bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase II trial of oral capecitabine (C) and weekly docetaxel (D) in patients with metastatic androgen independent prostate cancer (AIPC)
Authors: Marur S. , Eliason J. , Heilbrun L. , Smith D. , Dickow B. , Santucci R. , Cher M. , Forman J. , Vaishampayan U. 
Published: March 2020

5121 Background: Due to demonstrated synergistic anti-tumor effect of D and C related to docetaxel-mediated up-regulation of thymidine phosphorylase (TP), a phase II trial with weekly D and C in metastatic AIPC was performed. Endpoints of response and survival were correlated with biomarker levels of TP, dihydropyrimidine dehydrogenase (DPD), thymidylate synthase (TS) in tumor tissue and DPD in serum Methods: Patients with metastatic AIPC, with no prior chemotherapy for metastatic disease were eligible to receive D 36 mg/m2/week IV on days 1,8, and 15 and C 1,250 mg/m2 /day in two divided doses on days 5–18. Cycles were repeated every 28 days and response was assessed every 2 cycles. Biomarker correlative study for Serum DPD and TP/DPD ratio and TS/DPD ratio on tissue were performed using mouse anti-TP, rat anti-DPD and mouse anti-TS monoclonal antibodies Results: 30 patients enrolled with median age of 69 years, median pretherapy PSA of 110 ng/ml (range 1.2 to 3716.9). 21(70%) had bone pain, Gleason score ≥ 8 in 18 (61%) patients; measurable disease progression in 9, bone scan progression in 18 patients and PSA only progression noted in 22 patients. 144 cycles have been administered (range 0–10 cycles). Grade 3 or 4 neutropenia seen in 3 patients and Grade 3 hand-foot syndrome in 2 patients. No treatment related deaths seen. PSA response (≥50% decline) noted in 22 (73.3%) with ≥90% PSA decline in 9 (30%) pts. Measurable disease PR noted in 5 of 9 patients (56 %). Median follow-up is 11 months (range 2.1 to 30.4). Median time to progression is 9.1 months (90% CI 6.2–15.1 months), and the median overall survival (OS) is 18.9 months (90% CI 14.9–26.4 months). 1 year PFS and OS is 44% and 84% respectively. Samples for DPD were available for 25 patients and pre-therapy tumor tissue for 23 patients. Quantitative fluorescence IHC has been performed on available samples, the final analysis is ongoing. Conclusions: The combination is well tolerated and demonstrates favorable and durable remission and survival outcomes. Correlation with biomarker analysis will be reported. This may help in selecting patients more likely to derive benefit from combination of D and C. Supported in part by Aventis Inc. No significant financial relationships to disclose.
RHAMM (CD168) is overexpressed on the protein level and may constitute an immunogenic antigen in advanced prostate cancer disease
Authors: Ringhoffer M. , Hofer M. , Perner S. , Varambally S. , Chinnayian A. M. , Rubin M. A. , Greiner J. , Schmitt M. , Kuefer R. 
