bluuebunny/crossref_metadata_2025 huggingface dataset:
Germline pathogenic variants in patients with pheochromocytoma.
Authors: Yao Shirley A , Wiley Elizabeth A , Susswein Lisa R. , Marshall Megan L. , Carter Natalie J. , McGill Anna K. , Klein Rachel T. , Wang Ying , Hruska Kathleen S.
Published: February 2018

668

Background: Approximately 25% of pheochromocytomas (PCC) have a hereditary basis, and germline variants in the SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127, MAX, VHL, FH, RET, MEN1, and NF1 genes have been associated with a predisposition to PCC and paraganglioma (PGL). Multi-gene hereditary cancer panel testing for PCC has become increasingly more common than single-gene testing algorithms. Identification of a pathogenic or likely pathogenic variant (PV/LPV) in one of these genes has important implications for surveillance in patients and their family members. Here we describe the spectrum of PV/LPV variants identified in individuals with PCC. Methods: We performed a retrospective review of clinical and molecular data for all individuals diagnosed with PCC who underwent panel testing through BioReference Laboratories that included at least SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127, MAX, VHL, FH, RET, MEN1, and NF1 between January 2016 and February 2017. Results: Seventy-nine individuals underwent testing due to a personal (n = 76) or family (n = 3) history of PCC. The positive yield was 14% (11/79). The majority of PV/LPV were in SDHB (n = 4; 36%), followed by RET (n = 2, 18%), with the remaining variants being identified in SDHA (1), SDHC (1), VHL (1), TMEM127 (1), and MAX (1). Approximately half (6/11) of those with a PV/LPV had a non-syndromic presentation of a unilateral PCC with no reported family history of PCC or PGL. The average age at tumor diagnosis was lower for probands testing positive than those without PV/LPV (34y±14 vs 44y±16). Conclusions: Our data support previous recommendations that patients with apparently sporadic, non-syndromic PCC be considered for genetic testing. Panel testing is a useful tool for identifying individuals with hereditary PCC.
Analysis of an online tool to explore evolving practice patterns in renal cell carcinoma (RCC).
Authors: Kim Won , Rosenthal Kristen , Hutson Thomas E. , Motzer Robert J. , Plimack Elizabeth R. , Obholz Kevin , Vinther Angelique , Rini Brian I.
Published: February 2018

674

Background: The complex and rapidly evolving treatment (Tx) landscape for advanced RCC poses challenges for healthcare providers (HCPs), particularly those in community settings, to make Tx decisions. To better understand current RCC Tx patterns, we analyzed patient (pt) cases entered by HCPs in an online tool developed by 5 experienced RCC experts from leading academic institutions. Methods: The tool, developed in 2016 and updated in 2017, includes over 500 case variations based on key factors defined by the experts. HCPs enter pt information and their intended Tx plan; the tool provides expert Tx recommendations for the pt case entered, followed by a survey to determine if the recommendations changed the HCP Tx plan. This analysis compares intended Tx of HCPs vs expert recommendations for 1027 cases entered into the tool (2016, n = 470; 2017, n = 557). Pearson chi-squared and Fischer’s Exact tests were used for analyses. Results: There was substantial Tx variation between HCPs and experts. In the first-line setting, 65% of HCPs vs 81% of experts selected sunitinib or pazopanib in both 2016 and 2017 (P = .0014). After disease progression (PD) on a first-line TKI, experts selected nivolumab (nivo) as second-line Tx more often than HCPs (98% vs 26% in 2016, P < .0001; 89% vs 37% in 2017, P < .0001). There were significant changes in practice patterns from 2016 to 2017 for both experts and HCPs in pts who received 2 prior lines of Tx. After PD on a first-line TKI and then nivo, experts recommended cabozantinib as the TKI of choice in 76% of cases in 2017 vs 40% in 2016. After PD on a first-line TKI and then either axitinib or everolimus, experts selected nivo more often than HCPs (84% vs 30%, respectively; P = .002) in 2016; however, expert and HCP Tx plans were not significantly different in 2017 (100% vs 70%, respectively; P = .08). Of the survey respondents, 46% of HCPs who differed from experts in their Tx selection indicated that the tool changed their intended Tx. Conclusions: Practice patterns between experts and HCPs differed substantially in pts with Tx-refractory RCC. Given that expert recommendations often changed the Tx plan of HCPs, the potential of an online tool to improve clinical outcomes in pts with advanced RCC warrants further investigation.
Cost-effectiveness of sunitinib or pazopanib for metastatic renal cell carcinoma in Brazil: A public health system perspective.
Authors: Sasse Andre Deeke , Carvalho Adriana Camargo
Published: February 2018

680

Background: The first-line treatment with tyrosine kinase inhibitors results in significant clinical benefits for patients with metastatic renal cell carcinoma (mRCC). However, in Brazilian public health system Interferon still remains as standard treatment. In an innovative way, the Brazilian Society of Clinical Oncology made a price negotiation directly with the pharmaceutical company, aiming to propose a formal request for the incorporation of these technologies to the National Committee for Health Technology Incorporation (CONITEC). Our objective was to estimate the cost-effectiveness of Sunitinib or Pazopanib versus Interferon in patients with mRCC, under the perspective of the Brazilian public health system. Methods: A cost-effectiveness analysis was conducted using a Markov model over a lifetime horizon. The model considers three health states: 1st-line treatment, disease progression and death. Transition probabilities were extracted from randomized studies. Costs of standard treatment, complications, and surveillance were obtained from Brazilian public hospitals. Sunitinib and Pazopanib prices were those negotiated with the manufacturing companies. Benefits are presented in life-years (LY) and costs in USD. The relation between costs and benefits were used to present the incremental cost-effectiveness ratio (ICER) per life-year saved. Results: Patients with mRCC treated with Interferon were projected to have 1.92 LY with a total cost of $2,000. Sunitinib or Pazopanib were projected to increase the life expectancy to 2.84 LY, with a total cost of $19,584 (Sunitinib) and $19,646 (Pazopanib). The ICERs for Sunitinib and Pazopanib were estimated at $18,565 and $18,634 per LY respectively. Conclusions: Using the discount prices, at a willingness-to-pay (WTP) threshold of $25,615 per LY (three times gross domestic product per capita), both Pazopanib and Sunitinib are cost-effective strategies compared to Interferon. Potential impacts of targeted therapies for mRCC on the overall health care expenditures need to be assessed in a budget impact analysis. A formal request for the incorporation of these technologies to the CONITEC is in progress.
Liver-directed therapy (LDT) for metastatic renal cell carcinoma (mRCC): Single center experience.
Authors: Raychaudhuri Ruben , Bylow Kathryn A. , Lea William , Byun John , Zellmer Timothy , Burfeind John D. , Riese Matthew John , Kilari Deepak
Published: February 2018

