in the distribution of nomogram-predicted survival probabilities within stage groups. Conclusions: The nomogram developed in this study overcomes some of the prognostic limitations associated with simple models by including all prognostic variables excluded from the AJCC/UICC staging system and may serve as an instrument for future refinements in determining individual patient prognosis necessary for accurate patients stratification.
Neutrophil/lymphocyte ratio (NLR) as a prognostic factor in biliary tract cancer (BTC).
Authors: McNamara Mairead Geraldine , Templeton Arnoud J. , Maganti Manjula , Walter Thomas , Horgan Anne M , McKeever Elizabeth , Min Trisha , Knox Jennifer J.
Published: March 2020

4130

Background: BTCs include intrahepatic (IHC), hilar, distal bile duct (DBD), and gallbladder carcinoma (GBC). Risk factors include conditions associated with chronic inflammation. NLR, an inflammatory marker, is prognostic in several cancers but has not been reviewed in large BTC series, hilar or GBC. Methods: Baseline demographics and NLR at diagnosis were evaluated in 864 patients (pts) with BTC from 01/87 - 12/12 treated at Princess Margaret Cancer Center. Their prognostic significance for overall survival (OS) was determined using a Cox proportional hazards model. Results: High NLR ≥3.0 was associated with poor survival using univariable analysis as was stage/site of primary (P<0.05), age >65yrs, lymphocytes ≤1.6 (P<0.01), neutrophils ≥5.0, platelets ≥280, hemoglobin (Hb) < 110 g/L (P<0.001). Median OS in pts with NLR<3.0 was 21.6 mo, 12.0 mo with NLR ≥3.0 (P<0.001). NLR retained its significance as a prognostic marker on multivariable analysis (Table), along with GBC (P<0.05), age>65yrs, DBD primary (P<0.01), stage and Hb <110g/L (P<0.001). NLR was prognostic for OS on multivariable analysis for hilar: overall (Table) and advanced grp (n=102) (HR 1.68, 95%CI 1.07-2.64, P<0.05) and in advanced DBD (n=102) (HR 1.63, 95%CI 1.03-2.57,P<0.05). On subgrp analysis, NLR was prognostic for OS in advanced BTC (ABTC) (n=538) (P<0.01) but not in surgical grp. NLR did not predict RECIST response to first line palliative chemotherapy in ABTC. Conclusions: Baseline NLR is prognostic in BTC, specifically ABTC and hilar subgrp, suggesting the importance of systemic inflammation influencing outcome in pts with ABTC, thus providing a simple inexpensive prognostic biomarker while also possibly identifying pts that may benefit from antiinflammatory mediation. NLR was not predictive for response in BTC. [Table: see text]
Everolimus in combination with octreotide LAR as the first-line treatment for advanced neuroendocrine tumors: A phase II trial of the I.T.M.O. (Italian Trials in Medical Oncology) group.
Authors: Bajetta Emilio , Catena Laura , Fazio Nicola , Pusceddu Sara , Biondani Pamela , Blanco Giusi , Ricci Sergio , Aieta Michele , Pucci Francesca , Valente Monica , Bianco Nadia , Bellomo Fernanda , Mauri Chiara , Buonandi Pasquale , Roberto Vincenza
Published: March 2020

