bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeting DNA damage response to overcome taxane resistance.
Authors: Chao Olivia , Goodman Oscar B. 
Published: February 2018

312 Background: Overcoming taxane resistance in metastatic castrate-resistant prostate cancer (mCRPC) is an unmet need. We and others have observed that a significant proportion of patients with docetaxel (Dox)-refractory disease exhibit sensitivity to DNA-damaging agents. Conversely, loss of DNA repair proteins has been shown to confer resistance to anti-microtubule agents. We hypothesize that Dox exposure alters expression of DNA damage response (DDR) genes, promoting Dox-resistance; and targeting these changes would restore Dox sensitivity. Methods: Dox-resistant prostate cancer cells were developed by exposing DU145 cells to stepwise increasing Dox concentration. Resistance was confirmed by comparing viability (MTT assay) of DU-R (Dox-resistant) and DU-P (age-matched parent) cells after 72 h exposure to Dox (0.1 – 100 nM). Changes in gene expression between DU-DR and DU-P were measured using a DDR-specific 84 gene PCR array. Genes with > 2-fold change in expression were confirmed by RT-PCR and immunoblotting. Sensitivity to Dox of DU-DR was measured in presence of candidate gene inhibitors. Effects of Dox + inhibitor on cell cycle and apoptosis were analyzed by flow cytometry. Results: DU-DR was significantly more resistant to Dox than DU-P (IC50 DU-DR vs DU-P: > 100nM vs 0.86 nM), cabazitaxel (Cab) (9.48 nM vs 0.32 nM), and etoposide (Eto) (4.67 μM vs 1.32 μM) but not 4-hydroperoxy cyclophosphamide (4-HC) (4.50 μM vs 3.16 μM). DDR PCR array revealed three genes were significantly upregulated ( TP73, PRKDC, CDK7) and two downregulated ( BBC3, MSH3); and confirmed by RT-PCR and immunoblotting. DNA-PKc inhibitor, NU7441, treatment significantly increased sensitivity of DU-DR cells to Dox (IC50 = 30.7 nM). Similarly, NU7441 also re-sensitized DU-DR cells to Cab and Eto but not 4-HC. Dox did not induce apoptosis in DU-DR cells (sub-G1 = 2.54 ± 0.15 %; Annexin V+/PI- = 3.60 ± 0.58%) unlike in DU-P (sub-G1 = 39.4 ± 0.28 %; Annexin V+/PI- 28.6 ± 1.1%). NU7441 increased sub-G1 (15.8 ± 0.99 %) and Annexin V+/PI- (14.5 ± 1.4 %) population in Dox-treated DU-DR cells. Conclusions: Targeting prostatic DNA-PKc restores sensitivity to taxanes in vitro. Co-targeting these genes may lead to novel mCRPC therapies.
Real world experience of docetaxel in elderly patients with advanced prostate cancer.
Authors: Fu Simon Yuen Fai , Barlow Paula , Jacobs Carmel Maree , Hanning Fritha J. , Fong Peter C.C. 
Published: February 2018

313 Background: Docetaxel (D) chemotherapy is a standard of care in men with advanced prostate cancer (APC), both metastatic castration sensitive (CS) and castration resistant (CR) disease. The risk of significant toxicities may deter D use in elderly patients. We aim to evaluate the real world efficacy and tolerability of D in men with APC. Methods: Between 04/2014 and 05/2017, data from men aged ≥75 with APC treated at Auckland City Hospital with 3 weekly D were retrospectively collected from the genitourinary medical oncology database. Results: 33 (CS 12, CR 21) men were identified. 70% had PSA decline ≥50% (CS 92%, CR 57%). Median time to next line of therapy was 0.5 y in the CR arm. One third (n = 2/6) of CR patients on opioid had improved pain control with D. 75% had upfront dose reduction (DR). The median dose intensity was 21 mg/m2/wk (CS) and 18 mg/m2/wk (CR). 9 patients had dose escalation after upfront DR, all but 3 needed DR later, and none was escalated to 75 mg/m2. 58% (CS 75%, CR 48%) completed 6 cycles, and only 6% (n = 2) completed 6 cycles at 75 mg/m2. 24% had ≥G3 hematological toxicities. Febrile neutropenia rate was 12% (CS 8%, CR 14%). Pegfilgrastim was used in 1 CS and 1 CR men. Admission rate was 39% (CS 25%, CR 48%), 77% (CS 100%, CR 70%) was treatment related, and 23% (CR 30%) due to malignancy. 15% (CS 25%, CR 9%) required RBC transfusions. 33% CR men progressed while on treatment, and two deaths from pneumonitis and disease progression were noted. Conclusions: Docetaxel is active in elderly men with APC. Toxicities are manageable but can be life-threatening. Admission is frequent especially in CR patients. Proactive dose reduction should be considered to balance benefits vs. risks in this population. [Table: see text]
Biological significance of novel populations of prostate cancer circulating tumor cells (CTC).
Authors: Davis Ian D. , Pezaro Carmel Jo , Wardan Hady , Sluka Pavel 
Published: February 2018

