bluuebunny/crossref_metadata_2025 huggingface dataset:
Response to PARP inhibitor therapy in metastatic castrate-resistant prostate cancer (mCRPC) patients with BRCA1/2 versus ATM mutations.
Authors: Marshall Catherine Handy , McNatty Andrea , Eisenberger Mario A. , Bryce Alan Haruo , Antonarakis Emmanuel S.
Published: March 2019

154

Background: Poly ADP-ribose polymerase inhibitors (PARPi) are being studied as a treatment option for men with mCRPC and deficient homologous recombination DNA repair. While the FDA has granted “breakthrough” designation status to olaparib for use in mCRPC patients with either BRCA1/2 or ATM mutations, it is not known if responsiveness to PARPi may be influenced by the mutation type. Because ATM functions as a sensor of DNA damage rather than a mediator of DNA repair, we hypothesized that patients with ATM mutations may not show robust responses to PARPi therapy compared to those with BRCA1/2 mutations. Methods: We conducted a retrospective analysis of mCRPC patients treated with off-label olaparib at Johns Hopkins Hospital and Mayo Clinic Scottsdale who had somatic or germline mutations in BRCA1/ 2 or ATM. The primary endpoint was PSA50 response. Secondary endpoints included overall survival (OS) and radiographic/clinical progression-free survival (PFS). Results: 40 men received olaparib for mCRPC of which 17 had pathogenic mutations (5 ATM-mutant, 12 BRCA1/2-mutant). Eleven (65%) had germline and 6 (35%) had somatic alterations. Five (29%) had Gleason sum ≤7 at diagnosis, 4 (24%) had Gleason sum 8, and 8 (47%) had Gleason sum ≥9. Three (18%) had metastatic disease at diagnosis. Mean age at start of olaparib therapy was 65.6 (range, 52-76) years. Prior chemotherapy was received by 59% of men, and prior abiraterone/enzalutamide by 88% of men. Eleven (65%) had extra-osseous metastases at start of therapy. PSA50 responses were achieved by 10/12 men (83%) with BRCA1/2 mutations and 0/5 men (0%) with ATM mutations (Fisher’s exact test, P= 0.003). Men with BRCA1/2 mutations had a median PFS of 12.3 mo versus 3.3 mo for those with ATM mutations (HR 0.14, 95%CI 0.03-0.60; P= 0.008). There was no difference in OS (HR 0.24, 95%CI 0.03-1.173; P= 0.16). Conclusions: Men with mCRPC harboring mutations in BRCA1/2 appear to have better PSA responses and longer PFS with olaparib compared to men with ATM mutations. ATM-mutant mCRPC patients may require alternative therapies ( e.g. chemotherapy, ATR inhibitors). Larger prospective studies are needed to confirm or refute these preliminary findings.
Predictors of germline DNA damage repair gene mutations (gDDRm) in patients (pts) with metastatic castration-resistant prostate cancer (CRPC).
Authors: Yip Steven , Sunderland Katherine , Beigi Arshia , Angeles Arkhjamil , Khalaf Daniel , Warner Evan W , Vandekerkhove Gillian , Sun Sophie , Annala Matti , Wyatt Alexander William , Chi Kim N.
Published: March 2019

159

Background: gDDRm are present in 6-12% of pts with CRPC and have implications for prognosis, treatment outcomes and familial screening. This study's aim was to identify clinical/pathologic characteristics associated with a higher risk of a pt harboring a gDDRm. Methods: 631 consecutive pts with metastatic prostate cancer were screened for germline mutations in 22 DNA repair genes (including ATM, BRCA1/2, MSH2/6, FANC/ERCC members). Clinical/pathologic characteristics (age at diagnosis, visceral metastases (mets) at time of CRPC, Gleason score, intraductal/cribriform histology (I/C) at diagnosis, family history (FHx) of prostate, breast, ovarian, or pancreatic cancer, time from androgen deprivation therapy initiation to CRPC) were compared between gDDRm+ and gDDRm- cases. A multivariate logistic model of gDDRm status was constructed using purposeful selection of covariates where clinical judgement was employed in addition to statistical significance. A weighted scoring system was created by multiplying each risk factor (RF) by its estimated β coefficient. A pt’s total score was calculated by the sum of each weighted RF. Results: gDDRm+ were identified in 38/631 pts (6.0%, BRCA2 = 28, ATM = 4, BRCA1 = 2, PALB2 = 2, MSH2 = 1, ERCC3 = 1). 29 gDDRm+ and 128 gDDRm- cases with complete clinical/pathologic information were included in the model. Multivariate modeling revealed that visceral mets, FHx and I/C were statistically significantly associated with gDDRm+; age ≤ 65 was included in the model because it was considered clinically relevant (Table). Based on the model results, the weights of each RF are: visceral mets (2), FHx (1), I/C (2), age ≤ 65 (1). Using a total score cut-off ≥ 1, the model achieves a sensitivity, specificity, positive predictive value, and negative predictive value of 97%, 31%, 24%, and 98%, respectively. Conclusions: In this cohort, visceral mets, FHx and I/C were independently associated with a higher risk of harboring a gDDRm. The predictive model may aid in selecting pts for gDDRm screening. Model validation is required. [Table: see text]
Experience with sipuleucel-T in metastatic castration-resistant prostate cancer (mCRPC) with visceral spread from PROCEED.
Authors: Vogelzang Nicholas J. , Kantoff Philip W. , Scholz Mark C. , Vacirca Jeffrey L. , Dakhil Shaker R. , Goel Sanjay , Harmon Matthew , Tang Hong , Brown Bruce , Armstrong Andrew J.
Published: March 2019

