bluuebunny/crossref_metadata_2025 huggingface dataset:
Defining the monocyte subset transcriptional signature associated with progression during androgen-target therapy in prostate cancer patients.
Authors: Cavassani Karen Angelica , You Sungyong , Meza Rebecca , Santiskulvong Chintda , Goodridge Helen , Posadas Edwin M.
Published: February 2020

157

Background: Myeloid-derived circulating monocytes are emerging as cells of interest in cancer biology. The role of circulating monocytes in human Prostate Cancer (PCa) is poorly understood. Here we asked what is the association of monocyte-specific subsets and their transcriptional signatures with PCa progression during (AR)-target therapy. Methods: Single-cell RNAseq analysis were performed in blood monocytes from 4 patients at two specific time points over their clinical, course: T1)responding to next generation androgen receptor signaling inhibitors (e.g. abiraterone or enzalutamide) as reflected by a decline in serum PSA and/or radiographic response, and T2)progressing through treatment as detected by increases in the serum PSA concentration and/or radiographic signs of progression .PBMC were subjected to Ficoll-purification, and FACS sorted to exclude dead cells and cells expressing B- and T- lineage markers. Samples were then pooled using a BD™ Single-Cell Multiplexing Kit. The samples for scRNA-seq analysis included monocytes defined as classical CD14++CD16−, intermediate CD14+CD16+, and non-classical CD14low/-CD16+++. Results: We have observed nine (9) transcriptionally-defined clusters.Clusters 0, 1, 4, 5, and 8 mapped closely to that of classical monocytes with high expression of CD14and low expression of FCG3RA (CD16). Clusters 2 and 3 mapped closely to that of NK cells with high expression of FCG3RA(CD16) and KLRB1(CD161), and clusters 6 and 7 corresponded to CD14low FCG3RAhigh SIGLEC10+ monocytes. Importantly, our preliminary data revealed a decrease in the percentage of cells in clusters 2 and 6 and an increase in the percentage of cells in cluster 4 in progressing patients (T2). At the transcriptional level, the three main clusters (classical, non-classical, NK-like) were distinguished by 32, 33, and 72 genes, respectively. Our preliminary findings show that progression was associated with several innate immune transcripts while cytotoxic genes were associated with response to Enzalutamide. Conclusions: These data suggest that monocytes transcriptional signature may be reshaped by PCa. Further study of monocytes in PCa progression are warranted.
Pain response and health-related quality of life (HRQL) analysis in patients with metastatic castration-resistant prostate cancer (mCRPC) receiving cabazitaxel (CBZ) versus abiraterone or enzalutamide in the CARD study.
Authors: Fizazi Karim , Kramer Gero , Eymard Jean-Christophe , De Bono Johann S. , Sternberg Cora N. , TOMBAL Bertrand F. , Castellano Daniel , Wülfing Christian , Liontos Michail , Carles Joan , Iacovelli Roberto , Melichar Bohuslav , Sverrisdottir Asgerour , Theodore Christine , Feyerabend Susan , Helissey Carole , Picard Pascaline , Ozatilgan Ayse , Geffriaud-Ricouard Christine , De Wit Ronald
Published: February 2020

16

Background: The CARD NCT02485691 study reported superior rPFS and OS with CBZ vs abiraterone or enzalutamide in patients with mCRPC who progressed on docetaxel and within 12 months on a previous alternative androgen-signaling-targeted inhibitor (ARTA). This analysis evaluated changes in pain and HRQL associated with CBZ and ARTA during the CARD study. Methods: Pain response was defined as a decrease > 30% from baseline in BPI-SF pain intensity score with no increased analgesic use. HRQL was assessed using the Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire. Patients were evaluable if they had received at least one dose of CBZ or ARTA and had a baseline FACT-P score plus at least one subsequent FACT-P measurement. A clinically meaningful improvement or deterioration of total FACT-P score was defined as a difference of ± 10 points from baseline. Clinically meaningful changes in HRQL and pain response were confirmed at two consecutive evaluations ≥ 3 weeks apart during the on-treatment period. Survival curves were generated by Kaplan–Meier estimates. Results: Of the 255 patients randomized, 172 (67.5%) had moderate to severe pain at randomization. Pain response and HRQL were evaluable for 111 (86.0%) and 108 (83.7%) for CBZ and 109 (86.5%) and 114 (90.5%) for ARTA. Pain response was 45.9% vs 19.3% for CBZ vs ARTA (p < 0.0001). The probability of not having pain progression after 12 months was 66.2% vs 45.3% CBZ vs ARTA (HR 0.55; 95% CI 0.32–0.97; p = 0.0348). An improvement in total FACT-P score from baseline was reported by 27 (25.0%) patients vs 26 (22.8%) for CBZ vs ARTA. FACT-P score was maintained or improved for 81 (75.0%) patients with CBZ and 86 (75.4%) patients with ARTA. A deterioration in FACT-P from baseline was reported by 22.2% with CBZ vs 24.6% with ARTA. Median time to FACT-P deterioration was 14.8 months for CBZ vs 8.9 months for ARTA (HR 0.72; 95% CI 0.44–1.20; p = 0.2072). Conclusions: CBZ was associated with a greater pain response and delayed pain progression vs ARTA. CBZ and ARTA were associated with similar trends in HRQL but time to FACT-P deterioration was longer with CBZ vs ARTA. Clinical trial information: NCT02485691.
Prostate cancer CTC-RNA Assay: A new method for contemporary genomics and precision medicine via liquid biopsy.
Authors: Teng Pai-Chi , Jan Yu Jen , Chen Jie-Fu , Kim Minhyung , Yao Nu , Garraway Isla , Chu Gina Chia-Yi , Chen Pin-Jung , Wang Jasmine Jiemei , Lee Yi-Te , Zhu Yazhen , Chung Leland WK , Feng Felix Y , Freeman Michael , You Sungyong , Tseng Hsian-Rong , Posadas Edwin M.
Published: February 2020

