bluuebunny/crossref_metadata_2025_split huggingface dataset:
Percent genome alteration and outcomes after radical prostatectomy in African American men.
Authors: Faisal Farzana A , Tomlins Scott A. , Schaeffer Edward M. , Lotan Tamara L. 
Published: March 2019

24 Background: African American (AA) men have a higher incidence of and mortality from prostate cancer (PCa) than European American (EA) men. The potential biological determinants of these racial disparities are unknown. Cancer genome evaluations with available clinical outcome data have been limited to EA cohorts. Here we characterize PCa genomes from a large cohort of AA men and identify the associations between genomic alterations and clinical outcomes. Methods: Cancer genomes from 205 AA men treated with radical prostatectomy (RP) were profiled for known somatic mutations and percent genome alteration (PGA; defined as percentage of tumor genome with copy number variation). Logistic regression and Cox proportional hazard analyses assessed the association of genomic alterations with clinical outcomes in multivariate models. PGA was dichotomized by quartiles in analytical models (≤75th percentile vs. >75th percentile). Results: The median PGA was 3.7% and increased with pathologic grade (p<0.001) and stage (p=0.02). Median follow-up was 5 years. AA men with the highest quartile of PGA had significantly worse biochemical recurrence (BCR)-free survival (10 year: 33.5% vs. 50.2%; p=0.006) and metastasis-free survival (10 year: 47.9% vs. 89.0%; p<0.001) than men with lower quartiles of PGA. PGAwas associated with increased risks of higher grade (OR 2.0, 95% CI 1.1-3.7, p=0.03), higher stage (OR 2.0, 95% CI 1.1-3.8, p=0.03), BCR (univariate: HR 1.9, 95% CI 1.2-3.2, p=0.01), and metastasis (HR 9.6, 95% CI 2.9-31.3, p<0.001). The most common somatic mutations were SPOP (12.5%, 123/184), FOXA1 (9.2%, 17/184), and TP53 (4.4%, 8/184). Only TP53 was associated with increased risks of adverse outcomes: higher stage (OR 5.3, 95% CI 1.5-19.4, p=0.01), BCR (univariate: HR 2.4, 95% CI 1.0-5.9, p=0.06), and metastasis (HR 9.5, 95% CI 2.2-40.6, p=0.002). Conclusions: In AA men, PCa genome profiles reveal unique genomic alterations. Notably, PGA in AA men predicts adverse pathologic and oncologic outcomes after RP and can potentially be considered a prognostic biomarker in this racial group. This research highlights the importance of racial ancestry in cancer genomics studies and precision medicine strategies.
Modeling time from bone metastasis to death in a racially diverse cohort of military health care beneficiaries.
Authors: Cullen Jennifer , Chen Yongmei , Kuo Huai-Ching , Rice Kevin R. , Rosner Inger L. , Forsberg Jonathan 
Published: March 2019

246 Background: Development of prostate cancer (PCa) metastasis, while uncommonly observed in US men, typically occurs to bone and ultimately leads to disease-specific death. The goal of this study was to estimate OS in a racially diverse cohort of military health care beneficiaries diagnosed with metastatic PCa to bone, to enhance understanding of factors such as patient race and receipt of palliative treatment, that potentially affect OS in advanced PCa patients. Methods: A retrospective cohort study was conducted, examining men consented to participate in the CPDR multi-center national database who underwent biopsy for suspicion of prostate cancer between 1989-2017 and subsequently diagnosed with bone metastasis, confirmed by bone scan, bone biopsy and/or MRI. Multivariable Cox proportional hazards (PH) analysis was used to model OS as a function of race and palliative treatment, controlling for clinical covariates. Hazard ratios (HR) and 95% Confidence intervals (CI) are reported. Results: Among 17,356 patients diagnosed with prostate cancer (PCa) between 1989 and 2017, 869 (5.0%) developed bone metastasis. Median patient age was 67 years; median follow-up time following diagnosis with bone metastasis was 2.4 years. Over one-fifth of patients (22.5%) self-reported as African American. Only 11.5% of all patients with metastasis received palliative treatment (radiation (RT) only, RT+ hormone therapy (HT), RT+HT, or RT+HT+chemotherapy). While race did not predict OS, receipt of palliative treatment was strongly predictive of better OS (p<0.0005). Conclusions: Patient race did not predict OS among those with distant metastatic PCa but receipt of palliative care and slower PSADT were critical factors in lengthening OS. This work is being extended to examine the combinations and sequencing of palliative care on OS, to provide improved patient-tailored prediction tools for men with advanced prostate cancer. [Table: see text]
Pembrolizumab (pembro) in heavily pretreated metastatic castrate-resistant prostate cancer (mCRPC).
Authors: Moses Marcus Marie , Ledet Elisa , Manogue Charlotte , Lewis Brian E. , Barata Pedro C. , Sartor A. Oliver , Layton Jodi Lyn 
Published: March 2019