681

Background: Liver metastases arising from RCC are common and signify a poor prognosis. Given the negative impact of liver metastases on overall survival (OS) and quality of life, it is reasonable to to consider therapies directly targeting these lesions in select patients. Little is known about how minimally invasive LDT affects outcomes in patients with mRCC. Methods: Nine patients with mRCC underwent LDT for liver-dominant or liver-only metastatic disease between 2005 and 2015. Retrospective chart review was performed under an IRB protocol to identify patient and disease characteristics, imaging response, and time to next systemic treatment, OS and toxicities. Patients were seen in clinic at one month post-LDT to monitor for toxicities. Imaging was obtained within 2 months prior to treatment and at 3 and 6 months following LDT. Results: Each patient underwent a median of 2.3 procedures. A total of 18 transarterial chemoembolizations (TACE) and 5 yttrium-90 radioembolizations were performed. 2 patients had metastatic disease confined to the liver, and 7 had liver-dominant disease. 7 had multifocal disease involving < 25% of the liver, and 2 had multifocal disease involving > 25% of the liver. 8/9 patients received prior systemic therapies, receiving a median of 3 (0-4) distinct treatments. 4/9 patients were undergoing systemic therapy at the time of LDT, 1 patient declined further treatment, and the median time to initiation of the next systemic therapy in the remaining patients was 3 months (range 2-4 months). Median OS from first line systemic therapy was 39 months, 95% CI [25.9-53.3], and the median OS from the first LDT was 22 months (from 5-45 months). Follow-up imaging post-LDT showed PR or SD in 88% of cases at 3 months and 44% of cases at 6 months. At one month post-procedure, 8/9 patients maintained performance status, and only one patient experienced CTCAE grade 3-4 toxicity. Conclusions: The median OS in RCC patients with liver disease and systemic therapy alone is 14.3 months. The improved median OS of 39 months with LDT in our unmatched and heavily pretreated cohort suggests a role for LDT. LDT is generally well tolerated and should be considered for patients with liver-dominant mRCC with good performance status.
Real-world experience with cabozantinib in metastatic clear cell renal cell carcinoma (mccRCC).
Authors: Lemke Emily , Shah Amishi Yogesh , Chandramohan Anuradha , Campbell Matthew T. , VanAlstine Michael , Jonasch Eric , Tannir Nizar M.
Published: February 2018

684

Background: Cabozantinib (C) inhibits tyrosine kinase activity at MET, AXL, and VEGF receptors and is approved in mccRCC after progression on prior VEGFR-TKI. Little off-protocol data exists on tolerability and response. Methods: We retrospectively gathered baseline and treatment details on mccRCC patients treated with C at MD Anderson from 2015-present. Blinded radiologist determined best response by RECIST 1.1. Descriptive statistics were utilized. Results: We report on 38 patients with mccRCC treated with C in a “real-world” setting. Median age at mccRCC diagnosis was 58 years (range 37-71). 25 patients (66%) were male. 22 (58%) had de-novo metastatic disease. 4 patients had sarcomatoid dedifferentiation. 32 (84%) underwent nephrectomy. Cohort had a median of 3 sites of metastatic disease, including: bone 22 (57%), liver 9 (23%), and brain 6 (16%). 6 patients (16%) received C as 2nd line therapy, 10 (26%) as 3rd line, and 22 (58%) as 4th line or later. By IMDC risk score, 7 (18%) were favorable, 22 (58%) were intermediate, and 9 (24%) were poor risk. All patients had received at least 1 prior VEGFR-TKI and 24 (63%) had received prior immune checkpoint inhibitor. At C initiation, 20 (53%) patients had unfavorable neutrophil to lymphocyte ratio (NLR) of ≥ 3. 12 (32%) patients had favorable shift of NLR to < 3 on C. 22 patients (58%) required dose reduction and 24 (63%) required treatment break due to C-related toxicity. At time of analysis, 26 patients had discontinued treatment, with median time on treatment of 32.2 weeks (range 15.7-130.7 weeks). For the 12 patients remaining on C, median duration of therapy has been 54.3 weeks (range 26.6-68.9 weeks). 1 (3%) patient had CR, 11 patients (29%) had PR, 23 (60%) had SD, and 3 (8%) had PD as best response to C. Conclusions: C has a high disease control rate (92%) even as a late line of therapy in mccRCC. However, careful monitoring is warranted as many patients require treatment breaks and dose reductions for therapy-related toxicity. [Table: see text]
The probability of indolent versus aggressive histology based on renal tumor size: Implications for surveillance and treatment.
Authors: Bhindi Bimal , Thompson Robert Houston , Lohse Christine M. , Mason Ross , Frank Igor , Boorjian Stephen A. , Cheville John C. , Leibovich Bradley C.
Published: February 2018