174

Background: Trials of approved agents in mCRPC have reported shorter overall survival (OS) in men with visceral metastases (mets). The phase 3 IMPACT trial evaluated sipuleucel-T, an autologous cellular immunotherapy, in mCRPC but excluded visceral mets. PROCEED, a registry of mCRPC patients receiving sipuleucel-T, offers the first description of sipuleucel-T in patients with visceral mets. Methods: PROCEED enrolled men with mCRPC treated with sipuleucel-T biweekly x 3. Dose adjustment for organ dysfunction was unnecessary. Men were followed until death, study withdrawal, or a minimum of 3 years. OS is reported in this post-hoc subgroup analysis. Results: 1902 men received ≥1 sipuleucel-T infusion between 2011-2014. Visceral mets (n = 90) included liver (n=21), lung (n=61), and brain (n=2) involvement. Compared to patients without visceral mets (Table), men with visceral mets had poorer performance status (PS) and higher baseline prostate-specific antigen (PSA). Median OS was 20.5 and 31.2 mo in those with and without visceral mets. Patients with liver and lung mets had a median OS of 16.3 and 21.0 mo, respectively. Activation of antigen-presenting cells, a measure of immune activation and product potency, was similar in those with and without visceral mets. Conclusions: Initial observations suggest that patients with mCRPC and visceral spread can activate their immune cells to produce sipuleucel-T, but have a shorter OS than those with bone and/or lymph node spread. (NCT01306890). Clinical trial information: NCT00065442. [Table: see text]
Real-world PROCEED registry data: Sipuleucel-T in elderly men with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Armstrong Andrew J. , Olsson Carl A , Schnadig Ian D. , Concepcion Raoul S , Vacirca Jeffrey L. , Tutrone Ronald F , Dakhil Shaker R. , Chang Nancy N. , Tang Hong , Brown Bruce , Vogelzang Nicholas J.
Published: March 2019

177

Background: Managing patients ≥ 80 years old (yo) with mCRPC is challenging, given the high prevalence of comorbidities, polypharmacy, organ dysfunction, and reduced performance status (PS). Balancing treatment benefit with safety and quality of life is particularly germane for this group. Sipuleucel-T, an autologous cellular immunotherapy for mCRPC, is generally well-tolerated. Prior analyses from PROCEED, a large registry for sipuleucel-T in men with mCRPC, demonstrated that upregulation of immune cells in these elderly patients is similar to that of younger men. Here, we report on this clinical experience. Methods: PROCEED enrolled men with mCRPC treated with sipuleucel-T given every 2 weeks x 3, with no dose adjustment for organ dysfunction or drug interactions. The elderly cohort included those ≥ 80 yo. Men were followed until death, study withdrawal, or a minimum of 3 years. Results: Of 1902 patients who received ≥1 sipuleucel-T infusion, 374 (19.7%) were ≥ 80 yo. Compared to men < 80 yo (Table), this cohort was 14 years older, had worse Eastern Cooperative Oncology Group (ECOG) PS and higher prostate-specific antigen (PSA) at baseline. All grade (16.3% elderly v. 13.7% younger) and grade 3-5 (10.7% elderly v. 9.9% younger) serious adverse events were comparable between groups. However, the median overall survival (OS) of elderly men was 10.7 mo shorter than that of younger men (< 80 yo). Conclusions: Sipuleucel-T was generally well-tolerated in those ≥ 80 yo in a real-world setting and may be considered a first-line option for the elderly with asymptomatic or minimally symptomatic mCRPC. As expected, OS was shorter than in younger patients. Clinical trial information: NCT01306890. [Table: see text]
A noninvasive prognostic biomarker for metastatic castration-resistant prostate cancer: Very small nuclear circulating tumor cells.
Authors: Chen Pin-Jung , Jan Yu Jen , Teng Pai-Chi , Chen Jie-Fu , Cheng Shirley , Yao Nu , Reis-Sobreiro Mariana , Lozano Amber , Gomez Amy , Freeman Michael , Tseng Hsian-Rong , Posadas Edwin M.
Published: March 2019

179

Background: Circulating tumor cells (CTCs) have arisen as a contemporary biomarker for prostate cancer (PC). A subgroup of PC CTCs, with particularly small nuclei ( < 8.54 μm), were found to be correlated with poor prognosis and the emergence of visceral metastases (VM). This subgroup was named very-small nuclear CTCs (vsnCTCs). The findings led us to explore vsnCTCs as an aggressive biomarker in metastatic castration-resistant PC (mCRPC). We also explored a biological pathway that potentially drives this morphologic phenomenon. Studies showed that the disruption of the linker of nucleoskeleton and cytoskeleton (LINC) complex proteins, such as emerin, results in nuclear envelope instability and drives cancer cells to an amoeboid phenotype with increasing capacity of migration and invasion. We hypothesized that emerin mislocalization is associated with vsnCTC formation and may be a critical step of metastasis. Methods: Using our NanoVelcro CTC assay, we are able to capture and enumerate CTCs from patients' blood and correlate this data with clinical outcomes. We collected samples from 35 mCRPC patients who failed first-line androgen deprivation therapy and started treatment with abiraterone, enzalutamide, or taxane-based chemotherapy. Survival analyses were performed to exam the correlation between vsnCTC counts and patients’ prognosis. Concurrently, emerin staining was performed and the distribution and expression levels were analyzed in selected vsnCTC samples. Results: The presence of one or more vsnCTCs correlated with worse overall survival (P = 0.00013), progression free survival (PSA progression: P = 0.012; radiographic progression: P = 0.0015), and faster time to VM (P = 0.024). We also observed lower emerin content in vsnCTCs compared to WBC, and more prominent emerin mislocalization in vsnCTCs compared to CTCs with larger nuclei. Conclusions: Our study demonstrated the importance of morphologic characterization of CTCs and suggested that vsnCTCs is a putative biomarker for prediction of worse outcome. Additionally, our findings of emerin mislocalization in vsnCTCs suggested a potential biological pathway behind this nuclear morphologic phenomenon.
Treatment efficacy of abiraterone (abi), enzalutamide (enza) or cabazitaxel (caba) in metastasic castration-resistant prostate cancer patients (mCRPC) after progression to docetaxel plus androgen deprivation therapy (ADT) in hormone sensible disease.
Authors: Climent Duran Miguel Angel , Sáez M Isabel , Piulats Josep M. , Montesa A. , Chirivella Isabel , gonzalez Forastero Alejandro , Caballero Diaz Cristina , Heras Lucia , Mellado Begona , Vazquez-Estevez Sergio , Olmos David , Duran Ignacio , Juan Fita María José
Published: March 2019

