bluuebunny/crossref_metadata_2025 huggingface dataset:
Alternative inflammatory cytokines pathways in prostate cancer: In search of new therapeutic options.
Authors: Janiczek Marlena , Szylberg Łukasz , Antosik Paulina , Marszalek Andrzej
Published: May 2020

e17504

Background: The inflammatory reaction pathways have impact on tumor cells development or anti-tumor responses. Both by the activity of the innate and acquired immune response signalling pathways. A proper acquired immune response is considered as anti-tumor. While inadequate innate or acquired stimulation of the immune system can cause chronic inflammation that can lead to oncogenesis. Numerous reports have revealed a relationship between chronic prostatitis and prostate cancer (PCa). The aim of the study is to retrospectively assess the histological material of PCa with the Gleason grading score. The histological material evaluated the level of inflammatory factors of pathways initiated by IL-17A and IL-17F. The evaluation of the expression of pro-inflammatory factors such as IL-17A, IL-17F, IL-17RA, IL-17RC, AKT1, EBPbeta, TRAF 6 and NF-kB made it possible to assess the influence of the inflammatory process on the progression of PCa. Methods: Studies were carried out on archival tissue material in the form of paraffin blocks of 40 men with PCa after radical prostatectomy. The control group of 10 men with benign prostatic hyperplasia (BPH). The material was obtained by the transurethral resection of the prostate (TURP). The immunohistochemistry was performed on the material prepared in this way using specific primary antibodies against IL-17A, IL-17F, IL-17RA, IL-17RC, ACT1, TRAF-6, C/EBPbeta and NF-kB. The expression of the antibody to be examined using the light microscopy and the Remmele Stegner score (IRS) in cancer staining were then evaluated. Statistical analysis was performed using the non-parametric Kruskal-Wallis test. Results: In statistical analysis, it was shown that the inflammatory pathway IL17A/IL-17RC/TRAF6/NF-kB occurs in both BPH and PCa. IL-17 RA did not show expression in any group of patients and in the control group. In addition, along with the increase in the grading of Gleason score, a decrease in the expression of the tested inflammatory parameters was demonstrated. Conclusions: The inflammatory process has an impact on the cancer of prostate cancer. There is a correlation between the grades according to Gleason score and the level of expression of inflammation parameters. Activation of the inflammatory pathway through IL17A/IL-17RC/TRAF6/NF-kB cascade could correlate PCa development on the base of BPH. Evaluation of the inflammatory pathway in PCa, the initiated IL-17, may become a starting point for further research on an attempt to use, for example, immunotherapy in PCa.
Germline mutation in multiple primary malignancies associated with prostate cancer.
Authors: Gong Yiming , Fan Liancheng , Zhu Yinjie , Pan Jiahua , Sha Jianjun , Dong Baijun , Xue Wei , Lei Jianqiang , Wang Jianfei
Published: May 2020

e17505

Background: Multiple primary malignancies (MPM) are described as that one individual develop several malignancies that originate from different tissues at the same time or separated (different histology in different location). MPM are also considered as an indicator of germline mutation or hereditary disease. Here we performed next generation sequencing-based 642-gene panel test on the MPM patients to figure out the candidate germline mutation essential for multiple tumorigenesis. Methods: Blood samples from 27 patients diagnosed as MPM with prostate cancer and at least one additional primary cancer from 2018.12 to 2019.12 were collected to detect the germline variation of 642 gene panel. Meanwhile 25 blood samples from patients only diagnosed as prostate cancer were taken as control. After the sequencing results were obtained, the differences between the multiple primary and single primary cohorts were counted. Results: Statistical analysis of the mutations in the multi-primary and single-primary cohorts revealed that differences were concentrated in the following six genes: ESR1, PTPRB, CIC, ANKRD11, BRCA2, MLH1. It was found that the mutations of p.G145S and p.P146Q (frequency 18.5%) of ESR1 gene and p.G1150W (frequency 14.8%) of PTPRB gene which related to angiogenesis were only found in multiple primary cohort. And mutations of growth factor pathway gene CIC (frequency 22.2%), mutation of chromatin remodeling family gene ANKRD11, and two genes of DDR pathway (BRCA2, MLH1) appeared higher in multiple primary cohort, although there was no statistical difference. Conclusions: We found for the first time that the p.G145S and p.P146Q mutations of the estrogen receptor ESR1 gene and the p.G1150W mutation of the angiogenesis-related PTPRB gene may be the drivers of multiple primary prostate cancer, which need further study.
Circulating tumor cells with small nuclear size: A novel biomarker for survival and clinical outcomes in advanced prostate cancer.
Authors: Wang Jasmine Jiemei , Teng Pai-Chi , Jan Yu Jen , Chen Jie-Fu , Cook-Wiens Galen , Yao Nu , Chu Gina Chia-Yi , Chen Pin-Jung , Ho Hao , Lee Yi-Te , Huang Jiaoti , Li Ker-Chau , Chung Leland WK , Zhu Yazhen , Freeman Michael , Rogatko Andre , Yang Ju Dong , Tseng Hsian-Rong , Posadas Edwin Melencio
Published: May 2020