255 Background: KEYNOTE-199 has shown PSA responses of 11% to pembro in mCRPC. This study aims to further evaluate pembro in heavily pre-treated mCRPC patients (pts) correlating clinical outcomes with somatic and germline mutational burden. Methods: Single-institution retrospective analysis of mCRPC pts treated with pembro with germline panel testing and baseline ctDNA analysis using Guardant360 (Redwood City, CA). Baseline clinical annotation was collected and correlated with ctDNA data and clinical outcomes; ctDNA annotations included amplification (amp) and somatic mutation (mut; allele fraction ≥0.3%). Clinical outcomes were assessed after 3 cycles defined as: PSA≥50% PSA decline) or PSA≥30 response. Results: 27 mCRPC pts were treated with pembro between Oct 2016 and June 2018, median age 69 (56-82), 70% Caucasian, 26% African-American, and 4% Other, 70% Gleason 8-10, 59% bone-only, 22% bone+tissue, and 19% bone+LN metastases, were included. Pembro was given after a median 5 CRPC therapies with a median initial PSA of 76.1 ng/mL (4.85-1160), median treatment duration of 1.4 months (0-24.3). Prior treatments include abiraterone (n = 27), enzalutamide (n = 17), docetaxel (n = 19), and provenge (n = 16). 18 pts had ctDNA testing both pre- and post-pembro with a median time from testing to pembro of 0.9 months (0-3.9) and a median time from pembro to NGS testing of 0.7 months (0-2.6). Pre-pembro NGS had the following cfDNA alterations: 74% AR (mut = 8, amp = 8, both = 4), 55% TP53, and 0% DNA repair. ctDNA allelic fraction decrease occurred in 50% (6/12) of pts with AR mutations. 55% (15/27) of pts completed ≥3 cycles of pembro with the following responses: PSA≥50 13% and PSA≥30 20%. Two PSA complete responders (CR) (PSA < 0.01) had germline pathogenic alterations (BLM or MSH2). One of these pts was bone only; the other had radiographic CR. The MSH2 germline tumor was MSI-H and lacked MSH2/MSH6 on immunohistochemistry. The other PSA CR was not assessed given limited tissue. Conclusions: 33% of pts evaluated, achieved a PSA decline of ≥30% al response or greater signifying there is a subset of mCRPC pts that can benefit from pembro. Further evaluation is necessary to determine predictive biomarkers for this patient population.
Germline DNA repair mutations in men with prostate cancer are less frequent in African Americans as compared with Caucasians.
Authors: Nicolosi Piper L.W. , Ledet Elisa , Yang Shan , Michalski Scott T. , Vu James , Sartor A. Oliver 
Published: March 2019

258 Background: Pathogenic DNA repair defects are well described in Caucasian (C) men with prostate cancer (PCa) but comparative data on African-American (AA) men are sparse. Methods: Germline testing for DNA repair defects were assayed by Invitae (Invitae.com). Pathogenic variants in 14 genes were compared between AA and C men with PCa; these particular genes were also assessed by Pritchard et al NEJM 375:443, 2016. Identical gene panels were not used in all men, thus variations in assay numbers from gene to gene are noted. Chi square was used to compare proportions. Results: In the 14 genes, there were 16/214 (7.5%) AA men and 347/2488 (13.9%) C men with pathogenic findings (p=0.008). As shown in the Table, the most common pathogenic variants in AA men were BRCA2 (6/214, 2.8%), BRCA1 (3/213, 1.4%), PALB2 (2/182, 1.1%), ATM (2/206, 1.0%), RAD51C (1/148, 0.68%), CHEK2 (1/207, 0.48%), and PMS2 (1/212, 0.47%). In contrast to C men in this series, no AA men had pathogenic mutations in BARD1, BRIP1, MLH1, MSH2, MSH6, NBN, or RAD51D. Pathogenic CHEK2 was less commonly detected in AA as compared to C (p=0.03) in this dataset. Comparing our C men revealed no differences in the proportion of men with pathogenic findings compared to Pritchard et al (13.9% here vs 11.8%, P=0.15). Conclusions: AA men with PCa are less likely to have pathogenic DNA repair mutations among these 14 assayed DNA repair genes compared to C men. Limitations regarding lack of stage, Gleason scores, and FH are notable. Details on gene assays and comparison to Pritchard et al NEJM 375:443, 2016 [Table: see text]
ctDNA and copy-number variant quantification in mCRPC at the time of progression.
Authors: Cotogno Patrick , Moses Marcus Marie , Ranasinghe Lahiru , Christensen Bryce Raymon , Steinwald Peter , Chapman Lynne , Manogue Charlotte , Lewis Brian E. , Layton Jodi Lyn , Sartor A. Oliver , Ledet Elisa 
Published: March 2019