315 Background: Decisions regarding selection and sequencing of treatment in advanced prostate cancer (PC) are often made empirically, without information on the PC molecular profile at the time of treatment. CTC provide real time information regarding contemporaneous biologically relevant cancer subtypes. Current assays often rely on EpCAM or other epithelial markers and may underestimate or exclude other CTC populations of clinical relevance. We devised a novel, simple, rapid and cheap method for isolation of CTC subsets including those without epithelial markers. Methods: Five mL of blood was processed as follows: CD45+ depletion (RosetteSep Human CD45 Depletion Cocktail, Stemcell Technologies); Ficoll centrifugation; antibody staining (mix of EpCAM-PE, PSMA-APC, N-cadherin-AF488, E-cadherin-PerCP/Cy5.5, CD45-APC-H7); Sytox Blue live/dead cell stain; followed by sorting (Becton Dickinson FACSAria Fusion cell sorter). Live cells were sorted into 4 categories denoted E, E+P, P, N (Table). N and P are not identifiable using existing conventional CTC techniques. CTC were assayed for prostate markers ( AR, FOLH1 (PSMA), KLK3 (PSA), TMPRSS2, AMACR) and malignant markers ( PTEN copy number) using digital droplet PCR. Results: Preliminary data are derived from 62 patient samples providing 47 sorted populations. Details are in the Table. Spiking experiments reliably identified as few as 10 CTC / 7.5 mL of blood. P cells were detected in all patients, often outnumbering sum of E and E+P; E and N were never co-expressed. P and N samples frequently expressed prostate markers. Only 1/27 showed no expression of any of these five prostate markers. PTEN deletion assays are in progress. Conclusions: “Unconventional” EpCAMneg CTC appear to be derived from PC and can be detected using broader cell selection criteria. These CTC may provide information on treatment resistance or escape mechanisms. [Table: see text]
Evaluation of ability of OR51T1 expression to predict primary hormone therapy efficacy among men with hormone-naïve metastatic prostate cancer.
Authors: Mochizuki Taku , Miyoshi Yasuhide , Kawahara Takashi , Yokomizo Yumiko , Hayashi Narihiko , Yao Masahiro , Miyamoto Hiroshi , Uemura Hiroji 
Published: February 2018

317 Background: The olfactory receptor gene (OR) superfamily is the largest in the human genome. ORs are expressed not only in the neurons of the olfactory epithelium, but also in various other tissues in which their functions are largely unknown. We here investigated OR51T1 expression as a potential biomarker for predicting primary hormone therapy efficacy among men with metastatic hormone-naïve prostate cancer (mHNPC). Methods: Sixty-nine men with bone metastatic HNPC diagnosed from 2006 to 2015 were enrolled in this retrospective study. All patients had received hormone therapy as first-line treatment. Prostate cancer tissue obtained by needle biopsies before treatment were immunohistochemically stained for OR51T1. Correlations between the baseline clinical factors of age, PSA, Gleason score, T stage, N stage, extent of disease on bone scan (EOD), OR51T1 expression and primary hormone therapy efficacy (time to castration-resistant prostate cancer [CRPC]) were investigated by multivariate analysis using the Cox proportional hazard model. Continuous variables were classified as dichotomous. Results: Median age and PSA were 73.7 years and 263 ng/mL, respectively. Distribution of Gleason score of 9–10/6–8, T4/≤3, N1/0, and EOD 3–4/1–2 were 30 (43.5%)/39 (56.5%), 12 (17.4%)/57 (82.6%), 28 (40.6%)/41 (59.4%), and 26 (37.7%)/43 (62.3%), respectively. Median time to CRPC was 13.6 months. Patients with high OR51T1 expression had significantly shorter time to CRPC than those with low expression. Multivariate analysis showed that EOD (3–4 vs. 1–2, HR 3.1, 95% CI 1.6–6.2, p = 0.001) and OR51T1 expression (high vs. low; HR 2.3, 95%CI 1.2–4.4, p = 0.014) were significant biomarkers for predicting time to CRPC. Conclusions: OR51T1 expression could be a potential biomarker for predicting primary hormone therapy efficacy among men with mHNPC.
Advanced age and prostate cancer specific mortality among geriatric patients with metastatic prostate cancer.
Authors: Lu-Yao Grace L. , Kelly William Kevin , Chapman Andrew E. 
Published: February 2018