Published: March 2020

5129 Introduction: Treatment options for early stage prostate cancer are well defined, and localized prostate cancer can be cured by several strategies. However therapeutic outcome in advanced tumor stages is still disappointing. One approach is to deliver targeted therapy based on identified human tumor antigens, specifically expressed in neoplastic tissue and recognised by CD4/CD8 T-cells or antibodies. Materials and Methods: We employed serological identification of antigens by recombinant expression cloning (SEREX) and data mining in SEREX related databases to identify potential immunological target structures. Consequently, candidate antigens were screened by DNA microarrays consisting of approximately 20K genes, designed to profile benign and malignant prostate tissues. Genes overexpressed on the cDNA level were evaluated on the protein level by tissue microarrays representing various disease stages including about 900 tissue cores. Protein expression was measured by the Chromavision system. Results: Ten of the targets identified by SEREX and data mining showed a significant overexpression on the 20k cDNA array in localized prostate cancer compared to benign prostatic hyperplasia and in metastases compared to localized prostate cancer. One gene which has been identified earlier as an immunogenic antigen in leukemia by our group, CD168, showed a highly significant overexpression in prostate cancer metastases compared to localized disease (p=0.007). On the protein level CD168 was highest in metastatic tissue samples and significantly higher in neoplastic localized disease compared to benign tissue (p=0.03). High CD168 expression had an association to clinical parameters known to be associated with better clinical outcome. Patients with high CD168 expression in the primaries had a significantly lower risk for biochemical failure (log rank p=0.023; RR:0.621). In cell culture experiments, the number of viable cells was reduced in blocking experiments using hormone sensitive (LNCaP) and hormone insensitive metastatic (PC3 and DU 145) prostate cancer cell lines. Conclusion: Acknowledging the proven immunogenic effects of CD168 in leukemia, this antigen is an intriguing therapeutic target in advanced prostate cancer disease. No significant financial relationships to disclose.
The relationship between biochemical failure and TP53 genetic polymorphism in patients with prostate cancer
Authors: Silva E. , Calais da Silva F. M. , Sousa A. , Coelho A. , Medeiros R. 
Published: March 2020

5133 Background: TP53 is a tumour suppressor gene, located at chromosome 17p13, referred as altered in 50–55% of cancer cases. The p53 protein, encoded by the TP53 gene, is known as the cellular gatekeeper for growth and division, as it plays an essential role in safeguarding the integrity of the genome. This protein is involved in processes as cell cycle arrest, gene transcription, DNA repair and apoptosis and may influence cancer progression. Few studies have been published regarding TP53 codon 72 genetic polymorphism and prostate cancer behaviour. Methods: We analysed the frequency of TP53 codon 72 genetic polymorphism in DNA isolated from blood samples of 265 individuals with prostate cancer using the Real-time PCR methodology. Biochemical failure was defined as two successive post- treatment rises in serum PSA, greater than 50 %. Results: From the 265 prostate cancer cases, we observed that 54.7% were found to be homozygous for the Arg allele (AA), 38.1% were heterozygous (AP) and 7.2% homozygous for the Pro allele (PP). We find that individuals carriers of PP genotype have three fold increased risk of biochemical relapse (OR=3.43, 95% CI 1.31–9.01; p= 0.008). Furthermore, we observed that this genotype was not associated to the gleason score (OR=1.66, 95%CI 0.53–5.13; p=0.372) or the presence of advanced disease (OR=1.69, 95%CI 0.62–4.6; p=0.296). Conclusions: We demonstrate that TP53 codon 72 genetic polymorphism may influence the clinical progression of patients with prostate cancer. Furthermore, our results are consistent with literature regarding other neoplasia suggesting that the Pro allele was associated to a poorer prognosis and survival. No significant financial relationships to disclose.
Subclinical hemostatic activation and surgical volume predict peri-operative bleeding with radical prostatectomy
Authors: Tagawa S. T. , Dorff T. B. , Rochanda L. , Ye W. , Hannoun D. , Eiseler N. , Lieskovsky G. , Skinner D. G. , Liebman H. A. , Quinn D. I. 