198

Background: Different treatments efficacy for mCRPC when progression after docetaxel x 6 cycles + ADT (as CHAARTED scheme) are unknown as all pivotal trials where performed in patients who progressed to mCPRC after ADT. Methods: A retrospective analysis of 175 mCRPC patients of 10 spanish hospitals who were treated with docetaxel + ADT as first line treatment was performed. Patients characteristics at diagnosis (age, gleason) and at progression to mCRPC were analyzed (PSA, presence of visceral mets, type of progression). As efficacy endpoints, clinical and objective response, and survival from progression to mCRPC were analyzed. Results: Median age at diagnosis 65.2 years old (range 44-84). Metastatic at diagnosis 173. Bone metastasis 155 (88,5%), visceral 31 (17.7%), gleason >7 130 (74,3%), number docetaxel cycles: 6 (80%), 5 (5,7%), <5 (14,3 %). Median survival from diagnosis: 35 months. Progression to CRPC 78pts (44.5%) Type of progression: PSA 74/78 (94,9%), clinical 45/78 (57.7%), radiological 59/78 (75.6%). Median survival from progression to CRPC: 10.3 months. Treatments frequency, clinical benefit (RP/EE) and median survival: abi 30 (38.4%)/ 7(23.3%)/ 15.7 m; enza 12 (15.4%)/ 4 (33.3%)/ 10.4 m, caba 14(17.9%)/ 3(21.4%)/ 6.4m; Other treatments frequency: Ra223 4 (5.1%), docetaxel 4 (5.1%), others/no treatment/BSC 14 (17.8%). Clinical and radiological progression before treatment was 36.7%/63.3% in abi patients, 58.3%/63.7% in enza and 93.9%/93.9% in caba pts. Visceral (mostly hepatic) metastasis were more frequent in caba (57.1%) than in abi (11.8%) or enza (0%) pts. Median PSA value abi 375/ caba 1633. Conclusions: Although AA seems be more effective than cabazitaxel in mCRPC progressed after docetaxel + ADT in HSPC, patients treated with caba are of worse prognosis.
MiCheck performance: Comparator trial of MiCheck with PHI, % free PSA and PSA—The impact on decision making for prostate biopsy.
Authors: Shore Neal D. , Saltzstein Daniel R. , Pieczonka Christopher Michael , Beebe-Dimmer Jennifer Lynn , Ruterbusch Julie J. , Campbell Douglas , Walsh Brad
Published: March 2019

199

Background: A more accurate diagnostic test is still needed to enhance decision-making regarding prostate biopsy. MiCheck is a triage test to assist in a decision to proceed to prostate biopsy. It measures multiple cancer related proteins in blood while combining this information with clinical factors. It has been optimised to differentiate between aggressive (AgCaP) and non-aggressive (non-AgCaP) prostate cancer. The MiCheck-01 clinical trial collected samples from patients who proceeded to biopsy on the basis of an elevated age adjusted PSA. The performance of MiCheck was compared with PSA, %free PSA and PHI. Methods: Serum samples were tested according to the MiCheck manufacturer’s instructions. Patient samples were also tested using a standard PSA assay and additionally underwent PHI and % free PSA measurement. A range of different MiCheck cutpoints were examined for test performance and one chosen following consultation with Urologists and Clinical Chemists. This algorithm was applied to all evaluable patients from the trial and the outputs used for the development of a health economic model. The net cost impact of using MiCheck was assessed. Results: The best performing MiCheck algorithm demonstrated a high AUC when differentiating AgCaP from non-AgCaP. MiCheck demonstrated a higher AUC than PSA, %free PSA and PHI in this population. Furthermore, the algorithm was superior to the other tests in PSA 4-10ng/ml range. The derived algorithm was applied to patients from the trial using a high sensitivity cutpoint. At this cutpoint, 25% of biopsies were avoided while only 5 (4%) AgCaP patients underwent a later diagnosis. A diagnostic workflow model of how the test might be employed by the clinician was constructed. This was applied to a health economic analysis demonstrating significant cost savings (between $2,744 and 5,047 per patient in year one) when incorporating MiCheck to standard of care. Conclusions: The MiCheck test demonstrates a superior ability to discriminate between AgCaP and non-AgCaP in comparison to PSA,PHI, and % free PSA. Use of the MiCheck test would assist clinicians in assessing the need for a prostate biopsy and provide significant healthcare cost savings.
Metastasis-free survival as a predictor of overall survival in non-metastatic castration-resistant prostate cancer.
Authors: Gagnon Richard , Alimohamed Nimira S. , Batuyong Eugene , Chow Alyssa , Lee-Ying Richard M.
Published: March 2019

201

Background: Recent trials have shown that apalutamide and enzalutamide can improve metastasis free survival (MFS) in advanced non-metastatic (M0) castrate-resistant prostate cancer (CRPC). MFS is a novel clinical endpoint, demonstrated to be a strong predictor of overall survival (OS) for localized prostate cancer, yet it is unknown if this is also true for M0 CRPC. Our aim was to determine how strongly MFS in M0 CRPC correlates with OS in a real world population. Secondary analyses evaluated whether a rapid PSA-doubling time (PSADT), of ≤10 months, impacts outcomes. Methods: We performed an analysis of patients diagnosed with advanced prostate cancer, followed at the Tom Baker Cancer Centre, in Calgary, Alberta from 2001-2017. Patients were excluded if they did not develop M0 CRPC. MFS and OS were measured using the Kaplan-Meier method and the log-rank test was used to compare outcomes based on PSADT. Correlation between OS and MFS was determined using Pearson Correlation and Kendall’s Tau-B. Results: A total of 1310 patients were identified with advanced prostate cancer, of which 87 developed M0 CRPC. The median age of diagnosis of M0 CRPC was 72 years, with a median Gleason score of 7.0, initial PSA of 10.4, and PSADT of 5.1 months. Only 6 patients were treated with second-generation anti-androgens or chemotherapy. Median MFS and OS after M0 CRPC diagnosis were 44.1 and 83.7 months, respectively. Pearson Correlation between MFS and OS was strong with a coefficient of 0.850 (p < 0.001); with non-parametric Kendall’s Tau, correlation was also strong with a coefficient of 0.632 (p < 0.001). PSADT ≤10 months was identified in 70 patients, and associated with a significantly shorter MFS, compared to a PSADT > 10 months (40.2 vs. 90.4 months; p = 0.001), as well as shorter OS (76.2 vs. 104.3 months; p = 0.008). Conclusions: MFS for M0 CRPC is strongly correlated with OS in a real world population. PSADT of ≤10 months seems to be a useful prognostic tool in estimating MFS and OS in patients with M0 CRPC. MFS was better than expected even in patients with a PSADT of ≤10 months, which may due to our adherence to the biochemical definition of castration-resistant disease, as well as lack of standard imaging intervals in the real world.
The efficacy of enzalutamide for castration-resistant prostate cancer (CRPC) patients with intraductal carcinoma of the prostate (IDC-P).
Authors: Kawanishi Hideji , Kato Masashi , Yamamoto Akiyuki , Tsuzuki Toyonori
Published: March 2019

