bluuebunny/crossref_metadata_2025_split huggingface dataset:
Use of early tumor shrinkage as a response to VEGF inhibitors as a predictor of progression-free survival (PFS) and overall survival (OS) in patients with metastatic renal cell carcinoma (mRCC).
Authors: Gruenwald Viktor , Seidel Christoph , Fenner Martin , Woike Michael , Kalanovic Daniel 
Published: March 2020

4631 Background: Several novel targeted agents significantly prolong overall survival (OS) in metastatic renal cell cancer (mRCC) patients (pts.). Translational research, however, has not identified any prospectively validated prognostic or predictive biomarkers. Recently, progression free survival (PFS), overall response rate (ORR) and early tumor shrinkage were proposed as putative predictors for clinical outcome. In this study we aim to explore the potential role of treatment induced tumor remission as a prognostic or predictive parameter in mRCC. Methods: In our analyses we investigated the putative prognostic role of best response according to RECIST 1.1 criteria (complete remission (CR), partial remission (PR), stable disease (SD), progressive disease (PD)) in first line Tyrosine-kinase inhibitor (TKI) treatment in n=83 pts. Responders were defined by achieving CR, PR or SD at any time during the course of treatment. Furthermore, we tested whether tumor shrinkage of 10% or more within 12 weeks of treatment qualifies as a potential cut-off-parameter to predict PFS or OS. Uni- and multivariate analyses were performed using Log-rang test, Kaplan-Meier-, and Cox-regression analysis. Results: Univariate analyses revealed that first-line treatment non-responders had a significantly shorter OS than responders (p <0.0001). Tumor shrinkage of <10% or ≥10% also correlated with an OS of 14.5 vs. 29.1 mo. (p=0.001) and a PFS of 3.0 vs. 11.5 mo. (p <0.001). In multivariate analyses tumor shrinkage of ≥10% was tested with other common variables such as ECOG, MSKCC-score, histology, and metastatic sites and proved to be a significant independent prognostic (HR 0.361; 95% CI 0.156-0.833) and predictive (HR 0.306; 95% CI 0.152-0.612) parameter. Conclusions: Our results outline that sensitivity to first line treatment of mRCC is an important prognostic factor in mRCC. Hereby tumor shrinkage of ≥10% within 12 weeks of treatment reveals a novel cut-off-parameter, which showed to be a promising prognostic and predictive marker in mRCC. Further investigations are needed to validate this parameter.
Use of miRNA profiling in metastatic renal cell carcinoma to reveal a tumor suppressor effect for mir-215.
Authors: Yousef George M. , Chan Susanne M. , White Nicole MA , Khella Heba WZ , Grigull Joerg , Adzovic Sonja , Youssef Youssef M. , Honey R. John , Stewart Robert , Pace Kenneth T , Jewett Michael A. S. , Evans Andrew , Gabril Manal Y. , Bjarnason Georg A. 
Published: March 2020

4633 Background: Renal cell carcinoma (RCC) is the most common neoplasm of the adult kidney. Metastatic RCC is difficult to treat. The five-year survival rate for metastatic RCC is <10%. Recently, microRNAs (miRNAs) have been shown to have a role in cancer metastasis and potential as prognostic biomarkers in cancer. Methods: We performed a miRNA microarray to identify a miRNA signature characteristic of metastatic compared to primary RCC. Results were validated by quantitative real time PCR. Target prediction analysis and gene expression profiling identified many of the dysregulated miRNAs could target genes involved in tumor metastasis. The effect of miR-215 on cellular migration and invasion was shown in a RCC cell line model. Results: We identified 65 miRNAs that were significantly altered in metastatic when compared to primary RCC. Nine (14%) miRNAs had increased expression while 56 (86%) miRNAs showed decreased expression. miR-10b, miR-196a, and miR-27b were the most downregulated while miR-638, miR-1915, and miR-149* were the most upregulated. A non-supervised 2D-cluster analysis showed that a sub-group of the primary tumors clustered under the metastatic arm with a group of miRNAs that follow the same pattern of expression suggesting they have an inherited aggressive signature. We validated our results by examining the expressions of miR-10b, miR-126, miR-196a, miR-204, and miR-215, in two independent cohorts of patients. We also showed that overexpression of miR-215 decreased cellular migration and invasion in a RCC cell line model. In addition, through gene expression profiling, we identified direct and indirect targets of miR-215 that can contribute to tumor metastasis. Conclusions: Our analysis showed that miRNAs are altered in metastatic RCC and can contribute to kidney cancer metastasis through different biological processes. Dysregulated miRNAs represent potential prognostic biomarkers and may have therapeutic applications in kidney cancer.
Detecting prostate cancer in BRCA1 and BRCA2 mutation carriers: A role for EN2?
Authors: Killick Emma , Morgan Richard , Launchbury Francesca , Annels Nicola E. , Bancroft Elizabeth , Page Elizabeth , Castro Elena , Kote-Jarai Zsofia , Eeles Ros A. , Pandha Hardev S. ,   IMPACT Steering Committee and IMPACT Collaborators
Published: March 2020

