bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association of SPARC expression with metastatic progression and prostate cancer-specific mortality after radical prostatectomy.
Authors: Jeldres Claudio , Johnston Richard Bruce , Porter Christopher R. , Nelson Peter 
Published: March 2020

5071 Background: We assessed the expression of the glycoprotein SPARC (secreted protein, acidic, rich in cysteine) in patients with prostate cancer (PCa) treated with radical prostatectomy (RP) and studied its association with adverse clinico-pathological features at RP and long-term clinical outcomes, such as metastatic progression after surgery and cancer-specific death. Methods: Tissues from 78 patients with PCa were used to quantify SPARC expression using tissue microarray (TMA) and immunohistochemistry techniques (IHC). Anti-SPARC mouse monoclonal antibody were use to target the protein and for each patients 4 samples of tissue were used for cytoplasmic staining. Staining of each core was reviewed by an uropathologist who assigned a score (score 0-3) to each core and a global score also assigned to each patient (score 0-3). Analyses of the data relied in cross tables, T-test analyses, survival plots and Cox regression models. Results: Higher expression of SPARC protein was recorded in patients who develop metastases during follow-up after RP (p=0.025) and in patients who died of PCa after RP (p=0.002). Median follow-up of the cohort was 9.3 years after RP. At 5 years, 95.5%, 92.0% and 89.3% of patients were metastases-free for SPARC expression score 1, 2 and 3 respectively. For the same categories, 10 years after RP, 82.2%, 77.0% and 69.9% were metastases-free (Log-rank tests all p≤0.05). Similarly, patients with high SPARC expression had worse cancer-specific survival at 5 and 10 years after RP compared to those with low SPARC expression (Log-rank tests all p≤0.01 when score 1 was compared to score 2 or score 3). Finally, advanced stage at RP (T3-T4) [p=0.04] and high Gleason sum (8-10) [p=0.02] were also associated with higher expression of SPARC. Conclusions: High SPARC expression was associated with worse outcomes in men with prostate cancer treated with radical prostatectomy. Men who developed metastatic disease and men who succumbed to prostate cancer had higher levels of SPARC at radical prostatectomy than their counterpart. SPARC may have an important role in the progression of the disease and may eventually help clinician to better ascertain the risk of progression of the disease.
Quantifying copy number variations in cell-free DNA for potential clinical utility from a large prostate cancer cohort.
Authors: Schütz Ekkehard , Akbari Mohammad R , Beck Julia , Urnovitz Howard B. , Zhang William , Mitchell William M. , Nam Robert , Narod Steven 
Published: March 2020

5072 Background: Prostate cancer (PrCa) is the most frequent non-dermatological malignancy in the male population. Genomic instability resulting in copy number variation (CNV) is a hallmark of malignant transformation. CNV traces from tumors in cell-free DNA (cfDNA) of prostate cancer patients may be identified through massive parallel sequencing (MPS) of serum DNA. These CNV traces may be biomarkers of cancer with clinical applications for screening and follow-up. Methods: DNA was extracted from serum of 205 PrCa patients (Gleason 2 to10), 207 age matched male controls (HC), 10 men with benign hyperplasia (BPH) and 10 with prostatitis (PiS). DNA was amplified using random primers, tagged with a unique molecular identifier per sample, sequenced on a SOLiD system and aligned to the human genome (Build 37). Hits were counted in sliding 100kbp intervals and normalized. Using a random-resampling procedure, genomic regions showing copy number variations in cfDNA that distinguish PrCa from HC were selected. A model using 20 cfDNA regions was cross-validated and used as cfDNA biomarker. Receiver operator characteristics (ROC) curves were calculated for assessment of diagnostic performance by means of area under the curve (AUC). Results: To assess whether CNVs in cfDNA are indicative of PrCa, the number of regions with significant CNV deviation was counted in a first subset of 82 PrCa. Using only the number of regions as measure resulted in an AUC of 0.81 (0.7 – 0.9, p<0.001). Therefore, all samples were used to select regions (n=80) in random resampling (50/50). These regions were used to define a highly significant 20-regions model using five rounds of 10-fold cross-validation (AUC: 0.85±0.7; p< 10-7). This final model discriminated between PrCa and HC with an AUC of 0.92 (0.87 – 0.95) reaching a calculated accuracy of 83%. Both BPH and PiS could be distinguished from PrCa using the cfDNA CNV biomarker with a predicted accuracy of 90%. Conclusions: MPS revealed that only a limited number of chromosomal regions showing CNVs are necessary to achieve statistical separation between prostate cancer and controls. This technique may prove to be clinically useful for screening and follow up of men with prostate cancer.
A randomized double-blind phase II study of the combination of oral WX-671 plus capecitabine versus capecitabine monotherapy in first-line HER2-negative metastatic breast cancer (MBC).
Authors: Goldstein Lori J. , Oliveira Celia Tosello , Heinrich Bernhard , Stemmer Salomon M. , Mala Carola , Kastner Sabine , Bevan Paul , Richters Lisa , Schmalfeldt Barbara , Harbeck Nadia 
Published: March 2020