e17512

Background: Very-small-nuclear circulating tumor cells (vsnCTCs) as a subset of CTCs with nuclear size < 8.5 μm associated with visceral metastases (VM) in advanced metastatic, castration-resistant prostate cancer (mCRPC). As VM predicts foreshortened survival, we hypothesized that vsnCTCs would be directly associated with poor overall survival (OS). Methods: Clinically annotated, blood samples from patients with mCRPC with survival follow-up within the Translational Oncology Program Blood & Biospecimen Bank were selected for analysis. CTCs were isolated and analyzed using the NanoVelcro assay. The nuclear size from all CTCs from each patient sample was compared to OS and progression-free survival (PFS) from the time of the blood draw. Results: A total of 76 patients had samples suitable for analysis. Sixty-six (87%) had CTCs; 49 (64%) were vsnCTC+ (≥1 vsnCTC). vsnCTCs were more common in mCRPC patients with previous androgen receptor signaling inhibitor (ARSI) therapy and/or 2 or more lines of treatment. OS was significantly shorter for vsnCTC+ than vsnCTC- patients (median 34 vs. 149 weeks; log-rank HR = 2.6; 95% CI = 1.5 to 4.5; P = 0.0006). Fifty patient samples were available for PFS analysis (i.e. drawn within 4 weeks of starting therapy). vsnCTC+ patients experienced more rapid progression than vsnCTC- patients (median 12 vs. 26 weeks, log-rank HR = 2.2, 95% CI = 1.3 to 4.0; P = 0.004). Multivariable Cox regression revealed that vsnCTC status was independently associated with OS and PFS. P-spline plot analysis showed that the HR of OS increased as the minimum CTC nuclear size decreased. The minimum CTC nuclear size was also independently associated with OS and PFS in a multivariable Cox regression analysis. Patients with prior use of androgen receptor signaling inhibitor (ARSI) therapy had significantly smaller minimum CTC nuclear size compared to those without prior use of ARSI. Average and median nuclear size did not strongly associate with OS or PFS. Conclusions: vsnCTC+ patients are at risk for more rapid clinical progression and have greater risk of death than vsnCTC-. We posit that the vsnCTC may be a biomarker of aggressive mCRPC with foreshortened survival. Interestingly, the CTCs with the smallest nuclei appear to best reflect the observed clinical behavior. This has potential importance in optimizing therapeutic choices and may point toward a unique biology relating nuclear size to aggressive molecular features. Our group continues to explore the biology underlying the vsnCTC.
Germline mutations in DNA repair genes in a large series of unselected Chinese prostate cancer patients.
Authors: Wei Yu , Zhu Yao , Wu Junlong , Ye Dingwei , Zeng Hao , Li Yonghong , Freedland Stephen J. , Zhou Fangjian , He Cai-Yun , Sun Guangxi , Zhu Sha , Zhao Jinge
Published: May 2020

e17523

Background: Germline DNA repair gene (DRG) mutations has emerged as a potential determinant of cancer risk and therapeutic response in PCa. Despite substantial advances in delineating the germline mutation in DRGs among Caucasian population, the prevalence of mutations in DRGs are largely unknown among a large series of unselected prostate cancer patients in Chinese population. Methods: We enrolled 1003 prostate cancer patients from three different hospitals in China, unselected for family history of cancer or age at diagnosis. All patients received germline genetic testing using a clinician-selected multi-gene panel. The 18 DNA repair genes and HOXB13, which has established or emerging potential clinical actionability in PCa, were analyzed in our study. Results: A total of 94 (9.7%) deleterious germline mutations were identified among the 1003 unselected prostate cancer patients. Of these, 5.6% patients carried a BRCA1 or BRCA2 mutations (5.2% in BRCA2 and 0.4% in BRCA1), 3.6% patients carried other DRG mutations (including 10 genes) and 0.5% patients carried HOXB13 mutations. Besides, variants with uncertain significance (VUS) were found in approximately 45% patients. We also divided 633 metastatic PCa patients into 542 de novo metastastic PCa and 91 recurrent metastastic PCa and found mutation frequencies did not differ between these two groups (9.0% vs 11.6%, p = 0.6). Patients with younger age of onset or family history of cancers were more likely to harbour germline mutations in DRGs. However, the rate of germline mutations were still at a high level for patients more than 70 years old (6.7%) and patients without family history of cancers (7.5%). There is no statistically significant difference in the mutation frequencies between patients with metastasis and without metastasis (7.5% vs 9.2%, p = 0.4), which may be because 85% patients without metastasis in our cohort were in high to very high risk group or have lymph node metastasis. Conclusions: To our knowledge, our study reported the largested series of Chinese PCa patients who received germline genetic testing. Our study provided a rationality for germline genetic testing criteria from high risk to metastastic PCa regardless of family history considering the high proportion. In addition, we recommended a multigene panel covering 13 genes ( ATM, BRCA1, BRCA2, CHEK2, FANCA, HOXB13, MSH2, MSH6, NBN, PALB2, RAD51C, RAD51D, TP53) in China. Nevertheless, the high prevalence of VUS (45%) in Chinese PCa patients warrant further efforts.
Development and validation of a six-gene signature for predicting prognosis in prostate cancer patients with lymph node metastasis.
Authors: Guo Jinan , Xie Wenzhuan , Huang Mengli , Gao Chan
Published: May 2020

e17524

Background: Prostate cancer (PCa) patients with lymph node metastasis (LNM) always exhibit poor clinical outcomes. A gene signature that could predict survival in these patients would allow for earlier detection of mortality risk and will also guide individualized therapy. Methods: A prediction model was developed using a public cohort consisting of 623 patients with clinicopathologically confirmed PCa. Data were gathered from cBioPortal and UCSC Xena. Genes expressed differentially in patients with lymph node metastasis versus those without lymph node metastasis were identified. Uni-variate Cox regression analysis and LASSO Cox regression were applied to build a prediction model. Time-dependent receiver operating characteristic (ROC) and Kaplan-Meier curves were used to assess the prognostic capacity of the model, followed by external validation using the MSKCC dataset from cBioPortal. Gene Set Enrichment Analysis (GSEA) was performed to further understand the underlying molecular mechanisms. Results: We identified a six-gene signature (covering GSDMB, SSTR1, MX1, CCBE1, MYBPC1, and FAM3D) that could effectively identify a high-risk subset of PCa patients. ROC analysis indicated that the signature had a good performance (AUC > 0.7) in survival prediction in both the training and the testing/validation cohorts. Cox regression analysis showed that the six-gene signature could independently predict disease-free survival (DFS) as well, although with lower predictive power. Subgroup analyses showed that signature-based risk score may serve as a promising marker to predict DFS in different subgroups, including stage T2 (HR = 0.12, p < 0.001), stage T3 (HR = 0.29, p < 0.001), TP53-wild-type (HR = 0.22, p < 0.001), TP53-mutated (HR = 0.07, p < 0001), AR pathways-wild-type (HR = 0.2, p < 0.001) and AR pathways-mutated(HR = 0.16, p = 0.0419). The performance of the six-gene signature in LNM+ was stable for stratifying the patients according to risk of deatch (HR = 0.23, p = 0.0333). Moreover, GSEA revealed distinct pathway enrichment features in the different risk groups, where pathways related to DNA repair were more prominently enriched in the high-risk group while the low-risk group had higher enrichment of androgen response. Conclusions: We developed a robust six-gene signature that can effectively classify PCa patients into groups with low- and high-risk group, which may help select high-risk patients who require more aggressive adjuvant target therapy or immune therapy.
Inhibition of PIM kinase with fractionated radiation and docetaxel in preclinical prostate cancer models.
Authors: Rajkumar-Calkins Anne , Sagar Vinay , Wang Jian , Bailey Shania , Anderson Philip , Abdulkadir Sarki , Kirschner Austin Noah
Published: May 2020