209

Background: Enzalutamide (ENZ) was approved to prolong survival for castration-resistant prostate cancer (CRPC) patients before and after chemotherapy. No factor was identified to predict the effectiveness of ENZ so far. .Intraductal carcinoma of the prostate (IDC-P) was newly recognized on 2017 EAU guideline and considering as a poor prognostic factor、although there has been no reports to predict the therapeutic effects of ENZ according to the presence of IDC-P. In this study, we evaluated the efficacy of ENZ for CRPC patients with or without IDC-P. Methods: We retrospectively identified 199 CRPC patients treated with ENZ from 2014 to 2018 in author-affiliated hospitals. All needle biopsy slides were reviewed by a single genitourinary pathologist and IDC-P was defined according to the criteria of McNeal at initial biopsy. Endpoint is overall survival (OS) from the time of CRPC diagnosis and time to treatment failure of ENZ. PSA response is defined as over 50% PSA decline from baseline. Results: The median patient age was 71 (range, 49–90) years. The median initial PSA was 154 ng/ml (range, 3.9–24736 ng/ml). The patients who received docetaxel were 42/199 (21%). IDC-P was detected in 98 patients (49%) at initial prostate biopsy. PSA response was 70.5% in patients without IDC-P and 53.9% in patients with IDC-P. The median OS from the time of CRPC was 37.9 and 71.5 months with and without IDC-P, respectively (P=0.013). There was no significant difference on OS in CRPC patients with IDC-P between before and after docetaxel (P=0.941). Same result was observed in CRPC patients without IDC-P (P=0.86). In time to treatment failure by ENZ, patients with IDC-P showed worse prognosis than patients without IDC-P after docetaxel (P=0.068). On the other hand, the difference disappeared before docetaxel regardless the presence of IDC-P (P=0.94). Conclusions: IDC-P is a poor prognostic factor for CRPC patients treated with ENZ. ENZ may be most effective for CRPC patients with IDC-P before chemotherapy.
Genomic characterization of pulmonary-metastatic prostate cancer: A unique molecular subtype.
Authors: Shenderov Eugene , Velho Pedro Isaacsson , Awan Anas Hamid , Mirkheshti Nooshin , Eisenberger Mario A. , Pardoll Drew M. , Antonarakis Emmanuel S.
Published: March 2019

210

Background: Metastatic prostate cancer (mPC) rarely spreads to the lungs and lung-only metastatic disease has not been clearly defined. This study investigated the clinical and molecular features of lung-only mPC. Methods: This is a retrospective single-institution study. Medical records of 40 metastatic prostate patients with lung-only (N=25) or lung-predominant (N=15) disease were analyzed. Germline and/or somatic DNA sequencing results, when available, were recorded. Results: 25 lung-only mPC patients were identified, of which 14 underwent germline/somatic DNA analysis. Nine (64%) had a driver mutation in either: the WNT pathway (29%), PI3K/PTEN pathway (21%), homologous recombination DNA repair (HRD) (36%) or mismatch repair (MMR) (29%). 15 lung-predominant mPC patients were also analyzed, of which 10 underwent genomic analysis. Seven (70%) had a driver mutation in either: WNT (10%), PI3K/PTEN (40%), HRD (40%), or MMR (21%). Representative driver mutations for both cohorts summarized in Table. In comparison, in our genomic database, 52.1% had a driver mutation (in WNT 15%, PI3K/PTEN 33%, HRD 22% or MMR 4%). The lung-only and lung-predominant cohorts did not differ by age (p=0.41), race, PSA (p=0.16), Gleason sum (p=0.77), intraductal/ductal histology (p=0.71), lymphovascular invasion (p=0.64), perineural invasion (p=0.73), or having relatives with cancer (p=0.22). Our results are limited by the small sample size and retrospective nature of the analysis. Conclusions: In this exploratory study, the overall prevalence of DNA repair gene alterations was higher than anticipated (35%), suggesting a potential enrichment (esp. in MMR mutations) in men with lung-only or lung-predominant mPC. This finding may have important therapeutic implications. These results require prospective validation of the hypothesis that pulmonary-tropic mPC biology may be fundamentally different from non-pulmonary mPC, and that these patients may benefit from PARP inhibitor or anti–PD-1 treatments. Clinical outcomes data will also be presented. [Table: see text]
Quality-of-life (QoL) assessment and reporting in prostate cancer: A systematic review of phase III trials published between 2012 and 2016.
Authors: Marandino Laura , La Salvia Anna , Sonetto Cristina , De Luca Emmanuele , Pignataro Daniele , Zichi Clizia , Di Stefano Rosario F , Ghisoni Eleonora , Lombardi Pasquale , Mariniello Annapaola , Reale Maria Lucia , Trevisi Elena , Leone Gianmarco , Muratori Leonardo , ButtIgliero Consuelo , Tucci Marcello , Aglietta Massimo , Scagliotti Giorgio V. , Perrone Francesco , Di Maio Massimo
Published: March 2019