4653 Background: EN2 is part of the HOX gene family and plays a role in foetal development. More recently a potential oncogenic role for the protein has been postulated and its utility as a cancer biomarker has been explored in prostate cancer (PrCa) and breast cancer. Carriers of mutations in the BRCA1 and BRCA2 genes have an increased risk of PrCa (1.8-fold and 5-fold respectively) and their tumours tend to be more aggressive and advanced than sporadic cases. Currently there is no national screening program for BRCA mutation carriers in the UK, and the IMPACT study was set up to evaluate PSA screening in this particular group. Here we analyse the efficacy of the urinary EN2 protein as a marker of early cancer detection within this higher risk group. Methods: First pass urine (without preceding digital rectal examination) was collected as part of the IMPACT screening study which enrolled individuals aged between 40 and 69 who were unaffected by PrCa at time of enrolment into the study (n= 418). All participants were from families harbouring a BRCA1 or BRCA2 mutation and were either BRCA mutation carriers themselves or controls with a negative predictive BRCA genetic test. They underwent annual PSA test with a PSA of > 3.0 ng/ml triggering a diagnostic biopsy. EN2 protein was measured in the urine using an ELISA; (positive = > 42.5ng/ml). Results: Our initial results demonstrated urinary EN2 had a sensitivity of 66.67% and a specificity of 89.29% when discriminating which men had been diagnosed with PrCa; the ROC AUC was 0.816. The difference in EN2 level between those diagnosed with cancer and those who were not was significant (p = <0.001). There was trend towards higher EN2 levels in those with more aggressive tumours (median EN2 84.5ng/mL in Gleason ≤3+4 vs 111ng/mL in Gleason ≥4+3), however this was not statistically significant. In one PrCa case EN2 rise preceded PSA rise by 2 years. Further samples are in the process of being analysed, results from these will be included. Conclusions: Urinary EN2 protein measurement warrants further investigation as a PrCa biomarker in this higher risk group with genetic predisposition to PrCa.
Phase I results from a phase I/II study of orteronel, an oral, investigational, nonsteroidal 17,20-lyase inhibitor, with docetaxel and prednisone (DP) in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Petrylak Daniel Peter , Gandhi Jitendra G. , Clark William R. , Heath Elisabeth I. , Lin Jianqing , Oh William K. , Agus David B. , Kucuk Omer , Moran Susan , Wang Jingyuan , Bargfrede Michael , Liu Glenn 
Published: March 2020

4656 Background: The investigational agent orteronel (ortl, TAK-700) is a selective 17,20-lyase inhibitor that blocks androgen production. Since DP is standard chemotherapy in mCRPC, this phase 1/2 study examined ortl + DP in men with mCRPC. Methods: The primary phase I objective was to determine the maximum dose of ortl 200–400 mg BID that can be administered safely with DP in castrate men (testosterone [T] <50 ng/dL) with mCRPC, ≤1 prior chemotherapy and no ketoconazole/abiraterone ≤30 d prior. A 3+3 dose escalation was used with ortl 200 then 400 mg BID. Ortl dosed daily and D (75 mg/m2 q3w) + P (5 mg BID) was started on d8 of cycle 1 (28 d); cycles ≥2 = 21 d. Results: 14 men, median age 68 yrs (range 53–81), ECOG PS 0/1 (71%/29%), median PSA 59.4 ng/mL (5.2–1052), T 8.1 ng/dL (1.2–16.7), 9 with measurable disease, were treated. Median ortl exposure was 33.3 wks (6.3–59); 6 and 8 men received ortl 200 and 400 mg BID + DP, in cohorts 1 and 2, respectively. No dose-limiting toxicities (DLTs) occurred in cohort 1 (2 x 3 pts); in cohort 2 (2 x 4 pts), 1 pt in group 1 had DLT (Gr3 related febrile neutropenia); no DLTs occurred in group 2. 3 pts discontinued due to AEs (2 D infusion reactions, 1 at each dose; 1 unrelated cardiorespiratory death at 200 mg). All men had at least 1 AE Gr ≥3 which were treatment-related in 11 men. The most common Gr ≥3 AEs were seen at both doses and included neutropenia 50% (n = 7), hyperglycemia 21% (n = 3), febrile neutropenia, infusion reaction, hyponatremia, decreased neutrophil count (2 each); at 400 mg only: fatigue, hypophosphatemia, and decreased WBC count (2 each). 7 men had serious AEs (SAEs), which were drug-related in 5. The most common SAE was febrile neutropenia in 2 men. At 3 mo, PSA50 and PSA90 rates were 86% and 36%, respectively; 12/14 men had a median PSA decline ≥70%; and median T declined to ≤0.2 ng/dL (0–10.7). The Cmax of D + ortl was similar to D alone. Conclusions: Ortl 200 mg and 400 mg BID + DP appears safe and tolerable with androgen-lowering activity at the maximum planned dose in mCRPC. There is no evidence of AE potentiation when ortl is administered with DP. The phase II portion of the study will use ortl 400 mg BID + DP.
Regional variation in survival after metastatic prostate cancer diagnosis.
Authors: Lakdawalla Darius , Gupta Charu , Luna Yesenia L , Thompson Stephen F , Tangirala Muralikrishna , Ng Daniel B , Nicacio Leonardo , Perlroth Daniella 
Published: March 2020