e17534

Background: PIM kinases are highly expressed in high risk prostate cancer and are associated with aggressiveness and poor prognosis, presenting a therapeutic target. Methods: We studied PIM inhibition (PIMi) in both hormone-dependent (LNCaP) and -independent (DU145, 22Rv1) prostate cancer cell lines and mouse xenografts. We evaluated PIMi effects via Western blotting, immunofluorescence, and RNAseq of multiple relevant pathways, and performed radiosensitization analysis with colony formation assays. We also investigated xenograft tumor growth with PIMi +/- radiation (RT) or docetaxel. Results: Pretreating the cell lines with PIMi prior to RT caused marked changes in H2AX phosphorylation compared to no PIMi + RT, with most significant alteration in DU145. However, in colony formation assays, 22Rv1 showed greatest radiosensitization with colony survival reduced from 23% to 15% with PIMi. 22Rv1 xenografts were grown in castrated mice, which were randomized to 30 Gy in 15 treatments vs no RT over 3 weeks, -/+ PIMi on RT days. RT + PIMi eliminated gross tumor, compared to an average of 78% and 51% of initial tumor volumes remaining with PIMi alone and RT alone, respectively. Immunofluorescence and Western blotting of harvested tumors showed PIMi altered patterns in proteins involved with hypoxic response (COX-2), cell survival (MDM2), and androgen receptor and suggested interactions between RT and PIMi for both MDM2 and androgen receptor but not COX-2. RNAseq analysis of xenografts showed daily PIMi affected multiple pathways involved in metabolism, growth, and DNA repair. Finally, we tested PIMi -/+ docetaxel in castrated mice with hormone-sensitive (LNCaP) or -resistant (22Rv1) xenografts treated with PIMi -/+ docetaxel. With both xenografts, PIMi + docetaxel reduced tumor size best, with 22Rv1 xenografts most dramatically showing 74% volume reduction from baseline with PIMi + docetaxel compared to 50% and 25% reduction in volumes with PIMi alone and docetaxel alone, respectively. Conclusions: PIMi has multiple pathway effects in prostate cancer. PIMi significantly reduces disease burden, particularly in combination with RT or docetaxel. Our data provide rationale for testing PIMi in clinical trials for prostate cancer.
A web app nomogram based on real-life patients: Guide decision in first-line treatment for metastatic castration-resistant prostate cancer (mCRPC).
Authors: Vilbert Maysa Tamara Silveira , Pandolfi Natasha Carvalho , Cesca Marcelle Goldner , de Andrade Poliana , Calsavara Vinicius Fernando , Uchôa Bruno Cezar de Mendonça , Coelho Ricardo Lima , Corassa Marcelo , Rinck Jose A. , Dettino Aldo A. , Oliveira Thiago Bueno
Published: May 2020

e17538

Background: mCRPC phenotype involves androgen-receptor signalling mechanisms that support the use of abiraterone/enzalutamide (Abi/Ez). These therapies improve overall survival (OS) and quality-of-life, with a favourable safety profile. There is no validated data defining the best drug or sequence to be used. Methods: A retrospective study evaluated if a nomogram helps the decision-making of first-line for mCRPC. The nomogram evaluated time-to-treatment failure (TTF) from Abi/Ez and Docetaxel (Doc) treatment and had C-índex of 0.726. Time from start of androgen deprivation therapy to Abi/Ez or Doc, pain, Gleason score, testosterone and the lowest PSA in castration-sensitive scenario were analysed. All patients (pts) in Doc group used second-line Abi/Ez. The outcomes were: to evaluate whether the nomogram scores were associated with TTF/OS in Abi/Ez population; to compare OS between Abi/Ez and Doc poor prognostic (PP) groups based on the nomogram scores. Kaplan-Meier and Cox-regression models were used for time-to-event analyses. The cut-off was defined by Log-Rank. Statistical significance was fixed at 0.05. Results: From May/12 to Feb/20, 123 pts were assessed (79 received first-line Abi/Ez and 44 Doc). Median follow-up was 25.7 months (1.6 to 93.7). Nomogram scores based on Abi/Ez treatment (medium score of 65, 0-225) were statistically associated with OS (HR 1.02, 95% CI 1.01-1.02, p < 0.001) and TTF (HR 1.02, 95% CI 1.02-1.03, p < 0.001). 79 pts who received Abi/Enz were stratified as having good (GP) (score < 46), intermediate (IP) (score 46-112) and PP (score > 112), and it was associated with 75%, 25-75% and 25% probability to 1-year free from treatment failure, respectively. Pts with GP (n = 24) had a median TTF of 29.8m (15.4-44.2), IP (n = 44) 9.8m (4.1-15.4) and PP (n = 11), 4m (2.5-5.5), p = < 0.001. Pts with GP achieved higher TTF than IP (HR 2.3 95% CI 1.3-4.2 p = 0.005) and PP (HR 8.9 95% CI 3.8-20.6 p < 0.001). The results were similar for OS, once the median for GP was 54.0m (30.5-77.6); IP 34.8m (32.2-37.5); and PP 13.6m (9.3-17.9), p = 0.023 (GP versus IP: HR 2.1 95% CI 1.01-4.4 p = 0.046; GP vs PP: HR 3.6 95%CI 1.4-9.6 p = 0.011). Pts with a higher score and PP from Abi/Ez group were compared with Doc pts at first-line (n = 44), showing worse OS (HR 2.4 95%CI 1.03-5.6 p = 0.042) when treated with Abi/Ez. Conclusions: The nomograns scores showed good correlation with TTF/OS. In PP groups, treatment with Doc was associated with better OS than Abi/Ez, suggesting a possible tool on the first-line decision making.
Addition of carboplatin to chemotherapy regimens for metastatic castrate-resistant prostate cancer in post-second generation hormone therapy setting: Does it improve treatment response and survival outcomes?
Authors: Alamiri Jamal , Ahmed Mohamed E. , Andrews Jack R. , Alom Manaf , Motterle Giovanni , Higa Julianna , Karnes Jeffrey , Kwon Eugene D. , Bryce Alan Haruo
Published: May 2020