219

Background: We previously reported that QoL is not included among endpoints and QoL results are significantly underreported in a high proportion of recently published phase III trials in oncology. In this study our aim was to describe QoL prevalence and heterogeneity in QoL reporting in prostate cancer (PC) phase III trials. Methods: Whole database included all primary publications (P) of phase III trials evaluating anticancer drugs published between 2012 and 2016 by 11 major journals. For this analysis, we extracted the subset of PC trials. We analyzed QoL inclusion among endpoints, presence of QoL results and methodology of QoL analysis. Results: 35 P were identified (21 in castration-resistant [CRPC], 9 in advanced hormone sensitive [aHSPC], incl. both metastatic and biochemical relapsed, and 5 in earlier stages). In 13 (37.1%) QoL was not listed among study endpoints: 7/21 (33.3%) in CRPC, 3/9 (33.3%) in aHSPC, and 3/5 (60%) in earlier stages. Out of 22 primary P of trials including QoL among endpoints, QoL results were not reported in 9 (40.9%). Overall, no QoL data were available in 22/35 (62.9%) primary P (61.9% in CRPC, 44.4% in aHSPC and 100% in earlier disease). QoL data were not available in 15/25 (60%) trials with overall survival (OS) as primary endpoint, and in 7/10 (70%) trials with other primary endpoints. QoL data were not available in 7/16 (43.8%) trials with a positive result (25% in CRPC, 40% in aHSPC, 100% in earlier stages). In 18 trials with available QoL results (incl. secondary publications), most common QoL tools were FACT-P (11, 61.1%) and EORTC QLQ-C30 (6, 33.3%). Common methods of analysis were mean changes (6, 33.3%), mean scores over time (6, 33.3%), time to deterioration (6, 33.3%) and proportion of responders (3, 16.7%). QoL analysis was focused on the impact of toxicity in 10 cases (mostly in earlier stages), and on disease symptoms in 10 cases (mostly in CRPC). Conclusions: QoL is absent in a high proportion of recently published phase III trials in PC, although presence of QoL results is better in positive trials, especially in CRPC. Methodology of QoL analysis is heterogeneous in terms of type of instruments, analysis and presentation of results.
The role of enzalutamide-induced hyperactive Jak2-Stat5 feed-forward signaling loop on enzalutamide-resistant prostate cancer growth and as a therapeutic target for second-line treatment.
Authors: Udhane Vindhya , Maranto Cristina , Hoang David , Erickson Andrew , Devi Savita , Jacobsohn Kenneth , Iczkowski Kenneth , See William , Kilari Deepak , Mirtti Tuomas , Nevalainen Marja
Published: March 2019

221

Background: Androgen targeted therapy remains the mainstay for advanced prostate cancer (PC). Second-generation androgen receptor (AR) antagonist, enzalutamide (ENZ), re-targets persistent AR activity in castrate-resistant (CR) PC tumors, and is approved for CRPC. Despite initial clinical activity, acquired resistance to ENZ arises rapidly and most patients succumb to PC. Mechanisms underlying resistance to ENZ are incompletely understood. Prior work has established Stat5 as a potent inducer of PC growth. Here, we investigated the significance of Jak2-Stat5 signaling in ENZ-resistant growth of PC. Methods: Levels of Jak2 and Stat5 activation in PC cells, tumors and patient samples were evaluated by immunohistochemistry, 3D tumor explant cultures and western blotting. Jak2 and Stat5 were inhibited by lentiviral (expression of) shRNA or pharmacologically. Levels of mRNA were assessed by QPCR and gene expression profiling. Results: ENZ induced a robust increase in Stat5 activation in PC cells in vitro, in xenograft tumors in vivo and in patient-derived PCs during ENZ treatment. Mechanistically, ENZ activation of Stat5 involves a positive feed-forward mechanism where ENZ-liganded AR induces rapid and sustained Jak2 phosphorylation in PC cells through a process involving Jak2-specific phosphatases. This results in a formation of a positive feed-forward loop in PC where activated Stat5 induces Jak2 mRNA and protein levels in PC. We showed that active Stat5 increased viability of PC cells during ENZ treatment and, at the same time, inhibition of Stat5 as a second-line treatment induced excessive death of PC cells surviving ENZ treatment. Importantly, pharmacological Stat5 blockade inhibited CR growth of PC xenograft tumors after ENZ resistance developed. Conclusions: Collectively, this work introduces a novel concept for a pivotal role of Jak2-Stat5 signaling in mediating resistance of PC to ENZ. Pharmacological Jak2-Stat5 inhibition may provide efficacious therapy in advanced PC in combination with ENZ or after ENZ fails.
Plasma cell-free DNA-based prognosis in metastatic hormone sensitive prostate cancer.
Authors: Kohli Manish , Yadav Siddhartha , Tan Winston , Riaz Irbaz Bin , Zheng Tiantian , Wang Amy , Montesinos Carlos , Wong Calvin , Du Peter , Jia Shidong , Yu Jianjun
Published: March 2019