Published: March 2020

5136 Background: Subclinical activation of hemostasis and fibrinolysis is common in cancer and has been linked with outcome. We have previously presented (2007 Prostate Cancer Symposium) preliminary data on the relationship of laboratory markers to age and prognostic variables. We now expand our report on peri-operative (op) complication implications in early prostate cancer. Methods: With IRB approval and informed consent, blood was collected prior to open radical retropubic prostatectomy with lymph node dissection. Pre-op therapy, thrombosis, and anticoagulation were exclusion criteria. Plasma was assayed in duplicate for D-dimer, thrombin-antithrombin complex (TAT), IL-6, and IL-8. Relationships to peri-op bleeding/thrombotic events (pre-op to POD#2 hemoglobin (Hgb) drop, estimated blood loss (EBL), transfusion, post-op thrombosis) were analyzed in univariate then multivariable linear regression. Results: 153 subjects have been analyzed. Median age was 63.1 (range 35–81), pre-op PSA was 5.92 ng/mL (0.23–26.2), and 118 (77%) were clinical stage T1c. 117 (76.5%) had disease confined to the prostate; 36 had pT3 and/or lymph node involvement. Pathologic Gleason scores were 6 or less in 68 (44.4%), 7 in 71 (46.4%), and 8 or higher in 14 (9%). Median EBL was 400 mL (range 50-3000), median Hgb drop was 3.5 g/dL (-0.1–6.6), and 8 (5.2 %) required RBC transfusion. One subject experienced a DVT. On univariate analysis, pre-op TAT (p<0.001) and D-Dimer (p=0.023) levels correlated with hemoglobin drop. Platelet count, INR, and aPTT did not predict EBL nor Hgb drop. The 8 who required transfusions had lower pre-op platelet counts than those not requiring transfusion (p=0.004). Higher surgeon volume correlated with lower EBL (p<0.001) and Hgb drop (p=0.002). Multivariable linear regression showed that TAT remained significantly associated with Hgb drop (p=0.008) and surgeon volume with EBL (p<0.001) and Hgb drop (p=0.002). Conclusions: Pre-op activation of the hemostatic system is associated with less surgically related bleeding when assessed by objective measures, predicting drop in Hgb better than PT, aPTT, or platelet counts. Surgeon volume may also predict bleeding by subjective and objective measures. No significant financial relationships to disclose.
Using patient-reported outcomes for technology assessment (TA) and quality improvement (QI) in prostate cancer brachytherapy
Authors: Chen R. C. , Zietman A. L. , D’Amico A. V. , Kaplan I. , Clark J. A. , Manola J. , Talcott J. A. 
Published: March 2020

5139 Background: Despite their sensitivity, validity and increasing prominence in clinical reports, patient-reported outcomes have played little role in TA and QI. We used our validated disease-specific instrument to compare outcomes after alternative brachytherapy techniques for early prostate cancer, both experimental vs. standard technique and between implementations of the standard technique. Methods: One radiation oncologist performed experimental MRI-guided brachytherapy (MRB) on protocol and 2 performed standard ultrasound-guided brachytherapy (USB1 and USB2). We prospectively measured urinary and bowel function of 237 men before brachytherapy and at 1, 3 and 12 months after treatment. Each symptom index is scored from 0 (no dysfunction) to 100 (maximum dysfunction). We report outcomes both as mean change in scale score from baseline and as the distribution of functional categories, grouped by pretreatment functional level: normal, intermediate, and poor (severe dysfunction). Results: Among all patients, MRB caused less urinary obstruction/irritation at 3 months after treatment than ultrasound-guided brachytherapy (mean score change 9.2 vs. 23.6, p<.001). Significant differences in outcome also existed between USB1 and USB2 (19.5 vs. 29.0, p=.01). When baseline function was normal, 15% of MRB patients reported severe 3-month dysfunction, compared to 50% of USB1 and 71% of USB2 patients ( Table ). Outcomes of patients with pretreatment urinary dysfunction differed less. Preliminary results documenting inferior outcomes prompted modification of the USB2 brachytherapy technique, producing a trend toward improved outcomes in small patient numbers (mean score change: 30.4 vs. 22.8, p=.25). Bowel symptom outcomes varied less. Conclusions: Patient-reported outcomes can provide sensitive and valid indicators of TA and QI that may contribute to optimal patient-centered care. [Table: see text] No significant financial relationships to disclose.
Correlation of prostate-specific antigen (PSA) levels and survival in men with bone metastatic hormone-refractory prostate cancer (HRPC) and normal alkaline phosphatase (ALK)
Authors: Xie W. , Regan M. M. , Nakabayashi M. , Oh W. K. 