704

Background: While the probability of benign versus malignant histology based on renal tumor size has been described, this alone does not sufficiently inform decision-making in the modern era since indolent malignant tumors can be surveilled. Thus, we sought to characterize the probability of indolent versus aggressive histology based on radiographic tumor size. Methods: We evaluated patients who underwent radical or partial nephrectomy at Mayo Clinic for a pT1-2, pNx/0, M0 solid renal tumor between 1990-2010. Pathology was reviewed by one genitourinary pathologist. Benign tumors, low grade (1-2) clear cell and papillary renal cell carcinoma (RCC), and any chromophobe, clear cell papillary, mucinous tubular and spindle cell, SDH-B deficient, and tubulocystic RCC were considered indolent. All other histologies were considered aggressive, as were any malignancies with necrosis or sarcomatoid differentiation. Cancer-specific survival (CSS) was estimated using the Kaplan Meier method. Logistic regression models were used to estimate the probability of malignant and aggressive histology based on tumor size. Sex-stratified analyses were also performed. Results: Of the 2650 patients included, there were 1773 patients with indolent tumors (303 benign; 1470 malignant) and 877 with aggressive tumors. Ten-year CSS was 96% for indolent malignant tumors and 82% for aggressive tumors. The predicted probabilities of any malignant histology and aggressive malignant histology increased with tumor size (Table; 1-7cm point estimates shown). For example, a 3 cm tumor had an 87% probability of malignancy and a 27% probability of being aggressive. For any given tumor size, men had a greater probability of aggressive histology than women. Conclusions: We present tumor size-based estimates of the probability of aggressive histology for renal masses. This information should be useful for patient counseling and treatment decision-making. [Table: see text]
Laboratory eligibility criteria as potential barriers to participation by black men in prostate cancer clinical trials.
Authors: Vastola Marie , Yang David Dewei , Mahal Brandon Arvin Virgil , Muralidhar Vinayak , Lathan Christopher S. , McGregor Bradley Alexander , Nguyen Paul L.
Published: February 2018

73

Background: Eligibility criteria may disproportionately affect black patients and contribute to their underrepresentation in clinical trials. We studied this potential barrier by examining clinical trials in prostate cancer, a disease in which black men face higher incidence and mortality. Specifically, we investigated the use of serum creatinine (sCr) alone instead of race-adjusted measurements for renal function, and the use of an absolute neutrophil count (ANC) threshold that could exclude men with benign ethnic neutropenia, which afflicts 6.7-8% of black patients and could lead to the exclusion of patients despite having healthy immune systems. Methods: We identified 401 interventional prostate cancer clinical trials with an overall survival endpoint. The list of trials was collected on January 16, 2017 from clinicaltrials.gov using the following criteria – study type: interventional studies; conditions: prostate cancer; interventions: drug; outcome measures: overall survival. Characteristics gathered from each trial included sponsor type, phase, accrual goal, start year, and toxicity. Results: Overall, 47.9% (192) of these trials used either sCr alone and/or required participants to have ANC ≥1.5×109 cells/L. Specifically, 25.2% (101) of the trials used sCr alone to determine eligibility, and 41.4% (166) of the trials required patients to have an ANC ≥1.5×109 cells/L. Conclusions: Of clinical trials in prostate cancer, 47.9% used criteria that disproportionately excluded black patients. The reevaluation of these two eligibility criteria could improve minority trial enrollment. First, lowering the ANC cutoff for patients with benign ethnic neutropenia would increase the number of eligible black participants, as 89% of these patients have an ANC ≥1.0×109 cells/L. Second, using race-adjusted equations for renal function would take into account racial differences in creatinine. While adopting race-based differences in trial criteria may add slight logistical challenges when ensuring patients meet trial eligibility, these adjustments would prevent healthy patients from being excluded solely because of benign laboratory differences caused by their race.
Nuclear factor-kappa B p65 evaluation on the Canadian Prostate Cancer Biomarker Network (CPCBN) TMA-series for biomarker validation.
Authors: Saad Fred , Ouellet Veronique , Grosset Andree-Anne , Caron Christine , Barres Veronique , Latour Mathieu , Trudel Dominique , Aprikian Armen G. , Bergeron Alain , Brimo Fadi , Chevalier Simone , Drachenberg Darrel , Fazli Ladan , Fleshner Neil Eric , Gleave Martin , Karakiewicz Pierre I. , Lacombe Louis , Lattouf Jean-Baptiste , van der Kwast Theodorus , Mes-Masson Anne-Marie
Published: February 2018

80

Background: The CPCBN has assembled a TMA-based resource comprising the specimens of 1512 prostate cancer patients treated by radical prostatectomy. This richly annotated and multi-institutional resource is available to researchers who wish to access a large cohort to validate prognostic biomarkers (http://www.tfri.ca/en/research/translational-research/cpcbn.aspx). Over the last decade, our laboratory demonstrated with an independent cohort (Gannon PO, et al. Eur J Cancer. 2013 Jul;49(10):2441-8, Labouba I, et al. PLoS One. 2015 Jul 17;10(7):e0131024), the reproducible association of nuclear factor-kappa B (NF-kB) p65 with patient’s risk of biochemical recurrence. Here, we evaluated the CPCBN TMA-series for p65 expression. Methods: Two independent observers scored the frequency of p65 nuclear localisation on digital images obtained after automated immunohistochemistry analysis of p65. Over the available minimum 3 cores of tumour tissue per patient, an average percentage of positive nucleus frequency was used. Statistical analyses were performed using SPSS software. Results: High nuclear frequency of NF-kB p65 (cut-off at 3%) was associated with an increased risk for patients to experience a biochemical relapse (p < 0.001; Exp(B) = 1.599; 95%CI = 1.321-1.937), develop bone metastasis (p = 0.007; Exp(B) = 2.126; 95%CI = 1.234-3.663)and die from their disease (p = 0.001; Exp(B) = 3.117; 95%CI = 1.55-6.266). In multivariate analyses, p65 also remained independent from clinical parameters (PSA, Gleason score and pTNM): biochemical relapse (p = 0.005; Exp(B) = 1.331; 95%CI = 1.092-1.623), bone metastasis (p = 0.033; Exp(B) = 1.82; 95%CI = 1.04- 3.158), mortality (p = 0.007; Exp(B) = 2.626; 95%CI = 1.298-5.312) Conclusions: Using a large cohort of Canadian men, our study reiterates the previous study linking NF-kB p65 with prostate cancer progression and highlights the suitability of CPCBN TMAs for biomarker validation. Our results also reveal the role of p65 as a predictor of bone metastasis development and prostate cancer-specific mortality.
Identification of occult prostate malignancy in a large patient cohort using a stereotactic transperineal prostate biopsy technique.
Authors: Moran Brian Joseph , Braccioforte Michelle H.
Published: February 2018