242

Background: We evaluated plasma cell free based genomic aberrations for prognosticating survival of newly diagnosed metastatic hormone sensitive prostate cancer (mHSPC) patients (pts). Methods: Plasma was collected from mHSPC pts enrolled between 2009-2014. Platelet poor plasma (PPP) fractions were processed uniformly and cell free DNA (cfDNA) extracted using Qiagen kits. Pts were followed after initiating hormonal therapy until death. Next Gen Sequencing (NGS) of cfDNA was performed using Illumina HiSeq X for a preselected panel of 128 genes (PredicineDDR-77 cancer driver genes; 29 genes in BRCA-FA homologous recombination deficiency (HRD) pathway; 22 DNA damage repair pathway genes). Statistical analyses of plasma genome based aberrations with overall survival (OS) were performed in R 3.5.1. Cox proportional-hazard models were used for survival analysis. Results: An average of 2.5 ml PPP from 99 pts yielded a median of 10.5 ng (range: 2.8-702) cfDNA per sample. 15/99 pt samples with a yield < 5 ng were excluded from sequencing; 9/99 samples failed NGS. Median follow-up time was 80.2 months (mths) (Range: 74.7, 87]); median OS was 69.1 mths (range: 54,NR). 29 pts with full NGS data had high volume metastatic disease. cfDNA yield correlated with metastatic volume (P = 0.01). Univariate analysis revealed both variables prognostic for OS (Metastatic volume: log-rank P=0.01, HR=2.1, 95% CI: 1.1-3.8; cfDNA yield: P =0.04, HR = 1.3, 95% CI: 1.03-1.7). Multivariate regression showed prognostic value of cfDNA yield remained independent of metastatic volume (P = 0.03, HR = 1.34, 95% CI: 1.02-1.76). 54/67 samples with NGS data had at least one mutation/copy number variation detected. Top mutated genes included TP53 (N=18), ATM (N=9), CHEK2 (N=7), FANCM (N=6), RB1 (N=6), BRCA2 (N=5), PIK3CA (N=4) and 37/67 pts harbored 1≥ variant in HDR pathways. These pts had a shorter survival (median: 58.6 mths) (P=0.04, HR= 2.28, 95% CI: 1.01-5.18) and pts with ATM mutations did significantly worse (median survival: 47.4 mths) (HR=4.03, P=0.0005, 95% CI: 1.73-9.37). Conclusions: Plasma cfDNA yield is prognostic for survival in newly diagnosed mHSPC state and presence of HRD pathway genomic aberrations in plasma cfDNA are associated with poor survival.
DNA repair germline pathogenic mutation associations with treatment duration and family history in prostate cancer.
Authors: Vu James , Moses Marcus Marie , Ranasinghe Lahiru , Cotogno Patrick , Manogue Charlotte , Lewis Brian E. , Layton Jodi Lyn , Sartor A. Oliver , Ledet Elisa
Published: March 2019

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Background: Germline mutation testing for metastatic prostate cancer patients creates a potential opportunity to personalize targeted therapies to improve treatment outcomes. The goal of this study was to characterize cancer family history, and evaluate treatment outcomes, in mCRPC patients with DNA repair pathogenic germline alterations. Methods: A retrospective study of metastatic PCa patients at Tulane Cancer Center identified 246 patients undergoing germline testing using panels (30-80 genes) (Color.com or Inviate.com). Clinical annotations included family history, life-extending treatments, and treatment duration. Statistical analyses including chi-square and Wilcoxon Rank Sum. Results: In the 246 patients tested for germline mutations, 27 patients (11.0%) had ≥1 DNA repair germline pathogenic mutation (BRCA2 = 11, BRCA1 = 3, CHEK2 = 5, ATM = 3, NBN = 1, PMS2 = 2, MSH2 = 1, PALB2 = 1) while 219 patients (89.0%) possessed no pathogenic mutation in these genes. Patients 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 = 0.04). In the DNA repair population, 5 pathogenic patients had no family history of cancer (18.5%, n = 5). Patients were more likely to have a germline alteration if they had 1 or more first degree relatives affected with breast cancer (p = 0.00001). Median lines of life-extending treatments to date between the pathogenic and non-pathogenic population were equal at 2. There were no significant differences in treatment duration for abiraterone (p = 0.49), enzalutamide (p = 0.99), docetaxel (p = 0.28), cabazitaxel (p = 0.53), carboplatin+docetaxel (p = 0.41), or radium-223 (p = 0.59) between the two groups. Conclusions: In this study, DNA repair pathogenic germline mutations did not affect treatment durations or lines of therapy but these studies are underpowered. The relationship between a family history of breast cancer and a DNA repair pathogenic mutation has not previously been reported.
Safety of high dose rate prostate brachytherapy in patients with high baseline international prostate symptom scores.
Authors: Morgan Tiffany , Rossi Peter John , Cutrell Patrick , Zhang Chao , Press Robert H. , Rahnema Sara , Sanda Martin George , Pattaras John , Cimmino Cara B. , Jani Ashesh B. , Patel Pretesh R.
Published: March 2019

25

Background: Though a high baseline international prostate symptom score (IPSS) is considered a relative contraindication for low dose rate (LDR) brachytherapy, use of high dose rate (HDR) technique has several theoretical advantages including increased ability to sculpt dose and spare normal tissue via post-implant dosimetry. We report our institutional QOL data for those undergoing HDR with an IPSS score ≥15 compared to those with an IPSS score <15. Methods: The charts of 95 patients with localized adenocarcinoma of the prostate treated with HDR as monotherapy or as a boost after external beam radiation (EBRT) at a single institution between 2012 and 2015 were reviewed. All patients completed the IPSS and Expanded Prostate Index for Prostate Cancer–Clinical Practice (EPIC-CP) quality of life assessments prior to treatment and at least one follow-up survey. Linear mixed models were performed to test for significant changes and differences in each outcome over time. Results: Median follow-up in the IPSS <15 group (n=79) was 23 months and 16 months in the IPSS ≥15 group (n=16). Median IPSS score was 6 (range 0-14) and 19 (range 15-30), respectively. A majority of patients in both groups were diagnosed with National Comprehensive Cancer Network (NCCN) intermediate risk disease. Median prostate volume was 45.4cc in the IPSS ≥15 group and 46.3cc in the IPSS <15 group (p=0.901). IPSS, incontinence, and urinary irritation/obstruction scores were significantly higher in the IPSS ≥15 group compared to the IPSS <15 group at baseline (all p≤0.05). By the >24 months time point, these scores had decreased below baseline and were not significantly different from those with a baseline IPSS score <15 (all p>0.1). 12.5% in the IPSS ≥15 group developed a new grade 2 GU toxicity requiring an alpha-blocker compared to 26.5% in the IPSS <15 group (p=0.34). No patients required emergency placement of a foley catheter within 30 days of treatment. Conclusions: Given the low rates of GU toxicity, including a low risk of urinary obstruction requiring catheterization after HDR brachytherapy for those with a baseline IPSS score ≥15, this technique appears appropriate even for those with high baseline urinary symptoms.
Clinical characteristics of men with prostate cancer and evaluation of NCCN prostate cancer guidelines on germline genetic testing outcomes.
Authors: Greenberg Samantha , O'Neil Brock , Cooney Kathleen A. , Pappas Lisa M. , Tward Jonathan David
Published: March 2019