4136^

Background: Everolimus has shown antitumor activity in patients (pts) with advanced pancreatic neuroendocrine tumors (NETs). We aimed to assess efficacy and safety of everolimus in combination with octreotide long-acting repeatable (LAR) in patients with well differentiated NETs of gastroenteropancreatic and of lung origin. Methods: We performed a phase II, multicenter trial using a Simon two-stage minmax design. Pts with advanced well differentiated, previously untreated NETs of the gastroenteropancreatic tract and of the lung received octreotide LAR 30 mg every 28 days in conjunction with everolimus 10 mg per day continuously. The primary endpoint was objective response rate (ORR). Results: A total of 50 pts (58% males) were enrolled. The median age was 60.5 years (range 25-76). Primary tumor site was pancreas in 14 (28%), unknown in 14 (28%), lung in 11 (22%), ileum in 9 (18%) and jejunum and duodenum in 2 (4%) of pts. 13 (26%) pts had carcinoid syndrome. The ORR, calculated on the ITT population, was 20.0% (95% CI 8.9-31.1): 2 patients (4%) had a complete response (CR), 8 (16%) a partial response (PR). Thirty-six patients (72%) achieved stable disease (SD). All CR and all PR as well as 91.7% of SD had a duration ≥ 6 months. Clinical benefit (CR+PR+SD) was 92%. At a median follow-up of 277 days, the median time to progression (TTP) was 16.3 months (95% CI 10.7-20.1). Overall survival could not be assessed. Treatment-related adverse events (AEs) were mostly of grade 1 or 2; the only grade 4 AE was mucositis in 1 patient, while grade 3 AEs included skin rash in 1 case, stomatitis in 4 cases (8%) and diarrhea in 11 cases (22%). Conclusions: Everolimus in combination with octreotide LAR has shown to be active and well tolerated in advanced NETs and, in this study, not only in primary pancreatic tumors. Compared to other clinical trials with everolimus in NETs, the observed ORR in this study was higher. Aknowledgements: The Authors thank the Italian Trials in Medical Oncology (I.T.M.O.) group and Novartis Pharma for the support provided. Clinical trial information: 2008-007153-13.
Study on activation of the IGF-1R mTOR pathway in neuroendocrine tumours (NETs).
Authors: Casanovas Oriol , Teule Alex , Villabona Carles , Serrano Teresa , Fabregat Joan , Salazar Ramon
Published: March 2020

4139

Background: NETs are a heterogeneous group of rare neoplasms. Preclinical studies have shown that IGFR overestimulation can lead to constitutional activation of mTOR pathway. The main objective of this study is to describe the activation status of IGF1R-mTOR pathway by immunohistochemistry in a series of NETs and to assess the association with IGF1R expression. Methods: We studied 69 paraffin tumour blocks: 28 pancreatic NETs (pNETs) (2 gastrinomas, 1 glucagonoma, 4 insulinomas and 21 non-functioning (nf) pNETs), 32 GI NETs (4 stomach, 8 colorectum, 18 ileum and 2 dudodenum) and 9 NETs from other origins (2 anterior mediastinum, 2 ovary, 3 bile duct and 2 kidney). The expression of IGF1R, phosphorylated (p) mTOR and (p)S6 has been determined by immunohistochemistry using anti-IGF1Rβ (sc-713), anti-Phospho-mTOR (S2448) (49F9, Cell Signaling) and anti-Phospho-S6 Ribosomal Protein (S235/336)(91B2, Cell Signaling). Results: Expression of IGF1R has been observed in 46 of 69 (66%) samples with the highest expression in 2/4 (50%) insulinomas, 5/21 nf pNETs (23%) and 3/18 ileum (17%). We have observed activation of the mTOR pathway by immunodetection of (p)mTOR in 14 of 69 samples (20%): 2/21 nf pNETs (9.5%), 1/8 colorectum (12.5%), 8/18 ileum (44%), 1/2 anterior mediastinum, 1/2 ovary, 1/3 biliar tract. We haven’t detected any (p)S6 activation in these samples. Consistent IGF1R-mTOR pathway activation was detected in 11/14 (78%) samples with mTOR positivity that also showed expression of IGF1R. The most relevant finding is that all of the 8 samples from ileum with activation of mTOR showed some degree of expression of IGF1R. Conclusions: 2/3 of NETs show varying levels of expression of IGF1R, but only 16% demonstrate activation of the IGF1R-mTOR pathway. While the positivity of (p)mTOR in pNETs is lower than expected, we have identified a subgroup of ileal NETs with consistent activation of both IGF1R and (p)mTOR which could help stratify patients in clinical trials involving modulation of this pathway. In contrast, none of the 69 samples studied was positive for (p)S6 which suggests this marker is not valid to be used in the clinic. Further validation studies are required to help clinical stratification for therapies against IGF1R mTOR pathways.
Tivozanib in patients treatment-naive for metastatic renal cell carcinoma: A subset analysis of the phase III TIVO-1 study.
Authors: Sternberg Cora N. , Eisen Tim , Tomczak Piotr , Strahs Andrew Louis , Esteves Brooke , Berkenblit Anna , Motzer Robert John
Published: March 2020