9

Background: Continued rising PSA, despite prior transrectal prostate biopsy (TRPB), can cause significant anxiety for patients and physicians. This study investigates the detection rate of non-palpable, isoechoic occult malignancy using a stereotactic transperineal prostate biopsy (STPB) technique in patients with previous negative TRPB. Methods: 2,565 men with continued rising prostate specific antigen (PSA) with a minimum of 1 prior benign TRPB, underwent STPB at a single out-patient institution between 04/04 - 02/17 (See table). Specimens were obtained according to x, y, and z coordinates from 8 equal octants with pathology reported accordingly. A greater number of specimens were obtained from the apical half than the basilar half of the prostate; this was attributed to smaller glands in which the apical specimens sufficiently sampled the anterior curvature of the gland. Results: STPB yielded adenocarcinoma in 965/2,565 (37.6%) patients. The number of biopsy cores obtained per patient approximated the prostate gland volume in cm3. Statistical analysis demonstrated there was a significant difference in detection rates with the apex having a higher incidence of malignancy than the base of the prostate gland (p=.000). Furthermore, the anterior apex harbored significantly more adenocarcinoma when compared to the posterior apex (p=.026). Conclusions: STPB is efficacious for diagnosis of non-palpable, isoechoic occult prostate malignancy. Repeated sequential analysis of malignancy identification has consistently resulted in approximately 40% positive yield. Furthermore, a possible explanation for the significant finding in this study that occult malignancies occupy a higher percentage of apical biopsies using STPB may be related to difficulty and limitations of apical sampling using a standard transrectal biopsy approach. [Table: see text]
Urinary toxicity in men treated with stereotactic body radiation therapy (SBRT) for localized prostate cancer following procedures for benign prostatic hyperplasia (BPH).
Authors: Kataria Shaan , Tsou Harry , Datta Subhradeep , Gurka Marie Kate , Lei Siyuan , Ayoob Marilyn , Danner Malika , Yung Thomas M. , Collins Brian Timothy , Krishnan Pranay , Suy Simeng , Lynch John J. , Collins Sean P.
Published: February 2018

91

Background: Patients with a history of procedures for BPH experience worse urinary toxicity following interstitial brachytherapy for localized prostate cancer. This retrospective study sought to evaluate the rates of urinary toxicity following SBRT in men with a history of procedures for BPH. Methods: Localized prostate cancer patients, treated with SBRT from August 2009 to February 2015 and a minimum follow up of 2 years, with a history of at least 1 procedure for BPH associated with a prostatic defect identified on the treatment planning MRI were evaluated. Radiotherapy was delivered in 5 fractions to a dose of 35 or 36.25 Gy using the CyberKnife system with fiducial tracking. Urinary QOL was assessed pre- and post-treatment using the International Prostate Symptom Score (IPSS) and the Expanded Prostate Cancer Index Composite (EPIC-26). Cystoscopy findings were retrospectively reviewed. Toxicities were scored using the CTCAE v4. Results: Thirty nine men with a median age of 72 years, 7 with a history of more than 1 procedure for BPH, were treated with a median follow up of 49 months. Grade 1, grade 2, and grade 3 urinary toxicity occurred in 11, 24, and 3 men, respectively; there were no grade 4 or 5 toxicities. Overall, 22 men experienced hematuria; the median time to the onset hematuria from the start of SBRT was 13 months (range 1-70). Cystoscopy was performed on 12 of these patients and bladder neck/prostatic urethra hyperemia were found in a majority of cases. Active bleeding from the bladder neck or prostatic urethra was found in 4 men. A mean baseline IPSS score of 9 did not significantly change at any point during follow up. A mean baseline EPIC-26 obstructive/irritative score of 84 significantly decreased to 76 at 1 month (p = 0.023). There was no significant change from the mean baseline EPIC-26 urinary incontinence score at any point during follow up. Conclusions: A history of procedures for BPH may lead to worse urinary quality of life and high rates of hematuria following SBRT for localized prostate cancer. Stricter urethra/bladder neck dose constraints or an alternative fractionation schedule may be required to decrease the risk of urinary toxicity.
Integrative molecular profiling challenges robustness of prognostic signature scores in multifocal prostate cancer.
Authors: Hovelson Daniel , Salami Simpa Samuel , Kaplan Jeremy B , Mathieu Romain , Udager Aaron , Curci Nicole , Lee Matthew , Lazo De La Vega Lorena , Susani Martin , Rioux-Leclercq Nathalie , Spratt Daniel Eidelberg , Morgan Todd Matthew , Davenport Matthew , Rubin Mark A. , Shariat Shahrokh F. , Tomlins Scott A. , Palapattu Ganesh S.
Published: February 2018

