bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase II trial of consolidation nivolumab or nivolumab plus ipilimumab following concurrent chemoradiation in unresectable stage III NSCLC: BTCRC LUN16-081.
Authors: Durm Greg Andrew , Perkins Susan M. , Hanna Nasser H.
Published: February 2018

TPS179

Background: Unresectable stage III NSCLC demonstrates poor 5-yr OS outcomes. The current standard of care for fit patients in this setting is concurrent chemoradiation. Previous studies evaluating the addition of induction or consolidation chemotherapy, EGFR-targeted agents, ant-angiogenic agents, and higher doses of radiation have failed to definitively improve OS over chemoradiation alone. Recently, a trial of consolidation PD-L1 inhibition demonstrated improved PFS over chemoradiation alone, and a second trial of consolidation PD-1 inhibition is awaiting data maturation. This may herald a change to the standard of care in this setting. The addition of CTLA-4 inhibition to anti-PD-1 monoclonal antibodies has shown improved OS in melanoma and has demonstrated encouraging early phase data in stage IV NSCLC. Therefore, we initiated a trial evaluating the addition of a CTLA-4 inhibitor to PD-1 inhibition for consolidation treatment of unresectable stage III NSCLC. Methods: This is a multi-center, randomized, phase II study of nivolumab or the combination of nivolumab and ipilimumab as consolidation therapy following concurrent chemoradiation in unresectable stage III NSCLC. Patients will receive concurrent chemoradiation with one of three standard chemotherapy backbones (Cis-Etop, Cis-Pem, or Carbo-Pac), and repeat imaging will be done 4-8 weeks following completion of therapy. Patients without progressive disease will be randomized 1:1 to receive either niv 480mg IV every 4 weeks or the combination of niv 3mg/kg IV every 2 weeks and ipi 1mg/kg IV every 6 weeks for up to 6 months. The trial will enroll a total of 108 patients with 54 in each arm. The two arms are non-comparator arms and will be compared with historical controls. The primary endpoint is the improvement of PFS at 18 months, and key secondary endpoints include OS and the toxicity of consolidation niv and niv/ipi. Exploratory endpoints will look at the correlation between multiple clinical, radiographic, and laboratory parameters and outcomes, as well as the association of these parameters with the development of pneumonitis. This trial opened to accrual in September 2017. Clinical trial information: NCT03285321.
KEYNOTE-355: Randomized, double-blind, phase III study of pembrolizumab (pembro) + chemotherapy (chemo) vs placebo (PBO) + chemo for previously untreated, locally recurrent, inoperable or metastatic triple-negative breast cancer (mTNBC).
Authors: Cortés Javier , Guo Zifang , Karantza Vassiliki , Aktan Gursel
Published: February 2018

TPS18

Background: In the phase Ib KEYNOTE-012 study, the anti–PD-1 antibody pembro demonstrated promising antitumor activity and acceptable safety as monotherapy in pretreated patients (pts) with PD-L1+ mTNBC. Adding pembro to chemo may enhance antitumor activity. KEYNOTE-355 (NCT02819518) is a global phase III study of pembro+chemo vs PBO+chemo in pts with previously untreated, locally recurrent, inoperable TNBC/mTNBC. Methods: Eligible pts are ≥18 y and have centrally confirmed, locally recurrent, inoperable TNBC or mTNBC not previously treated with chemo (prior chemo in [neo]adjuvant setting is allowed); measurable disease per RECIST v1.1; ECOG PS 0-1; ≥6 mo between definitive surgery or last dose of adjuvant chemo, whichever was last; and first disease recurrence (≥12 mo if prior treatment with same-class agent). Part 1 is an open-label, unblinded safety run-in of ~30 pts in 3 arms (pembro+nab-paclitaxel, pembro+paclitaxel, pembro+gemcitabine/carboplatin). Part 2 is a double-blind, PBO-controlled study of ~828 pts randomized 2:1 to pembro 200 mg every 3 weeks + chemo (nab-paclitaxel 100 mg/m2 on d 1, 8, and 15 every 28 d; paclitaxel 90 mg/m2 on d 1, 8, and 15 every 28 d; or gemcitabine 1000 mg/m2+ carboplatin AUC 2 on d 1 and 8 every 21 d) or PBO+chemo. Crossover is not allowed. Stratification factors are study chemo (taxane vs gemcitabine/carboplatin), tumor PD-L1 expression (+/-), and prior therapy with same-class agent in the (neo)adjuvant setting (yes/no). Treatment will occur for ≤35 administrations (pembro/PBO only) or until confirmed disease progression, unacceptable toxicity, withdrawal of consent, or decision to discontinue. Primary end points are safety in part 1 and PFS (by RECIST v1.1, central radiology review) and OS in part 2; secondary end points include ORR (by RECIST v1.1, central radiology review) and duration of response. AEs will be graded per NCI CTCAE v4.0. Response will be assessed at wk 8, 16, 24, then at 9-wk intervals up to 1 y, and at 12-wk intervals thereafter. Interim safety analysis will occur after pts complete 1 treatment cycle in part 1. Clinical trial information: NCT02819518.
Focused ultrasound therapy combined with pembrolizumab in metastatic breast cancer.
Authors: Dillon Patrick Michael , Horton Bethany J , Bullock Timothy , Brenin Christiana , Brenin David R.
Published: February 2018