e17540

Background: The clinical course in metastatic castrate-resistant prostate cancer (mCRPC) can be complicated when patients have disease progression after treatment with 2nd generation hormone therapy (2nd-HT), such as enzalutamide or abiraterone. Currently, limited data exist regarding the optimal choice of chemotherapy for mCRPC after failing 2nd-HT. We sought to evaluate three common chemotherapy regimens in this setting. Methods: We retrospectively identified 150 patients with mCRPC with disease progression on enzalutamide or abiraterone. 92 patients were chemo-naïve, while 58 patients had previously received docetaxel chemotherapy prior to 2nd-HT. After failing 2nd-HT, 90 patients received docetaxel-alone (group A), 33 patients received carboplatin plus docetaxel (group B), while 27 patients received cabazitaxel-alone (Group C). Favorable response was defined by ≥50% reduction in PSA level from baseline after a complete course of chemotherapy. Survival outcome was assessed for 30-month overall survival. Results: Mean (SD) age was 71.2 (8.28), 69.5(8.38) and 67.2 (8.36) for group (A), (B) and (C), respectively. Mean (SD) pre-chemotherapy PSA was 63.8 (138.18), 58.5 (118.15) and 53.7 (88.15) for group (A), (B) and (C), respectively. Mean (SD) Gleason score was 7.9 (1.1), 8.4 (0.88) and 8.1 (1.06) for group (A), (B) and (C), respectively. Patients in group (B) were 2.6 times more likely to have a favorable response compared to group (A) (OR = 2.625, 95%CI: 1.15 - 5.99) and almost 3 times compared to patients in group (C) (OR = 2.975, 95%CI: 1.04 – 8.54) (p-value = 0.0442). We report a Hazard Ratio (HR) of 3.1 (95% CI 1.31-7.35; p = 0.0037) between patients in group (A) versus group (B), and a HR of 4.18 (95% CI 1.58-11.06; p = 0.0037) between patients in group (C) versus group (B). Thirty-month overall survival was 70.7%, 38.9%, and 30.3% for group (B), (A), and (C) respectively (p-value = 0.008). Conclusions: Our data demonstrate improved response and cancer-specific survival in patients with treatment-refractory mCRPC on docetaxel plus carboplatin compared to docetaxel or cabazitaxel alone. Selection bias is inherent in any retrospective study; however, our finding suggests that clinicians may consider docetaxel plus carboplatin in mCRPC patients who fail 2nd-HT. Further prospective studies are warranted.
Efficacy and safety of 177Lu-PSMA radionuclide treatment in patients with diffuse bone marrow involvement: A multicenter retrospective study.
Authors: Gafita Andrei , Fendler Wolfgang Peter , Wang Hui , Sandhu Shahneen Kaur , Weber Manuel , Esfandiari Rouzbeh , Czernin Johannes , Rathke Hendrik , Rauscher Isabel , Tauber Robert , Delpassand Ebrahim , Weber Wolfgang A , Herrmann Ken , Calais Jeremie , Eiber Matthias , Hofman Michael S
Published: May 2020

e17543

Background: 177Lu-labelled prostate-specific membrane antigen (LuPSMA) radionuclide therapy of metastatic castration-resistant prostate cancer (mCRPC) is currently under investigation in phase III trial (VISION). However, patients with diffuse bone involvement, diagnosed with a superscan by bone scintigraphy at baseline, were excluded due to lack of efficacy and safety data. We therefore aimed to investigate the feasibility of LuPSMA in patients with diffuse bone marrow involvement on baseline PSMA-targeted PET/CT. Methods: Patients with progressive mCRPC treated with LuPSMA at six centers in Germany, USA and Australia were considered for inclusion.Eligible patients had 50% or greater bone involvement of the axial skeleton on the baseline PSMA PET. The primary endpoints were PSA response (PCWG3), toxicity (CTCAE v4.02), and overall survival (OS). Secondary endpoints included quality of life (assessed with Brief Pain Inventory-Short Form questionnaires) and radiological response (as measured by CT using RECIST 1.1). Results: 43 of 352 (12%) screened patients met inclusion criteria and were retrospectively analyzed. Median baseline PSA was 1000 (IQR 431-2151) ng/ml. PSA decline ≥50% was achieved in 26/43 (65%) patients, while median PSA progression-free survival was 4.8 (95%CI 2.4–7.1) mo. 15/42 (36%) evaluable patients exhibited pain progression with a median time-to-pain progression of 8.3 (95%CI 5.4–11.3) mo. After a median follow-up of 18.9 mo, median OS was 11.6 (95%CI 8.8-14.3) mo. Objective response in nodal or visceral disease was reported in 7/18 (39%) patients with evaluable target lesions on CT. Grade 3/4 anemia, thrombocytopenia and neutropenia occurred in 9/43 (21%), 10/43 (23%) and 3/43 (8%) patients, respectively. Of note, all patients had grade 1 anemia at baseline, with a median hemoglobin of 9.6 g/dl. 2/43 (5%) patients experienced an adverse event that required a reduction to the LuPSMA activity beginning with the third cycle. Conclusions: Patients with diffuse bone marrow involvement demonstrate similar LuPSMA efficacy and safety when compared to phase II evidence. Acceptable safety outcomes do not support exclusion of patients with a superscan from future LuPSMA treatment protocols.
Combinatorial expression of androgen receptor splice variants: No predictive value in castration-resistant prostate cancer patients treated with enzalutamide (enza) or abiraterone (abi).
Authors: Schlack Katrin , Seitzer Konstantin , Boegemann Martin , Krabbe Laura-Maria , Schrader Andres Jan , Grundmann Norbert , Tiedje Dorothee , Steinestel Julie , Bernemann Christof
Published: May 2020