4513

Background: Tivozanib (T) is a potent, selective inhibitor of all three VEGF receptors with a long half-life of 4.5–5.1 days. Superior progression-free survival (PFS) and overall response rate (ORR) with T versus sorafenib (S) were demonstrated in a Phase III trial (TIVO-1) in patients (pts) with metastatic renal cell carcinoma (mRCC) (in ITT population, PFS: 11.9 vs 9.1 months HR=0.797, 95% CI 0.639–0.993; P=0.042; ORR: 33% vs 23%, P=0.014). Hypertension was more common with T, while lower rates of certain off-target AEs and fewer dose adjustments relative to S were reported (J Clin Oncol 2012;30[suppl]:Abstract 4501). Here we present efficacy and safety analyses for the pre-specified subset of pts who received no prior systemic therapy for mRCC. Methods: In the ITT population (N=517), pts were treatment-naïve or had received no more than 1 prior systemic therapy for metastatic disease; pts receiving prior VEGF- or mTOR-targeted therapy were excluded. Pts were randomized 1:1 to T 1.5 mg/d (once daily, 3 weeks on, 1 week off) or S 400 mg/d (twice daily, continuously). Of these, 181 pts (70%) in each treatment arm had not received prior systemic therapy for mRCC. Results: In pts who received no prior systemic therapy for mRCC, demographics were well balanced between the 2 arms. Median PFS was 12.7 for T vs 9.1 months for S (HR=0.756, 95% CI 0.580–0.985, P=0.037). ORR was 34% for T vs 24% for S (P=0.038). The most common adverse event (AE; All grades/Grade ≥3) for T was hypertension (T: 40%/25% vs S: 35%/18%), suggesting “on-target” biological activity and was manageable medically, while the most common AE for S was hand-foot syndrome (T: 11%/2% vs S: 52%/16%). Other common AEs were diarrhea (T: 22%/2% vs S: 32%/7%), fatigue (T: 19%/6% vs S: 15%/3%), and weight decrease (T: 18%/1% vs S: 17%/2%). Dose reduction (T: 12% vs S: 42%) and interruption (T: 18% vs S: 35%) rates were lower in the T arm and similar to the ITT population. Conclusions: T demonstrated significant improvement in PFS and ORR compared with S in pts who had received no prior systemic therapy for metastatic RCC. T was generally well tolerated, with low rates of treatment-related reduction/interruption in this pre-specified subgroup of pts. Clinical trial information: NCT01030783.
Gemcitabine, paclitaxel, and doxorubicin as first-line therapy for patients with advanced urothelial carcinoma and renal insufficiency: A phase II study.
Authors: Pagliaro Lance C. , Munsell Mark F. , Harris Deborah , Carolla Robert L. , Siefker-Radtke Arlene O.
Published: March 2020

4528

Background: The role of cisplatin-based chemotherapy for the treatment of locally advanced or metastatic urothelial carcinoma is well established. For patients (pts) who cannot receive cisplatin owing to renal insufficiency, substitution with carboplatin was associated with inferior response rate and overall survival (OS). To address this unmet need, we conducted a phase II study of gemcitabine (Gem), paclitaxel (Tax), and doxorubicin (Adria) in this group. Methods: The primary endpoint was overall response rate (ORR); secondary endpoints were toxicity, OS, and the safety and efficacy of pegfilgrastim 6 mg (G-CSF) given immediately after chemotherapy on Day 1. A Simon 2-stage design was chosen to detect ORR of 40% and to reject ORR of 25%. Eligible pts had metastatic or unresectable urothelial carcinoma, no prior chemotherapy, performance status ≤ 2, glomerular filtration < 60 ml/min, and no need for dialysis; all gave informed consent. Brain metastases were excluded, as were clinically significant heart disease, peripheral neuropathy, and liver or bone marrow dysfunction. Treatment consisted of 900 mg/m2 Gem (fixed rate of 10 mg/m2/min), 135 mg/m2 Tax, and 40 mg/m2 Adria administered with same-day GCSF every 14 d to a maximum of 9 cycles. Tumors were evaluated after every 3 cycles. Results: Forty pts were enrolled January 2008 through November 2011, and 39 could be assessed for response. Median age was 72 (range, 51–89) and 11 pts (28.2%) were women. There were 7 complete and 15 partial responses, for an ORR of 56.4% (95% CI 39.6-72.2). Notable grade 3 and 4 nonhematologic toxicities in the first 2 cycles were dyspnea and mucositis (1 pt each). There were no treatment-related deaths and no toxicity attributed to same-day G-CSF. Median OS was 14.4 mo with median follow-up of 12.6 mo for all pts, 15.6 mo for 10 who were alive. Conclusions: Gem-Tax-Adria is effective as first-line treatment for metastatic or locally advanced urothelial carcinoma, and it can safely be given to pts with renal insufficiency. Same-day G-CSF also appears to be safe and effective in this setting. Phase III study is warranted. Clinical trial information: NCT00478361.
Preclinical and correlative studies of cabozantinib (XL184) in urothelial cancer (UC).
Authors: Apolo Andrea Borghese , Lee Young H. , Cecchi Fabiola , Agarwal Piyush K. , Parnes Howard L. , Khadar Kattie , Summerell Amelia , Gulley James L. , Compton Kathryn , Figg William Douglas , Dahut William L. , Bottaro Donald P.
Published: March 2020