508 Background: uPA and its inhibitor PAI-1 play a key role in tumor invasion, metastasis and tumor growth. uPA and PAI-1 are biomarkers validated at highest level of evidence in breast tumors and are recommended for clinical decision making by ASCO. WX-UK1 is a competitive inhibitor of uPA with an inhibition constant in the submicromolar range. WX-671 (upamostat) is an oral prodrug of WX-UK1. Methods: Female patients aged >18, with HER2 negative MBC were randomized in a double-blind fashion to receive upamostat (200 mg orally daily for 21 days) plus C (1000 mg/m2 orally twice daily for 14 days) vs. C (same regimen) in 3 week treatment cycles until progressive disease or unacceptable toxicity. 132 from five countries were enrolled. The primary objective was to evaluate the efficacy of the combination of upamostat and C compared to C alone by assessment of progression free survival (PFS). The study also evaluated the objective response rate and safety as well as pharmacokinetics (PK). Efficacy was evaluated by RECIST by independent central read. Results: Median treatment duration was 8 cycles in both arms. In the total study population (intent to treat; ITT) upamostat led to an increase of median PFS from 7.5 months (95% CI: 4.2; 12.8) in the control group to 8.3 months (95% CI: 5.6; 9.6) in the combination therapy. An unexpectedly high rate (50%) of study patients presented within their first two years after initial diagnosis. In patients who had received prior adjuvant chemotherapy, PFS improved from 4.3 months (95% CI: 2.6; 9.7) in the C alone group to 8.3 months (95% CI: 5.6; 10.9) in the upamostat plus C group. The overall response rate was higher in the combination group compared to C alone (20% vs. 12% at Week 24). PK analysis demonstrated no drug-drug interactions between upamostat and C. The combination therapy was safe and well tolerated. Conclusions: This is the first proof of efficacy of an anti-uPA therapy in breast cancer. The heterogeneity of the patients in this study may underestimate the potential treatment effects of upamostat. Additional subset analyses will be presented. Future biomarker-stratified strategies may reveal better efficacy. Clinical trial information: NCT00615940.
Circulating miR-337-3p as a novel biomarker for prostate cancer.
Authors: Valladares Ayerbes Manuel , Medina Villaamil Vanessa , Martinez Breijo Sara , Santamarina Cainzos Isabel , Aparicio Guadalupe , Gonzalez Dacal Jose , Portela Pereira Paula , Vazquez Pazos Dario , Gomez-Veiga Francisco , Antón Aparicio Luis M. 
Published: March 2020