170

Background: Transcriptome-based analysis has begun to reshape the approach to prostate cancer (PC). Two different gene expression signatures have shown that PC can be divided into 3 subclasses reflecting luminal-basal biology. These subtypes point toward biological drivers that may strongly influence how care should be personalized including optimization of androgen receptor targeted therapy. The majority of work done in this area has been based on tissue-based gene expression. With the advent of newer nanotechnology platforms for isolation of circulating tumor cells (CTCs), profiling of PC gene expression from blood is now possible. Methods: We recruited 34 patients with metastatic castration resistant PC at Cedars-Sinai Medical Center who had available blood specimens prior to initiation of androgen receptor signaling inhibitor (ARSI, e.g. abiraterone, enzalutamide and apalutamide) therapy.We utilized the NanoVelcro Assays which allow for capture and release of CTCs with intact mRNA. Gene sets from the PCS and PAM50 signatures were re-reviewed to optimize signal detection in the blood and enriched for genes upregulated in PC. The NanoString nCounter platform was used for RNA profiling. Results: The final assay was tested in banked blood samples and provided classifications of patients that associated with clinical responsiveness to therapy. Validation was conducted to examine the performance of the CTC-specific PCS/PAM50 panel in public databases (including Prostate Cancer Transcriptome Atlas and GenomeDx). Our pilot study showed that the median overall survival was significantly worse in PCS1 patients. Conclusions: This study shows initial proof of principle that genomic classification in blood is possible using contemporary tool for blood component isolation and RNA profiling. Additional technical and clinical validations are needed prior to widespread implementation, but these methods may make it possible to increase the utilization of genomic classifiers in clinical studies and in practice.
Circulating-free DNA (cfDNA) as biomarker of taxane resistance in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Francini Edoardo , Ou Fang-Shu , Rhoades Justin , Wolfe Eric G. , O'Connor Edward , Ha Gavin , Gregory Gydush , Kelleher Kaitlin , Bhatt Rupal Satish , Balk Steven P. , Sweeney Christopher , Adalsteinsson Viktor , Taplin Mary-Ellen , Choudhury Atish Dipankar
Published: February 2020

174

Background: Docetaxel (D) and cabazitaxel (C) are standard chemotherapies for mCRPC. A reliable biomarker predictive of resistance to D or C is yet to be identified. We aimed to assess the association between genetic amplification of the multidrug resistance transporter ABCB1 (ABCB1 amp) and primary resistance (RES) to D or C for mCRPC, using cfDNA. Methods: A cohort (A) of 136 patients (pts) with at least 1 plasma sample drawn and stored within 1 year prior to starting D for mCRPC (2002-2014) and a cohort (B) of 42 pts with at least 1 plasma sample from within 1 year prior to starting C for mCRPC (2010-2016) were identified from the Dana-Farber Cancer Institute IRB approved database. Whole genome sequencing (WGS) at 0.1x coverage, termed ultra-low pass WGS (ULP-WGS), was performed on cfDNA extracted from the selected samples (1000μL/subject) and sequencing data were analyzed using a tool called ichorCNA to identify cases with sufficient tumor DNA content (>7%) for accurate detection of copy number alterations (CNAs) including ABCB1 amp. Primary objective was the association between ABCB1 amp and RES to D or C. RES was defined as lack of response (no PSA50 decline or radiologic response per RECIST criteria 1.1, within 4 months from treatment start). Odds ratio (OR) was used to compare odds of RES to D or C for pts with ABCB1 amp and P-values were calculated by Fisher’s exact test. Results: Of the selected 178 pts, 66 had tumor fraction >7%: 45 pts in cohort A and 21 in cohort B. No significant association was noted between ABCB1 amp and RES to D (P=0.7123; OR=1.600) or C (P=1.000; OR=1.0606). RES was observed in 26 pts (57.8%) of cohort A and 18 (85.7%) of cohort B. ABCB1 amp was found in 9 pts (20%; 95% CI, 9.6-34.6) in group A and 6 of them (66%) had RES to D. ABCB1 amp rate among D-resistant men was 23.1% (95% CI, 9.0-43.7). In group B, 2 pts (9.5%; 95% CI, 1.2-30.4) had ABCB1 amp and both of them had RES to C. ABCB1 rate among C-resistant pts was 11.1% (95% CI, 1.4-34.7). Conclusions: In this study, ABCB1 amp using cfDNA did not show statistically significant correlation with RES to D or C for pts with mCRPC. Future studies including ABCB1 amp in a suite of putative biomarkers and larger sample size may aid drawing definitive conclusions.
The association between PSA pattern changes and progression in patients with metastatic hormone-sensitive prostate cancer (mHSPC) treated with abiraterone and prednisone (AA/P).
Authors: Sheng Iris Yeong- Fung , Fallah Jaleh , Gupta Ruby , Li Hong , Allman Kimberly D. , Martin Allison , Barata Pedro C. , Ornstein Moshe Chaim , Gilligan Timothy D. , Rini Brian I. , Garcia Jorge A.
Published: February 2020

18

Background: Despite treatment with AA/P, many patients with mHSPC will develop castrate resistant disease (CRPC). Early recognition of progression is difficult. Changes in PSA patterns in patients with mHSPC treated with AA/P may help identify evolution to mCRPC. Methods: All patients with mHSPC who initiated ADT and AA/P from June 2017 to February 2019 at the Cleveland Clinic were eligible. Patterns of PSA change were evaluated using a longitudinal mixed model at time 0, 3, 6, 9, and 12 months (mo) from AA/P initiation. Time to PSA<0.03 and CRPC were estimated using Kaplan-Meier method. Progression was defined as a PSA rise at two consecutive time points. Results: Of the 143 patients who initiated AA/P, 134 men (median Gleason score 8, baseline PSA 15.0 ng/mL) with follow up were included. 52% had de novo mHSPC, 47.8% had prior therapy (21% surgery, 20% radiation, 7% both), and 16% had visceral disease. PSA levels dropped 98.2% in the first 3 mo (p<0.001), slowed from 3-9 mo (p<0.05) and plateaued after 9 mo. The % PSA reduction from time 0 to the other time points was small. The median time to PSA<0.03 was 11 mo. Of those who progressed to CRPC, the reduction within the first 3 mo was more significant than in those who did not (Table). Measurable PSA was higher in patients who progressed to CRPC at all-time points and plateaued by 6 mo. 12-mo CRPC-free after AA/P was 86.7% (95% CI: 79.2, 94.1). Patients with ≥ 98% 3-mo PSA reduction had better CRPC-free survival than patients with <98% reduction (12-mo CRPC-free: 94.4% vs 78.4%), p<0.001. Conclusions: The degree of PSA decline within 3 mo of AA/P may be used as treatment efficacy measurement. Tracking PSA pattern changes may alert clinicians for potential progression, consider frequent PSA and imaging, as well as initiate sequential therapy.[Table: see text]
CDK12 upregulation and adverse correlation with tumor-associated immune cell infiltrates in prostate cancer.
Authors: Hupe Marie C. , Offermann Anne , Schreiber Cleopatra , Merseburger Axel Stuart , Perner Sven
Published: February 2020