e17547

Background: Playing an important role in prostate cancer, androgen receptor (AR) signaling is a common therapeutic target. Novel hormonal treatment (NHT) using enza or abi prolongs overall survival in men with metastatic castration-resistant prostate cancer (mCRPC). However, biomarkers predicting therapy response are limited. AR-V7, as the most abundant AR splice variant, has gained clinical interest. Nonetheless, current discussions on its predictive power are diverse. Given that AR-V7 as a sole biomarker is not efficient in predicting response to NHT, we aimed to increase the predictive potential by analysis of combinatorial AR splice variant (AR-V) expression in mCRPC patients undergoing NHT. Methods: We prospectively enrolled 60 patients who started on either abi or enza. Presence of circulating tumor cells (CTC) as well as expression of AR-V3, -7 and -9 were assessed. Outcomes in CTC-, CTC+/AR-V- and CTC+/AR-V+ patients were analyzed considering PSA reduction, PSA-PFS, PFS and OS. Results: PSA reduction of 50% was predominantly found in CTC- patients (78.5%) compared to CTC+/AR-V- (55.5%) and CTC+/AR-V+ (39.3%) without statistical significance (P = 0.059). When taking co-expression of two or more AR-V into account there was no difference in PSA response either (one AR-V 42.9%, two AR-V 33.3%, three AR-V 41.6%, P = 0.154). Median PSA-PFS was 17 months (95%CI 15.7 – 18.3), 13 months (95%CI 6.8 – 19.2) and 5 months (95%CI 3.6 – 6.4) for CTC- pts, CTC+/AR-V- pts and CTC+/AR-V+ pts, respectively (P = 0.005). However, comparing CTC- and CTC+ pts, differences become even more apparent (P = 0.004), CTC+/AR-V- and AR-V+ pts showed less statistically significant differences (P = 0.029). Median PFS and OS were not reached for CTC- pts. PFS was 10 months (95%CI 6.2 – 13.8) for CTC+/AR-V- pts and 9 months (95%CI 1.1 – 16.9) for CTC+/AR-V+ pts (P = 0.004, only CTC- vs. CTC+ P = 0.002). OS was 28 months (95%CI 16.8 – 39.2) for CTC+/AR-V- pts and 15 months (95%CI 7.9 – 22.1) for CTC+/AR-V+ pts (P = 0.014, only CTC- vs. CTC+ P = 0.006). Regarding PFS and OS, there was no difference comparing only CTC+/AR-V- and AR-V+ pts (P = 0.356 and P = 0.244). Conclusions: AR splice variants have prognostic power in stratifying mCRPC patients suffering from a more advanced stage of disease. Nonetheless, our study clearly demonstrates the lack of predictive power of AR splice variants for response to NHT. Additionally, we prove the importance of CTC analysis rather than AR-V expression being more valuable in mCRPC.
Treatment decision making in metastatic prostate cancer (mPC).
Authors: Schumacher Frank , Xu Jiahui , Oswald Laura , Lee Benjamin , Gonzalez Brian , Zhang Hui , Morgans Alicia K.
Published: May 2020

e17552

Background: Multiple treatments with similar efficacy exist for mPC, leaving patients (pts) with complicated treatment choices. Shared decision-making (SDM) can facilitate treatment decisions. The extent to which SDM is used in mPC is unknown. We assessed mPC pt, caregiver, and physician perceptions of decision locus of control (DLOC) (SDM vs. physician- or pt-directed decisions), and the degree of agreement between groups. Methods: Pt/caregiver/physician triads completed surveys of decision-making practices between 12/2016 and 11/2017 after a clinic visit in which a decision occurred. Pts were included only if they had a caregiver present. To evaluate the degree of agreement between pt, caregiver, and physician perceptions of DLOC, we used the quadratic-weighted kappa coefficient (κ). Agreement was evaluated on an overall basis and by pt age group (5-year increments). Results: 50 pt/caregiver/physician triads participated, with median pt age of 72 yo. Most pts were white (96%) and married (90%). A majority of pts, caregivers, and physicians reported SDM (66%, 56%, and 52%, respectively). No group reported completely pt-directed decisions. Pts and physicians demonstrated agreement about DLOC for most encounters (weighted κ = 0.35; P = 0.01). Overall, pts and physicians agreed on the DLOC in 44% of cases, and SDM was the most common agreed-upon DLOC (36%). Relative to physicians, 34% of pts reported more pt influence on DLOC, and 22% of pts reported less pt influence on DLOC. In contrast, caregiver reports of DLOC were independent of physician reports (weighted κ = 0.23; P = 0.55). Overall, caregivers and physicians agreed on DLOC in 38% of cases, and SDM was the most common agreed-upon DLOC (32%). Relative to physicians, 46% of caregivers reported more pt influence on DLOC and 16% of caregivers reported less pt influence on DLOC. There was a statistically significant difference in the degree of agreement by pt age group between pts and physicians (P = 0.045) and caregivers and physicians (P = 0.002), although no specific pattern according to pt age was noted. Conclusions: A majority of pts, caregivers, and physicians reported SDM occurring in routine clinical visits for mPC. Pts reported a higher degree of agreement with their physicians in DLOC than caregivers. Both pts and caregivers perceived greater pt influence on treatment choice than physicians. Efforts to explore the association between SDM, pt satisfaction, and quality of life are ongoing.
Using longitudinal PSA values and machine learning for predicting progression of early stage prostate cancer in veterans.
Authors: Danciu Ioana , Erwin Samantha , Agasthya Greeshma , Janet Tate , McMahon Benjamin , Tourassi Georgia , Justice Amy
Published: May 2020