Published: March 2020

5140 Background: PSA and ALK are recognized factors for predicting survival in men with metastatic HRPC. However, few studies have evaluated the combined effects of PSA and ALK on survival of patients with metastatic HRPC. Methods: 224 patients treated with chemotherapy for bone metastatic HRPC between 1999 and 2006 were identified from an institutional database. 143 patients had ALK as well as PSA values at start of chemotherapy. There were no statistically significant differences in baseline characteristics (including age, Gleason score, PSA, clinical stage at diagnosis or at the initiation of chemotherapy) between groups with and without available ALK (p>0.05). The primary endpoint was overall survival (OS) after chemotherapy. ALK was dichotomized to normal and abnormal groups based on institutional normal range (38–126 U/L). The effect of PSA was evaluated both as categorical (low, median and high group using the 33%, 66% cut-off values) and continuous values with log transformation in Cox regression. Results: Of 143 eligible patients, median ALK was 159 U/L (range: 52–2,020 U/L); 89 (62%) had elevated ALK. Median PSA at start of chemotherapy was 147 ng/mL; 93 ng/mL in patients with normal ALK and 171 ng/mL in those with elevated ALK. With median follow-up of 30 months after chemotherapy, 93 patients have died. Median OS after chemotherapy was 15.8 (range 0–57) months and was significantly longer if ALK was in the normal range (21.3 vs. 14 months, p=0.005). For the group with normal ALK, median OS was 12.5, 24.5 and 36.9 months for patients with low, median and high PSA, respectively; while there was no effect of PSA on survival if ALK was beyond the normal range (16.5 vs. 11.9 vs. 12.1 months) (p=0.21 for the interaction). In multivariable analysis after adjusting for age, the interaction effect of PSA and ALK on OS was statistically significant (p=0.02). The relative risk due to one unit increase in the value of Ln(PSA) was 0.68 (95% CI: 0.51–0.92) if ALK in the normal range, compared to 1.07 (95% CI: 0.85–1.35) in the group with elevated ALK. Conclusions: ALK was a significant factor in predicting OS for men with bone metastatic HRPC. In patients with normal ALK, a higher PSA was associated with improved survival. No significant financial relationships to disclose.
Randomized trial of toremifene to reduce high grade prostatic intraepithelial neoplasia (HGPIN) prior to radical prostatectomy (RP)
Authors: Day R. , Mohanty S. , Bisceglia M. , Acquafondata M. , Dhir R. , Becich M. , Trump D. , Nelson J. 
Published: March 2020

5150 Background HGPIN may be a precursor lesion for prostate cancer (PCA). The selective estrogen-receptor modulator toremifene (TOR) has shown chemopreventive activity in preclinical models of PCA. The effect of TOR on HGPIN was studied in men with PCA prior to RP. Methods Men with biopsy-proven PCA, scheduled for RP were randomized (2:1) either to TOR 40 mg po qd for 3 to 6 weeks prior to RP or to no therapy. The primary endpoint was the proportion of HGPIN in the RP specimen. Planned sample sizes were 35 and 17 per arm respectively, providing 93% power if treatment increased the proportion of patients with no RP HGPIN from 15% to 35% and decreased the mean log nonzero HGPIN values from 1 to ¼ standard deviation. Expression of bcl2, ki67, and CD31 were determined on biopsy (BX), and RP tissues, separately for normal adjacent to tumor (NAT), HGPIN, and PCA tissues. Serum hormone levels and toxicity were also assessed. Results The treatment arm accrued 31 patients, the control arm 13 patients. RP HGPIN ranged from 0.5% to 12%. There was no difference in HGPIN means between treatment (3.8%) and control (3.3%) (P=0.77 one-sided Wilcoxon) HGPIN at baseline predicted HGPIN at RP (Spearman correlation=0.64, P=0.0005) but 66% of patients had no detected HGPIN at baseline. Bcl2, ki67, and CD31 were mutually positively correlated in all 3 tissues, in both BX and RP specimens. In both BX and RP specimens, bcl2 was highest by far in HGPIN, and lowest in PCA. Ki67 was lowest in NAT, elevated in HGPIN and highest in PCA. CD31 showed no differences. In treated patients but not in controls, dihydrotestosterone, testosterone, androstenedion, and estradiol increased significantly between baseline, day 14 and final. TOR was well tolerated. Conclusions These data do not support an effect of TOR on HGPIN over 3 to 6 weeks at 40 mg po qd. No significant financial relationships to disclose.