181

Background: Biallelic loss of CDK12 has recently been identified as a novel subtype of prostate cancer (PCa). CDK12 altered PCa associates with elevated neoantigen burden and thus may be suitable for checkpoint inhibition. Up to now, data about CDK12 refer to its genetic alterations in PCa while its characterization on protein level and its association with tumor infiltrating T-cells are lacking. Methods: Immunohistochemistry (IHC) for CDK12 was performed on a PCa cohort including 74 benigns, 391 primary tumors from 222 patients, 63 locally advanced tumors, 92 lymph node (LN) metastases, and 56 distant metastases. CDK12 was categorized into negative, weak, moderate and high expression. Density of tumor associated T-cells per tumor area was assessed by IHC for CD3 and graduated into negative (<1%), slight (1-5%), weak (5-10%), moderate (10-50%) and high (>50%). Results: CDK12 significantly increases during PCa progression showing highest levels in LN and distant metastases while benign samples harbor no or weak CDK12 expression (ANOVA p<0.001). Kaplan-Meier curve reveals 5-year-biochemical recurrence free survival rates of 89.5%, 69.1%, 59.1% and 20.0% for primary tumors expressing no, weak, moderate and high CDK12 (log-rank p=0.05). High CDK12 expression significantly associates with attenuated tumor associated T-cells (p=0.009) revealing CD3 negativity in 64.7% of CDK12 high expressing tumors. Intratumoral CDK12 and density of CD3 positive T-cells correlates adversely in particular in locally advanced tumors (p=0.007). Overall, tumor associated T-cells are significantly reduced in distant metastases compared to local PCa (p<0.001). Conclusions: Our study highlights the prognostic potential of CDK12 for PCa and its overexpression in advanced tumors. Of note, CDK12 overexpressing tumors can be designated as immunologic “cold” tumors which is in line with their more aggressive phenotype. Concordantly, distant metastases show attenuated tumor associated T-cells supporting the poor response to immunotherapy.
Comparison of Caucasian and African-American DNA repair alterations in men with metastatic prostate cancer.
Authors: Jaeger Ellen , Burgess Earle Frederick , Zhu Jason , Dellinger Beth , Elrefai Sara , Hatton Whitley , Moses Marcus W. , Lankford Anjali , Zaheri Alexa , Ledet Elisa Marie , Barata Pedro C. , Layton Jodi Lyn , Lewis Brian E. , Sartor A. Oliver
Published: February 2020

199

Background: Data on germline DNA repair defects and VUS rates are sparse in African American (AA) men with metastatic prostate cancer (PCa). Methods: Germline testing data from two centers with a significant percentage of metastatic AA PCa patients were combined and compared to Caucasian American (CA) with metastatic PCa. Fourteen canonical DNA repair genes (ATM, BARD1, BRCA1, BRCA2, BRIP1, CHEK2, MLH1, MSH2, MSH6, NBN, PALB2, PMS2, RAD51C, RAD51D) were assessed in all tested patients (pts) using a pathogenic/likely pathogenic (P/LP) classification. Variants of unknown significance (VUS) were assessed in an Invitae-derived dataset with consistent VUS reporting. Results: A total of 105 AA men with metastatic disease were evaluated and 7/105 of these men (6.67%) had P/LP alteration. Among the AA pt alterations, there were 4 pts with BRCA2, 2 pts with BRCA1, and 1 pt with PALB2. A total of 39/417 (9.3%) of CA metastatic patients had P/LP alterations in the canonical 14 genes. No differences were detected in the AA vs CA metastatic comparison (p=0.39). A total of 1/105 (0.95%) AA pts and 23/418 (5.5%) CA had non-BRCA P/LP mutations. The number of non-BRCA P/LP mutations were lower in the AA as compared to the CA men (p=0.045). When evaluating VUS calls in the metastatic AAs using Invitae multi-gene panels, 28/92 (30.43%) pts had a VUS in the canonical 14 genes as compared to 67/366 (18.31%) of the CA men. AAs were more likely than CA to have a VUS (p=0.010). These data indicate that metastatic AA pts and CA are not significantly distinct in the P/LP alterations in 14 canonical DNA repair genes but that there were lower percentages of P/LP in the AA non-BRCA gene subset. Further, when assessing these genes, it is clear that a VUS is more likely to be called in the AA men. Conclusions: Among men with metastatic PCa, AAs have similar rates of inherited P/LP alterations in 14 well accepted DNA repair genes as compared to CA men, however the non-BRCA gene P/LP alterations were less frequent among the AAs. Variants classified as a VUS were clearly higher in these AA pts as compared to the CA pts.
Regression tree analysis to identify the best candidates for neoadjuvant chemotherapy (NAC) in patients with clinically lymph node-positive penile squamous cell carcinoma (PSCC).
Authors: Bandini Marco , Zhu Yao , Ye Dingwei , Ornellas Antonio Augusto , Watkin Nick , Ager Michael , Hakenberg Oliver W. , Heidenreich Axel , Raggi Daniele , Catanzaro Mario , Haidl Friederike , Pederzoli Filippo , Briganti Alberto , Montorsi Francesco , Chipollini Juan , Azizi Mounsif , Albersen Maarten , Brouwer Oscar , Spiess Philippe E. , Necchi Andrea
Published: February 2020