319 Background: Data from clinical trials has shown that octogenarians are at increased risk for prostate cancer specific mortality (PCSM). Patients with significant comorbidities were excluded from the trials; consequently, the findings from clinical trials may not be applicable to the general population. Data on patients age 80+ with metastatic prostate cancer in the general population are limited. This population-based study assesses PCSM for metastatic prostate cancer patients diagnosed at age 70+. Methods: Using the Surveillance, Epidemiology, and End Results (SEER) database, identified 418,982 patients diagnosed with prostate cancer at age 70+ between 01/01/2004-12/31/13, of which 12,749 had metastatic prostate cancer. The SEER database covers about 28% of the US population from all racial/ethnic groups. We used Cox proportional hazards (PH) model to calculate cause specific hazard ratio adjusted by age, race, marital status, urban-rural classification, income level, insurance type, primary cancer therapy, stage, and diagnosis period. Results: Of the 12,749 patients, 49.4% of the patients were in their 70's and 8.3% in their 90's+, with 79.1% of patients white and 57.1% married. About 17% of these patients received radiotherapy as their primary cancer treatment. The distribution of M1 subtype is: M1a (4.2%), M1b (68.5%), M1c (22.7%), M1 Not Otherwise Specified (or NOS,4.6%). The median survival for patients with M1 prostate cancer aged 70-79, 80-89 and 90+ were 25, 15, and 7 months, respectively. Compared to patients diagnosed in their 70's, there was 38% and 109% increase in PCSM among those diagnosed at ages 80-89 and 90+ respectively (Table). Conclusions: PCSM increases among geriatric patients with metastatic prostate cancer after accounting for potential confounding factors. Further investigation is needed to shed light on the underlying biological mechanisms. [Table: see text]
Patterns of response to androgen deprivation therapy in younger patients with locally advanced or metastatic prostate cancer.
Authors: Keating Matthew , Giscombe Lisa , Desouza Andre , Mukkamalla Shiva Kumar Reddy , Rathore Ritesh 
Published: February 2018

324 Background: Androgen deprivation therapy (ADT) remains a standard of care in the treatment of locally advanced prostate cancer. But thanks to a few key trials (STAMPEDE, CHAARTED, and LATITUDE) reported within the past three years, docetaxel and abiraterone now have roles in extending overall survival in a patient population traditionally treated with ADT alone. These treatments when combined with ADT have been shown to extend overall survival in metastatic hormone-sensitive prostate cancer patients. The role of ADT in relation to other therapies continues to evolve rapidly. We intend to revisit ADT’s longstanding role in prostate cancer treatment using a national cancer database. Our aim is to look beyond traditional standards of care to identify patients more likely to have overall survival benefit from ADT. Are there any subgroups of patients with intermediate or high risk disease that have improved survival outcomes with androgen deprivation therapy, besides patients with localized disease that underwent radiation? Could there be other variables besides PSA and localization of the prostate cancer that should be considered when identifying ADT treatment candidates, or identifying survival trends in these groups? Methods: We are currently analyzing variables present in the National Cancer Database to retrospectively identify predictive factors for overall survival and progression to metastatic castrate resistant prostate cancer in locally advanced prostate cancers treated with ADT. We will evaluate time-to-death from the initiation of ADT and from the diagnosis of metastatic castrate resistant prostate cancer. The following variables in localized, locally advanced, and metastatic prostate cancer will be analyzed with Statistical Analysis Software: age, locally advanced, site-specific metastasis (M1a, M1b, M1c), Gleason score, local treatment (radical prostatectomy or radiation), stage (T, N, and M), prostate lobe (one vs. both; T2a/b vs. T2c), chemotherapy (date, time from M1 stage), comorbidity score, ethnicity, facility type, insurance, and risk groups (low/intermediate/high as per NCCN guidelines).
Treatment and clinical outcomes of very elderly (≥ 80 yrs) metastatic castration-resistant prostate cancer (mCRPC) patients (pts): A single-institution retrospective analysis.
Authors: Caffo Orazio , Kinspergher Stefania , Maines Francesca , Macrini Sveva , Veccia Antonello 
Published: February 2018

