bluuebunny/crossref_metadata_2025_split huggingface dataset:
Gene expression in circulating tumor cells (CTC) and plasma androgen receptor (AR) gene copy number (CN) for castration-resistant prostate cancer (CRPC) patients (pts) treated with cabazitaxel.
Authors: Gurioli Giorgia , Conteduca Vincenza , Basso Umberto , Fornarini Giuseppe , Mosca Alessandra , Nicodemo Maurizio , Banna Giuseppe Luigi , Lolli Cristian , Schepisi Giuseppe , Gargiulo Stefania , Altavilla Amelia , Testoni Sara , Scarpi Emanuela , De Giorgi Ugo 
Published: February 2020

154 Background: Cabazitaxel demonstrated overall survival (OS) benefit for the treatment of CRPC progressing after docetaxel. CTC profiling could help to establish novel predictive biomarkers. In this prospective study (NCT03381326), we evaluated the prognostic role of CTC biomarkers expression and the association with plasma AR CN in pts treated with cabazitaxel. Methods: We enrolled pts receiving cabazitaxel from January 2015 to December 2018. Plasma DNA was isolated and digital PCR was performed to assess AR CN status. CTC enrichment was evaluated with AdnaTest EMT-2/StemCell kit. Expression analyses using real time PCR were performed for 17 genes and CTC positivity (CTC+) was defined as the expression of at least 1 of the following 7 relevant markers: AR-V7, AKT, AR, EPCAM, PSMA, PI3KCA, PSCA. Results: We enrolled 100 pts, 80 fully evaluable for this analysis. Median age was 72 years (range 49-82). All pts received prior docetaxel and 85% prior abiraterone and/or enzalutamide. Median OS and progression-free survival (PFS) were 16.4 months (mo) (95% CI 11.1-27.0) and 6.7 mo (95% CI 5.2-8.3), respectively. Fifty-eight (72.5%) showed CTC+ at baseline, whose 15 (26%) had >3 markers expressed in CTC. Significantly worse OS was observed in pts with >3 markers expressed in CTC compared to those with ≤3 markers and CTC negative pts [4.7 mo vs 15.2 vs 31.7 mo respectively, hazard ratio (HR) 6.05 (95% CI 2.07-17.73), p=0.004]. No significant difference was observed for PFS and PSA response. AR-V7 was expressed in 11 (19%) CTC+ pts, whose 10 (91%) had >3 markers expressed in CTC (p=0.0274), and 8 (73%) had plasma AR CN gain (p=0.048). A shorter OS was observed in AR-V7+ vs AR-V7- pts [10.6 vs 18.1 mo, HR 2.48 (95% CI 1.00-6.18), p=0.051]. Significantly worse OS and PFS were found in AR CN gain pts compared to AR normal [11.1 mo vs 27.0 mo, HR 2.28 (95% CI 1.19-4.38), p=0.013 and 5.9 mo vs 8.5 mo, HR 1.81 (95% CI 1.05-3.13), p=0.032], respectively. Conclusions: Liquid biopsy profiling may improve prognostication of CRPC patients treated with cabazitaxel. Further larger studies are warranted. Funding: Partially funded by Sanofi Genzyme. Clinical trial information: NCT03381326.
Combination of AMG 160, a PSMA x CD3 half-life extended bispecific T-cell engager (HLE BiTE) immune therapy, with an anti-PD-1 antibody in prostate cancer (PCa).