TPS19

Background: Focused ultrasound (FUS) is an ablative therapy which can heat tumors rapidly to cell damaging temperatures and simultaneously perturb the microenvironment, the microvasculature, and the lymphatics. At typical energy levels, FUS can induce controlled apoptotic cell death rather than liquefactive necrosis. FUS does not involve radiation. FUS is a partially ablative therapy using high energy ultrasound waves to induce heat shock proteins, cytokine release and cellular mediated mechanisms resulting in T cell activation and recognition of tumor antigens. FUS has been demonstrated to be an effective method for inducing tumor antigen exposure and presentation to dendritic cells, thus acting as an auto-vaccine. Pembrolizumab (PBZ) is a PD-1 targeted antibody used in multiple solid tumors to augment T cell activation. It is hypothesized that the combination of these two modalities will result in T cell infiltration into breast tumors as well as systemic immune responses. Methods: In this pilot study, we will examine PBZ therapy in combination with FUS to assess for immune stimulation and antitumor effects at local ablation sites, distant non-treated sites and in the blood. Biopsy before and after treatments will examine the tissue in the peripheral zone of ablation as well as at distant metastatic sites for CD8 and CD4 T cells, MDSC’s, T-regulatory cells and cytokine responses. Twelve patients will be randomized to receive either PBZ 14 days before or 7 days after a single time FUS partial tumor ablation on day 15. Biopsies will be on days 1, 22 and 64 and tumor imaging will be every 12 weeks. Patients must have metastatic or unresectable breast cancer, adequate organ function, and prior therapy in the metastatic setting. They must also have a tumor in the breast or axilla amenable to FUS and biopsy. Clinical trial information: NCT03237572.
BrUOG 324: Adjuvant nivolumab and low-dose ipilimumab for stage IIC, III, and resected stage IV melanoma: A phase II Brown University Oncology Research Group trial.
Authors: Constantinou Maria , Vezeridis Michael P. , Weinstock Martin A. , Walker Joanna , Miner Thomas J. , Barth Peter , Rosati Kayla , Mitchell Kristen , Dionson Sopha , Turchetti Wendy , Vatkevich John , Rafelson William Matthew , Mantripragada Kalyan C. , Safran Howard
Published: February 2018

TPS202

Background: Adjuvant ipilimumab improves survival in stage III melanoma. Adjuvant nivolumab improves progression-free survival as compared to ipilimumab with reduced toxicity. Checkpoint 067 showed that the combination of ipilimumab and nivolumab is more active in advanced melanoma than either agent alone. The Brown University Oncology Research Group sought to evaluate dual checkpoint inhibition in the adjuvant setting. This may be particularly beneficial to patients with melanoma with low PD-L1 expression. To balance safety and efficacy, the combination of low dose ipilimumab and standard dose nivolumab was investigated. Methods: Patients with stage IIc, III and resected stage IV disease are eligible. No prior treatment for melanoma other than surgery or radiation was allowed. All patients received nivolumab 3mg/kg (maximum 240 mg) every 2 weeks and ipilimumab 1mg/kg every 6 weeks for 6 months. The primary goal is to determine the toxicity of adjuvant ipilimumab and nivolumab in patients with melanoma. Unacceptable toxicity has been defined as the development of grade 4 hematologic toxicity (neutropenia or thrombocytopenia), any transient grade ≥3 or persistent grade 2 treatment-related non-hematologic toxicity that prevents completion of the planned 6 month course of treatment in more than 35% of the enrolled patients; thus, if such events occur in 10 or more patients out of 25 evaluable patients, the study will have exceeded the limit for unacceptable adverse events. Secondary objectives are to determine the recurrence-free and overall survival. Results: Between August 2016 and August 2017, 17 patients have been enrolled, 11 male and 6 female. Median age is 59 (range 25-84). Twelve patients were Stage III disease, 2 patients were stage IIC and 3 were stage IV. Conclusions: BrUOG 324 represents one of the first trials investigating adjuvant dual checkpoint inhibition in melanoma. Preliminary safety and efficacy are being assessed. Acknowledgements: This study was supported in part by the Washington Trust Company and LIFEcycle Clinical trial information: NCT02656.
CREAM study: Clinical correlation between immunotherapy-RElated clinical outcome and intestinal microbiote in metastatic patients.
Authors: Orgiano Laura , Cubeddu Alessio , Camera Silvia , Mascia Roberta , Dessi Mariele , Pedditzi Elisabetta , Murru Maura , Piredda Paolo , Barca Michela , Saba Emma , Palmas Vanessa , Camboni Tania , Massa Elena , Astara Giorgio , Manzin Aldo , Madeddu Clelia , Scartozzi Mario
Published: February 2018

TPS215

Background: It's known that composition of intestinal flora can influence the development of inflammatory gastrointestinal diseases, even though the association of inflammation with specific intestinal microbes is still unknown, because the inflammation and its treatment can change the composition of microbiote. Some bacterial species are essential to maintain the mucosal physiological tolerance, although species such as Bacteroides, Clostridium and Faecalibacterium can induce the up-regulation of T-cells and stimulate the production of anti-inflammatory cytokines. Innovative therapies such as anti-CTLA-4 antibody and inhibitors of the PD-1 receptor are particularly involved in the up-regulation of lymphocyte system: among their side effects, the most relevant are those immune-mediated such as hypophysitis, thyroiditis and colitis. In particular this last one usually occurs within 16weeks from the start of treatment: about one third of patients develop intestinal inflammation of any grade as a result of immune system dysregulation. So, the high incidence of colitis in patients treated with immunotherapy offers the possibility to characterize the intestinal microbiote before the development of immune-mediated inflammation. In addition, our curiosity has been oriented to the response to immunotherapy and the HLA class expressed by our patients: which any better predictor of response to immunological treatment than this one? Methods: Our is a single-center study of clinical and biological parameters prospectively stratified. Specifically, we collect from patients eligible for immunotherapy a blood sample to analyze HLA class and an other one to analyze serum cytokines levels, inflammatory indices and a sample of fecal material at baseline and at least after 3 administrations of treatment: actually we enrolled 34 out of 40 planned patients; we suppose to complete the enrollment in 2 months. According to preliminary data published in literature, we expect to find an alteration of intestinal microbiote in metastatic patients treated with immunotherapy. Once we'll identify it, we want to assess whether there is any correlation with the patient's clinical outcome.
Phase I adoptive cellular therapy trial with ex-vivo stimulated autologous CD8+ T-cells against multiple targets (ACTolog IMA101) in patients with relapsed and/or refractory solid cancers.
Authors: Tsimberidou Apostolia Maria , Stewart Chad , Reinhardt Carsten , Ma Hong , Walter Steffen , Weinschenk Toni , Jazaeri Amir A. , Andersson Borje , Hwu Patrick , Yee Cassian , Singh Harpreet
Published: February 2018

