bluuebunny/crossref_metadata_2025_split huggingface dataset:
Relationship between VHL mutation status, tumor VEGF expression and plasma VEGF measurement in sporadic renal cell carcinoma
Authors: Fergelot P. , Rioux-Leclercq N. , Zerrouki S. , Bensalah K. , Patard J. 
Published: March 2020

4602 Background: The relationship between VHL mutation status and prognosis in renal cell carcinoma (RCC) remains controversial. The aim of this study was to evaluate prospectively the association between VHL status, tumor VEGF expression, plasma VEGF levels and usual prognostic parameters in RCC. Methods: 70 patients with clear cell RCCs were included in this study. Genomic DNA was extracted using the QIAmp DNA mini kit (Qiagen) from frozen tumor samples. Four amplimers covering the whole coding sequence and exon/intron junctions of the VHL gene were synthetized by PCR followed by Big Dye sequencing (Applied Biosystems). Mutation bearing sequences were confirmed in a second round of PCR and sequencing reactions. Tumor VEGF expression was determined by immunohistochemistry and plasma VEGF was measured by enzyme-linked immunosorbent assay (Quantikine immunoassay, R&D systems). Results were expressed in pg/ml. Qualitative and quantitative variables were compared by using Chi-square (Fischer exact test) and Student t tests, respectively. Results: A VHL mutation was found in 46 cases (65.7%). VHL mutations were localized in exon 1, 2 and 3 in 23, 16 and 7 cases respectively. Median tumor VEGF expression was 45% (5–100). Median plasma VEGF was 104 pg/ml (13–1430). A significant association was found between VHL mutation and N stage (p: 0.01), Fuhrman grade, symptoms at presentation (p: 0.02) or tumor size (p: 0.007). A VHL mutation was found in 83.5% of low grade (G1–2) and 80% of incidental tumors respectively. A trend towards more frequent VHL mutations was observed in T1 tumors (87% mutation rate, p: 0.07) and in good performance status patients. Interestingly, VEGF tumor expression and plasma VEGF levels were not significantly different among patients with tumors having or not mutated VHL (p: 0.7). Conclusion: VHL mutations are more frequent in small incidental low stage or low grade tumors. Although VHL inactivation was not specifically determined in this study, we failed to show any association between VHL mutational status and VEGF tumor or plasma expression suggesting that other pathways than the VHL/HIF axis are required for explaining the angiogenic phenotype of RCC. No significant financial relationships to disclose.
Randomized phase II study comparing 4 monthly doses of ipilimumab (MDX-010) as a single agent or in combination with a single dose of docetaxel in patients with hormone-refractory prostate cancer
Authors: Small E. , Higano C. , Tchekmedyian N. , Sartor O. , Stein B. , Young R. , Vestal J. , Moseley W. , Fischkoff S. , Lowy I. 
Published: March 2020

4609 Background: Ipilimumab is a fully human anti-CTLA-4 IgG1 monoclonal antibody that blocks CTLA-4 and augments immune responses. The current study evaluated the safety and activity of ipilimumab alone or with a single dose of docetaxel in hormone-refractory prostate cancer (HRPC). Methods: 43 chemotherapy naïve patients (pts) with HRPC, were treated; 23 were in arm A (ipilimumab at 3 mg/kg q 4 weeks × 4 doses) and 20 in arm B (ipilimumab as in Arm A and one dose of 75 mg/m2 of docetaxel on day 1). Results: Six pts, 3 in each arm, demonstrated a decrease in PSA of > 50%. Three pts, 2 in arm A, and 1 in arm B had confirmed PSA responses with durations of 79+ days, 169+ days, and 280 days, respectively. There were no radiologic responses with these PSA responses. Thirty-six (84%) of the 43 pts experienced 1 or more adverse events considered to be related to treatment with ipilimumab. The most common adverse events included fatigue (44%), pruritus (26%), nausea (19%), rash (12%), constipation (12%), and weight loss (12%). Serious adverse events (SAEs) occurred in 18 patients (42%), who experienced 52 SAEs. The majority (42 out of 52, 81%) were judged by the Investigator to be unrelated or unlikely to be related to treatment with ipilimumab. Five of the 52 SAEs reported in 3 pts were considered to be possible immune breakthrough events (IBEs), associated with drug exposure and consistent with an immune-based mechanism of action. These were adrenal insufficiency (1), diarrhea, colitis, and melena (all in one patient) and colitis (1). One of these pts had a confirmed PSA response. Conclusions: Ipilimumab was well tolerated in this group of pts with HRPC. Three pts overall (6%) experienced an IBE, a phenomenon that has been correlated in other studies with efficacy. There were several confirmed responses as assessed by PSA, one of which was correlated with an IBE. There was no apparent enhancement of activity by coadministration of a single dose of docetaxel. Further studies exploring ipilimumab in prostate cancer are warranted, either as monotherapy at higher doses, or in combination with immune modulators or vaccines. [Table: see text]
Skeletal related events (SREs) in metastatic androgen independent prostate cancer (AIPC) treated with docetaxel-based chemotherapy: Results from ASCENT
Authors: Chan J. S. , Ryan C. W. , Venner P. M. , Petrylak D. P. , Chatta G. S. , Ruether J. , Chi K. N. , Young J. , Shen C. , Beer T. M. 
Published: March 2020