Authors: Paweletz Katherine L. , Li Shyun , Bailis Julie M. , Juan Gloria 
Published: February 2020

155 Background: AMG 160 is an HLE BiTE immune therapy that binds prostate-specific membrane antigen (PSMA) on tumor cells and CD3 on T cells, leading to T cell activation, cytokine production, and tumor cell lysis. A phase 1 study of AMG 160 in patients with metastatic castration-resistant PCa is ongoing (NCT03792841). We investigated whether the combination of AMG 160 and an anti-PD-1 antibody could increase AMG 160 cytotoxicity against PCa cells in vitro and ex vivo. Methods: C4-2B human PCa cells engineered to overexpress PD-L1 were treated with a range of AMG 160 doses (0.144–30,000 pM) +/– a fixed dose of anti-PD-1 in the presence of activated human T cells. Cell viability was assessed by Steady-Glo after 1 day. PD-1 expression on T cells was evaluated by flow cytometry. A human tumor explant model consisting of thin sections of fresh surgically resected human PCa tumors was also used to evaluate the AMG 160 + anti-PD-1 combination. Explants were incubated in media over 2 days and treated with buffer alone, AMG 160, or AMG 160 + anti-PD-1 at fixed doses. Activation of autologous T cells within the tumor slices was assayed by flow cytometry, and secretion of cytokines into culture supernatants was measured by Meso Scale Discovery (MSD). Immune-response profiles of the culture tissues were assessed by NanoString. Results: In the PCa in vitro study, AMG 160 treatment induced upregulation of PD-1 on T cells. Cotreatment with AMG 160 + anti-PD-1 increased the potency of cell killing by 2–5x and killed a greater percentage of cells than AMG 160 alone. In the tumor explant model, which preserves tumor architecture and microenvironment, AMG 160 treatment induced activation of the autologous infiltrating T cells, and this activation was increased by cotreatment with anti-PD-1. AMG 160 treatment increased cytokine production, and cotreatment of tumor explants with AMG 160 + anti-PD-1 increased cytokine production further. Conclusions: Together these data suggest that antitumor efficacy of the AMG 160 HLE BiTE immune therapy can be increased by co-treatment with anti-PD-1. These data provide a rationale for evaluating this combination in future clinical studies.
Linking the Aggressive Variant Prostate Cancer (AVPC) molecular signature (-ms) to androgen indifference in a prospective clinical trial.
Authors: Viscuse Paul Vincent , Zhang Miao , Liu Jingjing , Slack Tidwell Rebecca , Subudhi Sumit Kumar , Zurita Amado J. , Corn Paul Gettys , Tu Shi-Ming , Araujo John C. , Wang Jennifer , Efstathiou Eleni , Wang Jianbo , Pilie Patrick Glen , Troncoso Patricia , Zhang Jianhua , Logothetis Christopher , Aparicio Ana 
Published: February 2020

156 Background: AVPC are morphologically heterogeneous tumors that share clinical features with the rare, virulent, androgen-indifferent and platinum-sensitive, small cell histologic variant. The AVPC-ms is composed of ≥2 defects in TP53, RB1 and PTEN, is detectable in »30% of advanced prostate cancers and predicts for benefit from platinum combinations (Corn et al. Lancet Oncol, 2019). Preclinical studies link the AVPC-ms with androgen indifference, but a prospective clinical association with decreased sensitivity to androgen signaling inhibitors is lacking. Methods: In a phase II trial (NCT02703623), men with metastatic castration resistant prostate cancer (mCRPC) treated with abiraterone and apalutamide were classified at week 8 as having a ‘satisfactory’ decline in PSA (≥ 50% from baseline) and CTC (≤5/7.5mL) or ‘unsatisfactory’. Pretreatment biopsies were obtained for immunohistochemistry (IHC) for TP53, RB1 and PTEN and RNA sequencing. Results: 198 men were registered. 59 (31.5%) of 187 evaluable had ‘unsatisfactory’ marker declines. Age, race/ethnicity, and baseline ECOG, PSA and LDH were similar between the groups. Men in the ‘unsatisfactory’ group had higher median total alkaline phosphatase (120 vs. 86; p=0.002), bone-specific alkaline phosphatase (21 vs. 16; p=0.01), CTC (9 vs. 1; p<0.001), and urine n-telopeptides (338.5 vs 182.5; p=0.003) levels. Unsupervised clustering of RNA profiles from 45 tumor biopsies revealed two distinct clusters. The top enriched gene set (FDR q-val<0.000) included ‘epithelial mesenchymal transition’, ‘E2F targets’ and ‘G2M checkpoint’ genes in one (n=18) and ‘androgen response’ in another (n=27) cluster. Six (33.3%) and 9 (33.3%) of the samples respectively belonged to patients in the ‘unsatisfactory’ decline group. IHC and RNA sequencing of the remaining samples are ongoing. Conclusions: Signaling pathways associated with androgen indifference can be identified in the tumor biopsies of men with early mCRPC, prior to exposure to secondary androgen signaling inhibitors. Their association with the AVPC-ms and patient outcomes will be presented. If confirmed, these markers could be used to inform therapy selection. Clinical trial information: NCT02703623.
