bluuebunny/crossref_metadata_2025_split huggingface dataset:
Determining biomarkers of response to docetaxel for patients with metastatic castration-resistant prostate cancer (mCRPC) using circulating cell-free tumor DNA (ctDNA).
Authors: Khalaf Daniel , Herberts Cameron , Vandekerkhove Gillian , Annala Matti , Beja Kevin , Eigl Bernhard J. , Kollmannsberger Christian K. , Nappi Lucia , Vergidis Joanna , Wyatt Alexander William , Chi Kim N. 
Published: February 2018

260 Background: Docetaxel is associated with improved outcomes for mCRPC. There are currently no predictive molecular biomarkers for docetaxel to assist with patient selection. Methods: Patients commencing docetaxel for mCRPC between November 2015 and August 2017 were enrolled on a prospective cohort study evaluating circulating biomarkers. A plasma sample for ctDNA analysis was collected before initiation of docetaxel. Targeted sequencing of 73 prostate cancer-relevant genes was performed on leukocyte DNA (germline) and plasma cell-free DNA. Patient records were reviewed for baseline clinical characteristics, PSA response (≥ 50% decline from baseline), and time to PSA progression (TTPP) (PCWG3 criteria). Results: There were 33 patients enrolled; all patients had received prior abiraterone or enzalutamide and none had received prior taxanes. At baseline, the median age was 69.9 years, 30.3% had ECOG performance status 2, 66.7% had bone metastasis and 9.1% had liver metastases. The PSA response rate (RR) was 39.4% and 33.3% had a TTPP less than 3 months. 82% of patients had a ctDNA fraction >5%. Deleterious BRCA2 or ATM defects were present in 12.1% (4/33) of patients (3 somatic and 1 germline). TP53 alterations were identified in 39.4% (13/33), RB1 loss in 21.2% (7/33), PTEN loss in 21.2% (7/33), and Androgen Receptor (AR) amplification in 42.2% (14/33). PTEN deletion was associated with a trend toward inferior RR and TP53 had no discernible effect on PSA RR (Table). BRCA2/ATM defects were associated with a trend toward a lower rate of PSA progression within 3 months (Table). Conclusions: In this preliminary analysis, TP53 alterations had no discernible effect on efficacy of docetaxel chemotherapy. Accrual is ongoing in order to further clarify whether there is an association between PTEN, RB1, AR and BRCA2/ATM alterations and benefit from docetaxel. [Table: see text]
Prognostic impact of DNA repair germline variants in hormone sensitive prostate cancer stage.
Authors: Kohli Manish , Hart Steven , Lilyquist Jenna , Hu Chunling , Hillman David W. , Lee Kun , Gnanaolivu Rohan David , Polley Eric , Couch Fergus 
Published: February 2018

262 Background: Inherited and somatic aberrations in DNA repair genes in castrate resistant prostate cancer (CRPC) are associated with poor prognosis, but respond well to poly ADP ribose polymerase (PARP) inhibitors. We evaluated the prevalence and prognostic impact of harboring germline DNA repair variants in hormone sensitive prostate cancer (HSPC). Methods: Germline DNA from buffy coat was sequenced on HiSeq4000 with a median coverage of 200X for DNA repair variants in 20 genes in HSPC and CRPC patients (pts) enrolled in a hospital registry. Pts were divided into two groups; Group A: pts enrolled at the time of CRPC stage; Group B: treatment naïve HSPC stage pts. The primary endpoints were to determine any impact of harboring DNA repair variants on time to progression from HSPC to CRPC and, from CRPC to death. Group A pts were retrospectively analyzed for time to progression from HSPC to CRPC while Group B patients were followed prospectively for outcomes. Statistical analysis included Cox proportional hazard models and Wilcoxon Rank sum test with significance at p≤0.05. Results: In Group A, 51/562 CRPC pts (9.07%) had variants in the 20 genes (most frequently in BRCA2; n = 15). 44/51 pts with variants and 399/511 without variants had died. Median time of progression from HSPC to CRPC with/without variants was 22.1 vs. 25.1 months (mths); p-value = 0.679. Median time from CRPC to death with/without variants was 32.2 Vs. 27.7 mths (p = 0.6). In HSPC Group B, 14/100 pts were identified with germline variants in ATM (n = 5), CHEK2 (n = 3), BRCA1 (n = 2), BRCA2 (n = 2), RAD50 (n = 1), and MSH2 (n = 1). 31/100 have died and median time to progression from HSPC to CRPC with/without variants was 15.6 vs.11.8 mths, p-value = 0.76. Conclusions: Pts with germline DNA repair variants detected in HSPC stage were not associated with poor prognosis. Presence of additional somatic DNA repair gene aberrations in cell-free DNA, not investigated in this cohort may add to the prevalence of DNA repair gene variations in HSPC and together impact prognosis adversely so as to provide a rationale for PARP inhibitor therapy in select HSPC stage pts.
cfDNA TP53 mutations with treatment history and disease progression in metastatic CRPC.
Authors: Chapman Lynne , Ledet Elisa , Moses Marcus Marie , Shahbandi Ashkan , Steinwald Peter , Christensen Bryce Raymon , Cotogno Patrick , Schiff Joshua , Layton Jodi Lyn , Lewis Brian E. , Sartor A. Oliver 
Published: February 2018