4543

Background: Mounting evidence supports Met as a therapeutic target in urothelial cancer (UC). Activated Met can promote angiogenesis and tumor growth by upregulating VEGF and may play a role in UC pathogenesis. Cabozantinib inhibits VEGFR2 and Met pathways. In this study, we assessed shed Met (sMet) levels in the urine and serum of UC patients (pts) and cabozantinib’s effects on HGF-driven UC cell growth and invasion. Methods: sMet levels in serum and urine samples from 31 pts with UC (23 metastatic, 8 muscle-invasive) were correlated with stage, presence of visceral metastases and urinary source. The effects of cabozantinib on 4 human UC-derived cell lines were studied in vitro. Intact RT4, TCC-SUP, T24M2 and T24M3 cells at 80% confluence were serum deprived 16 h, then left untreated or treated with hepatocyte growth factor (HGF) and/or cabozantinib prior to analysis of Met, phospho- (p)Met, pAkt, Akt, pMAPK and MAPK by immunoassay or immunoblotting. Cabozantinib effects on basal and HGF-induced UC cell invasion, proliferation and soft agar growth were measured. Results: Median serum Met levels were modestly higher in pts with metastatic versus muscle-invasive disease. Urinary Met levels were clearly higher in pts with visceral metastasis (P=0.0111) and in urine from ileal conduits and neobladders compared to normally voided urine, regardless of stage (P=0.0489). Met content in UC cell lines was low in RT4 and higher in T24M2, T24M3 and TCC-SUP. Basal pMet content was universally low, increased significantly by HGF and this was reversed by cabozantinib. HGF-driven increases in pAkt/Akt and pMAPK/MAPK in all 4 cell lines were reversed by cabozantinib, as were HGF-enhanced UC cell invasion, proliferation and anchorage independent growth. Conclusions: Median urinary sMet is significantly higher in pts with visceral metastasis and in specimens from ileal conduits and neobladders relative to normally voided urine. UC cell Met content in culture increased with disease grade; HGF stimulated activation of Met and known effectors, and enhanced invasion, growth rate and anchorage-independent growth; cabozantinib effectively reversed these HGF-driven effects. These data support evaluation of cabozantinib in pts with metastatic UC.
Association between pioglitazone (PZD) therapy and bladder cancer (BC): A meta-analysis of epidemiologic evidence.
Authors: Shimanovsky Alexei , Appiah Juliet , Njei Basile M. , Clement Jessica Mary
Published: March 2020