Doublecortin expression in prostate adenocarcinoma and neuroendocrine tumors.
Authors: Tabrizi Shervin , Alshalalfa Mohammed , Mahal Brandon Arvin Virgil , Davicioni Elai , Liu Yang , Mouw Kent William , Feng Felix Y , Nguyen Paul L. , Muralidhar Vinayak 
Published: February 2020

161 Background: Recent work using prostate cancer mouse models implicated doublecortin (DCX)-expressing neural progenitor cells in prostate adenocarcinoma, reporting a strong association between DCX expression and disease progression and outcome. We sought to evaluate the relationship between DCX expression and these outcomes in human prostate cancer. Methods: DCX expression was measured in transcriptome-wide microarray data from 18,501 patients with localized prostate cancer and 290 patients with metastatic castration-resistant prostate cancer (mCRPC). Pairwise comparisons were performed using the Mann–Whitney U test. Metastasis-free survival (MFS) and overall survival (OS) were analyzed using Cox-proportional hazards. Results: DCX expression was not significantly different between normal prostate (n=29), primary prostate cancer (n=131), or metastases (n=19) (p > 0.5), and did not differ across Gleason score in a large cohort of RP samples (n=17,967, p=0.21). The lack of difference persisted after adjusting for stromal contribution using a 141-gene stromal signature. Those with DCX expression above and below the median did not have significant differences in MFS (HR 1.2 [0.84-1.7], p=0.3) or OS (HR 1.15 [0.7-1.84], p =0.56). In a cohort of untreated prostate cancer, DCX expression was higher in neuroendocrine tumors (n=10) compared to Gleason 9-10 prostate adenocarcinoma (n=110) (p=0.007). Similarly, in two cohorts with mCRPC (n=290), DCX expression was higher in lesions with neuroendocrine features than adenocarcinoma (p<0.001). Consistently, in a patient-derived xenograft model subjected to host castration, DCX expression was initially low, but increased significantly once tumors underwent neuroendocrine differentiation and treatment escape. Conclusions: Contrary to recent data using mouse models, DCX expression did not differ by disease state, grade, or outcome in a dataset of human patients with prostate adenocarcinoma. However, DCX expression appeared to correlate with neuroendocrine prostate cancers, a subgroup that can arise de novo or in the castrate-resistant setting. Further work is needed to define the role of DCX expression and its prognostic significance in prostate cancer.
MicroRNA-based biomarkers of the radiation response in prostate cancer.