e17554

Background: The ability to understand and predict at the time of diagnosis the trajectories of prostate cancer patients is critical for deciding the appropriate treatment plan. Evidence-based approaches for outcome prediction include predictive machine learning algorithms that harness health record data. Methods: All our analyses used the Veterans Affairs Clinical Data Warehouse (CDW). We included all individuals with a non-metastatic (early stage) prostate cancer diagnosis between 2002 and 2017 as documented in the CDW cancer registry (N = 111351). Our predictors were demographics (age at diagnosis, race), disease staging parameters abstracted at diagnosis ( Stage grouping AJCC, Gleason score, SEER summary stage) and prostate specific antigen (PSA) laboratory values in the last 5 years prior to diagnosis (last value, the value before last, average, minimum, maximum, rate of the change of the last 2 PSAs and density). The predicted outcome was disease progression at 2 years (N = 3469) and 5 years (N = 6325) defined as metastasis - taking either Abiraterone, Sipuleucel-T, Enzalutamide or Radium 223, registry cancer related death or PSA > 50. We used 4 different machine learning classifiers to train prediction models: random forest, k-nearest neighbor, decision trees, and xgboost all with hyper parameter optimization. For testing, we used two approaches: (1) 20% sample held out at the beginning of the study, and (2) stratified test/train split on the remaining data. Results: The table below shows the performance of the best classifier, xgboost. The top five predictors of disease progression were the last PSA, Gleason Score, maximum PSA, age at diagnosis, and SEER summary stage. The last PSA had a significantly higher contribution than the other predictors. More than one PSA value is important for prediction, emphasizing the need for investigating the PSA trajectory in the period before diagnosis. The models are overall very robust going from outcome at 2 years compared to 5 years. Conclusions: A machine learning based xgboost classifier can be integrated in clinical decision support at diagnosis, to robustly predict disease progression at 2 and 5 years. [Table: see text]
Real-world outcome with abiraterone low-dose plus prednisone in patients with mCRPC in a Brazilian Public Cancer Center.
Authors: Zucca Luis Eduardo Rosa , Neif Joao Antonio Junior , Preto Daniel D Almeida , Cordeiro Dias Isadora Clarissa , Araujo Hadson Silva , Carcano Flavio Mavignier ,   OncoGU
Published: May 2020

e17563

Background: Abiraterone acetate (AA) is a potent selective and irreversible inhibitor of CYP17 used as standard treatment for metastatic Castration Resistant Prostate Cancer (mCRPC). In the pivotal trial COU-AA 301, AA 1000 mg/day plus prednisone increased overall survival after docetaxel in patients with mCRPC. A recent trial demonstrated not inferiority with respect to PSA metrics in the reduced dose of 250mg/day AA associated with dietary intake, which is described as AA low dose (AALD). The introduction of generic AA in the Brazilian Pharma Market and after the endorsement of AALD from international guidelines, the use of AA in limited resourced hospitals became feasible. Since december 2018 our institution has incorporated AALD in patients with mCRPC in first or second line therapy, always after chemotherapy with Docetaxel (either in the sensitive or castration scenario). Methods: We retrospectively reviewed 49 patients with mCRPC that received AALD after chemotherapy with Docetaxel from December 2018 to January 2019. The primary end point was PSA response rate (decrease of ≥ 50% in the PSA concentration from pretreatment PSA value). Univariable analysis were performed to explore association between clinical and pathological features. Results: After a median follow-up of 5 months, 25 patients (51%) had PSA response rate ≥ 50%. Median age was 69 years-old and most patients (73.5%) were ECOG 0 and 1. Despite good ECOG, the population had aggressive disease characteristics with 57.1% being ISUP 4 and 5 and 69.4% being clinical stage IV at initial diagnosis. Seventeen patients (34.7%) were exposed to AALD at first line and 32 patients (65.3%) in second line. It was observed that patients in the first line had better PSA response rate them those treated in the second line (70,6% vs 40,6%. p 0.04). Conclusions: Despite the premature data, this retrospective analyses shows PSA response rate in about 50% of patients treated with AALD in the overall population and about 70% in those treated in first line therapy. Serum PSA response rate is known as a surrogate marker for overall survival in those patients. The protocol will for more mature data. AALD might be an alternative dose for treating patients in institutions with limited resources.
Plasma IL-8 and PD-L1 and overall survival in metastatic castration-resistant prostate cancer patients (mCRPC).
Authors: Polimera Hyma Vani , Pomerantz Mark , Leitzel Kim , Farah Subrina , Xie Wanling , Steinharter John A. , Shaw Grace , Ali Suhail , Drabick Joseph J. , Pancholy Neha , Menon Harry , Bartock Matthew Tyler , Shah Neal , Moku Prashanth Reddy , Maddukuri Ashok , Halstead E. Scott , Umstead Todd , McKeone Daniel , Spiegel Howard , Lipton Allan
Published: May 2020