265 Background: Tumor burden is a prognostic biomarker in cancer; however, in metastatic castration resistant prostate cancer (mCRPC), quantification of tumor burden markers is difficult. Circulating ctDNA is an accessible biomarker which can be used to characterize somatic DNA. The goal of this study was to evaluate the utility of ctDNA quantification and characterization at time of disease progression in mCRPC. Methods: From 2015 to 2018, 221 mCRPC patients underwent ctDNA screening with Guardant 360 (Guardant Health, Inc. Redwood City, CA) at times of disease progression. This analysis consisted of exonic coverage of 70 genes as well as amplifications in 18 genes, with pathogenic mutations categorized by effect and mutant fraction ctDNA. Clinical annotation including lines of life-extending therapies (LET) before and after testing were collected. Statistical analyses included repeated measure ANOVA, logistic regression, and parameter estimations. Results: An increasing number of LETs resulted in a clinically significant increase in mutant ctDNA fraction (P < 0.001). Subjects that received ≥ 5 or 3-4 LETs had significantly higher total mutant ctDNA fraction compared to subjects exposed with either 0 (p = 0.0007 and 0.0196, respectively) or 1-2 LETs (p = 0.0013 and 0.0432, respectively). 1-2 LETs did not demonstrate a significantly different total mutant ctDNA compared to subjects with 0 LETs (p = 0.4578). The estimated mean total mutant ctDNA fraction demonstrated a positive trend with an increasing number of LETs, including 2.08% (95% CI 1.24-3.49) without a LET, 2.62% (95% CI 1.71–4.01%) with 1-2 LETs, 4.58% (95% CI 2.92–7.17) with 3–4 LETs, and 7.79% (95% CI 4.51-13.48) for subjects with ≥5 LETs. The presence of copy number gain variations (CNVs) demonstrated an increased frequency with exposure to more LETs (p = 0.0005). Subjects with ≥5 or 3-4 LETs were 5.192 (p = 0. 0.0011, 95% CI 1.934-13.942) and 4.808 (p = 0.0019, 1.780-12.983) times more likely to have CNVs present compared to those without LETs. Conclusions: As mCRPC patients progress through lines of therapy, both the mutant ctDNA fraction and frequency of copy number gain variations increase.
Assessing the real-world (RW) efficacy and toxicity of docetaxel (D) for the treatment of metastatic castrate sensitive prostate cancer (mCSPC): A single institution experience.
Authors: Delos Santos Seanthel , Phillips Cameron , Emmenegger Urban 
Published: March 2019

270 Background: While D has been shown to prolong survival and improve quality of life in men with mCSPC in clinical trial settings, less is known about its effectiveness in the RW setting. Furthermore, it is uncertain whether the timing of D affects toxicity and outcome. We aimed to identify effectiveness and toxicity outcomes as well as patient (pt) characteristics and prescribing patterns at our institution. Methods: In this retrospective chart analysis, we identified 70 pts with mCSPC who were treated with D between June 2014 and September 2018 at an academic cancer centre in Toronto. The main outcomes studied included time to castrate resistance (TCR), change in PSA, number of cycles completed, and rates of febrile neutropenia (FN). We also analyzed pt subgroups including pts starting D <50 days after the start of androgen deprivation therapy (ADT) versus those starting >50 days after ADT initiation. Results: The median age of our pts was 69 (IQR: 64-74). The median follow-up time was 598 days. 79% of pts had high volume disease per CHAARTED criteria, 73% had de novo metastatic disease and 85% had bone-only disease. The median TCR from the start of ADT was 12.3 months. The median change in PSA from pre-ADT to post-D nadir was 99%. The mean D dose intensity was 86% of the ideal dose and 91% of pts completed all 6 cycles of D. 11% of pts were diagnosed with FN during treatment. 6% of pts required treatment delays and 19% required toxicity-related dose reductions. Subgroup analysis showed that patients (n=41) who received D >50 days from the start of ADT did not have significant differences in TCR, rates of FN, need for a decrease in dose intensity or treatment delays compared to those starting <50 days after ADT (n=29). Conclusions: D can be delivered safely in RW pts, with low rates of FN, however, there is evidence of an efficacy-effectiveness gap with a shorter TCR compared to that observed in CTs. The timing of D (<50 days vs. >50 days) does not appear to have an impact on outcome or toxicity.
Clinical and molecular analysis of patients treated with prostate-specific membrane antigen (PSMA)-targeted radionuclide therapy.
Authors: Conteduca Vincenza , Oromendia Clara , Vlachostergios Panagiotis J. , Hackett Amy , Thomas Charlene , Case Aidan , Manohar Jyothi , Eng Kenneth , Sboner Andrea , Ballman Karla V. , Elemento Olivier , Nanus David M. , Beltran Himisha , Tagawa Scott T. 
Published: March 2019