5087 Background: Recent studies have demonstrated that the aberrant expression of microRNAs (miRNAs)is related with the development of prostate cancer (PCa). Detection of circulating tumor cells (CTC) may provide diagnostic and prognostic information inPCa. The purpose is identifying circulating miRNAs potentially useful for CTC detection in patients with PCa. Methods: In the first study phase we examined blood levels of 92 miRNAs in 49 patients grouped in pools by risk classification: low-risk 42.8%, intermediate-risk 22.5% and high-risk 34.7% and healthy volunteers (N=10) using SYBR-green-based microARN RT-qPCR arrays (Exiqon). Prostate cancer diagnosis was obtained by transrectalultrasound guided biopsy of 10 cores, PSA and digital rectal examination was done previously. In the second study phase using quantitative real-time polymerase chain reaction (qPCR) by TaqMan Human MicroRNAAssays (Life Technologies), we compared the expression levels of miRNAs in blood samples from 34 patients of low-risk, 31 of intermediate-risk, 18 of high-risk localized disease and 22 healthy volunteers paired by age with cases. Receiver-operator characteristic (ROC) curve was used. Results: Blood samples from patients with low, intermediate, high-risk and healthy controls exhibit distinct circulating miRNA signatures. microRNAsdifferential expressed between risk groups (p<0.01) (low, intermediate and high) and control group: 0microARNs upregulated (MU), 12 MU and 68 MU respectively. Highlight the significantlyoverexpression in the intermediate risk group and maintained at the high-risk of microRNAs: 337-3p[247 PicTar predictions (PTP)], 330-3p (307 PTP) and 218 (551 PTP). Preliminary results of the second study phase showed that the median level of miRNA,337-3p was significantly higher in patients with high-risk than that in healthy controls (p=.001). ROC curve analyses indicated that this blood miRNA may beuseful for discriminating patients with high-risk from healthy controls (AUC=.724). Conclusions: miRNAs in the circulation are relatively stable, very accessible, low invasive and easily testable biomarkers. Our preliminary promisingresults suggest miR-337-3p as novel stable blood-based marker for PCa detection.
Effects of abiraterone acetate and enzalutamide on muscle and adipose mass in men with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Ileana Ecaterina , Antoun Sami , Albiges Laurence , Massard Christophe , Di Palma Mario , Escudier Bernard J. , Fizazi Karim , Loriot Yohann 
Published: March 2020

5088 Background: Abiraterone acetate (AA) and enzalutamide (MDV3100), two androgen receptor-directed compounds, have been shown to improve survival for patients with metastatic castration-resistant prostate cancer (mCRPC) progressing after Docetaxel.. Since these drugs might be used at an early-stage in the future, and skeletal muscle (SM) and adipose tissue (AT) are known to be prognosis parameters, the aim of this study was to evaluate the body composition changes in patients with mCRPC treated with AA and MDV3100. Methods: Patients included in AFFIRM (n=62 treated with MDV3100 and placebo n=28) and COU-AA-301 (n=24 treated with AA+Prednisone (P)10mg/day and placebo+P n= 13) trials at the Institute Gustave Roussy were included in the analysis. Cross-sectional areas (cm2) of visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT) and SM were assessed by computed tomography imaging at 3rd lumbar vertebra and were indexed for height (cm2/m2) with Slice-O-Matic software V4.3 at baseline, 3, 6 and 12 months of treatment. The data from patients treated with AA or MDV3100 were compared to placebo-patients and tissues changes were compared to baseline. We used the validated sarcopenic definitions as SM index less than 52.4 (cm2/m2). Results: For all cohort, median age was 69 years (range: 48-83), median weight was 79 kg (range: 47-150) and median BMI was 25.9 kg/m2(range: 18-46). At inclusion, 74 patients (58%) were overweight or obese (BMI>24.9 kg/m2), and only 2 patients were underweight (BMI<18.5kg/m2). 97 patients (81%) were sarcopenic, and 56 (75%) of overweight or obese patients were sarcopenic. Over 3 months, the patients from the entire cohort lost muscle mass (mean change: 4.5±7.5% (» 0.7 kg of muscle)) (P=0.01) . A non significant loss of SAT -4.6±19.2% and a non significant increase of VAT (+10.7±50.3% ) were observed. A similar pattern was observed at 6 months. There was no significant difference between body composition changes in treated groups and placebo. Conclusions: Sarcopenia is highly prevalent in patients with advanced CRPC. Unexpectedly, no difference in body composition changes was observed between patients treated with MDV3100 or AA and placebo.
Overall survival in hormone-resistant prostate cancer patients with different transition of care within the Veterans Affairs (VA) system.
Authors: Sutton S Scott , Rao Gowtham A , Norris LeAnn B. , Hardin James , Prasad Sandip M. , Bennett Charles L. 
Published: March 2020