2

Background: PSCC patients (pts) with palpable inguinal lymph node (ILN) disease have a poor overall survival (OS). For them, use of neoadjuvant chemotherapy (NAC) is recommended in guidelines, but limited data are available to inform pt selection. We aim to identify predictors of poor OS in clinically ILN-positive (ILN+) pts to define the optimal candidates for NAC. Methods: Within an international, multicenter database of 924 PSCC pts, we identified 334 ILN+ pts with available data. ILN involvement was defined either with the presence of palpable ILN disease or based on preoperative CT-scan. FDG-PET/CT-scan was performed based on clinical judgment of the treating physician. Univariable and multivariable analyses (MVA) assessed predictors of overall mortality (OM). A regression-tree method for censored data was used to generate a risk stratification tool for prediction of 24m OM after diagnosis of ILN+ PSCC. Kaplan-Meier method was used to define the OS benefit related to the use of NAC according to the regression-tree stratified sub-groups. Results: Median age at diagnosis was 58yrs, and 105 (31.4%) had ECOG≥1. Of all, 120 (35.9%), 152 (45.5%), and 62 (18.6%) harbored cN1, cN2, and cN3 disease. Additionally, 152 (45.5%) and 117 (35%) had monolateral vs bilateral clinical ILN involvement. FDG-PET/CT was adopted in 42 (12.2%) pts, and 16 (4.8%) had pelvic LN uptake. Median OS was 107m, with 24m OS = 66%. At MVA, cN2 (HR: 2.28, p=0.006), cN3 (HR: 2.15, p=0.02), PET/CT scan-detected pelvic and ILN involvement (HR: 2.57, p=0.007) were independently associated with higher OM, whether bilateral clinical ILN+ was only univariably significant (HR: 1.56, p=0.02). At regression-tree analysis (AUC 70%), pts with cN3 and cN2 with PET/CT-detected pelvic and ILN involvement had the higher risk of 24m OM (>54%). NAC was associated with improved 24m OS rates (54 vs. 33%) only in this pt subgroup (p=0.002). Conclusions: NAC improves OS in pts with cN3 or cN2 and pelvic FDG-PET/CT scan-detected disease. Our regression-tree may serve to screen ILN+ pts, to identify the optimal NAC candidates before radical treatments.
Circulating tumor DNA (ctDNA) landscape in metastatic castrate-resistant prostate cancer patients with germline alterations.
Authors: Moses Marcus W. , Steinwald Peter , Jaeger Ellen , Hatton Whitley , Cotogno Patrick , Manogue Charlotte , Layton Jodi Lyn , Lewis Brian E. , Barata Pedro C. , Sartor A. Oliver , Ledet Elisa Marie
Published: February 2020

200

Background: Circulating tumor-DNA (ctDNA) in mCRPC patients (pts) provides a viable approach for examining the genetic landscape of prostate cancer. In this follow-up, we report ctDNA variants in germline tested mCRPC pts. Methods: ctDNA alterations in 73 genes were detected using Guardant360 (G360) assays. Alteration types assessed were missense, frameshift, insertions, splice variants, truncations, amplifications (amp), deletions, and other. Pts included in the analysis received germline genetic testing (Invitae Corporation, San Francisco, CA) and ctDNA assays at various treatment timepoints. Statistical analyses were performed using chi-square and fisher exact test with p-value <0.05 for significance. Results: Germline and ctDNA testing was completed in 270 mCRPC pts. 13% (35/270) of pts had pathogenic germline alterations. Germline alterations detected were BRCA2 (43%, n=15), ATM (8.5%, n=3), CHEK2 (8.5%, n=3), and BRCA1 (6%, n=2). Of the 673 alterations detected in G360 assays, TP53 (25%, n=167) and AR (17%, n=117) were most commonly observed. ctDNA alteration breakdown for germline negative/positive pts is summarized in Tables A/B. Germline negative pts had more AR alterations compared to germline positive (p = 0.023). Also, germline negative pts presented with more amps (p < 0.001) and germline positive pts with more frameshift alterations (p = 0.005). The association of ctDNA alteration to clinical outcomes in germline positive/negative pts was also assessed and is ongoing. Conclusions: Pts with germline positive alterations had few somatic AR alterations and higher frequency of deleterious mutation in comparison to their germline negative counterparts.[Table: see text][Table: see text]
Family history and germline alterations in metastatic prostate cancer patients.
Authors: Hatton Whitley , Jaeger Ellen , Moses Marcus W. , Zaheri Alexa , Cotogno Patrick , Manogue Charlotte , Lewis Brian E. , Barata Pedro C. , Layton Jodi Lyn , Ledet Elisa Marie , Sartor A. Oliver
Published: February 2020

231

Background: Recent literature has highlighted the importance of germline genetic testing in metastatic prostate cancer (PCa)patients (pts). This retrospective study evaluated family history (FH), evaluate treatment outcomes in metastatic patients with pathogenic germline mutations, and compared family history in Caucasian (CA) and Africans Americans (AA). Methods: At Tulane Cancer Center, 428 metastatic PCa pts had germline testing in at least 79 genes. Comprehensive family histories were obtained in all. Analysis of prevalent FH, including breast, ovarian, prostate, and pancreatic cancers was assessed for all metastatic pts. Statistical analyses including chi square were performed. Results: 64 (64/428; 14.9%) pts had at least one or more pathogenic mutations, while 166 (166/428; 38.7%) had were normal. The remaining 199 (199/428; 46.4%) of pts had a variant of uncertain significance (VUS). Pts with a DNA repair pathogenic mutation were more likely to have >2 family members affected by cancer, regardless of cancer type or degree of relationship (p=0.0047); 6 pts without any family history of cancer had a pathogenic mutation. In CA, the presence of either a breast or PCa family history was associated with pathogenic germline findings (p=.022/.0367) However, in AAs neither breast nor prostate cancer predicted pathogenic germline alterations. Conclusions: The correlation between family history of breast and PCa cancer in CA pts with pathogenic mutations is notable as is the finding of >2 family members with cancer predicting germline pathogenic alterations. With AA pathogenic pts, there was no correlation of family history of breast and PCa, which highlights the need to learn more about the genetic factors which influence AA prostate cancer risk.[Table: see text]
Survey of ADT-induced estrogen deficiency-related side effects in a contemporary cohort of men with advanced prostate cancer.
Authors: Getzenberg Robert H. , Scholz Mark C. , Scholz Alexandra , Steiner Mitchell S.
Published: February 2020

