bluuebunny/crossref_metadata_2025 huggingface dataset:
Targeting checkpoint kinases in prostate cancer cells resistant to poly ADP-ribose polymerase inhibitors.
Authors: Atiq Mohammad Omar , Chakraborty Goutam , Nandakumar Subhiksha , Mazzu Ying Zhang , Stopsack Konrad Hermann , Jehane Lina E. , Yoshikawa Yuki , Khan Nabeela , Lee Gwo-Shu Mary , Kantoff Philip W.
Published: May 2019

e16543

Background: The identification of DNA damage response (DDR) gene abnormalities in various cancers has provided potential therapeutic targets including the poly ADP-ribose polymerase enzyme (PARP). PARP inhibitors are now approved for use in ovarian, breast, and prostate cancer (PC). Olaparib and rucaparib have been given Breakthrough Therapy designation by the FDA for use in patients with metastatic castration-resistant prostate cancer and germline BRCA1/2 or ATM mutations. However, drug resistance limits the efficacy of PARPi. Somatic reversion mutations of BRCA1/2 have been described as one potential mechanism of resistance to PARPi in patients with germline BRCA1/2 mutations. However, in PC, the BRCA2 gene is frequently deleted, in contrast to other cancers, where it is mutated. Thus, we hypothesize that resistance to PARPi in PC may involve alternative molecular mechanisms. Methods: We performed cell viability assays to determine the inhibitory growth (IG) concentrations of olaparib and talazoparib on human castration-resistant PC cell lines (PC-3 and LNCaP-Abl) that have heterozygous genomic deletions of BRCA2. Parental PC-3 cells were cultured in sublethal concentrations (IG 50% and IG 90%) of talazoparib-supplemented media for approximately 2 months to develop talazoparib-resistant cells. We then performed an analysis of phosphorylation status in untreated and treated parental PC-3 and talazoparib-resistant clones with a phosphokinase array. We confirmed this with Western blot. Results: Talazoparib-resistant PC-3 clones showed significantly enhanced cell growth compared to parental cells when cultured in media supplemented with the IG 90% concentration of talazoparib or olaparib. The phosphokinase array revealed a significant increase in the phosphorylation of CHEK2 in talazoparib-resistant clones compared to parental PC-3 cells. Interestingly, a similar increase was seen after 72 hours of treatment with talazoparib, indicating an early connection between PARP inhibition and CHEK2 phosphorylation in PC cells. Moreover, a pan-CHEK inhibitor, prexasertib, led to significant cell growth inhibition in talazoparib-resistant PC-3 clones and a significantly lower IG 50% concentration compared to parental PC-3 cells. Conclusions: We speculate that early activation of CHEK2 may be a primary mechanism of resistance to PARPi in PC cells with deletion of BRCA2. Furthermore, our preliminary data showed that CHEK inhibition can overcome PARPi resistance, indicating a potential for CHEK inhibitor-based therapy for PC patients.
Pilot study to enhance FDG-PET imaging of prostate cancers with the metabolic inhibitor ranolazine.
Authors: Schlaepfer Isabel R. , Kessler Elizabeth R , Kwak Jennifer J , Liebman Lauren , Maroni Paul , Karki Ramesh , Lopez Paniagua Dan , Koo Phillip , La Rosa Francisco G. , Gao Dexiang , Glode L. Michael , Flaig Thomas W. , Lam Elaine Tat
Published: May 2019