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Background: Growing evidence suggests up to 12% of men with metastatic prostate cancer (PC) harbor a pathogenic variant (PV) in genes associated with hereditary cancer risk. Updated NCCN PC guidelines include consideration for germline testing (GT) in men with high risk, very high risk, regional, or metastatic PC. As a result, we expanded our criteria for GT in men with PC to include these groups and men with a strong family history for PC beginning in January 2018. This study reports the clinical characteristics and germline findings before and after this expansion. Methods: Men with PC underwent multi-gene genetic testing (GT) for PVs from June 2016-June 2018 with genetic counselors. Clinical information and germline GT results were analyzed. Results: Of 285 eligible men who met with a genetic counselor, there were 201 evaluable GT results. One PV was excluded for suspicion of clonal hematopoiesis of indeterminate potential. Twenty-seven PVs were identified in 24 men (12.4%). Three men had two PVs identified (1.5%), at least one PV of which was in ATM or BRCA2. The most common PVs were ATM (n = 6, 3.0%), BRCA2 (n = 7, 3.5%), MYH (n = 4, 2.0%), and HOXB13 (n = 4, 2.0%). Rate of PVs were not statistically different across the two timeframes of GT, (2016-17, 14%; 2018, 11.2%; p = 0.60). PVs were not statistically associated with a higher ISUP group (1-3: 10.1%, 4-5: 13.6%; p = 0.49) and were distributed across multiple NCCN risk groups. Almost all men tested reported a family history of cancer, with the most frequent cancers reported including PC (n = 79, 39.3%), breast (n = 55, 27.4%), and colon cancer (n = 23, 11.4%). Family history of PC was not statistically associated with genetic test results (PV: 54%, no PV: 37%; p = 0.11). Conclusions: Expanding germline GT criteria will substantially increase patient volume without significant changes to the PV rate. Higher PC risk defined by ISUP or NCCN was not associated with the rate of PVs. Given this finding, further broadening the criteria for GT in PC may be warranted.
Treatment patterns and outcomes for metastatic castration-resistant prostate cancer (mCRPC) in a real-world setting: A retrospective study of greater than 2500 patients.
Authors: Higano Celestia S. , Sternberg Cora N. , Saad Fred , TOMBAL Bertrand F. , Miller Kurt , Kalinovsky Jan , Jiao XiaoLong , Tangirala Krishna , Sartor A. Oliver
Published: March 2019

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Background: In the era of expanding therapeutic options for mCRPC, there is a growing need to develop an optimal treatment sequence. This real-world study evaluated treatment patterns and outcomes in mCRPC patients. Methods: This retrospective cohort study used the Flatiron prostate cancer core registry (Jan 2013 to Sep 2017) to assess real-world treatment patterns (lines of therapy and transitions to subsequent lines) and outcomes (overall survival, OS) in patients with mCRPC. Descriptive analysis was performed for treatment patterns, and the Kaplan–Meier method was used to analyze OS. Results: This study comprised 2559 patients with mCRPC who received up to three lines of therapy. 23% of patients did not receive a life-prolonging therapy after the initial diagnosis of mCRPC. In the first-line (1L) setting, abiraterone (Abi, 37%) was the most-prescribed therapy, followed by enzalutamide (Enza, 28%) and docetaxel (15%). In the second line (2L), combination therapies were frequent (17%), with rates similar to taxane-based chemotherapy (docetaxel or cabazitaxel). Enza was the most-common 2L therapy used after Abi, and vice versa. Radium-223 (Ra-223) was prescribed as 1L therapy in 5% and 2L therapy in 9% of patients, either as monotherapy or part of a combination regimen. When Ra-223 was used in the 1L setting, similar proportions of patients received subsequent therapy with Enza (14%), Abi (13%), or chemotherapy (11%). Ra-223 was commonly used in the third line (14%), but less frequently than chemotherapy (36%). After each line, ~50% of patients did not receive a subsequent life-prolonging agent. Overall, 66% of patients used bone health agents at any time (denosumab, 48%; zoledronic acid, 24%). The median OS from the diagnosis of mCRPC was 21 months. Conclusions: This real-world study shows that not all patients with mCRPC received a life-prolonging therapy. Among patients who received an anti-cancer therapy, approximately half did not receive a subsequent life-prolonging therapy. Abi and Enza were the most-common 1L therapies, and their back-to-back use was common despite reported cross-resistance and limited benefit.
Radiation-related lymphopenia after pelvic nodal irradiation for prostate cancer.
Authors: Dutta Sunil W , Schad Michael D , Muller Donald A , Wijesooriya Krishni , Showalter Timothy N
Published: March 2019