4614 Background: Docetaxel prolongs survival in AIPC patients and zoledronic acid (ZA) reduces the incidence of SREs. The SRE incidence of patients treated with docetaxel-based chemotherapy has not previously been reported. Methods: ASCENT was a randomized clinical trial that compared weekly DN-101 (calcitriol, 45 μg p.o. on day 1) plus docetaxel (36 mg/m2 iv on day 2 for 3 weeks of a 4-week cycle) to placebo plus docetaxel in patients with chemotherapy-naïve metastatic AIPC. ZA use was not restricted. SRE-free survival was described for the entire group and then compared for patients randomly assigned to DN-101 or placebo and stratified by ZA use. Statistical comparisons were conducted using Cochran-Mantel-Haenszel for incidence and log-rank for SRE-free survival. Results: With a median follow-up of 18.3 months, 33% of subjects experienced at least one SRE and the overall median SRE-free survival was 13 (95% CI 10.5–14.3) months. The incidence of SRE by type was: radiation to bone (18.8%), fracture (10%), spinal cord compression (4%), surgery to bone (0.4%). Eighty-five (34%) patients received ZA. The study was not adequately powered to measure the impact of DN-101 or ZA on SRE endpoints. Exploratory analyses showed a trend for an increase in SRE-free survival (HR 0.78, p = 0.13) of DN-101-treated patients. SRE-free survival and incidence for subgroups were examined ( Table ). Conclusions: This is the first report of SRE incidence in a large, prospective study of docetaxel-based therapy. Improved therapies for reducing SREs in AIPC are needed because the risk of SREs remains high despite the use of modern chemotherapy and ZA. [Table: see text] [Table: see text]
The influence of nodal status on progression outcomes in patients with prostate cancer: Data from the Early Prostate Cancer program at 7.4 years
Authors: Iversen P. , Wirth M. P. , See W. A. , McLeod D. G. , Morris T. , Armstrong J. 
Published: March 2020

4628 Background: The Early Prostate Cancer (EPC) program is an ongoing study of the effect of adding bicalutamide (CASODEX) 150 mg to standard care (radiotherapy [RT], radical prostatectomy [RP], or watchful waiting [WW]) for men with localized or locally advanced prostate cancer. At a median 7.4 years’ follow-up, bicalutamide significantly improved objective progression-free survival (PFS) in men with locally advanced disease, irrespective of standard care, and improved overall survival in the RT setting. There was no PFS benefit in patients with localized disease. Lymph-node involvement is an established risk factor for progression, so we conducted an exploratory analysis among patients with locally advanced disease to assess the influence of this risk factor on PFS. Methods: The EPC program (n = 8113) comprises 3 randomized trials designed for combined analysis. Patients with localized (T1–2, N0/Nx) or locally advanced (T3–4, any N; or any T, N+) non-metastatic prostate cancer received bicalutamide (n = 4052) or placebo (n = 4061) once daily plus standard care. This subanalysis studied the effect of nodal status (N−, N+, Nx) in locally advanced disease. Results: In patients with locally advanced disease, PFS improvements were irrespective of nodal status. The treatment effect increased as the risk of progression increased from N− to Nx to N+ disease. The greatest reduction in risk was seen in RP patients with N+ disease. Conclusions: The reduction in risk of progression with bicalutamide was seen irrespective of nodal status. The most significant reduction in risk of progression was in RP patients with N+ disease; survival data by nodal status for these patients will be presented. [Table: see text] [Table: see text]
Clinical benefit of atrasentan for men with metastatic hormone-refractory prostate cancer metastatic to bone
Authors: Sleep D. J. , Nelson J. B. , Petrylak D. P. , Isaacson J. D. , Carducci M. A. 
Published: March 2020