327 Background: The development of mCRPC is generally observed in senior adults and in the daily clinical practice it is frequent to treat pts ≥ 80 yrs. In this population comorbidities can influence the treatment choices and, consequently, the clinical outcomes. The aim of this retrospective study was to describe management and clinical outcomes in mCRPC pts ≥ 80 yrs treated in the daily clinical practice. Methods: We retrospectively evaluated all mCRPC pts treated in our Institution from 02/2002 to 06/2015 and recorded their medical history, anticancer treatments and survival outcomes. Results: We evaluated a consecutive series of 45 pts aged ≥ 80 yrs: median age was 83 yrs (range 81-90 yrs). At the time of mCRPC development bone, nodal, and lung mets were present in 84%, 60%, and 9% of the cases, respectively; no pts with liver mets were observed. Pain was present 53.3% of the pts, the ECOG PS 2 rate was 17.1%. These baseline characteristics were not statistically different compared to those of the younger counterpart. Most of the elderly pts received docetaxel (78%), although this rate was significantly higher (96%) in the younger population (p < 0.0001); similarly elderly pts received less frequently cabazitaxel (CAB) (2% vs 16%, p = 0.01). On the contrary elderly population received more frequently only new generation hormonal agents [abiraterone (AA) or enzalutamide ENZ)] without any chemotherapy (22% vs 4%, p < 0.0001). The median cumulative overall survival (OS) from the start of the first treatment line for mCRPC was 20.5 mos (compared to 21.1 of younger pts). In the elderly population a significant different median OS was observed by comparing pts who received the new agents [NAs (AA, CAB, ENZ, Radium 223)] e those who did not (22.9 vs 13.0 mos, p = 0.001). Conclusions: Although the limitation due to its retrospective nature, our analysis showed that mCRPC pts ≥ 80 yrs were managed differently than younger ones. Nevertheless, the survival outcomes did not differ from the younger counterpart and also very elderly pts benefitted from the introduction of NAs in the daily clinical practice.
Approaches to shared decision-making for PSA screening in primary care practice.
Authors: Litvin Cara B , Ornstein Steven M. , Nemeth Lynne 
Published: February 2018

33 Background: In April 2017, the United States Preventive Services Task Force published a draft statement recommending that clinicians inform men ages 55 to 65 about the potential benefits and harms of prostate-specific antigen (PSA)-based screening for prostate cancer. The HIT-OVERUSE study is an ongoing 2 year group randomized study in 20 primary care practices to test a practice-based intervention to reduce overuse, including avoidance of routine PSA screening without shared decision making. The purpose of this report is to present qualitative findings about approaches participating practices have adopted to facilitate shared decision-making for PSA screening. Methods: Eleven practices in ten states randomized to the HIT-OVERUSE intervention group have hosted on-site visits for academic detailing and participatory planning and sent two practice representatives to a one day meeting to share ‘best practices.’ Detailed notes from site visits, follow-up emails, and the ‘best practice’ meeting were reviewed to identify strategies adopted by practices to facilitate shared decision-making for PSA screening for prostate cancer screening. Results: All practices adopted at least one strategy to promote shared-decision making for PSA screening. Four practices removed standing orders for routine PSA screening. Four practices educated their clinical staff about the test; three developed scripts for staff to use when asked by patients about the test. Six practices began using patient education handouts about PSA screening. One provider started showing a brief YouTube video with patients, while another practice developed a slide show to show in the waiting room. Most providers in nearly all practices reported modifying their conversation about PSA screening with patients to include some discussion about the benefits and the harms of screening. Conclusions: Primary care practices participating an intervention to reduce overuse have adopted varied approaches to facilitate shared-decision making for prostate cancer screening. While having face-to-face conversations is one approach, other strategies may employ staff or utilize patient education or videos to convey the benefits and harms of screening.
Analysis of prognostic biomarkers of response in patients with metastatic castration-resistant prostate cancer treated with abiraterone: A. C. Camargo Cancer Center experience.
Authors: Silveira Pedro Henrique Ferraro , Corassa Marcelo , Lourenço Abbade Dettino Aldo , Rinck José Augusto , Oliveira Thiago Bueno , Barbosa Luiza Damian Ribeiro , Oliveira Audrey , Formiga Maria Nirvana Cruz 
Published: February 2018