Authors: Weidhaas Joanne B. , Telesca Donatello , Kishan Amar Upadhyaya , Guldvik Ingrid Jenny , Schulz-Jaavall Melanie-Birte , Stensvold Andreas , Tran Phuoc T. , Lilleby Wolfgang 
Published: February 2020

163 Background: Intermediate and high-risk prostate cancer can be cured with radiation (RT) to the prostate and pelvic lymph nodes with androgen deprivation therapy (ADT), but both acute and late toxicity of the GU and GI systems are common. There are no biomarkers predicting radiation outcomes, limiting the opportunity to best personalize prostate radiation therapy. Methods: A prospectively enrolled single arm trial for locally advanced prostate cancer patients (T1-T4N0-N1M0) treated with definitive RT (74Gy IMRT) plus ADT was studied. Biologic samples were available in 108 of 138 patients. Toxicity was recorded using the RTOG morbidity grading system. We applied a panel of microRNA-based germline mutations shown to predict cancer therapy endpoints. Machine learning techniques were used to simultaneously identify prognostic features and perform classification of the biomarkers. Upsampling nested LOO-CV was used to assess performance and generality. Independent Fisher’s exact tests were performed to identify statistically significant marginal associations. Three classifiers were studied: logistic regression with elastic net regularization (EN-LR), classification trees (CT), and random forests (RF), with corresponding hyper-parameters of regularization weights (EN-LR), minimum split and bucket level sample size (CT), number of trees and mtry (RF). Normalized on the simplex, feature importance was defined as absolute value of regression weights for EN-LR, and cumulative decrease in Gini impurity for primary and surrogate splits at each node/splits for CT and RF. Results: Grade 2 or higher toxicity included acute GI (11%), acute GU (34%), late GI (3%) and late GU (16%). GI and GU toxicity and acute and late toxicity had unique predictive biomarkers. The top three marginal genetic associations for late GU toxicity were microRNA site variants in CD6 and CD274 (PDL1)(p.val < 0.01) and BRCA2 (p.val = 0.014). Using RF, CT and EN_LR we could predict late GU toxicity with up to 70% sensitivity, 96% specificity, and 90% accuracy. Conclusions: We have identified microRNA-based biomarkers that can predict late GU toxicity. Work incorporating patient reported outcomes and to identify biomarkers for additional endpoints is ongoing.
Impact of DNA damage repair (DDR) mutations on treatment outcomes in men receiving conventional therapy for metastatic castration resistant prostate cancer (mCRPC).
Authors: Carlson Alex S. , Acevedo Rigo , Lim Daniel M. , Gulati Roman , Yu Evan Y. , Schweizer Michael Thomas 
Published: February 2020

172 Background: Nearly 25% of patients with mCRPC harbor DDR alterations, with some of these mutations associating with increased tumor susceptibility to PARP inhibitors and platinum-based chemotherapies. While, mutations in some DDR genes (e.g. BRCA1/2) have been associated with a more aggressive clinical course, prior studies correlating DDR mutational status with treatment response to androgen receptor (AR) signaling inhibitors (ASIs) or taxane-based chemotherapy have yielded conflicting results. Methods: We conducted a single center retrospective analysis to assess clinical outcomes to standard therapies in mCRPC patients with/without DDR mutations as determined on clinical grade next-generation sequencing assays. The primary endpoint was PSA50 response (i.e. ≥50% PSA reduction from baseline), estimated using Bayesian logical regression; secondary endpoints included PSA progression-free survival (PFS), estimated using Kaplan-Meier methods. Results: A total of 93 patients were included in this analysis, with DDR mutations identified in 40/93 (43%). No significant correlations were found between DDR status and PSA50 response within treatment modalities even after adjusting for receipt of prior therapies within the same class (Table). DDR status was not associated with PSA PFS in patients treated with ASIs. There was evidence of decreased PFS in patients with BRCA1/2 and PALB2 mutations treated with Docetaxel (p = 0.008) and Cabazitaxel (p = 0.005), but limited patient numbers precluded significant pairwise analysis with Cabazitaxel. Conclusions: DDR gene mutational status was not associated with inferior clinical outcomes following treatment with ASIs or taxane-based chemotherapy. Additional prospective studies are needed to confirm these findings.[Table: see text]
Association of circulating tumor cell chromosomal instability with worse outcomes in men with mCRPC treated with abiraterone or enzalutamide.
Authors: Brown Landon Carter , Halabi Susan , Schonhoft Joseph , Luo Jun , Nanus David M. , Giannakakou Paraskevi , Szmulewitz Russell Zelig , Danila Daniel Costin , Healy Patrick , Anand Monika , Somarelli Jason , Scher Howard I. , Wenstrup Rick , Berry William R. , Tagawa Scott T. , Antonarakis Emmanuel S. , George Daniel J. , Armstrong Andrew J. 