4630 Background: Hormone-refractory prostate cancer (HRPC) metastasizes most commonly to bone. Treatment of advanced HRPC patients focuses on alleviating bone pain that afflicts 85% of patients. New therapies are needed that not only prolong survival but slow the progression of morbidity. Atrasentan, a selective endothelin A receptor antagonist that blocks the effect of endothelin in the bone microenvironment by slowing osteoblast proliferation, may slow disease progression in HRPC patients with bone metastases. Methods: Patients enrolled in a randomized, double-blind, placebo-controlled multinational trial of atrasentan 10 mg with independently confirmed bone metastases (N = 690) were followed until the first event of disease progression, which could be by radiographic (≥2 new lesions on bone scan) or clinical means (eg, pain requiring significant opioids or other interventions, spinal cord compression). Analyses were performed on time to disease progression and separately on time to clinical and radiographic progression. The difference between treatments was analyzed using Kaplan-Meier methods and Cox proportional hazards modeling. Results: N = 335 for placebo; N = 355 for atrasentan. Atrasentan therapy resulted in fewer disease progression events relative to placebo and reduced the risk of disease progression by 19% ( Table ). The differential effect of atrasentan on disease progression was most notable against clinical progression (32% reduction in risk vs placebo). Conclusions: In men with HRPC metastatic to bone, atrasentan delays disease progression, especially clinical events, relative to placebo. [Table: see text] [Table: see text]
Hormonal adjuvant treatment plus radiotherapy versus exclusive radiotherapy in locally advanced prostate cancer: Pooled analsys of 6 randomized trials
Authors: Carlini P. , Bria E. , Ciccarese M. , Milella M. , Arcangeli G. , Gallucci M. , Ruggeri E. , Terzoli E. , Cognetti F. , Giannarelli D. 
Published: March 2020

4642 Background: The magnitude of the benefit of adding adjuvant hormonal treatment to radiotherapy for locally advanced prostate cancer is still unclear. We performed a pooled-analysis of phase III trials, to quantify the eventual benefit in recurrence decrease. Methods: All prospective phase III trials were considered eligible. A pooled analysis was accomplished, and event-based relative risk ratios (RR) with 95% confidence interval (CI) were derived through both a fixed- (FEM) and a random-effect model (REM) approach. Significant differences in primary outcome (recurrence rate), and secondary outcomes (overall survival), were explored. Magnitude outcome measures were: absolute benefits and number of patients needed to treat (NNT) for 1 patient to benefit. Heterogeneity test was applied as well. Results: Six trials designed to look if hormonal treatment plus radiotherapy decreases recurrence rate (3,571 patients) were gathered. In the primary outcome, the combined approach significantly improves the recurrence rate when applying the FEM (RR 0.72, 95% CI 0.68, 0.77, p < 0.0001), with an absolute benefit of 10.7%. The NNT was 9 patients. Although significant heterogeneity was found (p = 0.00001), the benefit remains significant at the REM as well (RR 0.67, 95% CI 0.54, 0.82, p < 0.0001). Although significant at FEM (RR 0.93, 95% CI 0.86, 1.00, p = 0.039) but heterogeneous (p = 0.0007), the overall survival demonstrated a not-significant trend in favour of the combined strategy at REM (RR 0.90, 95% CI 0.75, 1.10, p = 0.263). Conclusions: Considered all the available phase III trials, the combination of adjuvant hormonal treatment with radiotherapy over standard exclusive radiotherapy significantly decreases the recurrence rate in patients affected by localized prostate cancer. The significant heterogeneity in the analysis underscores the existing difference in patient’ characteristics. No significant benefit in overall survival was found. No significant financial relationships to disclose.
Bevacizumab in patients with advanced platinum-resistant ovarian cancer
Authors: Cannistra S. A. , Matulonis U. , Penson R. , Wenham R. , Armstrong D. , Burger R. A. , Mackey H. , Douglas J. , Hambleton J. , McGuire W. 
Published: March 2020