e17565

Background: We previously reported the significant prognostic and predictive utility of pretreatment serum PD-L1 in the CCTG MA.31 breast cancer serum bank (SABCS 2018, abstr PD3-10). IL-8 (CXCL8) is a pro-inflammatory cytokine that binds to CXCR1 and CXCR2 and promotes tumor immune escape and progression. High serum IL-8 levels are associated with poor prognosis in many cancers, and have recently been reported to predict for reduced overall survival (OS) to nivolumab in lung cancer and melanoma (ASCO 2018, abstr #3025). Here we correlated plasma IL-8 and PD-L1 levels with OS in mCRPC patients. Methods: 201 metastatic CRPC patients had EDTA plasma available for this retrospective analysis. Patient eligibility included chemotherapy-naive mCRPC patients. The ELLA immunoassay platform (ProteinSimple, San Jose, CA) was utilized to quantitate plasma IL-8 and PD-L1. Cox regression assessed hazard ratio (HR) for OS using both categorical (median) and continuous (log-transformed) biomarkers. Results: In univariate analysis, higher plasma IL-8 levels were significantly associated with reduced OS when analyzed as a continuous variable (HR = 1.53; p = 0.003) and were of borderline significance at the median cutpoint (HR = 1.32; p = 0.069; 20.9 vs 31.5 mos median OS). Plasma PD-L1 levels were not significantly associated with OS when analyzed as a continuous variable (p = 0.17), but increased levels were significant when analyzed at the median cutpoint (HR = 1.36; p = 0.044; 21.9 vs 29.0 mos median OS). When plasma IL-8 and PD-L1 levels were combined (median cutpoints), plasma IL-8 high / PD-L1 high patients (n = 58) had a significantly shorter OS vs the plasma IL-8 low / PD-L1 low patients (n = 58) (HR = 1.69; p = 0.009; 19.3 vs 32.9 mos median OS, respectively). In multivariate analysis, when adjusted for biopsy Gleason score, age, PSA, and ECOG PS (all at time of blood draw), only high plasma IL-8 (on a continuous basis) was significantly associated with reduced OS (HR = 1.43; p = 0.019). Conclusions: In mCRPC patients, high plasma IL-8 and PD-L1 levels were associated with reduced OS (separately and combined). Circulating IL-8 and PD-L1 evaluation may inform prognosis in mCRPC and could be considered as biomarkers in future studies determining response to immune checkpoint inhibitor and anti-IL8 therapy.
The study of the treatment efficacy in metastatic castration-resistant prostate cancer of low dose abiraterone with food.
Authors: Makphanchareonkit Kanta , Dejthevaporn Thitiya Sirisinha , Muntham Dittapol , Chansriwong Phichai
Published: May 2020

e17571

Background: Abiraterone acetate and prednisolone (AAP) + ADT has been approved for treatment metastatic castration-resistant prostate cancer (CRPC) in the standard dose 1,000 mg with fasting state. Data in Ramathibodi hospital showed patients who had treated with standard dose of Abiraterone acetate (AA); had PSA response 47.83%. Previous studies showed using low dose AA of 250 mg with food had the non-inferiority results in efficacy. AA was not be reimbursed in Thailand, so the ability to use a highly effective drug at a quarter of the dose, could help in patient accessibility to cancer treatments. We sought to test the hypothesis that low-dose AA with food would have the comparable activity in Thai CRPC patients in both of the pre-Docetaxel and post Docetaxel treatment groups, and exploring the quality of life (QOL) of these patients. Methods: An observational cohort enrolled newly diagnosed metastasis CRPC at Ramathibodi hospital from 1st Jan 2019 to 31st Dec 2019. Patients were assigned to AA (250mg) with actual daily life meal. We collected the data of serum PSA and the adverse events every 4 weeks for 4 months. The QOL data was collected with the EuroQoL (EQ-5D) questionnaire which were done at baseline and every 4 weeks. The primary end point was PSA response that defined as PSA decreased ≥ 50% from PSA level at baseline. The secondary endpoint were the depth of PSA change, QOL and adverse events by using Fisher's exact test and T-test. Results: 21 patients were enrolled. At 12 weeks, there were 11 patients (52.38%) achieved 50% PSA response and 6 patients (28.57%) achieved 90% PSA response. The adverse events occurred 23.8%, and mostly were mild grade. The adverse events were comparable with the historical data in standard dose of AA. Low dose AA has significantly shown the improvement in quality of life from baseline (p < 0.001), and especially the significant improvement in pre-Docetaxel subgroup. Conclusions: Low-dose AA with food has good efficacy in PSA response, adverse events and QOL. Moreover, low dose AA shows more efficacy especially in pre-Docetaxel mCRPC patients. Low dose AA may be helping in reducing cost of cancer care, enabling in delivering affordable cancer care and increasing value of treatment.
Phase II study of biweekly docetaxel plus androgen-deprivation therapy (ADT) in patients with previously-untreated, metastatic, prostatic adenocarcinoma.
Authors: Byeon Seonggyu , Kim Hana , Kim Hongsik , Jeon Hwang Gyun , Jeon Seong Soo , Lee Hyun Moo , Park Se Hoon
Published: May 2020

e17580

Background: To evaluate the efficacy and safety of biweekly docetaxel (bD) plus androgen-deprivation therapy (ADT) in metastatic castration-naïve prostate cancer (mCNPC). Methods: This was an open-label, prospective, single-arm phase II trial. 42 patients with mCNPC were treated with docetaxel 40 mg/m2 every two weeks plus ADT. The primary end point was one year castration-resistant prostate cancer (CRPC)-free survival rate and the secondary end points were prostate-specific antigen (PSA) response, time to CRPC and safety. Results: Most patients (87.5%) had Gleason score 8 or more. The median value of PSA at initial treatment was 66.9 ng/ml (range 0.04 to 2339). After bD plus ADT, 39 patients (92.9%) had a PSA response (reduced PSA level 50% or more). The time to CRPC (one-year CRPC free survival 73.6%) and the duration of PSA response (18 months response 80.4%) did not reach the median. The bD plus ADT regimen was well-tolerated. The most common adverse events included neutropenia, nail changes and diarrhea. Conclusions: bD plus ADT treatment demonstrated favorable treatment outcomes with tolerability. Clinical trial information: NCT03061643 .
Pre-therapy visceral metastases in castrate resistant metastatic prostate cancer: Role in tumor progression.
Authors: Ruchalski Kathleen , Kim Hyun J. , Douek Michael , Raman Steven , Patel Maitraya , Gutierrez Antonio , Levine Benjamin D. , Fischer Cheryce , Auerbach Martin S. , Gupta Pawan , Coy Heidi , Villegas Bianca , Goldin Jonathan
Published: May 2020