5091 Background: Prostate cancer patients with locally advanced /metastatic disease have a poor prognosis and although hormonal therapy can induce long-term remission, development of hormone-resistant prostate cancer (HRPC) is inevitable. The goal of this study is to evaluate overall survival in HRPC patients with different transition of care in the Veterans Affairs (VA) system. We hypothesized that prostate cancer patients with late referral to medical oncologists were more likely to have decreased overall survival. Methods: This is a retrospective, observational analysis of patients enrolled in the Veterans Health Administration system from October 2003 to March 2011. Patients were followed from initial evaluation and treatment by urology until an endpoint of death or the end of the study period. VA patients with a diagnosis of HRPC were identified; prostate specific antigen (PSA), medical and pharmacy records were collected. HRPC was defined as PSA doubling after treatment with hormonal therapy. Transition of care was defined as two encounters with the medical oncology service and at least one encounter was a medical oncologist. Three cohorts were created: patients transitioned to oncology before HRPC, those transitioned to oncology after HRPC, and patients who were never transitioned to oncology. Primary outcome was overall survival (OS). The Charlson score was utilized for comorbidity assessment. Statistical analysis was conducted using chi square test for categorical variables. Results: Total number of patients evaluated was 8,281; 2,168 in transition before HRPC (tbHRPC) cohort, 2,052 in transition after HRPC (taHRPC), and 4,061 patients that never transitioned (tnHPRC). The mean ages for the respective cohorts were: 69.35, 69.69, and 71.64. The Charlson comorbidity scores were 3.79 (tbHRPC), 3.06 (taHRPC), and 3.14 (tnHRPC); p-values < 0.05. Mortality rates among the cohorts were 57% tbHRPC, 69% taHRPC, and 62% tnHRPC; p-values <0.001. PSA doubling within 10 months were: 57% tbHRPC, 60% taHRPC, and 54% tnHRPC; p-values < 0.05. Conclusions: Overall survival was improved among prostate cancer patients that transitioned to oncology before becoming HRPC.
A phase Ib study of an anti-HER2 inhibitor, lapatinib, in combination with a c-MET and VEGFR inhibitor, foretinib, in HER2-positive metastatic breast cancer (MBC): Results from NCIC CTG IND.198.
Authors: Chia Stephen K. L. , Ellard Susan , Mates Mihaela , Welch Stephen , Mihalcioiu Catalin Liviu Dragos , Miller Wilson H. , Gelmon Karen A. , Lohrisch Caroline A. , Kumar Vikaash , Taylor Sara Kristina , Hagerman Linda , Eisenhauer Elizabeth A. , Bradbury Penelope Ann 
Published: March 2020

518 Background: The mechanisms of resistance to targeted anti-HER 2 therapy are unclear. Proposed pathways include MET, VEGF and AXL. Multi-targeted pathway inhibition may delay or prevent acquired resistance to HER2 inhibition. Foretinib, an oral multi-kinase inhibitor of MET and VEGFR2, as well as PDGFRB, AXL, FLT3, TIE-2, RET and RON kinases, has pre-clinical anti-tumor activity in breast tumor models. This phase 1b study sought to establish the associated toxicities, pharmacokinetics (PK) and recommended phase II doses (RP2D) of this combination of oral tyrosine kinases inhibitors in a cohort of HER-2 positive MBC patients. Methods: Women with HER2 positive (determined locally) MBC, PS 0-2, and no limit on number of prior chemotherapies or lines of anti-HER2 therapies were enrolled. A 3+3 dose escalation design was utilized. 4 dose levels were planned with starting doses of foretinib 30 mg and lapatinib 750 mg PO OD (dose level 1) on a q 4 weekly cycle. Correlative studies from primary archival tissue are planned. Results: 19 patients were enrolled, all of whom were evaluable for toxicity assessment and 16 were evaluable for response. Median age was 60 years (34-86), 95% were PS 0-1, 53% were ER- and 95% had at least one prior anti-HER2 based regimen. A median of 2 cycles (range: 1-20) was delivered across 4 dose levels. At the 4th dose level (foretinib 45 mg/lapatinib 1250 mg) dose limiting toxicities were documented in 4/7 patients. These included grade 3 fatigue (2 cases); grade 3 ALT elevation; grade 3 diarrhea and grade 2 joint effusion. There was only one grade 4 non-hematological toxicity (grade 4 vomiting: dose level 1) across all dose levels. One patient discontinued treatment due to toxicity with grade 3 limb edema and grade 3 proteinuria. PK of both drugs from DL1-3 did not appear to demonstrate a significant interaction. The RP2D was declared to be foretinib 45 mg and lapatinib 1000 mg PO OD. The full efficacy data and correlative studies will be presented at the meeting. Conclusions: The combination of foretinib and lapatinib can safely be delivered together, though at lower doses than either agent alone.
Treatment (tx) patterns and clinical outcomes for patients (pts) with de novo versus recurrent HER2+ metastatic breast cancer (MBC).
Authors: Brufsky Adam , Yardley Denise Aysel , Kaufman Peter Andrew , Ulcickas Yood Marianne , Rugo Hope S. , Mayer Musa , Quah Cheng Seok , Yoo Bongin , Tripathy Debu 
Published: March 2020