96

Background: Tissue based biomarkers are increasingly utilized in men diagnosed with low grade prostate cancer (PCa) to guide definitive management vs. active surveillance. PCa is uniquely multifocal, suggesting ideal prognostic biomarkers should be robust to both undersampling of a high grade component of a mixed-grade tumor focus, as well as unsampled multifocal high grade tumor foci. Methods: To assess the robustness of prognostic biomarkers to multifocality, we designed a comprehensive multiplexed targeted RNA sequencing assay (mxRNAseq) capable of assessing multiple classes of transcriptional alterations and deriving available prognostic signature scores (e.g. Prolaris CCP and OncotypeDX GPS). We applied this assay to a retrospective cohort of 176 FFPE tissue samples representing the range of PCa progression. Single candidate biomarkers and derived prognostic signatures were analyzed in multifocal cases with only low-grade disease as well as those with extreme grade differences across tumor foci. Results: Our mxRNAseq assay robustly detected known coding gene/lncRNA expression, gene fusions, splice variants, and expressed somatic and germline mutations. Supervised clustering of target gene expression confirmed expected transcriptional module deregulation and derived prognostic signatures across PCa progression. Prognostic biomarkers (including derived signatures) showed no significant expression differences between low grade foci from prostates with and without high grade disease foci and were uniformly higher in high vs. low grade foci from the same case. In four cases of extreme multifocality (Gleason score 6 vs. ≥ 8 foci), prognostic signatures were significantly lower in low vs. high grade foci. In a clinical prostatectomy cohort of 1,418 men with diagnostic biopsy Gleason score 3+3 = 6 or 3+4 = 7, 21 (1.5%) had Gleason score ≥ 4+4 = 8, suggesting the initial biopsy missed or undersampled the most clinically relevant focus. Conclusions: Using a novel comprehensive mxRNAseq assay, our results challenge the robustness of prognostic biomarkers between multifocal low and high grade PCa foci, critically important in the context of un/under-sampled aggressive tumor foci.
Three-month post-treatment PSA as a biomarker of treatment response in intermediate or high-risk prostate cancer treated with androgen deprivation therapy and radiotherapy.
Authors: Alex Bryant , D'Amico Anthony Victor , Nguyen Paul , Einck John Paul , Kane Christopher J. , McKay Rana R. , Simpson Daniel Robert , Mundt Arno James , Murphy James Don , Rose Brent Shane
Published: February 2018

99

Background: Prostate-specific antigen (PSA) measurement after definitive radiation therapy (RT) and androgen deprivation therapy (ADT) for localized prostate cancer (PC) has been proposed as an early prognostic biomarker. We investigate the association between 3-month post-RT PSA and biochemical progression-free survival (bPFS), prostate cancer-specific survival (PCSS), and overall survival (OS). Methods: We identified 5,783 patients with intermediate- or high-risk localized PC diagnosed between 2000-2015 and treated with RT and ADT from Veterans Affairs data. Patients were divided into groups based on 3-month post-RT PSA values: < 0.10 ng/mL, 0.10-0.49 ng/mL, and ≥0.50 ng/mL. The effect of 3-month PSA group on bPFS, PCSS, and OS were evaluated in multivariable Cox models adjusting for potential confounders. Results: There were 2,651 intermediate risk and 3,132 high risk patients; 11% had a 3-month PSA of ≥0.50 ng/mL. Higher 3-month PSA was strongly associated with each outcome; compared to the < 0.10 ng/mL group, we noted greater hazards for the 0.10-0.49 ng/mL group (HR for bPFS: 2.41, p < 0.001; PCSS: 2.29, p < 0.001; OS: 1.21, p = 0.003) and the ≥ 0.50 ng/mL group (HR for bPFS: 5.23; PCSS: 3.97; OS: 1.50; p < 0.001 for all). When analyzed separately, 3-month PSA group was predictive of OS in the high-risk group (p < 0.001) but not the intermediate-risk group (p = 0.21). Conclusions: 3-month post-RT PSA is a strong prognostic biomarker for bPFS and PCSS in patients with intermediate and high-risk PC, and OS in patients with high-risk PC. 3-month PSA measurement may augment clinical decision-making and holds promise as a potential surrogate endpoint in clinical trials.
Randomised phase 3 trial of enzalutamide in androgen deprivation therapy (ADT) with radiation therapy for high risk, clinically localized prostate cancer: ENZARAD (ANZUP 1303).
Authors: Williams Scott , Davis Ian D. , Sweeney Christopher , Stockler Martin R. , Martin Andrew James , Hague Wendy , Coskinas Xanthi , Yip Sonia , Tu Emily , Lawrence Nicola Jane , Nayar Namrata , McDermott Ray , Kelly Paul , Deignan Olwyn , Hughes Simon , Fonteyne Valerie , Tombal Bertrand F. , Nguyen Paul L.
Published: February 2018

TPS156

Background: Adjuvant ADT with an LHRH analog (LHRHA) given before, during and after radiotherapy (RT) is standard of care for high risk localised prostate cancer (PC). Enzalutamide improves overall survival (OS) in castration-resistant, metastatic prostate cancer. We hypothesized that the addition of enzalutamide to adjuvant ADT and RT will improve outcomes. The aim is to determine the effects of enzalutamide versus a conventional non-steroidal anti-androgen (NSAA) as part of neoadjuvant and adjuvant ADT in men undergoing RT for high risk, localized PC. Methods: DESIGN: Open label, randomised, phase 3 trial including ANZ, USA, UK, Ireland and Europe. ENDPOINTS: OS (primary), cause-specific survival, PSA progression free survival (PFS), clinical PFS, time to subsequent hormonal therapy, time to castration-resistant disease (PCWG2 criteria), metastasis free survival (MFS), adverse events and health-related quality of life (HRQOL). CORRELATIVE OBJECTIVES: identification of prognostic/predictive biomarkers from archival tumour tissue and serial blood samples. SAMPLE SIZE: 800 participants with a minimum follow-up of 5.5 yrs is designed to give 80% power to detect 33% reduction in the hazard of death assuming 5-year survival rate of 76% amongst controls. TREATMENT: Enzalutamide 160mg daily for 24 months versus conventional NSAA for 6 months. All participants receive LHRHA for 24 months, and RT starting about week 16 delivered as 78Gy in 39#, or 46Gy in 23# plus brachytherapy (nodal RT optional for N0, mandatory for N1). ASSESSMENTS: Baseline, then every 8 weeks until year 2, then 3-4 monthly until year 5, 6-monthly until year 7, then annually. Imaging with CT/MRI and bone scan at baseline, PSA progression, then 6 monthly until re-initiation of ADT, when PCWG2 criteria for CRPC are met and then 3 monthly until evidence of metastases. 623 participants recruited from 61 sites as of 16 October 2017. ENZARAD is an investigator-initiated cooperative group trial led by ANZUP Cancer Trials Group with funds and product from Astellas. Clinical trial information: NCT02446444.
ARASENS: A phase 3 trial of darolutamide in combination with docetaxel for men with metastatic hormone-sensitive prostate cancer (mHSPC).
Authors: Smith Matthew Raymond , Saad Fred , Hussain Maha , Sternberg Cora N. , Fizazi Karim , Yamada Karin Sayuri , Kappeler Christian , Kuss Iris , Tombal Bertrand F.
Published: February 2018