e16551

Background: 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography (FDG-PET) is a widely-used imaging modality for many cancers; however, its utility in prostate cancer is limited. Fatty acid oxidation (FAO) is a primary source of energy for early prostate cancer. We previously demonstrated that FAO inhibition in prostate cancer mouse models resulted in increased glucose metabolism and enhanced tumor FDG uptake, with peak uptake at 24 hours. To validate these preclinical findings, we conducted a pilot study to evaluate whether a partial FAO inhibitor, ranolazine, increases tumor FDG uptake on PET imaging for prostate cancer. Methods: Prostate cancer patients with untreated localized cancer (arm 1) and with metastatic disease on hormonal or other therapy (arm 2) were enrolled and underwent baseline and post-treatment FDG-PET/CT scans (standard dose of 10 mCi FDG). Ranolazine 1000mg PO BID x 2 doses was given within 24-48 hours of the second scan. The primary objective was to evaluate the rate of successful enhancement of FDG uptake on PET imaging, based on one or more of the following criteria: 30% increase in maximum SUV with an absolute change of 2 units; 30% increase in mean SUV with an absolute change of 0.75 units; or 20% increase in mean SUV with an absolute change of 1 unit. Results: Eleven patients (four in arm 1, seven in arm 2) were enrolled. Ranolazine was well tolerated by all participants, with no adverse effects observed. Both increases and decreases in SUV uptake were observed on the post-ranolazine scans. No patient met the predefined criteria for successful enhancement of FDG uptake. There was an incidental finding of thyroid cancer seen in one patient that was discovered on PET imaging. The study was closed early due to the emerging clinical availability of alternative and effective PET imaging modalities such as [11C] choline, [18F] fluciclovine, [68Ga] PSMA, and [18F] sodium fluoride. Conclusions: Given the small sample size, we were not able to make any firm conclusions. In this limited study, ranolazine treatment did not result in enhanced FDG-PET-tumor detection. ClinicalTrials.gov identifier: NCT01992016. Supported by the William Meyn Foundation; NIH/NCI P30CA46934, 5K12CA086913, CA168934; ACS RSG-16-256-01-TBE; Colorado Translational Research Imaging Center Pilot Award; Paul Sandoval Cancer Research Summer Fellowship. Clinical trial information: NCT01992016.
IMPACT of putative chemopreventative agents on prostate cancer diagnosis.
Authors: Goldberg Hanan , Moshin Faizan , Klaassen Zachary William Abraham , Chandrasekar Thenappan , Wallis Christopher J.D. , Herrera Cáceres Jaime Omar , Ahmed Ardalan , Alibhai Shabbir M.H. , Berlin Alejandro , Saskin Refik , Hamilton Robert James , Fleshner Neil Eric
Published: May 2019

e16553

Background: Prostate cancer (PC) is the most common non-cutaneous cancer in men and the third most common cause of cancer death in males. Several studies have shown that use of commonly prescribed medications, is associated with improved survival in various malignancies, including PC. There has not been any large population-based study, examining the effects of these and other commonly prescribed medications, such as proton pump inhibitors (PPI), on the rate of PC diagnosis, PC advanced disease and PC-specific death. Methods: A retrospective population-based study using data from the institute of clinical evaluative sciences, including all male patients aged 65 and above in Ontario who have had a negative first prostate biopsy between 1994 and 2016. We assessed the impact of commonly prescribed medications on PC outcomes. The analyzed medications included Statins (hydrophilic and hydrophobic), most commonly used diabetes drugs (metformin, insulins, sulfonylureas, and thizolidinedions), PPIs, 5 alpha reductase inhibitors, and alpha blockers. Time dependent Cox regression proportional hazards models were performed to determine predictors of PC diagnosis, PC advanced disease (defined as usage of hormonal therapy), and PC-specific death. Medication exposure was time varying and modelled as “ever” vs. “never” use or as cumulative exposure. Results: A total of 21,562 men were analyzed over a mean (SD) follow-up time of 8.06 (5.44) years. Overall, 5,187 patients (24%) were diagnosed with PC, 7861 (36.5%) had died, and 647 (3%) died of PC. On multivariable analysis usage of hydrophilic statins modelled as “ever vs. never” was associated with a lower diagnosis rate (OR 0.832, 95% CI 0.732-0.946, p = 0.005) and a significantly decreased PC-specific death (OR 0.676, 95% CI 0.528-0.871, p = 0.0024). In contrast, Pantoprazole was associated with a higher rate of advanced PC disease when modelled as cumulative exposure of 6 months (OR 1.03, 95% CI 1.003-1.06, P = 0.031), and PC-specific death, when modeled as “ever vs. never” (OR 1.26, 95% CI 1.02-1.576, p = 0.031). Conclusions: Hydrophilic statins were associated with a clinically and statistically significant lower PC diagnosis and PC-specific death, while pantoprazole was associated with a higher rate of advanced PC disease and PC-specific death.
Survival in men diagnosed with castration resistant prostate cancer: A population-based observational study in Sweden.
Authors: Aly Markus , Schain Frida , Leval Amy , Liwing Johan , Lawson Joe , Vago Emese , Nordström Tobias , Gronberg Henrik , Andersson Therese M-L , Sjöland Erik , Wang Chen , Eloranta Sandra , Akre Olof
Published: May 2019