523 Background: Use of adjuvant trastuzumab (T) in pts with HER2+ early breast cancer is associated with decreased recurrence. As fewer patients relapse, the proportion of pts with de novo metastatic disease in the first-line (1L) setting will increase, which could have implications for the design/interpretation of results from HER2+ MBC trials. To date, little data exist on potential differences in prognosis and outcomes between pts with recurrent vs de novo HER2+ MBC. Methods: registHER is an observational cohort of pts with HER2+ MBC diagnosed ≤6 mo from enrollment and followed until death, disenrollment, or June 2009 (median follow-up: 27 mo). Demographics and 1L tx patterns (using descriptive analyses), as well as clinical outcomes (median PFS and OS estimated by Kaplan-Meier method) were examined for pts with de novo vs recurrent HER2+ MBC. De novo was defined as disease-free interval (DFI) between initial and metastatic diagnosis ≤90 days; recurrent was defined as DFI >90 days. Cox regression analyses were used to generate hazard ratios (HRs). Results: Pts with de novo HER2+ MBC (327 of 1001 enrolled) were more likely to be younger and non-white; have lymph, bone, and/or liver metastases and >4 sites of metastatic disease; less likely to have lung or CNS metastases; and have received 1L regimens of TCH or AC more frequently vs pts with recurrent disease (who received T + vinorelbine more frequently). PFS and OS were longer in the de novo vs recurrent group (Table). Conclusions: Despite presenting with more advanced-stage disease accompanied by higher tumor burdens, pts with de novo HER2+ MBC had more favorable clinical outcomes vs those with recurrent disease. Differences in disease characteristics and tx patterns resulting in more refractory disease (including acquired resistance from adjuvant tx) may account for these observations. Clinical trial information: NCT00105456. [Table: see text]
Long-term (8 years) assessment of trastuzumab-related cardiac events in the HERA trial.
Authors: De Azambuja Evandro , Procter Marion Jennifer , van Veldhuisen Dirk , Agbor-Tarh Dominique , Metzger Filho Otto , Steinseifer Jutta , Untch Michael , Smith Ian E. , Gianni Luca , Baselga Jose , Jackisch Christian , Cameron David A. , Bell Richard , Leyland-Jones Brian , Dowsett Mitchell , Gelber Richard D. , Piccart-Gebhart Martine J. , Suter Thomas 
Published: March 2020

525 Background: Trastuzumab-related cardiac dysfunction may occur in patients (pts) treated with adjuvant therapy and it is mostly reversible. We report the long-term outcome of pts with cardiac dysfunction treated with adjuvant trastuzumab (T) in the Herceptin Adjuvant (HERA) trial. Methods: HERA is a three-arm, randomized trial that compared 1 year or 2 years of T with observation (Obs) in women with HER2-positive early breast cancer (EBC). Eligible pts had a left ventricular ejection fraction (LVEF) ≥ 55% at study entry (i.e. after completion of (neo)adjuvant chemotherapy with or without radiotherapy). Cardiac function was closely monitored throughout the trial. This analysis at 8-year median follow-up considers pts randomly assigned to 1 year or 2 years of T therapy or observation. Results: 5102 pts were randomized to HERA. The “as treated” safety population is considered: 2 years T (N=1,673), 1 year T (N=1,682) and Obs (N=1,744). Cardiac events leading to T discontinuation in the 1-year and 2-year arms were observed in 5.2% and 9.4% of pts, respectively. Cardiac death, severe congestive heart failure (CHF) and confirmed significant LVEF drop remained low in all three arms (Table). In the 1 year T arm, 71.4% of pts with severe CHF, and 81.2% of pts with confirmed LVEF drop recovered cardiac function (at least 2 sequential LVEF assessments > 50%). The median time to recovery was 9.7 months and 6.3 months, respectively. In the 2 years T arm, 87.5% of pts with confirmed LVEF drop recovered cardiac function and median time to recovery was 8.3 months. Conclusions: At 8-year median follow-up the incidence of cardiac events during adjuvant T remains low and these events are mostly reversible. These results confirm low cardiac events when T is given as part of the adjuvant therapy for pts with HER2-positive EBC. Clinical trial information: NCT00045032. [Table: see text]