26

Background: Given uncertainty regarding the effectiveness of pelvic nodal irradiation (PNI) for prostate cancer, we aimed to determine whether prostate cancer patients treated with PNI are at a higher risk of developing radiation-related lymphopenia (RRL) and whether RRL is predictive for worse treatment outcomes. Methods: The electronic charts of 886 consecutive patients treated with radiation therapy (RT) for prostate cancer from 2006 to 2018 at our institution were retrospectively analyzed. Qualifying patients were those with total lymphocyte counts (TLCs) within one year prior to and 3–24 months after the start of RT. Lymphopenia was the primary outcome; overall survival (OS) and biochemical progression-free survival (bPFS) were secondary outcomes. Results: Thirty-six patients with PNI and ninety-five patients without PNI qualified. In the PNI cohort, 61.1% of patients developed RRL (median follow-up TLC < 1000 cells/µL), versus 26.3% of non-PNI patients. On univariate analysis, initial prostate specific antigen (iPSA), baseline lymphopenia, treatment modality, PNI status, increased planned target volume, and androgen deprivation therapy administration were all significant predictors of RRL ( p < 0.05). On multivariate analysis, PNI status was a significant predictor of RRL ( p < 0.001; HR 3.42; 95% CI 1.22–9.61) as well as iPSA ( p = 0.006; HR 1.05; 95% CI 1.00–1.11) and baseline lymphopenia ( p = 0.007; HR 8.32; 95% CI 2.19–31.6). RRL was not predictive for bPFS, distant metastasis, or OS on multivariate analysis, though the numbers of events were likely insufficient for these analyses. Conclusions: The higher risk of RRL among PNI patients comports with other papers that show increased treatment volumes are associated with higher rates of RRL. Mounting evidence for the adverse effects of RRL on clinical outcomes supports the significance of our findings and suggests further studies are needed on RRL as a potential harm of PNI that may affect interpretation of results from clinical trials of PNI.
The effect of the timing of biochemical failure after external beam radiotherapy or low-dose-rate brachytherapy for definitive prostate cancer treatment.
Authors: Ciezki Jay P. , Reddy Chandana A. , Mian Omar Y. , Tendulkar Rahul D. , Ulchaker James , Angermeier Kenneth , Campbell Steven , Stephenson Andrew J. , Stovsky Mark , Klein Eric A.
Published: March 2019

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Background: To assess the effect of the timing of biochemical failure (bF) after definitive radiotherapy with external beam (EBRT) or low dose-rate brachytherapy (LDR) on clinical failure (cF) and prostate cancer-specific mortality (PCSM). Methods: From 1996 to 2009, 4478 patients were treated and by 2010, 456 patients were noted to have a bF. They were categorized as early (< 5 years post-therapy) or late (≥ 5 years post-therapy) failures. Factors thought to influence cF and PCSM were scored. Cox regression was used to assess the timing of bF on cF and Fine and Gray regression was used to assess the timing of bF on PCSM. Results: There were 330 (72.4 %) patients categorized as early and 126 (27.6 %) as late failures. The median PSA follow-up post-radiotherapy for the early bF group is 82 months vs. 155 months for the late bF group, and the median PSA follow-up post-bF is 54 months for the early bF group vs. 69 months for the late bF group. The early failures were more likely to be high-risk (p = 0.0080), have a higher Gleason score (p = 0.0008), and use ADT (p = 0.0325). The five-year rate of cF post early bF is 61% vs 43% post late bF (p <0.0001). The five-year rate of PCSM post early bF is 27% vs 9% post late bF (p <0.0001). The multivariable analyses assessing the cF and PCSM are shown in Table. Conclusions: Early bF is associated with higher rates of cF and PCSM. Patients treated with LDR have a lower risk of PCSM. [Table: see text]
Can we avoid radiotherapy with 18FCH PET/CT?
Authors: Iorio Julieta , Eleta Martin , Bambacci Florencia , Cuneo Lucrecia , Montenegro Constanza , Brisco Maria Agustina
Published: March 2019

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Background: The aim of this study was to assess the utility of 18 fluorocholine (FCH) positron emission tomography (PET)/computed tomography (CT) in detecting local recurrence in patients with prostate carcinoma treated with radical prostatectomy surgery. Methods: 432 patients with prostate cancer were enrolled in our institution between July 2015 and August 2018. 176 were treated with radical prostatectomy surgery and presented elevated levels of PSA (0.02-1600 ng/ml). All of them underwent “Dual phase” PET-CT consisting of initial pelvis starting 20 minutes after the injection of 18 F-Choline followed by 1 hour delayed PET of the whole body. 18 F-Colina PET/TC findings were compared with other imaging techniques and/or clinical monitoring. Patients were divided in three subgroups according to PSA levels: <1 ng/ml; ≥1-5ng/ml y >5 ng/ml. Results: 39 (22%) patients had PSA levels <1 ng/ml; 90 (51%) had between 1-5 ng/ml and 47 (27%) >5 ng/ml. 120 (68%) patients showed radiotracer uptake, on the other hand, 56 (32%) patients had negative PET-CT. 153 lesions showed increased uptake on FCH-PET, only 36 (23%) of them were interpretated as local recurrence the rest of them were interpretated as extraprostatic involment (table). Conclusions: 18 FCH PET/CT has clinical implications in patients with prostate carcinoma treated with radical prostatectomy surgery not only because it avoids unnecessary radiotherapy in the surgical wound, but also, it has the ability to detect local recurrent disease and lymphatic/haematogenous involvement. [Table: see text]
Utilization and outcomes of surgical castration in comparison to medical castration in metastatic prostate cancer.
Authors: Garje Rohan , Chennamadhavuni Adithya , Mott Sarah L , Chambers Isaac Matthew , Gellhaus Paul , Zakharia Yousef , Brown James A.
Published: March 2019

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Background: Androgen deprivation therapy (ADT) is the gold standard for metastatic prostate cancer (mPC) which can be achieved either by surgical or medical castration (SC, MC). In this study we evaluate the trends of utilization of SC and also assess survival difference compared to MC. Methods: National Cancer Database was used to identify patients with mPC from 2004 to 2014. Logistic and Cox regression models were utilized to estimate the odds of utilization of SC and effect of treatment on overall survival (OS). Results: A total of 33712 pts with mPC were identified; 31722 (94.1%) had MC and 1990 (5.9%) underwent SC. There was significant decline in the trend of utilization of SC from 8.5% in 2004 to 3.1% in 2014. On multivariable analysis, being a non-caucasian race, lower household income levels, having non-private insurance and earlier years of Dx were found to be associated with increased odds of choosing SC over MC. Notably, the odds of SC were lower at academic centers. On univariate analysis, a survival difference between ADTs was evidenced (p<0.01); 5-yr OS for MC and SC was 24.8% and 18.2%. However, on multivariate analysis there was no OS difference between SC and MC (p=0.14). Conclusions: In this large contemporary analysis, the utilization of SC has declined overtime with no OS difference when compared to MC. With rising health care costs, changing the practice by utilizing SC can help reduce healthcare expenditure. [Table: see text]