235

Background: Androgen Deprivation Therapy (ADT) is a mainstay in the treatment of advanced prostate cancer. ADT-induced estrogen deficiency related side effects may cause men to delay, pause, or discontinue ADT, increases morbidity and mortality, and can significantly impact quality of life. ADT-induced effects include hot flashes, bone loss and fractures, fatigue, decreased libido, and metabolic and lipid changes. Currently there are no FDA approved treatments for ADT-induced hot flashes in men with advanced prostate cancer. In this study, a survey was conducted on the impact of hot flashes, one of the hallmark ADT-induced estrogen deficiency effects, in a contemporary cohort. Methods: During the period of August/September 2019, 212 men with advanced prostate cancer on ADT participated in a digital survey conducted by the Prostate Cancer Research Institute (PCRI) focused on the frequency, severity and impact of their hot flashes. The men were at least 50 years of age with 61% being 70 or older. ADT types included LUPRONÒ(64%), ELIGARDÒ(12%), ZOLADEXÒ(7%) and other forms of hormonal therapy (17%). Results: Of the 212 men surveyed, 99% reported hot flashes with 80% indicating that they experience clinically significant, moderate to severe hot flashes. 77% of men reported that the number of hot flashes stayed the same or increased during their hormonal therapy. 37% of the men experienced more than 5 hot flashes per day and 23% indicated that they felt embarrassed about their hot flashes. Only 51% had either researched how to address their hot flashes or discussed them with their physician. Importantly, 16% considered halting ADT as a result of their hot flashes. Conclusions: This contemporary survey underscores the significant unmet medical need to treat moderate to severe hot flashes which occurred in 80% of the men studied. As about half of the men have not discussed their symptoms with a physician either because of embarrassment or lack of treatment options, the number of men with moderate to severe hot flashes appears to be greatly under-reported. As men on ADT are living longer with prostate cancer, finding an effective and safe treatment for debilitating hot flashes must be a priority.
Lymph node metastasis to predict overall survival in oligometastatic prostate cancer in Asian patients.
Authors: Rii Junryo , Sakamoto Shinichi , Yamada Yasutaka , Imamura Yusuke , Nakamura Kazuyoshi , Komiya Akira , Nakatsu Hiroomi , Ichikawa Tomohiko
Published: February 2020

237

Background: The oligometastatic cancer has been suggested as an intermediate state between localized disease and wide range metastases. Clinical significance of local treatment in oligometastatic prostate cancer (PCa) has been a recent topic. However, due to racial differences, there are no standard definitions of oligometastasis, especially in Asians. Here we studied the risk factor among Japanese oligometastatic PCa patients. Methods: We retrospectively analyzed the medical record of 207 patients, including locally advanced (T3 or T4N0M0), lymph-node-positive (N1), and ≤10 bone metastases cancer. All patients received androgen deprivation therapy only. The number of bone metastasis and clinical factors were evaluated in association with OS. Results: Median age, PSA at baseline and OS were 73 years, 48.8ng/ml and 121 months respectively. The cutoff value for the number of bone metastases that have the greatest impact on OS was ≥2 (HR 3.05, p = 0.0001), followed by ≥7 (HR 3.03, p = 0.0005). In multivariate analysis, lymph node metastasis (HR 2.54, p = 0.003) and ≥2 bone metastases (HR 2.67, p = 0.009) were independent predictors of OS. In risk classification based on independent predictors, OS was significantly classified in High (3-4 factors), Intermediate (1-2 factors), and Low (no factor) risk groups (p <0.0001). Furthermore, even among same risk factors group, inclusion of lymph node metastasis significantly increased the HR by 2.34 (p = 0.039). Conclusions: Not only the number of bone metastasis but also lymph node metastasis predict OS of oligometastatic PCa patients.[Table: see text]
Blood platelet volume to predict treatment-specific outcomes of metastatic castration-resistant prostate cancer.
Authors: Fukuokaya Wataru , Kimura Takahiro , Urabe Fumihiko , Kimura Shoji , Tashiro Kojiro , Tsuzuki Shunsuke , Koike Yusuke , Sasaki Hiroshi , Miki Kenta , Egawa Shin
Published: February 2020