e16555

Background: Data focusing on the castration resistant phase of prostate cancer (PC) outside clinical trial settings are scarce. This study aims to investigate PC-specific and overall survival (OS) in men with castration resistant prostate cancer (CRPC) on a population level. Methods: The STHLM-0 cohort (n = 400 000) with data on all prostate specific antigen (PSA) values and prostate biopsies taken in Stockholm, Sweden, from 2003 to 2015 were linked to other population registries. All men with a PC diagnosis and rising PSA after three months consecutive use of gonadotropin-releasing hormone or surgical castration were defined as CRPC (n = 1712). Kaplan-Meier was used to estimate median time-to-event and 95% confidence intervals (CI). Patients were stratified by metastasis status at PC diagnosis and multivariable Cox regression was used to adjust for clinical subgroups, including Gleason, age, T stage and calendar period (2006-2011 vs 2012-2015). Results: Metastasis at PC diagnosis was associated with shorter OS from castration resistance. From CRPC onset the median OS was 22.8 months (95% CI 21.2-25.5) and 13.1 (95% CI 11.5-14.2) months for patients without and with metastasis at PC diagnosis, respectively. The median PC-specific survival from CRPC was 30.7 (95% CI 27.9-34.7) months and 13.5 (95% CI 12.3-16.1) months for patients without and with metastasis at PC diagnosis, respectively. For patients with metastasis at PC diagnosis, factors influencing OS from CRPC were; entering CRPC stage in the later vs earlier calendar period (HR 0.61 95% CI 0.48-0.78, p < 0.001), age > 80 vs < 70 (HR 1.46, 95% CI 1.05-2.02, p < 0.02), T4 vs T1 stage (HR 1.56, 95% CI:1.02-2.37, p < 004). For patients without metastasis at PC diagnosis, developing CRPC in the later vs the earlier calendar period was associated with superior survival from CRPC (HR 0.78 95% CI 0.65-0.92, p < 0.004). Conclusions: Metastasis at PC diagnosis was associated with worse survival outcomes in CRPC patients. Individuals who became castration resistant in the later calendar period survived longer compared to those in the same stage in the earlier calendar period, most likely due to the introduction of novel agents for CRPC patients and more accurate staging methods.
Predictors and rates of adverse events (AEs) among non-metastatic prostate cancer (nmPC) patients (pts) treated with bicalutamide, abiraterone, or enzalutamide following surgical/medical castration.
Authors: Shah Anuj , Hussain Arif , Shah Ruchit , Ikeme Shelly , Mohamed Ateesha F. , Botteman Marc , Waldeck Reg
Published: May 2019

e16556

Background: The castration-resistant nmPC treatment landscape has evolved following the recent approval of enzalutamide and abiraterone. Skin rash, fractures, and central nervous system (CNS) AEs have been reported among pts treated with these drugs as well as other antiandrogens (eg. bicalutamide). We assessed the rate and predictors of AEs among nmPC pts treated with abiraterone, enzalutamide, or bicalutamide (“study drugs”) in a real-world setting. Methods: nmPC pts initiating one of the study drugs ≥1 year after medical/surgical castration were identified in the MarketScan Commercial database (2012-17). We included pts who had all the following: a claim for a prostate-specific antigen test or an oncologist visit ≤6 months (mos) before study drug initiation (baseline period), no claim for hormonal therapies (except castration) nor metastasis before study drug, and ≥3-mos metastasis-free follow-up while on study drug. Kaplan Meier analyses were used to describe the rates and median time to onset for 18 CNS AEs (including, but not limited to, fatigue, cognitive impairment, or falls) or any AE (i.e., CNS AE, skin rash, or fracture). Baseline period AE predictors were identified using multivariate Cox-proportional hazards models. Results: 532 pts were included (bicalutamide: 89.7%, enzalutamide: 4.3%, abiraterone: 6.0%). The percentages of pts experiencing CNS AEs/any AE were 19%/22% at 3 mos, 28%/35% at 6 mos, and 43%/52% at 12 mos. Median time to AE onset since study drug initiation was 17.9 mos (CNS AE) and 11.0 mos (any AE) respectively. Significant predictors of having any AEs included baseline period AEs (hazard ratio [HR]: 3.07 [2.35-4.02]), Charlson comorbidity index (1 vs 0) (HR: 1.51 [1.04-1.19]), surgical castration (HR: 1.50 [1.07-2.08]), and older age (HR: 1.021 [1.002-1.040]). Similar predictors were found for CNS AE. Conclusions: nmPC pts treated with bicalutamide, enzalutamide or abiraterone experience high AE rates. Balancing the risks/benefits of treatment in this largely asymptomatic population is paramount to maintaining their quality of survival while optimizing survival outcomes.
Cell cycle progression score differentiates indolent from aggressive prostate cancer in men diagnosed by TURP.
Authors: Cuzick Jack M. , Stone Steven , Rajamani Saradha , Møller Henrik , Berney Daniel M. , Cohen Todd , Scardino Peter T.
Published: May 2019