263 Background: Cell free DNA (cfDNA) has made it possible to actively monitor alterations of genes during the course of therapy. Herein we evaluate cfDNA pathologic mutations in TP53 after treatment resistance to AR targeted therapy and taxanes in mCRPC. In addition to the presence or absence of pathologic mutations, the quantity of the mutations was characterized as present/absent, quantitatively as > or < 1%, or >or <10%. Methods: A retrospective study was done for 111 patients, with 226 separate cfDNA testing dates. Each cfDNA test was treated as an individual sample; of the 226 tests, 112 were positive for pathologic TP53 mutations, and 114 were negative. Treatment histories were collected and TP53 data analyzed in relation to resistance for abiraterone (abi), enzalutamide (enza), abi + enza, or abi + enza and a taxane. Treatment resistance was categorized as being present for those patients completing therapy with an agent. Results: Patients with pathologic TP53 mutations were more likely to have had progression after a novel hormone and a taxane (P = 0.005). Higher concentrations of TP53 mutational loads as measured by cfDNA concentration of >1% and >10% were more likely to be present in patients progressing after a taxane, abi, and enza. Common alterations associated with TP53 included AR amplifications and mutations, MYC amplifications, and BRCA2 mutations. Conclusions: TP53 mutations in cfDNA of mCRPC are progressively more likely to be present in patients, especially after patients receiving both taxanes and a novel hormonal agent. The predictive and prognostic significance of these changes are being further evaluated.[Table: see text]
Molecular profiles of small cell bladder and prostate cancer and comparisons with small cell lung cancer.
Authors: Dawson Nancy Ann , Geynisman Daniel M. , Burgess Earle Frederick , Somer Bradley G. , Arguello David , Hauke Ralph J. , Vaena Daniel A. , Raghavan Derek , Heath Elisabeth I. 
Published: February 2018

264 Background: Small cell bladder cancer (SCBC) and small cell prostate cancer (SCPC) are rare and aggressive cancers. Standard therapy remains a platinum agent combined with etoposide, with few options after recurrence. Advances in molecular genomics and drug development have altered our approach to cancer. These same novel approaches may alter how we approach SCBC and SCPC. The purpose of this study is to identify potential targets and compare molecular profiles of SCBC and SCPC to SCLC. Methods: In total, 21 SCBC and 19 SCPC were identified from a de-identified database (Caris Life Sciences). Specimens were evaluated for genetic aberrations (Sanger or next generation sequencing [NGS], ISH) and/or protein expression (immunohistochemistry [IHC]). Comparisons were made against a de-identified cohort of SCLC (n = 428). Results: Pathogenic/presumed pathogenic mutations in SCBC were found in TP53 (91.7%, 11/12), RB1 (18.2%, 2/11), PTEN (8.3%, 1/12), EGFR (7.7%, 1/13), and PIK3CA (7.1%, 1/14). SCPC genetic aberrations were detected in TP53 (72.7%, 8/11) and RB1 (25.0%, 2/8). No carcinomas in this cohort had a high mutational burden or MSI-high status (0%, 0/7). Amplified genes found in SCBC included DDR2 (50%, 1/2) and EGFR (25.0%, 1/4). In SCPC, gene amplification was found in AKT2 (20%, 1/5), CCNE1 (20%, 1/5), FGFR1 (20%, 1/5), and MYC (20%, 1/5). The highest protein expression rates in SCBC involved MRP1 (100%, 5/5), TOP2A (94.1%, 16/17), and RRM1 (81.3%, 13/16). The highest protein expression rates in SCPC were MRP1 (100%, 6/6), TUBB3 (100%, 9/9), and TOP2A (94.4%, 17/18). Comparisons between SCBC and SCPC with SCLC revealed more similarities than differences. Significant differences were found in RRM1 by IHC between SCBC and SCLC. Also, significant differences were found between SCPC and SCLC in AR and PTEN by IHC. Conclusions: Comparisons of GU small cell carcinomas reveal similarities to SCLC. Both TP53 and RB1 mutations were found in both SCBC and SCPC. Amplification in genes CCNE1 and FGFR1, frequently identified in SCLC, were also found in SCPC. The high protein expression in biomarkers like MRP1 may explain the poor response to cytotoxic chemotherapy. Prospective studies are urgently needed.
3D Organoids from Milligrams of Genitourinary Cancer Patients Tissue Retain Key Features of Original Tumors.
Authors: Wang Yue , Souza Glauco R , Amato Robert J. 
Published: February 2018