Efficacy of CAB therapy in stage C prostate cancer: Exploratory analyses based on results of a double-blind, randomized, placebo-controlled phase III study of bicalutamide
Authors: Akaza H. , Arai Y. , Kanetake H. , Naito S. , Usami M. 
Published: March 2020

5154 Background: Although the efficacy of CAB in advanced prostate cancer (PC) has been demonstrated by the PCTCG and others, more evidence is required in locally advanced (Stage C) PC. The results of a Japanese P III study of bicalutamide in Stage C/D PC suggested the efficacy of CAB was better than monotherapy. When time to progression (TTP) was evaluated in Stage C and D separately, CAB had significant benefits in both stages and results in stage D were consistent with PCTCG data. Thus, this exploratory analysis was conducted to evaluate more thoroughly the efficacy of CAB in Stage C. Methods: 205 untreated PC patients with Stage C/D were randomized to CAB (goserelin 3.6 mg/4 weeks or leuprorelin 3.75 mg/4 weeks + bicalutamide 80 mg/day) or LHRHa monotherapy (same LHRHa + placebo). Among these patients, 99 had Stage C (52/47 on CAB/monotherapy). The median of the following parameters were calculated, and log-rank tests performed: TTP in all Stage C patients; TTP in Stage C patients by age, PSA value at diagnosis, and histopathological class; time to PSA normalization when normal level was defined as =4, =1 and =0.2 ng/mL. Results: The median observation period in Stage C patients was 144 weeks. The median TTPs by each parameter in Stage C are shown below. The median times to PSA normalization on CAB and monotherapy were 7 and 16 weeks (p<0.01), 8 and 93 weeks (p<0.01) and 20 weeks and NR (p<0.01) with normal values defined as =4, =1 and =0.2 ng/mL, respectively. Conclusions: These results suggest that CAB with bicalutamide possesses superior efficacy to LHRHa monotherapy in Stage C regardless of age, PSA value at diagnosis, or degree of tumor differentiation. It is suggested that CAB in Stage C could decrease PSA to lower levels in a shorter period than with LHRHa monotherapy. The study is ongoing to assess long term survival outcome. [Table: see text] No significant financial relationships to disclose.
Response to docetaxel (D)/carboplatin (C)-based chemotherapy as first- and second-line therapy in patients with metastatic hormone-refractory prostate cancer (HRPC)
Authors: Nakabayashi M. , Sartor O. , Jacobus S. , Regan M. M. , McKearn D. K. , Ross R. W. , Kantoff P. W. , Taplin M. , Oh W. K. 