TPS77

Background: Adoptive cellular therapy (ACT) has dramatically changed the landscape of immunotherapy; however, only a small proportion of solid tumor patients have benefited from these advances due to i) heterogeneity of tumor antigen expression, ii) tumor escape (e.g. only one target is addressed), or iii) off-target toxicities (e.g. expression of targets on normal tissues). The ACTolog concept, utilizing antigen specific T cells (IMA101) against targets identified by the Immatics’ proprietary XPRESIDENT technology, is intended to overcome these limitations by addressing multiple novel relevant tumor antigens per patient. ACTolog is a personalized, multi-targeted ACT approach in which autologous T-cell products are manufactured against the most relevant tumor target peptides for individual patients whose tumors are positive against a predefined target warehouse. Methods: This study is an open-label first-in-human phase I trial in patients with relapsed or refractory solid tumors expressing at least one target from a warehouse of 8 cancer targets. Key eligibility criteria include: HLA-A*02:01 phenotype, qPCR expression of warehouse target(s), prior established lines of therapy, RECIST v1.1 measurable lesions, and ECOG performance status 0 or 1. At baseline, patients will undergo leukapheresis to collect mononuclear cells for manufacturing of IMA101 cells. Patients will receive their last line of established therapy during the production phase of IMA101. IMA101 will be infused after a pre-conditioning regimen (lymphodepletion) followed by LD-IL2. The primary objective is to assess safety and tolerability of IMA101. Secondary endpoints include overall response rate (RECIST and irRC), PFS and OS. The translational objective is to assess the in vivo persistence and ex vivo functionality of transferred T cells in addition to evaluation of target expression in tumors. Enrollment to the study is currently ongoing. Clinical trial information: NCT02876510 .
Phase I study of immunotherapy for advanced ROR1+ malignancies with autologous ROR1-specific chimeric antigen receptor-modified (CAR)-T cells.
Authors: Specht Jennifer M , Lee Sylvia , Turtle Cameron , Berger Carolina , Veatch Josh , Gooley Ted , Mullane Erin , Chaney Colette , Riddell Stanley , Maloney David G.
Published: February 2018

TPS79

Background: CAR-T cells have demonstrated marked tumor regression in patients (pts) with hematologic malignancies. ROR1, a tyrosine kinase orphan receptor, is expressed in triple negative breast cancers (TNBC) and non-small cell lung cancers (NSCLC) and is a novel candidate for CAR-T cell therapy. ROR1-specific CAR-T cells are engineered with lentiviral vector encoding ROR1 scFv/4-1BB/CD3ζ and a truncated EGFR molecule to permit elimination of ROR1 CAR-T cells in case of toxicity. Methods: NCT02706362 is a phase I study evaluating the safety and anti-tumor activity of adoptively transferred autologous ROR1 CAR-T cells in pts with advanced ROR1+ TNBC and NSCLC. Eligibility criteria include: metastatic TNBC or NSCLC; measurable disease; prior standard therapy with no maximum on number of prior regimens; tumor ROR1 expression > 20% by IHC; KPS > 70%; age ≥18; negative pregnancy test for women of childbearing potential; informed consent; adequate organ function. Exclusions are: active autoimmune disease or uncontrolled infection, HIV seropositive status, contraindication to cyclophosphamide, anticipated survival < 3 months, and/or untreated CNS metastases. After screening, leukapheresis is performed, CD8+ and CD4+ T cells are selected, then transduced with the ROR1+ CAR lentivirus and expanded. Lymphodepletion with cyclophosphamide and fludarabine is followed 36-96 hours later by infusion of ROR1 CAR-T cells in escalating doses (3.3 x 105/kg - 1 x 107/kg cells with defined CD8+ and CD4+ composition). Pts are treated in cohorts of 2 to determine cell dose associated with an estimated toxicity rate of < 25%. Primary aim is to determine the maximum tolerated dose (MTD) and safety of ex vivo expanded ROR1 CAR-T cells. Secondary aims include persistence and phenotype of transferred T cells, trafficking of T cells to tumor site, in vivo function, and preliminary antitumor activity of ROR1 CAR-T cells by RECIST 1.1. Dose escalation is determined by CRM algorithm with minimum of 21-day interval following infusion between pts. Preliminary estimates of efficacy will be obtained among all pts and those treated at estimated MTD. Six of 30 pts have been enrolled with no DLTs observed. Clinical trial information: NCT02706392.
A phase I study to evaluate the safety of trigriluzole (BHV-4157) in combination with PD-1 blocking antibodies.
Authors: Silk Ann W. , Berman Robert , Coric Vlad , Ruggiero Laura , Reitz Allen B. , Shih Weichung , Kane Michael P. , Mehnert Janice M. , Pelletier Jeffrey C , Zloza Andrew , Goydos James Steven
Published: February 2018