TPS383

Background: The addition of either docetaxel or abiraterone acetate plus prednisone to androgen deprivation therapy (ADT) improves overall survival (OS) compared with ADT alone in men with mHSPC. It is hypothesized that other androgen receptor (AR)-targeted therapies could be combined with docetaxel for mHSPC. Darolutamide (ODM-201) is an investigational oral AR antagonist with a unique chemical structure and negligible blood-brain barrier penetration that inhibits tumor growth by binding to AR and AR mutants (eg, W742L and F877L) with high affinity and specificity. In phase 1/2 ARADES and phase 1 ARAFOR trials, darolutamide demonstrated antitumor activity and was well tolerated in men with metastatic castration-resistant prostate cancer (mCRPC). ARASENS will evaluate the addition of darolutamide to standard ADT and docetaxel in men with mHSPC. Methods: This international, randomized, double-blind, placebo-controlled phase 3 trial (NCT02799602) is being conducted at > 300 sites in 23 countries. ~1300 men with newly diagnosed mHSPC will be randomized 1:1 to darolutamide (600 mg orally twice daily) or matching placebo. All patients will receive standard ADT + docetaxel (6 cycles). Patients will be stratified by disease extent and alkaline phosphatase level. Key inclusion criteria: histologically or cytologically confirmed PC with documented metastases, started ADT ± first-generation antiandrogen therapy ≤12 weeks before randomization, and ECOG performance status 0-1. The primary end point is OS. Secondary end points include time to mCRPC, initiation of subsequent anticancer therapy, symptomatic skeletal event (SSE)-free survival, time to first SSE, first opioid use, pain progression, and worsening of physical symptoms. Safety will be assessed. ARASENS is actively enrolling at > 280 sites across 23 countries. Clinical trial information: NCT02799602.
c15-153: Randomized phase IB/II study of enzalutamide with and without ribociclib in patients with metastatic castrate resistant, chemotherapy naïve prostate cancer that retains RB expression.
Authors: Kelly William Kevin , Godwin James Luke , Hoffman-Censits Jean H. , Knudsen Karen E. , De Leeuw Renee , Leiby Benjamin E. , Southwell Traci , Hubert Christine , Smith David C. , Chatta Gurkamal S. , Aghalar Jahan , Scher Howard I. , Bose Rohit , Autio Karen A. , Abida Wassim , Slovin Susan F. ,   The Prostate Cancer Clinical Trials Consortium
Published: February 2018

TPS384

Background: Current data suggests RB function is often attenuated in tumors through hyperphosphorylation; thus, RB activity can be “re-awakened” in RB+ tumors by suppressing key kinases that phosphorylate RB (CDK4/6). Recent findings identified perturbations of the RB tumor suppressor as a major mechanism of androgen receptor (AR) deregulation and castration-resistant prostate cancer (CRPC) formation. Our preclinical studies indicate RB+ tumors are exquisitely responsive to CDK4/6 inhibitors, revealing tumor-specific cytostatic and cytotoxic effects. These analyses strongly support the use of CDK4/6 inhibitors to activate the RB pathway, and impede the transition to CRPC. We hypothesize the CDK4/6 inhibitor ribociclib (ribo) in combination with enzalutamide (enz) in patients (pts) with progressive metastatic CRPC (mCRPC) that retains RB expression will significantly increase the efficacy of enz. Methods: This is a phase IB/II study of pts with mCRPC with RB+ tumors who have not received chemotherapy. Since ribo and enz have not been combined together in pts, the standard doses of enz and a traditional 3x3 dose escalation schema will be used in phase I to establish the safe dose of the combination; this dose will be used in phase II. Since both drugs are metabolized via the liver, plasma concentrations of ribo and enz will be monitored. To determine if ribo will improve the clinical activity in pts treated with enz, a randomized (1:1) phase II study using enz as the control arm vs. the combination will follow. This study will evaluate an early clinical activity readout, thus the primary phase II endpoint will be a proportion of pts with ≥ 50% PSA decline at 12 weeks. Secondary endpoints are rPFS, PSA PFS, OS and safety. If there is clinical activity noted, further randomized testing will be required to establish ribo clinical benefit in combination with enz. 5 sites are participating, managed by the Prostate Cancer Clinical Trials Consortium. Dose Levels 1 and 2 have been completed without any DLTs in the phase I portion of the study. A review of Dose Level 3 is planned for October 2017. Clinical trial information: NCT02555189.
A randomized phase II study comparing cabazitaxel/prednisone to cabazitaxel alone for second-line chemotherapy in men with metastatic castrate resistant prostate cancer (mCRPC): CABACARE.
Authors: Buonerba Carlo , Bosso Davide , De Placido Sabino , di Lorenzo Giuseppe
Published: February 2018