5006 Background: Bevacizumab (BV), a recombinant, humanized monoclonal antibody directed against vascular endothelial growth factor, has demonstrated clinical benefit in multiple tumor types. Activity in ovarian cancer (OC) has been reported in phase II studies in patients (pts) with recurrent disease. We now describe the activity/safety of BV in pts with platinum-resistant OC (PROC) that progressed after topotecan or liposomal doxorubicin (LD). Methods: Eligibility criteria for this multicenter, Phase II study included primary or secondary PROC that progressed within 3 months of topotecan or LD, 3 or fewer prior chemotherapy regimens, and a performance status (PS) 0 or 1. BV was dosed at 15 mg/kg q 3 weeks until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) as defined by RECIST. A two-stage design was utilized with H1 set at 15%. Secondary endpoints included progression-free survival (PFS), duration of response, overall survival (OS), and safety. Results: The study enrolled 44 of the intended 53 pts, closing early due to a higher than expected rate of gastrointestinal perforations (GIP). Baseline characteristics included median age 60 yrs (range 31–87); PS 0 in 26 pts, 1 in 18 pts; 2 prior chemotherapy regimens in 20 pts, 3 in 24 pts. Preliminary efficacy: ORR (CR+PR), 7/44 (16%). Median duration of response was 12 weeks, with 2 pts continuing on study >5 months. Serious adverse events (SAEs) were reported in 18/44 pts (41%). Selected SAEs included GIP 5 (11%; one occurred more than 30 days after coming off study while on paclitaxel and commercial Avastin®), bowel obstruction 5 (11%), arterial thromboembolic events 4 (9%), delayed wound healing 2 (5%), and one case each of pulmonary hypertension, hypertensive encephalopathy, and hypoxia. Conclusions: BV has single agent activity in women with PROC, but is associated with substantial toxicity in this population. Trials are ongoing in less heavily treated, newly diagnosed pts with OC to evaluate the efficacy and safety of BV in these disease settings. Identification of risk factors for BV-associated adverse events requires further study. [Table: see text]
Phase I trial of KOS-953, a heat shock protein 90 inhibitor, and trastuzumab (T)
Authors: Modi S. , Stopeck A. , Gordon M. S. , Solit D. , Ma W. , Wheler J. , Cropp G. , Johnson R. G. , Hannah A. L. , Hudis C. 
Published: March 2020

501 Background: KOS-953 (17-AAG in Cremophor) is a potent Hsp90 inhibitor that in vivo induces rapid degradation of Her2, loss of pAKT and tumor growth inhibition in a Her2+ breast cancer xenograft. Objectives: Define the phase 2 dose of KOS-953 + T. Define toxicity and PK of KOS-953, its active metabolite and T. Assess changes in intracellular signaling proteins (such as Hsp70) in leucocytes. Describe antitumor activity. Methods: Eligible pts with advanced solid tumors (Her2 + was not required) received standard weekly doses of T followed by IV KOS-953 in escalating doses over 2 hrs. Results: 25 pts enrolled in 4 cohorts (225, 300, 375 and 450 mg/m2; 4, 3, 8 and 10 patients per cohort), receiving a total of 94 cycles (median 3, range <1 - 12+). Demographics: 21 female (17 with Her2+ metastatic breast cancer ‘MBC‘, 1 Her2 status unknown); median age/KPS 66 yrs/90; # prior T-containing regimens for MBC pts (n=18) equaled 2 (range 0–5). DLT was observed at the 3rd and 4th cohort (1 pt each): 2-week dose delay for recovery from Grade 4 fatigue/Grade 2 nausea & anorexia at 375 mg/m2; delayed recovery of platelets at 450 mg/m2. Drug-related Grade 3 toxicity: emesis, increased ALT and hypersensitivity (n=2); Grade 4 drug-induced thrombocytopenia in a pt with Hashimoto’s disease after 7 cycles. In general the drug was well tolerated. Grade 1 or 2 toxicities included fatigue, nausea, diarrhea, emesis, headache, rash/pruritus, increased AST/ALT and anorexia. Most toxicities (except headache) were not dose dependent. PK of parent (n=21): t½ 3.0 ± 2.1 h; clearance 31.8 ± 12.8 L/h; Vz 164 ± 101 L. Metabolite: Tmax 30–60 min after end-of-infusion with similar AUC and longer t½ of 6.1 ± 1.7 h. PK of T showed no changes compared to previous reports. Among 17 pts with Her2 + MBC s/p multiple regimens of T: PR= 1, MR = 3, 5 pts with SD (5, 7+, 9 and 12+ months). Pts with PR and MRs had confirmed progression of disease prior to study on T-containing regimen. Pharmacodynamic testing showed reactive induction of Hsp70/72 in leucocytes at all dose levels. Conclusions: KOS-953 added to T is active in refractory Her2 + MBC with no change in PK compared to single-agent therapy. The phase 2 dose of KOS-953 is 450 mg/m2; enrollment to the phase 2 trial of this combination in Her2+ MBC is on-going. [Table: see text]
EGF103009, a phase II trial of lapatinib monotherapy in patients with relapsed/refractory inflammatory breast cancer (IBC): Clinical activity and biologic predictors of response
Authors: Spector N. L. , Blackwell K. , Hurley J. , Harris J. L. , Lombardi D. , Bacus S. , Ahmed S. B. , Boussen H. , Frikha M. , Ayed F. B. 
Published: March 2020