242

Background: In the present guidelines for the management of metastatic castration-resistant prostate cancer (CRPC), it is unclear who benefits from androgen receptor axis-targeted agents (ARATs) or docetaxel as a first-line treatment. Methods: We conducted a single-institutional retrospective study to explore treatment-specific biomarkers for treatment response of metastatic CRPC. A cohort of 211 patients with metastatic CRPC treated with either ARAT (abiraterone acetate or enzalutamide) or docetaxel as a first-line treatment was evaluated. In addition to well-established biomarkers such as hemoglobin, neutrophil-to-lymphocyte ratio, alkaline phosphatase, and lactate dehydrogenase, we also assessed red cell distribution width, platelet count, and mean platelet volume (MPV). Laboratory measures were assessed within 1 month before starting treatment. Prostate-specific antigen progression-free survival (PSA-PFS) and radiographic progression-free survival (RPFS) were evaluated. Multivariable Cox regression models were used to assess the association between biomarkers and the risk of events. We also studied the statistical interaction between biomarkers and clinical outcomes. Results: Of all blood-based biomarkers, multivariable Cox regression models identified pre-treatment MPV (≤9.0 fL) as an independent prognostic factor of both PSA progression (hazard ratio [HR]: 2.62, 95% confidence interval [CI]: 1.25-5.48, P = 0.011) and radiographic progression (HR: 4.46, 95% CI: 1.79-11.1, P = 0.001). In addition, these models showed a lower risk of PSA progression (HR: 0.38, 95% CI: 0.15-0.96, P = 0.041) and radiographic progression (HR: 0.16, 95% CI: 0.05-0.50, P = 0.002) with docetaxel compared with ARAT when pre-treatment MPV was small. Conclusions: The present study identified MPV as a significant treatment-specific prognostic factor of PSA progression and radiographic progression in patients with metastatic CRPC treated with a first-line treatment. Furthermore, our results suggested that small MPV was associated with superior survival benefit on docetaxel over ARAT.
Exosomal TUBB3 mRNA expression level to predict prognosis for abiraterone treatment in metastatic prostate patients.
Authors: Zhu Sha , Sun Guangxi , Dai Jindong , Zhang Xingming , Chen Junru , Zhu Xudong , Zhao Jinge , Zhang Haoran , Ni Yuchao , Wang Zhipeng , Shen Pengfei , Zeng Hao
Published: February 2020

244

Background: TUBB3 (Class III β-tubulin), a dynamic component of microtubules, is considered a prognostic biomarker of tumor aggressiveness and poor survival. Previous studies have researched into its indication of resistance to chemotherapeutic drugs. However, its association with abiraterone, a next-generation androgen-axis targeting drug in prostate cancer has not been studied yet. In this study, we aimed to find out if exosomal TUBB3 expression could predict the efficacy of abiraterone in metastatic prostate cancer patients. Methods: Blood samples of metastatic prostate cancer patients during different disease stages were collected. We isolated the exosomes and extracted the RNA for analysis of TUBB3 by ddPCR. Absolute target mRNA concentration was measured by ddPCR as copies per milliliter (copies/20ul). Clinical data were collected for all patients. Primary study endpoint was progression-free survival (PFS). Statistical analyses were performed with SPSS 25.0. Results: A total of 54 metastatic prostate cancer patients who have received abiraterone treatment were enrolled. Baseline characteristics are comparable between high (≥10 copies/20ul) and low (<10 copies/20ul) TUBB3 expression groups. Univariate analyses revealed that baseline hemoglobin≤120g/L, baseline sodium concentration >140 mmol/L, baseline potassium concentration >4.39 mmol/L and high exosomal TUBB3 expression were associated with shorter PFS, while only baseline sodium concentration and exosomal TUBB3 expression were independent prognosticators in multivariate analyses. In subsequently subgroup analyses, high exosomal TUBB3 expression demonstrates particularly high hazard ratio in multiple subgroups (patients younger than 70 years old, without neuroendocrine differentiation and immunohistochemical androgen-receptor splice variant 7 expression, with baseline PSA >100 ng/mL, and patients receiving abiraterone as first-line therapy). Conclusions: Exosomal TUBB3 expression has potential in making treatment plan and predict prognosis in metastatic prostate cancer patients. High exosomal TUBB3 expression indicates poor response to abiraterone, especially as first line therapy.
Preliminary results of a prospective assessment of androgen receptor splice variants in mCRPC patients undergoing androgen receptor targeted agents.
Authors: Francolini Giulio , Loi Mauro , Detti Beatrice , Mangoni Monica , Desideri Isacco , Muntoni Cristina , Ciccone Lucia Pia , Aquilano Michele , Pinzani Pamela , Salvianti Francesca , Lucidi Sara , Mariotti Matteo , Garlatti Pietro , Salvatore Giulia , Sottili Mariangela , Livi Lorenzo
Published: February 2020

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Background: Different treatment options for metastatic castrate resistant prostate cancer (mCRPC) are currently available, including Androgen Receptor Targeted Agents (ARTA) and Taxane based chemotherapy. However, selection criteria aiming to drive the therapeutic choice in this setting are lacking, and no standardized therapeutic sequence is validated. In our institution, a prospective study testing predictive value of circulating tumor cells (CTC) in patients (pts) receiving a first line ARTA for mCRPC is currently ongoing (PRIMERA). Here, we present preliminary results from the first enrolled cohort. Methods: Pts affected by mCRPC eligible for Androgen Deprivation Therapy (ADT) plus ARTA were prospectively enrolled and underwent baseline determination of androgen-receptor splice variant 7 (AR-V7) and androgen-receptor-full length (ARFL) variants on CTC at baseline (ARTA start). Fisher Exact Test was conducted to explore the correlation between baseline features and CTC detection rate. Results: Overall, 26 pts were enrolled and baseline results are available for 13 pts. CTC were found in 5 (38.5%) pts. No significant difference was reported in terms of CTC detection probability for pts with high vs low burden of disease according to CHARTEED definition (p=0.42), neither for pts with PSA at CRPC diagnosis < or > 10 ng/ml, (p=0.2). However, a PSA > 10 ng/ml at ADT start in metastatic hormone sensitive setting (mHSPC) was significantly related to CTC detection probability (p=0.01). AR-V7 variants were found in 1 out 5 (20%) CTC-positive pts. Conclusions: PSA at ADT start may significantly be related to CTC detection rate. CTC detection could be particularly useful in pts with a high burden of disease at the beginning of systemic therapy. Metastatic disease could remain dormant until development of CRPC status, with consequent release of increased amount of CTC, more likely to be detected in this setting. AR-V7 expression was found in 20% of CTC positive pts, in line with literature data.[Table: see text]
Analysis of small non-coding RNAs in urinary exosomes to classify prostate cancer into low-grade (GG1) and higher-grade (GG2-5).
Authors: Klotz Laurence , Tilki Derya , Fleshner Neil Eric , DiRienzo Albert Gregory , Wang Wei-Lin Winnie , Tenniswood Martin
Published: February 2020