4546

Background: There is evidence suggesting that PZD use may be a risk factor for BC, yet these reports are controversial. The aim of this meta-analysis is to review available data and evaluate the association between PZD and BC. Methods: Two independent reviewers conducted a systematic search of the Cochrane Library, OvidSP and PubMed for articles published January 1970 to April 2012. MeSH search terms included PZD, Actos, thiazolidinediones, diabetes mellitus (DM), and BC. Only studies reporting an effect measure for the association between PZD and BC were included. Subgroup analyses by study design and country were performed. Analysis was done using a random effect model after a preliminary review showed evidence of study heterogeneity. This was then assessed using the Cochrane’s Q and I2 statistics. Publication bias was evaluated using the Begg’s and Egger’s tests, and funnel plots. All analyses were performed using REVMAN 5.1. Results: A total of 6 studies (3 cohort and 3 case control) met the inclusion criteria. The overall pooled risk ratio (RR) for the association between PZD and BC was 1.12 (95% CI 1.09, 1.15; P <0.001). The summary RR for cohort and case control studies were 1.13(95% CI 1.07, 1.19; P <0.001) and 1.11(95% CI 1.07, 1.15; P <0.001), respectively. The subgroup analysis showed a significant association with BC in the USA and Europe, but not in Asia (RR 0.98, 95% CI 0.71, 1.34; P = 0.88). The association of PZD and BC was more sensitive for treatment duration (>12 month). Conclusions: Our study analyzed 1,214,071 patients, demonstrating a weak association between PZD and BC. The results were significant with increase in treatment duration, which corresponds to previous studies. This meta-analysis has limitations. Not all studies reported known variables associated with BC, such as smoking or occupational exposure. They did not address patient BMI, time from DM diagnosis or previous drug therapy. These parameters reflect severity of disease and level of insulin-resistance. Future studies should evaluate markers of insulin-resistance with PZD use and correlate with BC. Understanding the link between PZD and BC in the context of DM may allow physicians to determine a more accurate risk of PZD use.
Preliminary safety, product parameters, and immune response assessments from a phase II randomized, open-label trial of DN24-02, an autologous cellular immunotherapy (ACI), in patients (pts) with surgically resected HER2+ urothelial cancer (UC) at high risk for recurrence.
Authors: Bajorin Dean F. , Sharma Padmanee , Lerner Seth P. , Sims Robert Brownell , Sanders Amanda , DeVries Todd , Sheikh Nadeem A. , Gomella Leonard G.
Published: March 2020

4547^

Background: DN24-02 is a HER2-targeted ACI, consisting of antigen presenting cells (APC) cultured with BA7072, a recombinant HER2-derived antigen (HER500) linked to GM-CSF; DN24-02 is based on the same manufacturing platform as sipuleucel-T, approved for asymptomatic/minimally symptomatic metastatic castrate resistant prostate cancer. NeuACT (N10E1; NCT01353222) is an open-label, randomized phase 2 trial comparing adjuvant DN24E02 to surveillance in HER2+ UC pts at high risk of relapse following cystectomy or nephroureterectomy. The primary endpoint is overall survival. Here we report preliminary evaluation of adverse events (AE), product potency, and immune response. Methods: Pts randomized to DN24-02 underwent leukapheresis followed by infusion of DN24-02 (total of 3 infusions with 2 wk intervals). AEs were assessed at each visit. Product potency was assessed for each infusion by measuring CD54 upregulation on APCs, a marker of APC activation. Antigen-specific immune responses were evaluated by ELISA to HER500 and BA7072. Results: As of November 2012, 13 pts had received ≥1 DN24-02 infusion. The most commonly reported AEs within 1 day after DN24-02 infusion were mild–moderate chills (54%), nausea (31%) and fatigue (23%). Ten pts completed all DN24-02 infusions and were assessed for product potency. Increased median APC activation at infusions 2 and 3 compared with infusion 1 was indicative of an immunological prime-boost effect; this effect was also seen in the 7/10 pts with prior neoadjuvant chemotherapy. Median anti-BA7072 and anti-HER500 titers (IgM) were 128- and 256-fold higher at week 6 vs baseline, respectively. The emergence of IgG indicated a memory antibody phenotype. Conclusions: Preliminary data indicate that DN24-02 product potency (CD54 upregulation) is comparable to sipuleucel-T. DN24-02 appears to be well tolerated in UC. Favorable immune responses were observed, including in pts with prior neoadjuvant chemotherapy. Updated results, including preliminary T-cell immune response data, will be presented. Clinical trial information: NCT01353222.
Phase I/II study of biweekly pemetrexed plus cisplatin in patients with locally advanced, nonresectable or metastatic urothelial cancer: Safety and efficacy results from phase II.
Authors: Lopez Martin Ana , Bellmunt Joaquim , Maroto José Pablo , Gallardo Enrique , Lopez Brea Marta , Perez-Gracia Jose Luis , Castellano Daniel E. , Valverde Claudia María , Bezares Susana , Calvo Emiliano , Paz-Ares Luis
Published: March 2020