e17586

Background: Visceral metastases in castrate resistant metastatic prostate cancer (mCRPC) are known to develop late in the course of disease and portend a poor prognosis. As patients with visceral metastases still derive a clinical benefit to treatment, understanding patterns of progressive disease (PD) may help differentiate important disease phenotypes in mCRPC. The aim of our study was to evaluate the differences in anatomic sites of PD in patients with pretreatment visceral or bone metastases on time to progression (TTP). Methods: A retrospective review of anonymized patients enrolled in phase 2 and 3 clinical trials was performed. Patients were excluded if lacked Tc bone scan or CT chest, abdomen and pelvis (CT CAP) at baseline. Bone disease was defined by automated bone scan lesion area (BSLA) criteria. All CT CAPs per clinical trial protocol were assessed by RECIST 1.1. Soft tissue PD was noted as target, non-target lesion growth and/or presence of new lesions by anatomic site. Bone PD was defined by > 20% increase in BSLA score. Results: Of the 169 subjects that met our selection criterion, visceral disease was present at baseline in 90 patients (53%). Baseline BSLA score was 90474 mm² in visceral and 80348 mm² in non-visceral patients (p = 0.395). Disease progression occurred in 93 patients (55%). With baseline visceral disease, PD was a result of BSLA in 26 (51%) and visceral disease only in 11 (22%) of patient. Lacking visceral disease at baseline resulted in PD by BSLA in 26 (62%) and visceral disease only in 3 (7%) of patients. There was no significant difference in PFS for baseline visceral/non-visceral involvement; median PFS = 4.5 months in visceral; median PFS = 4.34 months in non-visceral (HR = 1.28; p = 0.244). Conclusions: Patients with visceral disease may still derive a similar clinical benefit from treatment to those without. While the presence of baseline visceral disease was associated with higher rates of PD by visceral involvement, PD by bone disease remained the most common cause of PD regardless of presence of baseline visceral metastases.
Clinically relevant genomic alterations identified by targeted exome sequencing in U.S. veterans with prostate cancer.
Authors: Dadashian Eman , Nakazawa Michael , Parikh Neil Rohit , Kalpage Nathisha , Nickols Nicholas George , Rettig Matthew
Published: May 2020

e17599

Background: Amongst male United States Veterans, prostate cancer accounts for one third of cancer diagnoses and is the second leading cause of cancer death. Prostate cancers in the Veteran population may have differing frequencies of clinically relevant genomic alterations than the general population owing to chemical exposures, military service, or other unknown factors. Veterans, however, have been underrepresented in large-scale prostate cancer sequencing cohorts to date. Methods: Archival or fresh prostate cancer tissue from Veterans cared for by our team within the VA Greater Los Angeles Healthcare System (a VA Prostate Cancer Center of Excellence) undergo targeted sequencing as part of routine clinical care through the VA Precision Oncology Program. Sequencing covers over 181 genes frequently mutated in cancers. Prostate cancers from 81 Veterans (76 primary tumors, 5 metastases) have been sequenced through the Personalis ACE CancerPlus platform. Results: 43% of Veterans had primary tumors with clinically relevant genomic alterations, including 6.2% with activating mutations in MAPK pathway members (KRAS, ERBB2, or BRAF), 3.7% with somatic mutations in DDR genes (BRCA2 or ATR), 7.3% with mutations in TP53 or RB1, 4.9% in APC, 1.2% in the WNT pathway (CTNNB1), 3.7% with mutations in the PI3K/AKT pathway (PIK3R1 or AKT1), 3.7% with PTEN deletions, and 22.2% had alterations involving an AR regulated gene (SLC45A3 or TMPRSS). Of the five metastatic tumors sequenced, one had a mutation in TP53 and another had an ETS gene fusion detected. Half of the Veterans who underwent tumor sequencing consented for screening for, or enrollment on, active clinical trials at VA Greater LA. Conclusions: Large-scale sequencing of prostate cancers within VA is feasible and may facilitate enrollment in precision oncology trials specifically designed for Veterans. These data suggest that clinically relevant genomic alterations within the primary tumors may differ between Veterans and the general population; larger data sets along with more robust sequencing platforms are required for clarification.
MR guided high intensity focused ultrasound (MRgFUS) for the treatment of oligometastatic prostate cancer bone metastasis.
Authors: Napoli Alessandro , Marchetti Luca , Cortesi Enrico , Marchetti Paolo
Published: May 2020

e17600

Background: With improvements in diagnostic modalities such as functional imaging, oligometastatic prostate cancer is being diagnosed with greater frequency than ever before. Our aim was to determine MRgFUS ability to downstage patients with oligometastatic bone disease with single session of non-invasive metastasis-directed therapy. Methods: The study was designed with intention-to-treat metastatic bone lesions. Patients were enrolled if they had accessible bone metastasis and could safely undergo MRgFUS (InSightec, Israel). Baseline measurable characteristics included dynamic contrast enhanced MRI study (DCE; Gd-BOPTA, Bracco; GE 750 3T magnet) with semiquantitative perfusion analysis, PSA level (ng/ml) and choline PET (SUV). Measurable variables were obtained at treatment time, 3 months, 12 months and 24 months follow-up. Results: 18 patients fulfilled the inclusion criteria and safely underwent MRgFUS procedure of metastatic bone ablations. Lesions were located in the pelvis (11), scapula (3) and long bones (4). At baseline all lesions showed a significant DCE perfusion (highly vascular) with mean perfusion reduction of 88% at 3 months follow-up (CI: 100-50; p < 0.001) stable at subsequent follow-up scans. Similarly PSA levels decreased from a mean baseline of 19 (ng/ml) to 7.1, 2.9 and 2.1, at 3-12 and 24 moths respectively. SUV values showed similar trend with reduction from baseline (mean 8.9 to 3.0, 2.3 and 1.7: p < 0.001). In all patients single MRgFUS session was appropriate without any major or minor adverse events reported. Conclusions: MRgFUS is a totally non-invasive procedure that can obtain complete bone ablation in patients with oligometastatic prostate disease. The technique features a radiation-free approach that can be of incremental value in long-survivor subset on oncological patients, significantly reducing risk of toxic effects. Concurrent chemo regimen is not a contraindication.