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Background: To develop a new predictive test for prostate cancer, based on the interrogation of small non-coding RNAs (sncRNA) isolated from urinary exosomes. We report the development and performance of the miR Sentinel PCa Test, that distinguishes patients with prostate cancer from those with no evidence of prostate cancer (NEPC) and the miR Sentinel CS Test, that distinguishes low grade from higher grade disease. Methods: Affymetrix miR 4.0 arrays were used to identify informative sncRNAs isolated from urinary exosomes. sncRNA from 233 subjects undergoing a prostate biopsy [89 men with benign biopsies, 88 with grade group 1 (GG1) cancer and 56 patients with grade group 2-5 (GG2-5)] were interrogated on these arrays. A custom OpenArray platform was designed to interrogate the 280 most informative sncRNAs, identified using a data-driven selection algorithm. The platform was designed to categorize patients as either no cancer or cancer using the miR Sentinel PCa Test, and subclassify the patients with cancer into GG1 or GG2-5 cancer using the miR Sentinel CS Test. The performance of the miR Sentinel PCa and CS Tests was validated in an independent cohort. Results: In 233 men, theSentinel PCa Test correctly classified 89/89 subjects with no cancer and 144/144 with cancer. The Sentinel CS Test correctly identified 55/56 patients with GG2-5 and 87/88 patients with GG1. Sensitivity was 98%, Specificity 98%, NPV 98% and PPV 93%. For validation, a prospective observational study of 329 subjects (NEPC = 139; GG1= 88; GG2-5 = 102) with elevated PSA correctly classified 134/139 as no cancer [Sensitivity 98% (195/199); Specificity 96% (134/139), PPV 98% and NPV 97%]. The Sentinel CS Test classified 87/88 as GG1 and 102/102 as GG2-5 [Sensitivity 100% (102/102), Specificity 99% (87/88), PPV 99%, and NPV=100%]. Conclusions: Initial evaluation of the miR Sentinel PCa and CS Tests demonstrated the high precision of these tests to detect prostate cancer and distinguish high grade (GG2-5) disease. Further validation is ongoing.[Table: see text]
Risk factors which predict biopsy upgrading over time in active surveillance for prostate cancer.
Authors: Lonergan Peter Eoin , Washington Samuel L. , Zhao Shoujun , Cowan Janet E. , Nguyen Hao , Shinohara Katsuto , Cooperberg Matthew R. , Carroll Peter
Published: February 2020

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Background: Active surveillance (AS) is recognized as the preferred treatment for low risk prostate cancer (PCa). No validated clinical tools currently exist to standardize the frequency of biopsies. We aimed to determine predictors of biopsy upgrading in a contemporary cohort of patients on AS. Methods: Men enrolled on AS at UCSF between 2000-2016 were included. The genomic tests used were Oncotype DX, Decipher and Prolaris. Biopsy upgrade was defined as ISUP grade group ≥ 2 on subsequent biopsy. PSA kinetics was calculated using a linear mixed-effects model for log of PSA, adjusted for clinical characteristics. Multivariable Cox proportional hazards regression models were utilized to identify factors associated with risk of upgrade on follow-up at first surveillance biopsy and at 3, 5 and 10 years. Results: 1,303 men were included. Upgrade-free survival at 3, 5 and 10 years was 73%, 53% and 27% respectively. Median time between diagnostic biopsy and first surveillance biopsy was 13 months (IQR 9-16) with the risk of upgrade at first surveillance biopsy associated with PSA density (hazard ratio [HR] 2.761, 95% confidence interval [CI] 1.895-4.023), and “high” risk genomic score (HR 1.867, 95% CI 1.025-3.401) on multivariable analysis after adjustments. Independent variables significantly associated with risk of upgrade at first surveillance biopsy and at 3, 5 and 10 years on multivariable analysis after adjustments are shown. Conclusions: Our findings suggest that genomic scores and PSA density are risk factors for biopsy upgrading within 3 years of starting AS, however PSA kinetics is associated with risk of upgrade at 5 and 10 years. When used in tandem, genomic scores may identify a subset eligible for AS who could potentially adopt a less intensive surveillance regimen.[Table: see text]
Validation of biochemical definition of cure after low-dose rate prostate brachytherapy.
Authors: Crook Juanita M. , Tang Chad , Thames Howard , Blanchard Pierre , Sanders Jeremiah , Ciezki Jay P. , Keyes Mira , Merrick Gregory Stephen , Catton Charles N. , Raziee Hamid , Stock Richard , Sullivan Frank , Anscher Mitch , Frank Steven J.
Published: February 2020

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Background: Prospectively collected outcome data for 14,196 patients with localized prostate cancer treated with LDR brachytherapy (BT) from 7 institutions were analyzed. For the 80% of patients with a 4 year PSA < 0.2 ng/ml, 99% were free of clinical failure at 10 years and 96% at 15 years. We sought to validate this result with 2 independent data sets from mature prospective clinical trials. Methods: In the initial analysis, patients were treated with either BT alone (61%), or in combination with external beam radiotherapy (EBRT:8%), androgen deprivation (ADT:22%) or both (9%). 42% were low risk, 50% intermediate (IR) and 8% high risk(HR). KM analysis was carried out using clinical failure (local, distant, regional or biochemical triggering salvage) as endpoints for each of 4 PSA categories: PSA<0.2 ng/ml, PSA >0.2 to < 0.5, PSA > 0.5 to < 1.0, and PSA>1.0 ng/ml. Results were compared to 12 year follow up data on a phase 2 trial of BT for IR prostate cancer (n=223; MDAnderson Cohort 1) and 10-year data from the BT arm of the phase 3 randomized ASCENDE RT trial (n=160, Cohort 2) for upper tier IR and HR prostate cancer. Results: The results of the initial KM analysis showed that for the 80% of patients with PSA < 0.2 ng/ml at 4 years, 99% were free of recurrence at 10 years (95% CI: 98.4-99.1) and 96% at 15 years (95% CI: 95-97). The association of treatment success with PSA range was highly significant (p<0.0005). Independent validation against BT alone in IR patients (Cohort 1) confirmed that 99% of patients with PSA at 4 years < 0.2 ng/ml were NED at 10 years (CI: 95.8-99.9). For the unfavorable IR and HR patients receiving 12 months ADT + pelvic EBRT and BT in ASCENDE-RT (Cohort 2), PSA < 0.2 ng/ml at 4 years was associated with 96.7% (CI: 89.9-98.9) being failure free at 10 years. Conclusions: As over 80% of patients achieve a PSA < 0.2 ng/ml at 4 years post-LDR BT, and this is associated with 97%-99% being disease free beyond 10 years, we suggest that this biochemical definition of cure be adopted for LDR brachytherapy patients with ≥ 4 years’ follow-up.
Association of black race with improved outcomes following definitive radiotherapy with androgen deprivation therapy for high-risk prostate cancer: A meta-analysis of eight randomized trials.
Authors: Kishan Amar Upadhyaya , Romero Tahmineh , Rettig Matthew , Garraway Isla , Roach Mack , Pisansky Thomas Michael , Michalski Jeff M. , Lee W. Robert , Jones Christopher U. , Rosenthal Seth A. , Feng Felix Y , Boutros Paul Christopher , Nickols Nicholas George , Mahal Brandon Arvin Virgil , Dess Robert Timothy , Tran Phuoc T. , Steinberg Michael L. , Elashoff David , Sandler Howard M. , Spratt Daniel Eidelberg
Published: February 2020