268 Background: 3D organoid culture, especially that generated from patient samples, is becoming prevalent as 2D cell culture models fail to provide clinical relevance. However, a relatively large amount of starting tissue is still required for this process, and the turnover rate and overall success rate vary greatly if relying solely on spontaneous aggregation. Methods: Here, we report the successful use of magnetic 3D bioprinting to drive organoid formation derived from fresh tumor samples of patients with prostate cancer, renal cell cancer, and urothelial cancer. Results: Only milligrams to tens of milligrams of starting tissues (from fine-needle biopsies, core biopsies, or surgical excision) were used. Most organoids formed overnight, with a very high overall success rate ( > 95%, n = 25). We have demonstrated that these cultures can be maintained, passed, and cryopreserved like conventional 2D cultures. More importantly, we characterized the organoids derived from prostatic adenocarcinomas and neuroendocrine tumors by the means of immunostaining and showed that the organoids expressed the same signature proteins as the originating tumors. This clinical concordance is crucial for downstream translational and biological research. We also showed that these adenocarcinoma cells responded to enzalutamide, an androgen receptor inhibitor that is used clinically to treat prostatic adenocarcinoma. Conclusions: In summary, we have established an efficient and robust system to create patient-derived 3D organoids; molecular characterization shows clinical concordance with original patient tumors; and our system shows great potential in drug screening with patient-derived 3D cultures.
A microRNA-based signature predicting immune-related toxicity (iRAEs) to pembrolizumab in prostate cancer patients.
Authors: Weidhaas Joanne B. , Wilenius Kirk , Scheffler Aaron Wolfe , Higa Juliana , Telesca Donatello , Scholz Mark C. 
Published: February 2018

269 Background: The need to predict immune-related adverse events (iRAEs) for patients receiving checkpoint inhibitors is a pressing issue, with up to 25-30% Grade 2 or higher toxicity with single agent therapy, regardless of cancer type. Our group is studying a novel class of inherited mutations that disrupt the normal regulatory process of microRNAs as they function to control the genome. We have previously applied a panel of these mutations to predict iRAEs in melanoma and NSCLC patients receiving anti-PD1/anti-PDL1 therapy. We hypothesize that our mutations will predict iRAEs across cancer types. Here we have investigated their ability to predict iRAEs in a cohort of recurrent or advanced prostate cancer patients receiving Pembrolizumab (Pembro). Methods: We previously trained several statistical classifiers on a set of 86 melanoma and NSCLC patients evaluated for iRAEs. Subjects were classified as experiencing high toxicity (grade 2 or more) versus low toxicity (less than 2). We next tested the performance of the identified biomarkers on a set of 40 prospectively-treated prostate cancer patients who had received at least three cycles of Pembro, 200mg every 3 weeks. Samples were collected via cheek swab and germ-line DNA was isolated for testing. Predictive models of high-grade toxicity were based on 49 common markers between training and test samples. Classifiers were built comparing: classification trees, LASSO-regularized logistic regression, and random forests. All models were tuned at training using leave-one-out cross validation. The final extrapolation test errors were estimated on the prostate cohort as validation data not used in training. Results: Within the melanoma and NSCLC training sample we estimate toxicity with 71% accuracy (85% sensitivity, 43% specificity). We found that our biomarker panel when applied to prostate cancer patients extrapolates quite well, where our biomarkers predict toxicity with 68% accuracy (82% sensitivity, 38% specificity). Conclusions: We have identified a panel of microRNA-based, germ-line biomarkers which predict the risk of iRAEs. This panel appears to predict iRAEs across cancer types, including prostate cancer.
PSMA heterogeneity analysis in patients with metastatic castrate-resistant prostate cancer (mCRPC): Imaging versus CTCs.
Authors: Morris Michael J. , Vogelzang Nicholas J. , Sartor A. Oliver , Armour Alison A. , Messmann Richard Adam , Groaning Michael , Robarts Adam , Tolcher Anthony W. , Gordon Michael S. , Babiker Hani M. , Kuo Phillip , Kearney Megan , Jendrisak Adam , Wang Yipeng , Landers Mark Andrew , Petrylak Daniel Peter 
Published: February 2018