4550

Background: Pemetrexed (P) plus cisplatin (C) combination is effective against several malignant tumors. Single-agent P has shown antitumor activity in advanced urothelial cancer; we performed a phase I/II study to define the maximum tolerated dose of biweekly P plus C combination. Here, we report the final results of the phase II study. Methods: Eligible patients (pts) had locally advanced or metastatic transitional cell carcinoma of the urothelium not suitable for curative therapy, performance status (PS) 0-2, estimated life expectancy of at least 12 weeks, and adequate organ function. P and C were administered on days 1 and 15 of each 28-day cycle, up to a maximum of 6 cycles. Pts received the recommended dose from phase I, with P at 400 mg/m2 plus C at 50 mg/m2 (folic acid and vitamin B12 supplementation were also administered). Primary objective was overall response rate (ORR) according to RECIST 1.0. Results: Thirty-eight pts were recruited, 32 (84.2%) pts had bladder cancer with a mean diagnosis time of 1 (range 0-7) year and 30 (78.9%) had metastatic disease; 19 (50%) pts had visceral metastasis and 2 (5.3%) pts had a PS 2. Only 2 pts did receive adjuvant systemic therapy. Median number of cycles was 3 (range 0-7). Twelve (31.6%) pts discontinued the study treatment due to toxicity. The most common treatment-related AEs (> 20%) were asthenia (n=27 pts), nausea and vomiting (n=21, respectively), diarrhea (n=18), anorexia (n=17), mucosal inflammation (n=14), and constipation (n=8). Most treatment-related AEs were of mild or moderate severity. Neutropenia (n=5) and asthenia (n=3) were the most frequent Grade 3 or 4 treatment-related AEs. Serious related AEs were observed in 8 (21.1%) pts. ORR was 39.5% (95% CI 24.0-56.6): 2 (5.3%) pts achieved complete response and 13 (34.2%) pts, partial response. Median progression free survival was 6.7 months, and median overall survival was 10.5 months. Conclusions: In this study, biweekly P (400 mg/m2) plus C (50 mg/m2) combination showed anti-tumor activity in pts with advanced urothelial cancer, with an acceptable safety profile. Clinical trial information: NCT00374868.
Patterns of chemotherapy and survival in elderly patients with advanced bladder cancer: A large Medicare database study.
Authors: Chen Guoqing J. , Galsky Matt D. , Latini David M. , Sonpavde Guru
Published: March 2020

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Background: The frequency of employment of cisplatin-based chemotherapy in elderly patients (≥66 years) presenting with advanced (unresectable or metastatic) bladder cancer is unclear. We examined the use of and overall survival (OS) with chemotherapy regimens employed in elderly patients with newly diagnosed advanced bladder cancer (ABC). Methods: SEER-Medicare linked data were used to identify incident ABC patients presenting with the following stages of bladder cancer: T4bN0M0; Any TN1–N3M0; Any T, Any N, M1 between 2004 and 2007, with claims data until 2009. Outpatient and inpatient Medicare claims data were queried for receipt and type of chemotherapy used. The descriptive analyses were performed to examine associations between chemotherapy regimen, clinical characteristics and OS. Results: A total of 1,031 patients with ABC met inclusion criteria. The median age was 74 years, 69.8% were men. 4.6% (n=47) were T4bN0M0, 55.3% (n=570) were anyT,N1-3M0 and 40.1% (n=414) were any T, any N, M1. Overall, 20.5% (n=211) received cisplatin, 26.1% (n=269) received carboplatin, 5% (n=52) received no platinum and 48.4% (n=499) received no chemotherapy. There were no differences in regimen according to gender, race, stage and age. The median OS for cisplatin, carboplatin, no platinum and no chemotherapy groups were 1.67, 1.41, 1.5 and 1.41 years, respectively (F=5.36, p<0.001). Patients with Any TN1–N3M0; Any T, Any N, M1 receiving cisplatin had better OS compared to carboplatin. T4bN0M0 patients receiving carboplatin exhibited better OS relative to those receiving cisplatin, but this finding is limited by the small number of patients. Conclusions: Among patients presenting with ABC in the Medicare database aged ≥66 years, only 20.5% received cisplatin and 48.4% received no chemotherapy. Those with distant and nodal metastasis displayed better OS with cisplatin. Further analysis will control for baseline prognostic factors and comorbidities. Drug development in the ABC population, especially the elderly, should focus on chemotherapy-ineligible and cisplatin-ineligible patients.
Association between ERCC1 and XPA expression and polymorphisms and the response to cisplatin in patients with non-seminomatous testicular germ cell tumors.
Authors: Mendoza Julia , Martinez-Cedillo Jorge , Hernández Carlos Alberto , Pérez-Montiel Delia , Castro Clementina , Fabián-Morales Eunice , Santibañez Miguel , González-Barrios Rodrigo , Díaz-Chávez José , Andonegui Marco Alonso , Onate-Ocana Luis F. , Jimenez Miguel , Reynoso Nancy , Núñez Marlene , Dyer Richard , Herrera Luis A.
Published: March 2020