502 Background: Data from preclinical studies and small numbers of IBC patients inPhase I clinical trials suggest that IBC may be particularly sensitive to the anti-tumor effects of lapatinib, an inhibitor of ErbB1/ErbB2 tyrosine kinases. EGF103009 was initiated to confirm and expand these initial observations and identify a tumor profile predicting for the sensitivity of IBC to lapatinib. Methods: Patients with relapsed/refractory IBC based on clinical criteria, were assigned to Cohort A (ErbB2 overexpressors: 2/3+ IHC/FISH+) or B (ErbB1 +/ErbB2 non-overexpressors) after analysis of a fresh tumor biopsy in a central reference lab. Patients received lapatinib daily (1500mg/d). Clinical response was documented at day 56 and in the case of CR/PR, confirmed on day 84 and every 8 weeks thereafter. Target lesions were assessed according to RECIST criteria and response in skin disease documented by digital photography. Tumor expression of ErbB2, p-ErbB2, ErbB1, p-ErbB3, IGF-IR, PTEN, ER/PR, E-cadherin, β-catenin, and Rho B/C was analyzed by quantitative IHC from a fresh, pre-treatment biopsy. Results: Of 34 patients enrolled, clinical response data is available from 22 patients of which 17 had biopsies analyzed at a reference lab and assigned to Cohorts A (N=11) and B (N=6). Eight of 11 patients (72%) in Cohort A had a clinical response (CR/PR) to lapatinib documented by RECIST, skin disease, or both. There were no responders in Cohort B. All responders (i) overexpressed ErbB2 (2/3+ IHC or FISH+), (ii) increased p-ErbB2 (2/3+), (iii) co-expressed IGF-IR, and (iv) expressed activated, p-ErbB3. PTEN status did not affect response to lapatinib. Toxicity was generally grade I/II skin and G.I. with one grade III cardiotoxicity necessitating withdrawal from study. Conclusions: ErbB2 overexpression but not ErbB1 expression alone, predicts for sensitivity to lapatinib in IBC. High ErbB2, p-ErbB2 and IGF-IR co-expression predict for clinical response to lapatinib monotherapy in patients with relapsed/refractory IBC, illustrating the importance of selecting patients based on biology rather than histology alone, to maximize the clinical efficacy of ErbB kinase inhibitors in breast carcinomas. [Table: see text]
Prognostic impact of MAD1L1 promoter hypermethylation in advanced ovarian cancer
Authors: Jansen R. A. , Liu J. C. , Liyanarachchi S. , Crijns A. P. , Yan P. S. , Huang T. H. , Cohn D. E. , Fowler J. M. , Van der Zee A. G. , Brown R. 
Published: March 2020

5021 Background: Aberrant methylation of GC-rich gene promoters is a frequent epigenetic event in ovarian cancer leading to silencing of tumor suppressor genes. Identification of methylation biomarkers holds promise for impacting patient survival. Methods: High-throughput screening of hypermethylated CpG islands was conducted by differential methylation hybridization on stage III and IV epithelial ovarian carcinomas. Tumor DNA methylation status was interrogated by methylation-sensitive restriction enzymes, followed by co-hybridization on a custom promoter CpG island array with pooled normal ovarian surface epithelial cell (nOSE) DNA. Microarray findings were validated by quantitative methylation-specific PCR (qMSP) on 55–79 tumor samples. Results: Methylation levels of 6 novel genes (CYP39A1, EBP, FOXD4b, GTF2A1, MAD1L1 and YY1AP1) functioning in cell cycle control, transcription and drug metabolism/transport were identified as hypermethylated in ovarian cancer versus nOSE (nonparametric Wilcoxon rank sum test, p < 0.005). Using Fisher’s exact test, patients with shorter progression-free survival (PFS) (≤18 months) had higher methylation levels compared to those with longer PFS (p = 0.015) for the gene MAD1L1, a mitotic checkpoint protein and antagonist of c-myc that regulates cell proliferation and differentiation. Cox regression analysis of methylation levels and PFS identified a negative correlation for MAD1L1. This correlation achieved statistical significance when MAD1L1 methylation levels combined with chemotherapy response was tested against PFS (p = 0.021), suggesting an interaction of this gene in patient response to chemotherapy. Conclusions: Induced overexpression of MAD1L1 has been shown to delay cell proliferation and inhibit growth. Downregulation via hypermethylation of this gene results in cell cycle dysregulation, a pathway for disease progression. This epigenetic modification in MAD1L1 renders it a potential target for intervention therapies that could improve patient survival. No significant financial relationships to disclose.