4666 Background: Survival after diagnosis of metastatic prostate cancer (mPC) averages 2-3 years. Substantial regional differences in survival have been documented for PC prior to 2000. We investigated the extent to which regional variation exists in survival for mPC patients during 2000-2007. Methods: Using the Surveillance, Epidemiology, and End Results (SEER) database linked to Medicare claims, we identified men (mean age, 77.6 years) continuously enrolled in Medicare Parts A/B who were diagnosed with mPC between 2000 and 2007 and not diagnosed with another malignancy. The base-case model was limited to hospital service areas with >50 patients. A Cox proportional hazards model was used to estimate hazard ratios (HR) for overall survival (OS), adjusting for year of diagnosis, age, marital status, poverty and education covariates, Gleason score, comorbidities, and region covariates. Sensitivity of results was tested by limiting the analysis to patients surviving at least 6 months after diagnosis and by removing regional sample size limits. We report HRs for covariates, results of a Wald test of joint significance for region effects, and percentage difference from the mean for each region’s HR for death. Results: A total of 2696 patients with mPC met the inclusion criteria. OS was 37% at 3 years and mean HR for death was 4.8 (sd 2.1). HRs for death were positively correlated with age (HR=1.96, 95% CI: 1.6-2.3 for >80 years), PC-specific comorbidity index (HR=1.2, 95% CI: 1.1-1.3), and Gleason score (HR=6.6, 95% CI: 2.4-17.8 for poorly differentiated). Year of diagnosis, race, and socioeconomic status were not significantly associated with mortality. Wald test of joint significance for survival across regions of P=.019 indicated significant differences in survival across regions and was robust in sensitivity analyses. Patients living in regions with the worst survival rates had HRs for death that were 20% higher than the mean (HR=5.8) and those living in regions with the best survival rates had HRs 30% lower than the mean (HR=3.4). Conclusions: There are significant regional differences in survival for mPC patients in the 2000s. Further research is needed to determine if treatment differences play a role in this disparity.
Olaparib plus paclitaxel plus carboplatin (P/C) followed by olaparib maintenance treatment in patients (pts) with platinum-sensitive recurrent serous ovarian cancer (PSR SOC): A randomized, open-label phase II study.
Authors: Oza Amit M. , Cibula David , Oaknin Ana , Poole Christopher John , Mathijssen Ron H.J. , Sonke Gabe S. , Colombo Nicoletta , Špacek Jirí , Vuylsteke Peter , Hirte Hal W. , Mahner Sven , Plante Marie , Schmalfeldt Barbara , Mackay Helen , Rowbottom Jacqui , Tchakov Ilian , Friedlander Michael 
Published: March 2020