272 Background: PSMA targeted therapy has recently emerged as a promising approach for patients with advanced prostate cancer. However, there is still a need for reliable biomarkers that provide information about clinically meaningful outcomes and treatment responses. Methods: Baseline, treatment and outcomes data along with tumor whole-exome sequencing (WES) data were retrospectively evaluated in anti-PSMA-treated patients (pts). Statistical comparisons utilized Cox regression analysis and Kaplan-Meier method for association with overall/progression-free/survival (OS/PFS) and PSA response. Results: We analyzed 25 pts treated with PSMA targeted radionuclide therapies refractory to standard therapy. 15 received 177Lu-J591, 8 received 177Lu-PSMA-617, 1 received both, and 1 225Ac-J591. WES data (n=28) showed an incidence of AR, BRCA1, BRCA2, ATM alterations (copy number variations and point somatic mutations) in 71.4% (n=20), 11.1% (n=3), 29.6% (n=8), and 14.3% (n=4), respectively. Variables found with backward selection with AIC criterion for PFS and OS suggest significant clinical and molecular predictors of PFS/OS (Table). Conclusions: Knowledge of prognostic factors such as baseline narcotic use and ALP, and BRCA1/BRCA2 and TP53 alterations may have potential clinical utility in patients being considered for anti-PSMA targeted radionuclide therapies. Validation of these findings in larger prospective trials is warranted.[Table: see text]
Survival outcomes for adjuvant or salvage radiation in men with pN+M0 prostate cancer.
Authors: Tward Jonathan David , O'Neil Brock , Stephenson Robert A , Agarwal Neeraj , Farr Tyler , Petragallo Rachel , Lowrance William Thomas 
Published: March 2019

276 Background: The benefit of adjuvant or salvage radiation in pN+ men following radical prostatectomy (RP) is debated. Prior outcome studies are hampered either by missing prognostic variables or poor statistical analysis. We performed a rigorous outcome analysis in completely pathologically staged pN+ men treated with radical prostatectomy at the Univ. of Utah between the years 1998 and 2018. Methods: Men who were cN0M0 prior to surgery found with pN+ disease after RP were identified in our combined prospectively and retrospectively gathered institutional database. Those with metastasis found within 3 months of RP were excluded. The pathologic T and N stage, margin status, # of nodes resected, # of nodes positive, age, and NCI comorbidity scores were known for all subjects. Propensity weighted adjustment for the aforementioned covariates was performed to balance prognostic covariates in those who received EBRT + ADT (RT) versus those who didn’t (No-RT). Cox proportional hazards and KM analysis in the propensity-adjusted and original populations were used to evaluate metastasis free and overall survival. Results: Median follow-up time was 3.7 years. There were 129 men in the No-RT cohort and 72 in the RT cohort. Those in the No-RT group were twice as likely to develop metastasis (p < 0.05 in all statistical models) and 2-3 times as likely to die of any cause (p 0.03 to 0.12 depending on model) than those receiving RT at any time after surgery. The median time to metastasis in the No RT cohort was 7.3 years and was not-reached in the RT cohort. The median time to death was 11.9 years in the No-RT cohort and was not reached in the RT cohort. Conclusions: The addition of adjuvant or salvage pelvic nodal radiation with limited duration ADT results in clinically and statistically significant reduction in metastasis and death following RP. A nomogram has been created which can be used to predict metastasis and mortality for individual subjects based on pathologic findings after RP.
Abi1 loss drives prostate tumorigenesis through activation of EMT and noncanonical WNT signaling.
Authors: Nath Disharee , Li Xiang , Mondragon Claudia , Post Dawn , Chen Ming , Hryniewicz-Jankowska Anita , Caza Tiffany , White Julie , Kuznetsov Vladimir , Hehnly Heidi , Khanna Rakesh , Gleicher Stephanie , Jamaspishvili Tamara , Berman David Monty , Zhang Fan , Kung Sonia H.Y. , Fazli Ladan , Bratslavsky Gennady , Pandolfi Pier Paolo , Kotula Leszek 
Published: March 2019