Published: February 2020

183 Background: While AR-V7 is a known driver of hormonal resistance, most men with mCRPC lack AR-V7 detection and commonly experience cross-resistance to abiraterone and enzalutamide (abi/enza). Loss of AR dependence through neuroendocrine (NE) differentiation or chromosomal instability (CIN) may explain AR therapy cross-resistance in additional men. Methods: PROPHECY was a multicenter prospective study of men with poor risk mCRPC starting abi/enza. We assessed Epic CTC AR-V7, CIN and NE phenotypes before abi/enza and at progression. Radiographic/clinical progression free survival (PFS) and overall survival (OS) were associated with CIN (>3 CTCs) and NE (>3 CTCs) CTC phenotypes using the proportional hazards model adjusting for Cellsearch CTC, AR-V7, and clinical risk score. Results: 118 men with mCRPC starting on abi/enza were enrolled; 106 had evaluable CTCs for AR-V7, CIN, and NE on the Epic platform. Of these, 22.6% and 9.4% of men exhibited high CTC CIN and NE scores, respectively. High pre-treatment CIN and NE phenotypic scores were observed in 63 and 27% of AR-V7 (+) and in 17 and 7% of AR-V7 (-) men. CTC CIN phenotype but not NE phenotype was associated with a lower confirmed PSA response rate and OS (TABLE) with abi/enza, adjusting for CTC number, AR-V7 and risk score. Conclusions: A high chromosomal instability CTC phenotype is associated with worse outcomes in men with mCRPC treated with abi/enza and warrants further study as a prognostic or predictive biomarker. Clinical trial information: NCT02269982. [Table: see text]
Assessment of inherited DNA repair defects in African-American and Caucasian men with prostate cancer.
Authors: Sartor A. Oliver , Yang Shan , Ledet Elisa Marie , Moses Marcus W. , Nicolosi Piper L.W. 
Published: February 2020

185 Background: Pathogenic inherited DNA repair defects are well described in Caucasian American (CA) men with prostate cancer (PCa) but comparative data with large subsets of African-American (AA) men are limited. Methods: Herein we examine germline pathogenic/likely pathogenic defects (P/LP) in 14 well annotated genes involved in DNA repair pathways in a large Invitae Corporation (San Francisco) lab-derived dataset of men with PCa. Frequency of P/LP alteration were directly compared in AA men and CA men. Reliable data on metastatic rates, family history, and Gleason score are missing. These data are derived from “real-world” experiences using both academic and private practice sites in accordance with physician ordering practices. The number of men assessed for individual genes aberrations varied. The 14 genes were assessed in 148-213 AA men and 1760-2488 CA men. Results: Comparative data using Invitae assays have lower levels of P/LP DNA repair alterations (as a whole) in the assays from AA men as compared to CA men (7.5% vs 13.9%, P=0.008). The P/LP 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%). No AA men in this data set had P/LP mutations in BARD1, BRIP1, MLH1, MSH2, MSH6, NBN, or RAD51D. Lower frequency of P/LP findings in non-BRCA alterations were notably different in AA men as compared to CA men (0.48% vs 3.11%, P=0.03). The frequency of BRCA P/LP variants was not distinct between the AA and CA men. Additional comparisons show that Invitae CA data set is similar to a well cited previously published metastatic PCa data set. Conclusions: Taken together these data from comparable commercial assays indicate that AA men with PCa in this large dataset have lower rates of germline DNA repair P/LP alterations as compared to CA men. These findings are driven by lower rates of P/LP alterations in the non-BRCA genes.
Biomarker analysis (CTC and ctDNA/RNA) of GT0918 (Proxalutamide) new AR blocker in phase I mCRPC patients with dose escalation.