335 Background: Despite therapeutic progress in the management of advanced prostate cancer during the past decade, metastatic castration-resistant prostate cancer (mCRPC) remains a disease that causes substantial morbidity and mortality worldwide. A greater understanding of biomarkers permits to guide personalized therapy and can inform clinical trials tailored to men most likely to derive benefit from a given therapy. We aimed to identify prognostic biomarker candidates of Abiraterone Acetate (AA) response in mCRPC patients. Methods: A retrospective clinical records analysis of mCRPC patients treated with AA at A. C. Camargo Cancer Center between January 2012 to December 2016 was realized. Baseline clinical parameters evaluated were: Age, ECOG performance status, metastatic disease at diagnosis, Gleason score, prostate-specific antigen (PSA), Neuroendocrine differentiation, duration of previous androgen-deprivation therapy (ADT), PSA doubling-time (PSAdt), Timing of AA (chemotherapy-naïve or not), PSA response and alkaline phosphatase (ALP) level. Data were analyzed in relation to progression free survival (PFS) stratified by each parameter. Results: We included 141 patients with mCRPC treated with AA to correlate prognostic biomarkers with PFS. Five risk factors individually were associated with poor prognosis and a high risk to progression during AA therapy and were included in the final model: ECOG ≥2 [Relative risk (RR) = 1.52]; PSAdt < 3 months (RR = 2.7); PSA response ( < 50% decline) (RR = 3.03); AA post docetaxel (RR = 1.63) and duration of previous ADT < 12 months (RR = 1.52). The probability to progression free survival in patients receiving AA calculated in 1, 2 and 3 years, was 39,2%, 15,2% and 6,2%, respectively. Conclusions: This analysis identified five factors used to model survival in mCRPC patients treat with AA in our institutional series. Whereas no biomarker has been validated as a predictor of response to a therapy in mCRPC, these those potential clinical biomarkers may help clinicians in distinguishing patients with mCRPC who would obtain the best survival benefit from AA treatment.
Molecular and histopathologic correlates of imaging and biological responses to neoadjuvant GnRH agonist plus enzalutamide for high risk prostate cancer.
Authors: Sowalsky Adam G. , Wilkinson Scott , Ye Huihui , VanderWeele David James , Turkbey Baris , Hennigan S. Thomas , Atway Rayann , Trostel Shana Y. , Lake Ross , Karzai Fatima , Harmon Stephanie , Chun Guinevere , Kelly Kathleen , Pinto Peter A. , Choyke Peter L. , Dahut William L. 
Published: February 2018

34 Background: AR directed therapies are standard of care for metastatic prostate cancer, and their use for high-risk localized disease may improve survival. Previous trials showed low rates of complete pathologic responses to neoadjuvant ADT. The underlying biology and molecular features of tumors that fail to respond remain unknown. Methods: Men with localized prostate cancer with high risk features received 6 months of GnRH agonist plus enzalutamide. mpMRI was performed at baseline and prior to RP. MRI-US fusion guided biopsies were performed at study enrollment. RP specimens were sectioned in the same plane as mpMRI. Imaging and anatomical landmarks on pre- and post-treatment mpMRI were used to match targeted biopsies to RPs. IHC stains including AR, GR, and SYP were performed to guide laser capture microdissection (LCM) and characterization of residual disease. DNA was extracted from LCM biopsy and RP tissues. Whole exome sequencing with somatic mutation calling and copy number analysis was performed. Results: Most patients showed incomplete pathologic responses despite reductions in tumor volume. Several patients harbored multiple tumor clones prior to treatment, distinguished by distinct copy number alterations and mutations in biopsies. Alignment of biopsies to pre- and post-treatment mpMRI correlated with imaging response and histopathology of matched RP sections. Minimal genomic divergence from untreated clones on biopsy suggested intrinsic resistance, while extensive divergence indicated selection for pre-existing subclones. Most residual tumor was AR- and GR-positive adenocarcinoma, with some regions of AR-negative Panneth cell-like differentiation positive for synaptophysin. AR-V7 was rare in residual tumor and < 1% cells were positive for KI-67. The most common alteration in all samples was single-copy loss of chromosome 16q overlapping with ZFHX3. Conclusions: Our approach of repeated sampling by matching targeted biopsies to mpMRI demonstrates feasibility in comparing mpMRI response, pathologic treatment response, and the underlying genomic features that drive tumor development versus treatment resistance. Clinical trial information: NCT02430480.