TPS387

Background: In the TROPIC trial, cabazitaxel (CAB) plus daily prednisone (PDN) was associated with a significant advantage in OS and PFS in docetaxel (DOC)-pretreated patients. Whether daily prednisone may significantly contribute to cabazitaxel efficacy or improve its safety profile is unknown. In the CHARTEED trial, DOC was administered without daily PDN with no concerns about the lack of efficacy or greater toxicity. Safety data about CAB without PDN are missing. Corticosteroids present multiple biological effects, which may potentially be either positive, such as those mediated by adrenal androgen and cytokine suppression, or detrimental, such as those associated with the activation of the glucocorticoid receptor (GR) and of the androgen receptor (AR). Furthermore, PDN is a CYP3A4 inducer and can potentially negatively affect cabazitaxel clearance. Finally, AR-V7 positivity in circulating tumor cells and retinoblastoma (RB) loss/inactivation have been identified as potential mechanisms of resistance to hormonal and chemotherapy treatments in prostate cancer. For this reason, we also aim to evaluate if CAB activity is related to such biomarkers. Methods: CABACARE is a randomized, phase II, open label, multi center study comparing CAB at 25 mg/m2 q21 plus daily PDN (10 mg) vs CAB at 25 mg/m2 q21 alone in mCRPC pts progressed during or after DOC treatment. The study is designed to test non inferiority in terms of PFS, according PCWG-2, of CAB alone vs CAB plus PDN assuming that the two arms are equally effective. Each arm will enroll 110 pts. Main secondary objectives are: safety, QoL, pain assessment, overall response rate (ORR), PSA response, time to PSA progression, Time to radiological progression; OS; time to skeletal related events (SRE). The influence of Arv7 and RB status on CAB activity will also be evaluated. Clinical trial information: 2016-005251-25.
TRITON2: An international, multicenter, open-label, phase II study of the PARP inhibitor rucaparib in patients with metastatic castration-resistant prostate cancer (mCRPC) associated with homologous recombination deficiency (HRD).
Authors: Abida Wassim , Bryce Alan Haruo , Balar Arjun Vasant , Chatta Gurkamal S. , Dawson Nancy Ann , Guancial Elizabeth A. , Hussain Arif , Jha Gautam Gopalji , Lipsitz David Uri , Patnaik Akash , Petrylak Daniel Peter , Ryan Charles J. , Stanton Thomas S. , Vogelzang Nicholas J. , Zhang Jingsong , Simmons Andrew , Go Jowell , Golsorkhi Tony , Chowdhury Simon , Scher Howard I.
Published: February 2018

TPS388

Background: Up to 25% of patients with advanced prostate cancer, including mCRPC, have a deleterious germline or somatic mutation in BRCA1, BRCA2, ATM or another homologous recombination (HR) DNA repair gene that can serve as a molecular marker to select those who may respond to poly(ADP-ribose) polymerase inhibitors (PARPis). PARPis are lethal to cells with HRD, and PARPi treatment has shown preliminary evidence of an antitumor effect in patients with mCRPC who harbor a mutation in an HR DNA repair gene (Mateo et al. N Engl J Med. 2015;373:1697-708). These data provide a compelling rationale for evaluating rucaparib, a potent PARP1, PARP2 and PARP3 inhibitor, in patients with mCRPC associated with HRD. Methods: TRITON2 (NCT02952534) is a phase 2 study evaluating rucaparib 600 mg BID in patients with mCRPC. Patients with a deleterious germline or somatic BRCA1, BRCA2 or ATM mutation (per prior local test or central test during screening) will be enrolled into 1 of 2 cohorts based on the presence or absence of measurable visceral and/or nodal disease. An exploratory cohort will enroll patients with an alteration in any of 12 other prespecified HR genes (eg, RAD51C, RAD51D and PALB2), with or without measurable visceral and/or nodal disease. Patients must have progressed on androgen receptor signaling–directed therapy and 1 prior taxane-based chemotherapy for mCRPC. Patients who received prior treatment with a PARPi, mitoxantrone, cyclophosphamide or platinum-based chemotherapy are excluded. The primary endpoint is objective response rate measured using modified RECIST v1.1/PCWG3 for patients with soft-tissue disease and prostate-specific antigen response for patients with nonmeasurable disease. Secondary endpoints include duration of response, radiographic progression-free survival, overall survival, clinical benefit rate and safety. Pretreatment blood samples collected from all patients will enable development of a plasma-based companion diagnostic to select patients who may benefit from rucaparib treatment. Patients (≈160) will be enrolled at > 100 sites worldwide. Clinical trial information: NCT02952534.
A phase Ib/II trial of indomethacin and enzalutamide to treat castration-resistant prostate cancer (CRPC).
Authors: Pan Chong-xian , Lara Primo , Evans Christopher P. , Parikh Mamta , de Vere White Ralph , Dall'era Marc , Liu Chengfei , Robles Daniel , Gao Allen
Published: February 2018