TPS80

Background: The Metabotropic Glutamate Receptor 1 (GRM1) is expressed in 60-100% of human melanomas, breast cancers, and other solid tumors. Riluzole, an FDA-approved drug for ALS, inhibits GRM1 signal transduction. A phase 0 trial in melanoma patients demonstrated that riluzole suppressed signaling through the MAPK and PI3K/AKT pathways but no objective responses were seen in a phase 2 study.The clinical use of riluzole outside of ALS has been limited by: (i) poor oral bioavailability, (ii) extensive first-pass hepatic metabolism, (iii) high variability in PK parameters, (iv) food-related decrease in bioavailability, and (v) dose-related hepatotoxicity. Trigriluzole (BHV-4157) is a third generation prodrug of riluzole with improved PK/PD properties. In our MASS20 in vivo murine model of melanoma, GRM1 signal transduction appears to suppress tumor immunity through up-regulation of M-CSF and CCL2 expression with a subsequent increase in the percentage of M2 macrophages in the tumor microenvironment. In an immunocompetent mouse model, treatment with trigriluzole and anti-PD-1 antibody was more effective than either drug alone. Methods: Subjects with advanced or refractory solid cancers or lymphoma will be treated with increasing doses of trigriluzole in this phase 1b study. The dosing cohorts of trigriluzole will be using a semi-Bayesian modified toxicity probability interval dose escalation procedure. Trigriluzole monotherapy will be given for a 14-day lead in period and then patients will receive trigriluzole in combination with nivolumab 240mg IV every 2 weeks. After the maximum tolerated dose (MTD) of trigriluzole is identified, it will be checked in a cohort of 6 patients in combination with pembrolizumab. Total sample size will be 12 – 27 subjects. PD-1-directed therapy prior to entry is allowed. Blood samples and optional biopsies will be collected for correlative analysis. PBMCs and fresh tumor tissue will be grafted into NSG mice to create a patient-derived autologous double-humanized murine model for each participant. Clinical trial information: NCT03229278.
Phase 1, multicenter, open-label study of single-agent bispecific antibody T-cell engager GBR 1342 in relapsed/refractory multiple myeloma.
Authors: Richter Joshua Ryan , Wermke Martin , Kauh John S. , Back Jonathan , Salhi Yacine , Reddy Venkateshwar , Bayever Eliel , Landgren Carl Ola
Published: February 2018

TPS81

Background: Available therapies have improved outcomes in multiple myeloma but patients eventually relapse, requiring treatment with agents that are active in refractory disease. CD38, a transmembrane glycoprotein, is upregulated on myeloma cells and is a validated disease target, evidenced by the anti-myeloma activity of daratumumab, an anti-CD38 human IgG1κ monoclonal antibody. GBR 1342 is a CD3xCD38 bispecific antibody engineered (using Glenmark’s BEAT® platform) to direct T-cells to CD38-expressing myeloma cells. In preclinical studies, GBR 1342 redirected the cytotoxic potential of T-cells to human myeloma cell lines in vitro and in mouse xenograft models. This ongoing, 2-part, first-in-human study aims to: (1) evaluate the safety profile and maximum tolerable dose (MTD) of GBR 1342 monotherapy in subjects with relapsed/refractory multiple myeloma ( > 3 prior therapies); and (2) further elucidate the safety, tolerability, and preliminary clinical activity of GBR 1342 at the MTD. The study is also evaluating the mechanisms by which GBR 1342 redirects T-cells to tumor and enhances cytolytic activity of cytotoxic T-cells. Methods: In Part 1, intravenous GBR 1342 is administered on Day 1 and Day 15 in 28-day treatment cycles at escalating dose levels (Table). The first 4 cohorts consist of a single subject. Subsequent cohorts will enroll using a 3+3 design. In Part 2, 65 evaluable subjects will be treated at the MTD identified in Part 1 until disease progression or unacceptable toxicity occurs. Primary endpoints include frequency and severity of AEs, number of dose-limiting toxicities during Cycle 1 (Part 1 only), and objective response to GBR 1342 (Part 2 only). Secondary endpoints include pharmacokinetics and anti-tumor activity of GBR 1342 (objective response, progression-free and overall survival). [Table: see text]
Personalized risk stratification for patients with early prostate cancer (PRONTO): A Canadian team biomarker project.
Authors: Berman David Monty , Lesurf Robert , Lee Anna YW , Patel Palak , Jamaspishvili Tamara , Ebrahimizadeh Walead , Okello John , Rouzbeh Shaghayegh , Boufaied Nadia , Lee Laura A , Chevalier Simone , Brimo Fadi , Venkateswaran Vasundara , Park Paul C , Buttyan Ralph , Thomson Axel A , Lapointe Jacques , Boutros Paul Christopher , Bartlett John
Published: February 2018