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Background: Though Black men with prostate cancer are more likely to have aggressive disease features than White men, race-specific differences in initial treatment responses in localized disease remains unknown. Methods: Individual patient data were obtained for 9259 patients (including 1674 [18.1%] Black men and 7585 [81.9%] White men) enrolled on eight randomized controlled trials evaluating definitive radiotherapy (RT) ± short-term or long-term androgen deprivation therapy (STADT and LTADT). The primary endpoints were biochemical recurrence (BCR), distant metastasis (DM), and prostate cancer-specific mortality (PCSM). Fine-Gray subdistribution HR (sHR) models were developed to evaluate the cumulative incidences of all endpoints after stratification by National Comprehensive Cancer Network risk grouping. A meta-analysis was done to estimate pair-wise comparisons of treatments within and between Black and White men, after adjusting for age, Gleason score, clinical T stage, and initial PSA. Results: Black men were more likely to have NCCN high-risk disease at enrollment (656/1674 [39.2%] vs 2506/7585 [33%], p<0.001). However, within the high-risk stratum Black men had lower 10-year rates of BCR (46.1% vs. 50.4%, p=0.02), DM (14% vs. 21.6%, p<0.001), and PCSM (4.9% vs. 9.8%, p<0.001). After adjusting for age and disease characteristics, Black men with high-risk prostate receiving RT+STADT had lower rates of BCR (sHR 0.73, 95% CI 0.62-0.86, p<0.001), DM (sHR 0.64, 95% CI 0.49-0.84, p=0.001) and PCSM (sHR 0.49, 95% CI 0.25-0.95, p=0.04). There were no differences in BCR, DM, or PCSM among men receiving RT+LTADT. The interaction between race and the impact of adding STADT to RT alone on BCR was statistically significant (p=0.003). Conclusions: Black men enrolled on randomized trials with long-term follow-up have higher risk disease at enrollment, but have better BCR, DM, and PCSM outcomes with RT-based therapy compared with White men, particularly with the addition of STADT.
Tumor cell intrinsic androgen biosynthesis by 3β-hydroxy steroid dehydrogenase (HSD3B1) to modulate radiosensitivity in prostate cancer cells.
Authors: Ganguly Shinjini , Balyimez Aysegul , Lone Zaeem , Hardaway Aimalie , Patel Mona , Davicioni Elai , Ornstein Moshe Chaim , Garcia Jorge A. , Stephans Kevin L. , Ciezki Jay P. , Tendulkar Rahul D. , Klein Eric A. , Sharifi Nima , Mian Omar Y.
Published: February 2020

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Background: Resistance to ADT is associated with a gain of function mutation in the 3β-HSD enzyme, which catalyzes extragonadal/intratumoral DHT synthesis. As androgen signaling is known to upregulate the DNA damage response (DDR), we investigated whether HSD3B1 genotype modulates DDR and radiosensitivity in PCa. Methods: We stably knocked down HSD3B1 in LNCaP, C42 and VCaP cell lines (which carry the protein stabilizing variant allele) and overexpressed the variant HSD3B1 allele in LAPC4 (harbors a WT allele which readily undergoes degradation). We examined the proliferative and clonogenic capacity of these cells in presence and absence of substrate, DHEA, followed by treatment with IR (400-800 cGy, single fraction). We studied DNA DSB formation and resolution kinetics using γH2AX foci formation in response to radiation. We also measured changes in mRNA expression of DDR response genes pre- and post-radiation. Results: Control shRNA transduced cell lines had increased cell proliferation (p<0.001) and clonogenic survival (2 logs at 800cGy single fraction radiation, p<0.001) in the presence of DHEA compared to HSD3B1 knockdown cells. Variant HSD3B1 cell lines were more radioresistant and exhibited more efficient γH2AX foci resolution at 24 hrs (p <0.05) in a DHEA dependent manner. We observe increased mRNA expression of DDR genes from specific repair networks including non-homologous end joining (PRKDC, XRCC4, XRCC5) and homologous recombination (RAD51, RAD54) in variant HSD3B1 cells. Transcriptional induction of DDR genes following radiation in presence of DHEA was significantly more pronounced in HSD3B1 variant cells, suggesting a more permissive chromatin context. Conclusions: Increased intracellular 3β-HSD drives transcription of NHEJ and HR genes, more rapid resolution of γH2AX foci, and radioresistance in prostate cancer. This work has therapeutic implications related to strategies for combined radiation and androgen directed therapy in localized and metastatic prostate cancer. Prospective validation of treatment strategies combining blockade of adrenal steroid precursor synthesis, ADT, and XRT in high risk disease is warranted.