280 Background: Prostate cancer is characterized by heterogeneity of mechanisms which are poorly understood but pointing to epithelial plasticity as the key mechanism in progression to metastatic disease. ABI1, a member of WAVE complex and actin cytoskeleton regulator and adaptor protein, is proposed to act as tumor suppressor in prostate cancer, but the mechanism of tumor progression due to Abi1 loss is not clear. Methods: To address Abi1’s role in prostate cancer we used CRISPR-based gene editing and retroviral expression to manipulate Abi1 levels in prostate cancer cell lines. Levels of Abi1 expression in prostate organoid tumor cell lines were evaluated by Western blotting and/or RNA sequencing. Association of Abi1 loss with tumor grade was evaluated by immunohistochemistry. Results: Abi1 expression is downregulated in tumor organoid cell lines from metastatic bone and lymph node biopsies. Moreover, low Abi1 expression is associated with high-grade prostate tumors (GG3 or higher, p < 0.001). Disruption of Abi1 gene in a benign prostate epithelial cell line RWPE-1 resulted in a gain of invasive phenotype, which is characterized by loss of cell-cell adhesion markers and increased migratory ability of RWPE-1 Abi1 KO spheroids. Through RNA sequencing and protein expression analysis we discovered that Abi1 loss leads to activation of non-canonical WNT signaling and EMT pathways, which are rescued by re-expression of Abi1. Furthermore, increase in STAT3 phosphorylation upon Abi1 inactivation and evidence for high affinity interaction of FYN-SH2 domain with Abi1 pY421 support the model that Abi1 acts as a gatekeeper of the non-canonical WNT-EMT pathway activation downstream from FZD2 receptor. The gene expression profile of Abi1-EMT-WNT pathway overlaps with the reported gene signature of high-risk prostate tumors. Conclusions: Abi1 contributes to prostate cancer progression and epithelial plasticity through regulation of EMT-WNT pathways. Understanding of Abi1’s role may provide more mechanistic understanding of prostate cancer tumor progression.
Somatic alterations in a seven-gene DDR gene panel predicts platinum sensitivity in advanced prostate cancer patients.
Authors: Vlachostergios Panagiotis J. , Manohar Jyothi , Niaz Muhammad Junaid , Lee Aileen , Hackett Amy , Molina Ana M. , Nanus David M. , Beltran Himisha , Tagawa Scott T. 
Published: March 2019

283 Background: Genomic alterations in the DNA damage response and repair (DDR) pathways are common in advanced PC. Platinum compounds are active in CRPC pts. DDR-defective PC tumors have increased sensitivity to PARP inhibitors (PARPi); the mechanisms involved in sensitivity to platinum and PARPi may be similar but not identical. This study aimed to assess the impact of somatic DDR alterations on clinical outcome of platinum-treated patients with advanced PC. Methods: We reviewed records of advanced PC patients, who received platinum-based chemotherapy with available tumor tissue specimens. We used next generation sequencing (whole exome or targeted) to assess for mutations and copy number alterations in a selected panel of DDR genes, including BRCA1, BRCA2, ATM, ERCC3, ERCC5, TP53 and RB1. We used Kaplan Meier curves to predict PFS and OS after initiation of platinum chemotherapy. Results: Our cohort included 50 men, median age 69.5 years (45-91), median PSA 0.81 (0.008-2291.25), median LDH 264 (109-6714). 39 had visceral metastases (38 liver, 15 lung, 2 adrenal, 2 peritoneal, 1 brain). The majority or pts (33/50) received carboplatin, 17 received cisplatin (2 subsequently also received carbo with initial platinum used for data analysis). Most pts received chemotherapy doublets, and platinum was most frequently combined with etoposide (N=27) and paclitaxel (N=9). 39 pts had tumors harboring at least one DDR alteration. Somatic deletions in BRCA2 gene (N=18) were associated with a significantly longer PFS compared to men with wild-type BRCA2 (median PFS: 6 versus 3 months, P=0.019). No significant associations were identified between somatic DDR alterations and OS. Presence of ≥2 concomitant DDR somatic alterations predicted a favorable PFS compared to single-gene alterations or lack thereof (6 vs 3 months, P=0.006). Conclusions: Our study suggests that presence of ≥2 concomitant DDR somatic alterations from a 7-gene DDR panel, including BRCA1, BRCA2, ATM, ERCC3, ERCC5, TP53, and RB1, may predict longer PFS in pts with advanced PC treated with platinum-based chemotherapy. Further studies are needed to clinically qualify multiplex predictive biomarkers of DDR-defective PCs.