TPS394

Background: Enzalutamide (Enza) and abiraterone (Abi) are commonly used to treat CRPC. Resistance is the most common cause of treatment failure. We discovered that a critical steroidogenic enzyme AKR1C3 was significantly elevated and contributed to intratumoral androgen synthesis in Enza-resistant prostate cancer cells and tumors. Overexpression of AKR1C3 induced androgen receptor variant 7 (AR-V7) expression, while inhibition of AKR1C3 downregulated AR-V7. We then discovered that indomethacin (Indo) inhibited AKR1C3 activation and sensitized resistant CRPC cells to Enza and Abi. One patient accidentally took Indo and achieved biochemical as well as radiological response of his prostate cancer. These findings prompted us to design a clinical trial to test the combination of Indo with Enza for the treatment of CRPC and to study the underlying mechanisms of action and resistance. Methods: This investigator-initiated single-arm Phase Ib/II trial enrolls patients with progressive CRPC after Abi, adequate vital organ function, ECOG performance status 0-2, and serum testosterone < 50 ng/dl. Major exclusion criteria include prior Enza treatment, brain metastasis and history of seizure. In the Phase Ib cohort, patients receive Enza 160 mg po qd and Indo 50 mg po tid to determine toxicity. The Phase II expansion will enroll 26 patients with 21 evaluable patients. This sample size provides 90% power to detect, at the 0.05 level (1-sided), the difference between a PSA response rate of 50% expected with the study treatment and a historical control of 20% with Enza alone. Co-primary endpoints are safety and PSA response of ≥50% decrease. Secondary endpoints include overall response rate as determined by the Prostate Cancer Working Group 2 criteria (PCWG2), progression-free survival and overall survival. Molecular correlative studies are exploratory endpoints. Serum and intratumoral androgen levels, full-length AR, AR-V7 and AKR1C3 will be measured to assess the effect of the combination therapy. To date, 4 patients have been enrolled to the trial (clinicaltrials.gov Identifier No: NCT02935205; this trial is funded by DoD Prostate Cancer Research Program IMPACT award). Clinical trial information: NCT02935205.
Oligometastatic prostate cancer patients stratification: A molecular signature identified by liquid biopsy.
Authors: Triggiani Luca , Bardoscia Lilia , Colosini Antonella , Bernardi Simona , Bresciani Roberto , Foroni Chiara , Pasinetti Nadia , Borghetti Paolo , Caraffini Bruno , Orizio Flavia , Buglione Michela , Magrini Stefano M.
Published: February 2018

TPS400

Background: Oligometastatic prostate cancer (OPC) may represent the initial step of an unavoidable, rapid progression to a polymetastatic state, or the expression of a real oligometastatic phenotype related to a condition of stable disease for a long time. In the last scenario, stereotactic body radiation therapy (SBRT) can be considered as a potentially curative treatment option for hormone-naïve OPC. We propose a prospective, explorative trail with the aim of identifying by liquid biopsy a molecular signature (genes or differential expression of miRNA), and related clonal evolution, underlying metastatic prostate cancer progression after a course of SBRT. Methods: Study population will be 30 adult, hormone-naïve OPC undergoing SBRT. Table 1 summarizes gene and miRNA panel for molecular analysis. For each patient, 15 ml of peripheral blood will be collected before and at the end of SBRT, every 3 months for the first year, then every 6 months until disease progression, when another blood sample will be collected in case of instrumental evidence of failure (using PET-Choline or CT-scan plus bone scintigraphy). 7.5 ml of peripheral blood will be centrifuged to separate sera and 7.5 ml of peripheral blood will be centrifuged to separate plasma from the other blood components, respectively. Sera and plasma will be stored at -20°C and centralized to CREA Laboratory at our Institution, then immediately processed for cell free DNA (cfDNA) and miRNA extraction for NGS of target genes (by Illumina platforms MiSeq and MiniSeq) and dPCR analysis. Study duration will be 36 months. This protocol has been written and will be conducted in agreement with either the Declaration of Helsinki and subsequent amendments and ICH Harmonized Tripartite Guideline for Good Clinical Practice, and has received approval of local Ethics Committee. Panel for analysis. [Table: see text]
Phase II randomized study of abiraterone acetate plus ADT versus apalutamide versus abiraterone and apalutamide in patients with advanced prostate cancer with non-castrate testosterone levels. (LACOG 0415).
Authors: Maluf Fernando C. , Smaletz Oren , Schutz Fabio A. B. , Souza Vinicius Carrera , Fay Andre Poisl , Herchenhorn Daniel , Werutsky Gustavo , Santos Telma Murias
Published: February 2018

TPS404

Background: Androgen deprivation therapy (ADT) combined with abiraterone (AA) or docetaxel are considered the standard of care (SOC) for patients with hormone sensitive (HS) advanced/ metastatic prostate cancer (PC) (STAMPEDE, LATITUDE, CHAARTED). Treatment that could delay disease progression with less toxicities and better quality of life is warrant. Recently, enzalutamide monotherapy showed a 92% PSA response in patients with advanced/ mestatatic prostate cancer without previous hormone therapy. Our study aims to evaluate the efficacy of apalutamide, a second-generation AR inhibitor, monotherapy or in combination with AA vs. SOC in advanced/metastatic HSPC. Methods: This is a phase II, open label, randomized trial evaluating the efficacy of AA 1000mg po qd plus prednisone 5mg po bid and ADT vs. Apalutamide 240mg po alone vs. AA and Apalutamide in patients with advanced or metastatic PC with non-castrate testosterone levels. Main eligible criteria are: 1. Histologically confirmed prostate adenocarcinoma; 2. Hormone naïve patients with indication to ADT in the following settings: Advanced loco-regional disease not amenable to curative local therapy (T3/4 or node positive); Biochemical relapse after primary treatment (surgery or radiotherapy) with PSA >= 4 ng/ml and rising with doubling time less than 10 months or PSA >= 20 ng/ml or N+ or M+; 3. Newly diagnosed metastatic disease; 4. Patient is symptomatic or moderately symptomatic; 5. Non-castration level of testosterone >= 230 ng/dL. The primary endpoint is undetectable PSA levels (below 0.2ng/mL) at week 25. The study aims for 65% of undetectable PSA at week 25 (power of 80% and alfa of 5%) and a total sample size of 126 patients. Secondary endpoints are PSA progression and PSA response (50% and 80%) at week 25, radiographic progression-free survival, safety, health quality of life (FACT-P) and correlation of serum androgen levels with response. As of October 17th, 2017 the study enrolled 1 patient and the recruitment is planned for 12 months in a total of 10 sites in Brazil. This trial is registered at Clinical trial information: NCT02867020.