109

Background: Current practice stratifies men with prostate cancer into risk groups based primarily on Gleason grade. When applied to biopsy samples, the Gleason grading is inaccurate due to sampling error and inter-observer variation. The result is that men either receive unnecessary surgical treatment, or they don’t receive adequate treatment, leading to worse outcomes. Previously published genomic tests have not successfully distinguished indolent low grade (G6 or GG1) cancers from their more aggressive intermediate grade (G7 or GG2 and 3) counterparts. PRONTO is specifically aimed at creating a multi-modal risk stratification tool to improve treatment stratification following a core biopsy diagnosis. Methods: PRONTO links 7 projects, each with novel diagnostic assays for risk stratification that focus on analysis of copy number variations (CNV), DNA hypermethylation, trans-differentiation, cancer metabolism, or the tumor microenvironment. We merged the best transcripts from each project into a single NanoString gene expression assay, measuring 393 transcripts, in a cohort of 365 cases of radical prostatectomy from low-to-intermediaterisk patients. To minimize sampling error, we took multiple samples, and obtained high grade, low grade and benign areas for each radical prostatectomy case. Results: Our primary goal was to develop a multivariate molecular classifier of grade that distinguished G6 from G7 (3+4 or 4+3). Cases were randomly partitioned into five equally sized groups. A supervised machine learning algorithm (random forests) was trained on samples from four of the groups, and then evaluated by testing on the fifth group. This process was repeated for each of the five groups, yielding a combined clinical and molecular classifier. DNA methylation profiles and CNV profiles are currently being integrated into our classifier Conclusions: We have developed a multivariate classifier that distinguishes low grade from intermediate grade prostate cancer. It will be clinically validated in biopsy samples from large cohorts of early prostate cancer patients.
Active surveillance criteria in the age of targeted biopsies.
Authors: Bloom Jonathan , Hale Graham R. , Rayn Kareem , Gold Samuel , Valera Vladimir , Mehralivand Sherif , Wood Brad J. , Turkbey Baris , Parnes Howard L. , Pinto Peter A.
Published: February 2018

116

Background: Many urologists are now using active surveillance (AS) to manage patients with low-risk prostate cancer. A variety of criteria have been proposed to select patients for AS. A key feature of these criteria is Gleason Group as determined by systematic or “random” biopsies (SB). In this study, we examined the progression of Gleason Group (GG) detected only on SB compared to patients with positive MRI-fusion or “targeted” biopsies (FB). Methods: A prospectively maintained database was queried for all patients who underwent an MRI guided FB and SB from 2007 to 2016 and chose AS as their primary management strategy. Patents with GG 1 or 2 were eligible. Patients were then followed with yearly PSA, exam, MRI and biopsy if warranted. FBs were reviewed to determine GG progression. We divided patients into those who had cancer detected on SB only and those who had positive FBs with or without a positive SB. Results: A total of 162 patients met our criteria with 73 having an initial positive FB and 89 having cancer only on SB and a negative FB. Median follow-up was 27.62 (4.14 – 96.56) and 33.83 (3.45-99.84) months, respectively. The two groups were similar in age (64.49 ± 6.57 vs. 62.08 ± 6.92 years, p = 0.03) and PSA (6.23 ± 4.23 vs. 5.67 ± 3.98 ng/ml, p = 0.39). The median time to pathologic progression for GG 1 patients with initial FB positive was 53.88 months and those with GG 1 on initial SB was 80.81 months (p = 0.003). The median time to pathologic progression for GG 2 patients with initial FB positive was 36.26 months and those with GG 2 on initial SB was 76.01 months (p = 0.099). Conclusions: Previously accepted AS criteria have been based on SBs. However, those patients placed on AS after a positive FB progressed fast than cancer detected only on SB. With MRI and FBs more routinely used in clinical practice, clinicians could use this information from FBs to better stratify and closely monitor patients during AS. This research was supported by the Intramural Research Program of the National Cancer Institute, NIH.
Comparison of a low-cost immunohistochemistry marker panel with a cell-cycle progression assay for the prediction of outcome after radical prostatectomy.
Authors: Leapman Michael , Nguyen Hao Gia , Cowan Janet E. , Xue Lingru , Stohr Bradley , Simko Jeffry , Cooperberg Matthew R. , Carroll Peter
Published: February 2018

118

Background: Gene expression assays appear to stratify prostate cancer risk, however tests involving amplification techniques are expensive and may strain payment systems. We aimed to compare the prognostic utility of a low-cost immunohistochemistry (IHC) panel consisting of three validated markers with an RNA expression based cell-cycle progression (CCP) score. Methods: Among 5,748 patients with PCa within an institutional database, we identified 424 with localized PCa treated with radical prostatectomy (RP). IHC analysis was performed using tissue microarrays to examine the expression status of PTEN, Ki67, and ERG compared with previously calculated CCP scores derived from 31 genes normalized to 15 housekeeper genes. Associations of IHC status, CCP scores, adjusted for clinical and pathologic characteristics (Cancer of the Prostate Risk Assessment Score, CAPRA-S) were performed using Cox proportional hazards regression to examine risk of biochemical recurrence (BCR), and metastasis or PCa- specific mortality (PCSM). We compared models using concordance index (c-index) testing. Results: Median age at treatment was 59 years and patients were followed for a median of 114 months post RP. By 10 years after RP, 27% experienced BCR and 4% developed metastasis or PCSM. Adjusted for CAPRA-S, the triad of PTEN loss, high Ki67, and positive ERG expression was independently associated with risk of BCR (HR 2.3, 95% CI 1.1-4.7) and metastasis/PCSM (HR 8.3, 95% CI 3.3-21.2). In a model including CAPRA-S, IHC panel, and CCP, the CCP score was independently associated with both recurrence and metastasis/PCSM (HR 1.9, 95% CI 1.5-2.5 and HR 2.5, 95% CI 1.5-4.1, respectively), but IHC expression status of PTEN/Ki67/ERG remained an independent predictor of both endpoints. The addition of the CCP assay marginally improved the c-index of a combined IHC and CAPRA-S model from 0.78 to 0.81 for the prediction of metastasis/PCSM. Conclusions: A low-cost three-marker IHC panel examining PTEN, Ki67, and ERG expression was independently associated with downstream PCa endpoints following RP. Efforts are warranted to reduce the cost of PCa prognostic tools in order to expand access.
Ultrasound targeted gene therapy in a mouse model of prostate cancer: Evaluation of immune response.
Authors: De Carlo Flavia , Thomas Litty , Nande Rounak , Boskovic Olivia , Marshall Gailen , Claudio Pier Paolo , Howard Candace M
Published: February 2018