Published: March 2020

5156 Background: Effective treatment options for HRPC patients are limited. We evaluated efficacy of D/C-based chemotherapy as first- and second-line chemotherapy. Methods: We retrospectively identified all patients with HRPC treated with D/C-based chemotherapy at DFCI. Regimens either included estramustine (EDC) or not (DC). Patients treated with EDC received D 20–70 mg/m2 q1–4 weeks, E 140mg TID and C AUC 4–6 q 3–4 weeks. Patients treated with DC received D 50–70 mg/m2 and C AUC 4–5 q 3–4 weeks. PSA declines and measurable response were assessed per PSA Working Group and RECIST criteria, respectively. Time to event from chemotherapy initiation based on Kaplan-Meier method. Results: 58 patients were included: 27 patients received EDC, 35 received DC, and 4 received both regimens. Median age and PSA at initiation of chemotherapy was 58 years (range: 42–78) and 132.6 ng/ml (range: 0.3–5352.5), respectively. Table shows median duration of PSA response and TTP, by regimen. Most patients received EDC as first-line chemotherapy (89%). PSA declines ≥ 50% were observed in 24 patients (88.9%, 95% C.I. 71–98) and PSA declined in all 27 patients by a median of 81.3 % (range 33–100). Of 8 patients with measurable disease (MD), 2 had confirmed PR and 4 had SD. Median survival was 17.5 months (95% C.I. 12.0–24.5). 34 out of 35 patients received DC as ≥ 2nd line chemotherapy. PSA declines ≥ 50% were seen in 7 DC patients (20%, 95%C.I. 8–37) and PSA declined in 24 patients with a median of 37.7 % (range 2.0–100). Of 15 patients with MD at baseline, one had confirmed CR, one had PR, and 6 patients had SD. Median survival was 14.8 months (95% C.I. 9–19). The most common reversible grade 4 toxicity with either regimen was neutropenia (6.9%). Conclusions: D/C-based chemotherapy is well tolerated and active in HRPC. As first line chemotherapy, EDC demonstrated PSA declines ≥50% in 88.9% of patients. DC was active as ≥ 2nd-line chemotherapy with PSA declines ≥50% seen in 20%. [Table: see text] No significant financial relationships to disclose.
Molecular signatures characterize early stage breast cancer arising in young women and have prognostic and therapeutic implications independent of ER status
Authors: Anders C. K. , Hsu S. D. , Acharya C. R. , Zhang Y. , Wang Y. , Foekens J. A. , Marcom P. K. , Marks J. R. , Nevins J. , Potti A. , Blackwell K. L. 
Published: March 2020

522 Background: Breast cancer in young women [YW] has a poorer prognosis, is less likely hormone sensitive, and has yet to be defined as a unique biologic phenotype. The identification of molecular pathways unique to YW should enable refinement of treatment strategies. Methods: To optimize characterization of breast cancer arising in YW vs. older women [OW], we prospectively defined 2 age groups constituting pre- and post-menopausal women [YW = 45 yrs (median 40 yrs); OW = 65 yrs (median 71 yrs)]. Age groups were applied to 784 clinically-annotated microarray (Affymetrix) data. 411 patients (n = 200 = 45yrs; n = 211 = 65 yrs) were eligible. In addition to clinical parameters and differential gene expression analysis, genomic signatures of oncogenic pathway deregulation (Ras, E2F, β-catenin, PI3K, Myc, Src) and chemotherapeutic sensitivity were evaluated. Results: In the 2 age-defined tumor sets, there was no difference between ER or PR status by IHC (p = ns). Consistent with previous data sets, YW demonstrated higher IHC expression of ErbB2 (p = 0.037), higher grade tumors (p < 0.0001), larger tumor size (p = 0.0002) and greater lymph node positivity (p = 0.045). Quantitative ER expression (mRNA) was lower (p < 0.0001) among YW. In comparing deregulation of oncogenic pathways between age groups, a statistically higher probability of PI3K (p = 0.005) and Myc (p = 0.02) pathway deregulation was observed among YW. Importantly, hierarchical clustering revealed unique patterns of pathway deregulation. In YW, PI3K and β-catenin deregulation conferred a worse prognosis compared to those with Myc and Src deregulation (HR = 4.15; p = 0.008). In contrast, among OW, E2F deregulation with concurrent low probability of PI3K and Myc deregulation was associated with a poorer outcome (HR = 2.7; p = 0.006). Conclusion: Results of this large study demonstrate that breast cancer arising in YW represents a distinct biologic entity characterized by unique patterns of deregulated signaling pathways that are prognostic, independent of currently available clinical variables such as ER. Further data, including unique patterns of chemotherapeutic sensitivity as they relate to clinical parameters and oncogenic pathway status, will also be presented. [Table: see text]