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Background: Cisplatin-based chemotherapy cures over 80% of testicular germ cell tumors (TGCTs); nucleotide-excision repair (NER) modifies the sensitivity to cisplatin. In this work we explored the association between NER-proteins and their polymorphisms (SNPs) with cisplatin-sensitivity (CPS) and overall survival (OS) of patients with advanced non-seminomatous (ns)-TGCTs treated with bleomycin-etoposide-cisplatin (BEP). Methods: ERCC1, XPA-expression and gammaH2AX-presence, were tested in cisplatin-treated cancer cell lines. ERCC1 and XPA-expression were also analyzed in ns-TGCTs by qPCR. Immunohistochemistry was performed to detect ERCC1 protein in ns-TGCTs specimens. The SNPs were genotyped by PCR-RFLPs technique. Results: High basal ERCC1-expression was observed in non-CPS cancer cell lines; ERCC1-expression augmented further, as well as gammaH2AX, after cisplatin-treatment. Basal ERCC1 expression increases in the non-CPS patients in Mexican and Peruvian populations compared to CPS patients (p<0.001; p=0.002). XPAexpression levels weren’t different. These polymorphisms weren’t associated with CPS or OS. ERCC1-positive immunostaining was observed in 30/108 patients (27.8%). From 76 patients that were CPS, 59 (77.6%) were ERCC1-negative, compared with 17 (22.4%) that were ERCC1-positive (p=0.05). 5-year OS probability was smaller for those patients ERCC1-positive and non-CPS (15.38%) than tumor ERCC1-negative and CPS (89.3%) (p<0.001). Using the Cox Model, adjusted on the prognosis groups, the hazard ratio (HR) of death in patients with ERCC1-negative and non-CPS was >14.43 and in patients ERCC1-positive and non-CPS the HR was >11.86 (p<0.001). Conclusions: High-levels of ERCC1-expression and ERCC1-protein are associated with non-CPS, suggesting the use of ERCC1 as a potential indicator of response to cisplatin-based chemotherapy and the prognosis in patients with ns-TGCTs. Moreover, it’s important to identify patients potentially non-CPS in order to diminish the toxicity of cisplatin and improved quality of life avoiding adverse effects due to this agent. Work supported by CONACYT 83959 and PAPIIT IN213311-3.
Expression profiling of peripheral blood (PB) enriched for circulating tumor cells (CTCs) in testicular germ cell tumors (TGCTs).
Authors: Mego Michal , Gronesova Paulina , Miskovska Vera , Obertova Jana , Palacka Patrik , Rajec Jan , Sycova-Mila Zuzana , Vertakova-Krakovska Bibiana , Chovanec Michal , Janega Pavol , Svetlovska Daniela , Usakova Vanda , Bujdak Peter , Spanik Stanislav , Ondrus Dalibor , Mardiak Jozef
Published: March 2020