120

Background: Gene transfer to malignant sites using human adenoviruses (hAd) has been limited because of their immunogenicity. Murine cells often lack some of the receptors needed for hAd infection; therefore, are generally non-permissive for hAd infection and replication, which limits translational studies of adenoviral gene transfer techniques. We developed a gene transfer method, which uses a combination of lipid-encapsulated perfluorocarbon microbubbles (MBs) and ultrasound (US) to shield and deliver hAds to a specific tissue bypassing the requirement of the coxsackie and adenovirus receptor (CAR). Methods: Transduction efficiency and GFP protein expression of hAd.GFP was assessed by flow cytometry and fluorescence microscopy in murine TRAMP-C2 and human DU145 prostate cancer cells. Innate and acquired immunity response was determined by ELISA and CTL assay in C57BL/6 mice bearing TRAMP-C2 syngeneic tumor grafts following injections of MBs-Ad.GFP complexes in the presence or absence of ultrasound. Results: We observed that the murine prostate cancer cells TRAMP-C2 were transduced less efficiently by hAd.GFP than the human DU145 cells. We showed in vitro that the transduction rate was increased significantly in both TRAMP-C2 and DU145 prostate cancer cells when delivering the Ad particles by a combination of MBs and US. Moreover, we observed expression of the GFP transgene in both cell lines at 48 hours and 72 hours. Lack of activation of the innate and acquired immunity was observed in vivo by quantifying IL-6 and TNF-α cytokines, and by assaying neutralizing IgG antibodies and CTLs activity, following intratumoral or intravenous injections of MBs-Ad.GFP complexes in the presence or absence of ultrasound. Conclusions: This study demonstrates the feasibility of using the TRAMP-C2 murine model of prostate adenocarcinoma to translate our ultrasound-mediated MB-Ad delivery system from the bench to the clinic. Our data provides evidence that the TRAMP-C2 prostate cancer graft model is a suitable system to study in immune competent animals the capacity of lipid-encapsulated perfluorocarbon MBs and US, to shield and deliver hAds to a site-specific tissue bypassing the requirement of specific receptors.
Prognostic factors in men receiving androgen deprivation therapy (ADT) for recurrent prostate cancer: Using absolute PSA and PSA doubling time (DT) to guide timing of ADT initiation.
Authors: Ravi Praful Kumar , Karnes Jeffrey , Rangel Laureano J , Pagliaro Lance C.
Published: February 2018

129

Background: ADT is the first-line treatment for men experiencing recurrence after undergoing radical therapy for prostate cancer. However, timing of ADT initiation is controversial and there are limited data on prognostic factors in patients starting ADT. Methods: We identified consecutive men who underwent radical prostatectomy (RP) for localized prostate cancer at our institution between 1987 and 2007 and who subsequently received salvage ADT. Early progression on ADT was defined as development of metastatic disease within 2yrs of initiation. The primary outcomes of interest were cancer-specific (CSS) and overall survival (OS). Results: A total of 2418 men were included. Median age at RP was 64yrs and median follow-up was 13.9yrs. 48% and 20% of men had pathologic Gleason scores of 7 and 8-10 respectively. The median PSA was 2.6ng/ml, while 385 men (16%) had metastatic disease at receipt of ADT. Overall, 1060 men (44%) developed clinical metastases, with 625 (59%) of these doing so within 2yrs of starting ADT. On multivariable analysis, longer PSA DT before ADT was associated with lower odds of early progression on ADT (DT 3-9mths, OR = 0.19; DT ≥9mths, OR = 0.10, both p < 0.001). 10- and 20-year CSS were 89% and 70%, and 10- and 20-year OS were 82% and 40% respectively. Independent predictors of lower CSS included metastatic disease at time of ADT (HR = 2.60), PSA at ADT of 5-50ng/ml (HR = 2.68) and > 50ng/ml (HR = 4.33, all p < 0.001), while longer PSA DT was associated with higher CSS (DT 3-9mths, HR = 0.54; DT ≥9mths, HR = 0.45, both p < 0.001). PSA at ADT of 5-50ng/ml (HR = 3.10) and > 50ng/ml (HR = 5.20, both p < 0.001) were independent predictors of OS. Conclusions: PSA DT < 3mths and absolute PSA at ADT initiation of ≥ 5ng/ml are adverse prognostic indicators in men receiving salvage ADT for relapse after RP. For patients with these features, their risk of early progression and death should be part of a discussion about the timing of ADT and consideration given to more aggressive treatment strategies. Conversely, men with biochemical relapse who have longer DT and PSA < 5ng/ml are at lower risk and could make an informed decision to defer ADT initiation.
Do accountable care organizations affect race mediated differences in cancer screening?
Authors: Lee Daniel , Thapa Sunita , Graves Amy J , Buntin Melinda , Penson David F. , Resnick Matthew J.
Published: February 2018