5001 Background: The oral PARP inhibitor olaparib has shown antitumor activity in pts with SOC. Our multicenter study compared the efficacy of (Arm A) olaparib capsules plus P/C for 6 cycles then maintenance olaparib monotherapy vs (Arm B) P/C alone for 6 cycles and no further therapy in pts with PSR SOC (NCT01081951). Methods: Pts received 6 x 21-day(d) cycles of olaparib (200 mg bid, d1–10/21) + P (175 mg/m2 iv, d1) + C (AUC4 iv, d1), then olaparib monotherapy as maintenance (400 mg bid, continuous) (Arm A), or 6 x 21d cycles of P (175 mg/m2 iv, d1) + C (AUC6 iv, d1) then no further therapy (Arm B), until progression. Randomization (1:1) was stratified by number of platinum treatments and platinum-free interval. Primary endpoint: progression-free survival (PFS) by central review (RECIST 1.1). Secondary endpoints: overall survival (OS), objective response rate (ORR), safety. Archival tissue was collected where available for analysis of biomarker correlation. Results: Of 162 pts randomized (n=81 per arm), 156 received treatment (Arm A, n=81; Arm B, n=75) and 121 began the maintenance/no further therapy phase (Arm A, n=66; Arm B, n=55). Olaparib + P/C (AUC4) followed by maintenance olaparib showed a significant improvement in PFS vs P/C (AUC6) alone (HR = 0.51, 95% CI 0.34, 0.77; P=0.0012; median = 12.2 vs 9.6 months). OS data are immature (total events: 14%). ORR was similar for Arm A and Arm B (64 vs 58%). Most common AEs during the combination phase were alopecia (74 vs 59%), nausea (69 vs 57%) and fatigue (64 vs 57%) for Arm A vs Arm B, respectively. Pts with grade ≥3 AEs (65 vs 57%), serious AEs (SAEs: 15 vs 21%) and AEs leading to treatment discontinuation (19 vs 16%) were similar for Arm A vs Arm B. Most common AEs during maintenance/no further therapy were nausea (50 vs 6%) and vomiting (29 vs 7%). 29 vs 16% of pts had grade ≥3 AEs, 9 vs 7% had SAEs and 8% vs N/A discontinued due to AEs in the olaparib vs no treatment arms, respectively. There were no fatal AEs. Conclusions: In pts with PSR SOC, olaparib plus P/C (AUC4) followed by olaparib 400 mg bid monotherapy maintenance treatment resulted in a significant improvement in PFS vs P/C (AUC6) alone.
Outcome of patients with borderline ovarian tumors: Results of the multicenter AGO ROBOT study.
Authors: De Gregorio Nikolaus , Baumann Klaus H. , Keyver-Paik Mignon-Denise , Reuss Alexander , Canzler Ulrich , Wollschlaeger Kerstin , Kommoss Friedrich , Forner Dirk , Peters Martin , Schroeder Willibald , Münstedt Karsten , Richter Barbara , Ewald-Riegler Nina , Mahner Sven , Fotopoulou Christina , Schmalfeldt Barbara , Hilpert Felix , Kommoss Stefan , Hauptmann Steffen , Du Bois Andreas 
Published: March 2020

5005 Background: Borderline ovarian tumors (BOT) are a rare entity; current standard of care is based on the available data of predominantly small retrospective trials. Therefore we performed a pattern of care study including central pathology review. Methods: All consecutive patients diagnosed with BOT between 1998 and 2008 in 24 German institutions were included. Tumor samples were prospectively sent for central histopathological review to specialized gynecopathologists, clinical data were collected and patient follow-up was prospectively updated. Results: Pathological review was obtained in 1,042 of 1,236 pts resulting in 950 confirmed BOT cases analyzed here. Under- and overdiagnosis occurred in 3.8% and 5.0% of cases, respectively. Median age was 49 years; 84% of patients had FIGO stage I disease; serous type (S-BOT) was diagnosed in 64% and mucinous type (M-BOT) in 31%. Primary/re-staging surgery led to complete debulking in 92.3% of pts (residual disease 1.3%, unknown 6.4%). Adjuvant chemotherapy was given to 33 (3.5%) pts only. 165 (17%) underwent fertility preserving surgery and 31 (19%) of these patients had documented pregnancies thereafter. Overall, 74 (7.8%) pts experienced relapse and 43 (4.5%) died. Disease progression in the form of invasive carcinoma occurred in 30% of the relapses. Inadequate surgical staging, residual tumor, fertility sparing surgery and higher FIGO stage were associated with shorter progression-free survival (PFS). M-BOT showed a non-significant trend to longer PFS compared to S-BOT (p = 0.07). No differences were observed for laparatomy vs. laparoscopy as initial surgical approach or application of adjuvant chemotherapy. Conclusions: To this day, this is the largest data set available for BOT. Prognosis is favorable even without adjuvant therapy if correct surgical staging is performed. Both tumor characteristics and treatment variables had a significant impact on relapse rate and outcome. In contrast to previous studies, disease progression in the form of invasive carcinoma occurred in a significant amount of patients with relapsed disease.
Randomized phase II study of docetaxel plus vandetanib (D+V) versus docetaxel followed by vandetanib (D-V) in patients with persistent or recurrent epithelial ovarian, fallopian tube, or primary peritoneal carcinoma (OC): SWOG S0904.
Authors: Coleman Robert L. , Moon James , Sood Anil , Branham Donna , Delmore James Edwin , Bonebrake Albert J. , Anderson Garnet L , Alberts David Samuel , Markman Maurie 
Published: March 2020