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Background: CTCs are prognostic in several types of tumors and are easily accessible for repeat examination. TGCTs represent a model for the cure of cancer. Nonetheless, a small proportion of patients develop disease recurrence. We investigated expression profiling of PB enriched for CTCs in TGCTs aimed to identify expression signature associated with treatment resistance. Methods: This prospective study included 30 patients (pt) treated with first line (27 pt) or salvage (3 pt) chemotherapy. CD45- peripheral mononuclear cells (PBMCs) were isolated from 10mL of PB on day 1 and on day 22 of first cycle of chemotherapy. Isolated PBMC were depleted of cells of hematopoietic origin (CD45+) using RossetteSep kit negative selection with anti-CD45 antibody. CD45-depleted PBMC represent compartment enriched for CTCs, as showed previously. RNA was extracted from CD45-PBMCs and the expression profiles were obtained using Roche NimbleGen microarrays. Data analysis was processed in R using a limma package followed by GO analysis and MetaCore pathway analysis. Results: Six patients achieved unfavorable response to chemotherapy (other than CR or PR with negative serum markers). We identified 1,506 and 211 genes that were expressed at significantly different levels (FDR<0.05) on day 1 and day 22 of chemotherapy, respectively, with 108 overlapping genes. Cluster analysis using principal component analysis showed, that 5 of 6 samples from patients with unfavourable response to chemotherapy form clearly defined cluster opposed to samples from patients with favourable response. Based on pretreatment expression profiling using MetaCore pathway analysis software, we further identified 758 genes, belonging to several critical functional groups such as immune response, signal transduction, cell proliferation, cell cycle progression, or apoptosis, to be significantly differentially expressed in patients with favourable vs. unfavourable response. Conclusions: Our data suggests that expression profiling of PB enriched for CTCs in TGCTs is feasible, and show great promise in identifying new therapeutic targets and gene expression signature associated with treatment resistance.
Smoking history and disease outcomes in patients with malignant germ cell tumors.
Authors: O'Donnell Elizabeth , Gray Kathryn P. , Hirsch Michelle S. , Kantoff Philip W. , Beard Clair , Sweeney Christopher
Published: March 2020

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Background: In 2011, of 8260 cases of Germ Cell Tumor (GCT) in the US, about 350 (4%) died of disease. The impact of smoking on disease outcomes of relapse and death is unknown. Methods: Retrospective review of 891 GCT pts treated at Dana-Farber Cancer Institute (DFCI) between 1997 and 2010 was conducted. Inclusion criteria were men age>18 yrs treated for GCT with a quantified smoking history in an electronic medical record. The outcomes of interest were relapse after first-line chemotherapy and death from the disease. A Chi-square or Fisher’s exact test assessed the association of the disease outcomes and the smoking history (heavy smoker vs. less), and a Wilcoxon test for ordered categories assessed the association of the outcomes with the IGCCCG risk groups (good, intermediate, and poor), stratified by histology (seminoma vs non-seminoma (NS)). Results: 327 men with metastatic disease were identified. Median age was 31.5 years. 47(14%) had a history of smoking >10 pack-years (pyrs). Of the 256 NSGCT pts with metastases at time of chemotherapy, pts who smoked >10 pyrs constituted 27% of the 64 relapses vs. 11% of the 192 non-relapses (Odds Ratio (OR) 2.9, p=0.003). Of the 71 metastatic seminoma pts, 40% of the 10 relapses had smoked >10 pyrs compared with 8% of the 61 pts who did not relapse (OR 7.5, p=0.01). Smoking >10 pyrs was associated with (i) higher IGCCCG risk at time of metastatic disease [24% of poor-risk pts had a >10 pyr history compared with 12% who had good-risk or 19% who had intermediate-risk (p=0.01)] and (ii) higher staging at initial diagnosis, 23% of poor-risk pts were heavy smokers compared with 9% who were CS1 and 12% good-risk (p=0.002). Of the 50 pts who died of metastatic disease, 36% had smoked >10 pyrs compared to 9% who were cured, Pts who smoked >10 pyrs had significantly increased odds of death compared to those who smoked 0-10 pyrs (OR=5.5, p <0.0001). 3 out of 30 pts who smoked >10 pyrs received suboptimal bleomycin, and only 1 relapsed. Conclusions: Greater than 10 pack-year smoking history is a modifiable risk factor associated with a higher IGCCCG risk at diagnosis of metastatic disease, higher risk of relapse after 1st-line chemotherapy and higher risk of death from germ cell tumor.