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Background: Accountable care organizations (ACO) reflect a payment innovation aimed to orient incentives to improve quality and reduce waste. The objective of this study was to determine whether ACO enrollment affects racial disparities in cancer screening, and to characterize the impact on the appropriateness of prostate cancer screening in minority populations. Methods: We built a cohort of Medicare beneficiaries from 2007 to 2013 were comprising a cohort of 11,087,056 person-years among ACO beneficiaries and 37,187,979 person-years among non-ACO beneficiaries. A difference-in-difference-in-differences (DDD) approach was utilized to identify the effect of ACO enrollment on cancer screening in racial/ethnic minorities relative to non-Hispanic whites. We then characterized differences in screening appropriateness after ACO enrollment using age (65-74 vs. 75+) and predicted survival (top vs. bottom quartile). Results: ACO enrollment was associated with approximately a 5% reduction in prostate cancer overscreening for white beneficiaries, namely among the elderly and those with unfavorable predicted survival. Compared to white men in the lowest quartile of predicted survival, Asian and Hispanic men with similarly low survival had a 4.8% and 13.0% relative increase in prostate cancer screening associated with ACO enrollment (DDD p = 0.015, p = 0.011, respectively). Prostate cancer overscreening was common among Asian men, with 46% of elderly Asian men attributed to an ACO undergoing cancer screening compared to 28% of elderly white men. Furthermore, ACO enrollment was associated with a 2.7% increase in screening relative to whites (DDD p = 0.0005). Compared to white beneficiaries, black men had consistently lower rates of prostate cancer screening. ACO enrollment did not narrow the disparity of prostate cancer screening between healthier (DDD p = 0.75) or younger (DDD p = 0.27) black and white beneficiaries. Conclusions: This study provides evidence of ACO-mediated increases in low-value screening for prostate cancer among sick and elderly Hispanics and Asians. Furthermore, ACO enrollment did not narrow known disparities in high-value prostate cancer screening among healthier and younger black men.
Development and pilot testing of a decision support intervention for men with prostate cancer.
Authors: Chan June M. , Cooperberg Matthew R. , Neuhaus John , Bridge Mark , Stupar Lauren , Weinberg Tia , Broering Jeanette M , Tenggara Imelda , Lavaki Emil , Cowan Janet E. , Rosenfeld Stan , Kenfield Stacey A. , Van Blarigan Erin , Simko Jeff , Witte John , Carroll Peter , Belkora Jeffrey
Published: February 2018

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Background: We evaluated the feasibility and efficacy of a decision support intervention designed to help men with low-risk prostate cancer consider active surveillance and standard treatments. The intervention incorporated a decision aid with coaching and question-listing. Our decision aid is the first to include data on long-term survival and side effects from men with prostate cancer undergoing active surveillance, surgery, and radiation. Methods: To develop the intervention, we conducted focus groups using the Nominal Group Technique. We used a survey instrument from the International Patient Decision Aids Standards to measure the stakeholder endorsement of our intervention. To test the intervention, we administered it to newly diagnosed men with low-risk prostate cancer (Gleason sum < = 3+4, stage < = T2N0M0, PSA < = 10 ng/ml) seen at UCSF. Before and after the intervention, we administered a survey with questions from the Decision Quality Instrument for Prostate Cancer. Our primary outcome was change in knowledge as assessed by two multiple-choice items: How many men diagnosed with early stage prostate cancer will eventually die of prostate cancer? How much would waiting 3 months to make a treatment decision affect chances of survival? Correct answers were: “Most will die of something else” and “A little or not at all.” Results: The development phase involved 6 patients, 1 family member, 2 physicians, and 5 other health care providers and four iterations of the intervention until consensus endorsement was reached. In the pilot test, 57 men consented, and 44 received the decision support intervention and completed surveys at both timepoints. Before the intervention, 30/44 (68%) got both questions right, compared to 36/44 (82%) after the intervention. 82% maintained or achieved perfect scores; 16% answered 1 or more incorrectly both before and after the intervention; and 2% answered both items correctly before, but 1 wrong after. Conclusions: This novel decision support intervention was feasible, and appeared to improve knowledge and informed decision-making. Data will guide the development of a larger scale randomized clinical trial to improve decision quality in men with prostate cancer, in the community. Clinical trial information: NCT02451345.
A national survey of radiation oncologists and urologists on active surveillance for low-risk prostate cancer.
Authors: Kim Albert , Abouassaly Robert , Kim Simon P.
Published: February 2018

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Background: Due to the growing concerns about over-diagnosis and overtreatment of localized prostate cancer (PCa), active surveillance (AS) has become an integral part of clinical practice guidelines. However, many men with low-risk PCa still receive primary therapy with surgery or radiation. Little is known about the barriers regarding the use of AS in clinical practice. To address this, we performed a national survey of radiation oncologists and urologists assessing the current attitudes and treatment for patients diagnosed with low-risk PCa. Methods: From January to July of 2017, 915 radiation oncologists and 940 urologists were surveyed about perceptions of AS for low-risk PCa. The survey queried respondents about their opinions and attitudes towards AS and treatment recommendations for a patient having low-risk PCa with clinical factors varying from patient age (55, 65 and 75 years old), PSA (4 and 8 ng per dl), and tumor volume for Gleason 3+3 disease (2, 4 and 6 cores). Pearson chi-square and multivariable logistic regression were used to identify respondent differences in treatment recommendations for low-risk PCa. Results: Overall, the response rate was 37.3% (n = 691) and similar for radiation oncologists and urologists (35.7% vs. 38.7%; p = 0.18). While both radiation oncologists and urologists viewed AS as effective for low-risk PCa (86.5% vs. 92.0%; p = 0.04), radiation oncologists were more likely to respond that AS increases patient anxiety (49.5% vs. 29.5%; p < 0.001). Overall, recommendations varied markedly based on patient age, PSA, number of cores positive for Gleason 3+3 prostate cancer and respondent specialty. For a 55-year-old male patient with a PSA 8 and 6 cores of Gleason 6 PCa, recommendations of AS were low for both radiation oncologists and urologists (4.4 % vs. 5.2%; adjusted OR: 0.6; p = 0.28). For a 75-year-old patient with a PSA 4 and 2 cores of Gleason 6 PCa, radiation oncologists and urologists most often recommended AS (89.6% vs. 83.4%; adjusted OR: 0.5; p = 0.07). Conclusions: While both radiation oncologists and urologists consider AS effective in the clinical management of low-risk PCa, its use varies markedly by patient age, PCa volume, PSA and physician specialty.
Long-term outcomes of magnetic resonance image-guided partial prostate brachytherapy for favorable-risk prostate cancer.
Authors: King Martin T. , Nguyen Paul L. , Boldbaatar Ninjiin , Tempany Clare Mary , Cormack Robert A. , Beard Clair , Hurwitz Mark , Suh Warren , D'Amico Anthony Victor , Orio Peter F
Published: February 2018