272 Background: Prostate-specific membrane antigen (PSMA) is highly expressed in prostate cancers, making it an ideal imaging and therapeutic target of interest. The utility of the PSMA-targeted imaging agent 99mTc-EC0652 is being evaluated, along with biomarker analysis of circulating tumor cells (CTCs), in pts with mCRPC in a PSMA-targeted chemotherapeutic study. We now report the PSMA heterogeneity via CTC vs. imaging in the pt population treated to date. Methods: Patients were enrolled in 1 of 2 cohorts: mCRPC taxane naïve or taxane exposed. A total of 48 pts evaluated at the time of the data cut had baseline CT & bone scans performed in addition to a 99mTc-EC0652 SPECT/CT as a measure of imaging-based PSMA expression. 40 of 48 pts provided pre-treatment blood samples evaluable for CTC biomarker analysis, which included PSMA expression & were given percent homologous recombination deficiency (%HRD) scores. Four of the best and four of the worst responders were evaluated in more detail for imaging and CTC-based biomarker analysis as it related to clinical outcome. Results: 35 of 40 pts (88%) had detectable CTCs in their samples. 15 of the 35 (43%) pts had PSMA-positive CTCs. The 4 “non-responders” were on study for an average of 41 days and the 4 “responders” for an average of 256 days. Each group contained 2 taxane exposed & 2 taxane naïve patients. Of the 335 bone lesions analyzed by MDP, CT, 99mTc-EC0652, 333 (99.4%) were characterized as PSMApos based on their 99mTc-EC0652 SPECT/CT scan. Of the 26 soft tissue lesions analyzed by CT, all were characterized as PSMApos based on their 99mTc-EC0652 SPECT/CT scan. Seven (26.9%) of those lesions were CT positive (observed on CT scan). Each group had 2 pts that were CTC-based PSMApos & 2 that were PSMAneg. Their percent homologous recombination deficiency (%HRD) scores were of 0.60 [0.333, 1.0] for “non-responders” & 0.01 [0.0, 0.039] for “responders”. Conclusions: PSMA-based imaging showed a high percentage of positive lesions whereas CTC-based PMSA positivity is lower by comparison (43%). The discordance between the imaging results & CTC-based biomarkers, & the relative therapeutic predictive value, requires additional exploration. Clinical trial information: NCT02202447.
Application of the ASCO Value Framework and ESMO Magnitude of Clinical Benefit Scale to assess the value of abiraterone acetate (AA) and enzalutamide (E) in advanced prostate cancer: clinical value and cost considerations.
Authors: Wong Sarah , Everest Louis , Jiang Di Maria , Saluja Ronak , Chan Kelvin K. , Sridhar Srikala S. 
Published: February 2018

276 Background: AA and E improve overall survival (OS) in metastatic castration resistant prostate cancer (mCRPC). AA also improves OS in metastatic castration sensitive disease (mCSPC). However, concerns exist over the cost implications of earlier treatment versus the clinical benefit gained. We aimed to quantify and compare the clinical value of AA and E and their drug costs in both the mCRPC and mCSPC settings. Methods: We identified 6 randomized Phase 3 trials of AA and E in mCRPC and mCSPC. Net clinical benefit was quantified by the ASCO Value Framework version 2 (range < 180) and ESMO MCBS version 1.1 (range 1-5)—both consider benefits in overall survival, progression free survival, and quality of life, against increase in drug toxicity. A higher score indicates greater value. Incremental cancer drug costs were also calculated, using average wholesale price from the REDBOOK and the trials’ reported duration of treatment. Results: (Table). Conclusions: AA and E administered in early mCSPC do not provide consistent increases in net clinical benefit compared to mCRPC, but they incur exponential cost considerations. Alternatives such as chemotherapy, which may provide similar net clinical benefit at less incremental costs, still warrant major consideration for clinicians and patients. Until more information is available to define the optimal sequencing of AA, E and other available treatment modalities, current cost implications may hinder moving these agents to earlier treatment settings.[Table: see text]
The Metastatic Prostate Cancer project (MPCproject): Translational genomics through direct patient engagement.
Authors: Mullane Stephanie Anne , Painter Corrie , Dunphy Michael , Anastasio Elana , Simoncelli Tania , Zarrelli Kristen , Philippakis Anthony , McKay Rana R. , Choueiri Toni K. , Golub Todd , Lander Eric , Wagle Nikhil , Van Allen Eliezer Mendel 
Published: February 2018