5015 Background: Antiangiogenesis therapy has led to antitumor effects both preclinically and clinically. Vandetanib (V) is an oral tyrosine kinase inhibitor of VEGFR-2/3, EGFR and RET. These targets are of interest in OC care, as targeting has shown anti-tumor efficacy, particularly in combination with taxanes. We explored the efficacy, safety, and toxicity of docetaxel (D) and V in women with recurrent OC. Methods: Women with resistant, refractory, or progressive/persistent OC were eligible for this randomized phase II study provided they had not received D or V for recurrent disease. Patients were allowed to receive other anti-VEGF targeted agents for primary therapy (stratification variable). Up to 3 additional cytotoxic regimens for recurrence were allowed. Patients were allocated 1:1 to D(75 mg/m2, I.V.)+V (100 mg daily, p.o.) or D(75 mg/m2). Patients receiving single agent D were allowed to crossover to V upon progression (D-V). The primary endpoint was PFS. Other objectives were: OS, objective response (ORR), and frequency/severity of adverse events. The study was designed with 84% power to detect a 1.55 PFS hazard ratio using a one-sided P of 0.1. Results: 131 patients were enrolled; 5 were excluded (1 ineligible, 4 eligible but untreated). 9% had received prior anti-angiogenic therapy. 61 patients on D+V were assessable for toxicity; 19 (31%) had treatment-related G4 events, primarily hematologic. Similarly, 17 (26%) of 65 patients receiving D alone had G4 events, primarily hematologic. 34 (52%) patients crossed over to V; no G4 events were recorded among 32 evaluable patients. G3 diarrhea was observed in 14% of D+V patients; 5% D-V patients. G3 acneiform rash occurred in 2% and 0%, respectively. The median PFS estimates were 3.0 mos (D+V) vs 3.5 (D-V); HR (PFS): 0.98 (80% CI:0.75-1.27). For OS, the median estimates were 14 mos (D+V) vs 12 mos (D-V); HR (OS):0.84 (80% CI:0.56-1.28). ORR was 14% and 17%, respectively. Crossover V response was 4% (1/27 measurable patients). Conclusions: D+V was well tolerated in this population however, did not prolong PFS with respect to D.
A novel autologous oxidized whole-tumor antigen vaccine therapy for recurrent ovarian cancer.
Authors: Kandalaft Lana 
Published: March 2020

5023 Background: Despite surgical and chemotherapeutic advances, the death rate from ovarian cancer has not changed. We report here an enhanced dendritic cell vaccine platform developed for clinical testing. Furthermore we report the application of this novel platform comprising of dendritic cell (DC)-based autologous whole tumor antigen vaccination in a pilot study of patients with recurrent ovarian cancer. Methods: To determine the optimal tumor lysate preparation for loading DCs, ovarian tumor lines were prepared by HOCl-oxidation, UVB-irradiation or freeze and thaw. Normal donor DCs were evaluated for tumor lysate uptake, cytokine and chemokine productions and phenotype. The optimal lysate preparation, was used in a phase I study where five patients with recurrent ovarian cancer with available tumor lysate from secondary debulking surgery underwent intranodal vaccination with OC-DC, an autologous DC preparation pulsed with HOCL oxidized autologous tumor cells. Feasibility, safety, and biological and clinical efficacy were evaluated. Results: Normal donor DCs pulsed with HOCl-oxidized tumor lines demonstrated the highest tumor lysate uptake, matured efficiently after LPS and IFN-gamma stimulation, and produced higher levels of proinflammatory cytokines and chemokines. In vitro, these lysates loaded DCs primed T cell responses against ovarian tumor associated antigens and effectively expanded against tumor specific T cells from donors and patients. Therapy was feasible and well tolerated in all subjects. Vaccination with OC-DC produced limited grade 1 toxicities and elicited tumor-specific T cell responses. Moreover specific HLA-A2-restricted responses were documented following vaccination and HER-2/neu specific T cells were expanded following 10 days of in vitro culture. Patients exhibiting immune response demonstrated clinical benefit including two patients who demonstrated remission inversion on vaccine maintenance. Conclusions: We developed a DC-HOCl oxidized whole tumor lysate vaccine which was safe and well-tolerated by patients. The vaccine was highly proinflammatory and elicited cellular and humoral anti-tumor responses establishing a platform for immune-combinatorial therapy.