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Background: To report long-term outcomes of magnetic resonance image-guided partial prostate brachytherapy of the peripheral zone. Methods: We conducted an institutional-board approved retrospective review of all men who underwent 0.5 Tesla GE Signa SP MRI-guided partial prostate brachytherapy to the peripheral zone. We estimated actuarial rates of biochemical progression (nadir +2 definition), as well as cumulative incidences of biopsy proven local recurrence, distant metastasis, and prostate cancer specific mortality. Fine and Gray’s competing risk regression was utilized in order to evaluate clinical factors associated with times to metastasis and prostate cancer specific mortality. Results: Between 1997 and 2008, 354 men underwent MRI-guided partial prostate brachytherapy. The numbers of patients with low and intermediate risk disease were 295 (83%) and 59 (17%), respectively. Sixty-seven (19%) patients received supplemental external beam radiotherapy. The median follow-up was 8.6 years. For National Cancer Center Network (NCCN) low risk-disease, 8-year estimates of biochemical progression, local recurrence, metastasis, and prostate cancer specific mortality were 23.5% (17.4-29.1), 6.4% (3.6-10.2), 2.0% (0.6-4.8), and 0%. Corresponding estimates for intermediate risk disease were 51.2% (31.3-65.4), 21.2% (10.2-34.9), 6.6% (1.7-16.3), and 5.4% (0.9-16.2). Twenty of 45 biopsy proven local recurrences occurred outside of the implanted peripheral zone. Of the 22 patients who developed distant metastases, 14 events occurred more than 10 years from therapy. On multivariate analyses, biopsy proven local recurrence was the only factor to demonstrate a significant association with metastasis (hazard ratio 2.50; p = 0.05) and a trend with prostate cancer specific mortality (5.02; p = 0.09). Conclusions: MRI-guided partial prostate brachytherapy to the peripheral zone in men with favorable risk prostate cancer is suboptimal with respect to long term cancer control outcomes. Additional studies using contemporary MRI techniques including 3 Tesla based multi-parametric imaging and fusion biopsy may lead to improved outcomes.
Prospective clinical study of a prostate cancer (PCa) rule-out blood test for PSA gray zone patients using a sensitive circulating tumor cell assay.
Authors: Pang SEE-TONG , Chang Ying-Hsu , Lin Po-Hung , Chang Ying , Watson Drew , Segurado Oscar , Lu Si-Hong , Wu Jen-chia , Lai Jr-Ming , Shao Hung-Jen , Chang Shih-En , Hsieh Ben , Javey Mana , Mei Rui
Published: February 2018

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Background: The diagnostic confirmation of prostate cancer in patients with a PSA in the gray zone (4–10 ng/ml) is controversial, often leading to unnecessary biopsies. The sensitivity of the PSA test at a 4 ng/mL cut-off can be as low as 21%. We introduce a new test for prostate cancer detection in PSA gray zone patients, with the potential to decrease the number of unnecessary prostate biopsies. Methods: A single-center, multi-year, IRB-approved, prospective, blinded clinical study was conducted in 200 high-risk subjects. 4 mL of blood was drawn and processed for CTC analysis using the CellMax biomimetic platform (CMx). The CMx CTC test uses a proprietary microfluidic biochip that accurately captures and enumerates CTCs with antibodies to EpCAM, CK18 and PSMA. All patients underwent routine screening including PSA and digital rectal exam (DRE). Gray zone and those diagnosed as ‘diseased’ based on PSA & DRE also underwent a biopsy. Multivariate generalized linear models incorporating CMx test results were utilized to derive age adjusted CTC scores predictive of clinical outcomes. Results: A subset of 84 subjects with PSA levels in the gray zone (4–10 ng/ml) were included in this study. Prostate biopsy results were available for 42 patients; 10 had confirmed cancer. A CTC Score was calculated as a nonlinear weighted combination of the CTCs captured with CK18 and PSMA antibodies. After adjustment for age and PSA, the CTC score remained a significant predictor of clinical outcome in the PSA “gray zone” (likelihood ratio p-value = .015) whereas PSA was not. The sensitivity and specificity of the CTC Score were 80.0% (95% CI: 44.4%, 97.5%) and 93.8% (95% CI: 79.2%, 99.2%). Negative % agreement and Positive % agreement was 93.8% (95% CI: 79.2%, 99.2%) and 80.0% (95% CI: 44.4%, 97.5%). Given the observed odds ratio for CTC score in the study- approximately 0.90 (95% CI 0.79, 0.98), the study is appropriately powered. Conclusions: The CMx CTC assay is an accurate, affordable blood based assay, with the potential to reduce unnecessary biopsies in PSA gray-zone patients by up to 90%.