279 Background: While there has been substantial advancement in the genomic understanding of metastatic prostate cancer (MPC), there is still much to be discovered. Additional progress is dependent upon obtaining a large amount of clinically-annotated genomic data. Therefore, we piloted a direct-to-patient nationwide research initiative where patients can contribute their medical records and biospecimens to accelerate research ( mpcproject.org ). Methods: In collaboration with patients and advocacy groups, we have developed a website ( mpcproject.org ). Participants are asked to complete a 17-question survey about their experiences with prostate cancer and an electronic informed consent. All participants receive a saliva kit for germline DNA and blood kit for circulating tumor DNA (ctDNA). Additionally, medical records are collected and archived tissue samples are requested if available. Ultra low pass whole genome sequencing (ULP-WGS) and whole exome sequencing (WES) are performed on the whole blood samples. WES is performed on saliva samples. Genomic, clinical, and patient-reported data will be shared widely with the research community. Aggregate study results will be reported to patients. Results: As of October 2017, 12 pilot patients aged 47-74 from 7 states, provided informed consent. 7 saliva kits, 4 blood kits, and 2 medical records were received. 4 patients were diagnosed with de novo metastatic disease, 8 reported a family history of breast and/or prostate cancer, 6 reported a secondary malignancy. All blood kits were submitted for ULP-WGS and WES. Updated genomic, clinical, and patient-reported data will be presented. Conclusions: We have provided preliminary evidence that partnering directly with MPC patients enabled the remote collection of saliva and blood samples, medical records, and patient-reported data. At the conclusion of the pilot phase, the MPC Project will open enrollment for all men with metastatic and advanced prostate cancer in the US and Canada.
Evaluation of PUMA and NOXA expression as predictive biomarkers in prostate cancer.
Authors: Clairefond Sylvie , Péant Benjamin , Ouellet Veronique , Barres Veronique , Mes-Masson Anne-Marie , Saad Fred 
Published: February 2018

28 Background: PUMA and NOXA are two pro-apoptotic members of the BH3-only subgroup of the BCL-2 family. These two proteins play a role in the initiation of apoptosis. The objective of this study is to analyse their expression by immunofluorescence, alone or in combination, in benign and tumor prostate tissues to determine if there is a correlation between their expression and patient biochemical recurrence (BCR). Methods: Biomarker antibodies were verified for specificity and optimized by western blot and with tissue microarrays (TMA) containing prostate cancer cell lines and cell line derived xenograft tissues. Subsequently, quantification of expression for both biomarkers was performed on six TMA generated from radical prostatectomy samples (285 patients). The TMA were constructed using two cores of benign adjacent to the tumor and two cores of tumor tissue from each patient. Analysis of biomarker expression was semi-automated using the VisiomorphDP software. To optimize the analysis, we developed 2 different immunofluorescence masks: a cocktail of anti-cytokeratin-8 and -18 antibodies to identify epithelial cells and a combination of anti-p63 and anti-cytokeratin high marker weight to discriminate benign glands within tumor cores. Correlation with patient clinical outcome was determined with SPSS V20 software. Results: There was no correlation of PUMA and NOXA expression and BCR in tumor cores and stroma. In contrast, in benign epithelial cells Kaplan-Meier analysis showed a significant association between an extreme (low or high) PUMA expression and BCR (Log rank = 11.349, p = 0.001). Further analysis revealed a significant association between high NOXA expression in benign epithelial cells and BCR (Log rank = 6.133, p = 0.013). The combination of extreme PUMA and high NOXA identified patients with a poor prognosis (Log rank = 16.041, p = 0.000). In a multivariate Cox regression model, PUMA and NOXA proteins were also identified as independent predictive biomarkers of BCR. Conclusions: By studying benign epithelial cells adjacent to the tumor we identified two potential biomarkers that discriminate high-risk patients, independent of Gleason score or pathologic stage.