Authors: Zhou Karl , Zhang Phoebe , Tong Youzhi , Ma Liandong 
Published: February 2020

186 Background: AR blockade is an important treatment option for mCRPC in clinic and GT0918 is a new chemical entity of AR blocker in 2nd generation. A phase I dose escalation study was planned in pts with mCRPC progressed on multiple lines of SoC and experimental therapies. Daily oral administration of GT0918 has shown better clinical outcomes in 400mg and 500mg cohorts with no comprised toxicities. To study the tumor biology in response to study drug in clinical setting, CTC and cfDNA/RNA based biomarkers were explored. Methods: Pts with histologically confirmed mCRPC who progressed on enza, abi, docetaxel, etc were enrolled and treated with GT0918 continuously until PD, intolerable toxicity or withdraw. Blood samples were collected at baseline, on study drug every 8 wks during the trial and pts with ≥ 3 blood test samples were qualified for various assays for CTCs and cfDNA/RNA via EPIC and PredicinePlus platforms. Results: Total 40 pts were orally administrated GT0918 with dose increasing 50, 100, 200, 300, 400, 500 and 600 mg daily and shown well tolerated with mild to moderate toxicities. Pts received GT0918 over 16 weeks were run biomarkers in Predicine and/or Epic platforms. ctDNA/RNA based variants and CTCs are all detectable in selected pts samples. AR splicing variants (AR-V3 and AR-V7), AR hotspot mutations (W742C, T878A and S889G) and amplifications were detected and shown interesting trends with the clinical outcomes. Both exploratory biomarkers and CTCs suggested higher doses of GT0918 resulted in better clinical outcomes. Conclusions: This is a preliminary study to explore genomic alterations and the CTC enumeration in late stage of mCRPC pts in response to GT0918 treatment with dose increase. As non-invasive assays, both CTC and ctDNA/RNA assays provided valuable molecular insights for monitoring treatment effects besides PSA and imaging scan. Early detection of possible drug sensitivity/resistance mechanisms will facilitate clinical development programs. More patients will be tested in phase II study GT0918 in mCRPC progressed on either abiraterone or enzalutamide. Clinical trial information: NCT02826772. [Table: see text]
Testosterone recovery as biomarker for overall and cause-specific survival in combined treated patients with high-risk and locally advanced prostate cancer.
Authors: Deek Mathew , Vaage Victoria , Hole Knut H. , DeWeese Theodore L. , Stensvold Andreas , Seierstad Therese , Tran Phuoc T. , Lilleby Wolfgang 
Published: February 2020

188 Background: Androgen deprivation therapy (ADT) can cause considerable toxicity and may influence outcome. The study assessed the impact of testosterone recovery (TR) on survival after ADT and definitive radiotherapy in two independent cohorts. Methods: Two hundred and forty-four patients (high risk JHH cohort N=106, T1c-T3N0M0 [A], locally advanced OUH cohort N=138, T1c-T4N0-1M0 [B]) with adenocarcinoma of the prostate were included in this retrospective analysis. Short and long-term ADT was given (median 12 months A, 24 months B, respectively,) and along with conformal external beam radiation 76-80 Gy given to the prostate in cohort A, 74 Gy prescribed in cohort B and 46-50 Gy to the whole pelvis. Testosterone levels were measured at the end of ADT and at biochemical relapse. TR was defined as ≥ 9 nmol/L. Kaplan Meier plots were generated for overall survival (OS) and cause-specific survival (CSS) stratified by TR, in addition to patient characteristics median time to TR and FU were calculated. Results: The median age in the A cohort was 66.7 years and 64.7 years in the B group. FU was 6 years for A and 8 years in B. Patients in group A received median ADT of 12 months and 24 months in group B. The median time to TR was 1.6 yr in A and 2.5 yrs in B, respectively. Patients in group A stratified to TR showed no difference in overall survival (p=0.92)), on contrary, patients in group B showed improved overall survival depending on TR (Fig. 1, KM plot, 10 year OS 75.3% vs 59.9% p=0.034). CSS was seemed to trend towards improvement with TR for cohort A (p=0.19) and was improved in cohort B (p=0.022). The Univariate ADT length, age, and RT dose was associated with time to TR, but on multivariate analysis only longer ADT time (p = 0.03) was significantly associated with time to TR. Conclusions: TR was associated with improved OS in patients with unfavorable locally advanced disease a finding not seen in patients with high-risk disease.