e16560

Background: Improved selection of men with localized prostate cancer for conservative management remains a clinical need. We previously showed that the Cell Cycle Progression (CCP) score provides a significant amount of independent prognostic information in men with prostate cancer who opt for conservative management. Here, we extend those results by evaluating the performance of the CCP score in a newly analyzed cohort of conservatively managed men and in a large pooled cohort of men who deferred initial curative therapy. Methods: The CCP score (based on 31 CCP genes and 15 housekeepers) was derived from FFPE tumor sections as previously described. For this study, the CCP score was evaluated in several independent cohorts: 1) a newly studied retrospective cohort from the U.K. diagnosed by a transurethral resection of the prostate (TURP1B, N = 192); 2) a previously studied cohort from the U.K. diagnosed by TURP (TURP1A, N = 200); and 3) two previously studied cohorts from the U.K. diagnosed by needle biopsy (TAPG1, N = 180 and TAPG2, N = 585). The combined cohort included 1,157 conservatively managed men with complete clinical data. Median follow-up for all cohorts was 9.8 years. Hazard ratios (HR) are for a one-unit change in score, and the endpoint for this study was disease specific mortality (DSM). Results: The CCP score was a highly significant predictor of DSM in TURP1B. The univariate HR was 2.96 (95% CI 2.32, 4.04, p = 3.6x10-9), and the multivariate HR after adjusting for CAPRA was 2.27 (95% CI 1.59, 3.23, p = 1.3x10-5). These results are very similar to the HRs obtained in TURP1A cohort, and the test for HR heterogeneity was not significant after adjusting for CAPRA (p = 0.30). In the pooled analyses, the interaction between CCP and cohort was not significant after adjusting for clinical variables. Interestingly, sample type (TURP vs. Needle biopsy) was prognostic even after adjusting for clinical variables. Summaries of the pooled analyses are given in Table. Conclusions: The CCP score adds a significant amount of independent prognostic information for outcome in conservatively managed men. As such, it can be used to help select appropriate patients for deferred treatment regimens like AS or watchful waiting. [Table: see text]
The predictive power of free (vs. total) testosterone in aggressive prostate cancer.
Authors: Towe Maxwell M , Huynh Linda My , El Khatib Farouk , Osman Mohamad M , Yafi Faysal A , Ahlering Thomas Edward
Published: May 2019

e16570

Background: The role of testosterone in prostate growth and the development of prostate cancer is a controversial topic. Most current data suggest that lower testosterone leads to higher grade conversion, whereas higher testosterone may serve a protective role in preventing both development and recurrence. We seek to analyze whether free testosterone (FT) values can predict aggressiveness in prostate cancers. Methods: We retrospectively reviewed 830 patients who presented to a single surgeon for evaluation and management of prostate cancer. Total Testosterone (TT) and FT values were obtained on each patient at initial visit. All patients underwent radical prostatectomy and samples from surgery were sent for grading and staging. Patients were stratified by FT quartile (25th [≤ 4.42 ng/dL], 50th [4.43 – 5.60 ng/dL], 75th [5.61 – 6.95 ng/dL], and 100th [≥ 6.96 ng/dL]). Results: Of 830 patients, 168 (22.2%), 330 (39.8%), 188 (22.7%), 46 (5.5%), and 98 (11.8%) had GS 3+3, 3+4, 4+3, 4+4, and ≥4+5, respectively. Mean FT values for each Gleason grade group (GGG) were significantly different (p = 0.008). Mean FT was also lower in patients with higher stage disease (p = 0.01). In contrast, TT did not differ significantly among GGG (p = 0.489) or stage (p = 0.670). Patients who had a FT level in the lowest quartile (≤ 4.42 ng/dL) had a higher proportion of GGG 5 (15.6%) than patients in the highest quartile (≥ 6.96 ng/dL) (6.2%) (p = 0.002). After adjusting for age, prostate specific antigen (PSA), and body mass index (BMI) in multivariate analysis, lower FT was a significant predictor of high-risk score 9-10 (OR: 0.912, 95% CI: 0.836-0.994, p = 0.036). These trends showed strong correlation in pathologic stage (p = 0.057), but larger numbers are needed to gauge effect size. Conclusions: Based on our data, biochemically low FT may be a risk factor for high grade and high stage cancer. These results have implications for the current recommendations for testosterone therapy, which is contraindicated in men with prostate cancer. [Table: see text]
Impact of comorbidity and age on treatment choice among men with localized prostate cancer.
Authors: Pinsky Paul F , Pierre-Victor Dudith , Martin Iman K. , Miller Eric , McCaskill-Stevens Worta J. , Grubb Robert L.
Published: May 2019

e16585

Background: Prostate cancer (PCa) is the most commonly diagnosed cancer among men in the United States. A substantial proportion of PCa patients has at least one comorbidity. Comorbidities have a meaningful impact on cancer treatment choice. The objective of this study was to investigate the effect of comorbidity, as well as age, on treatment choice among men with localized PCa. Methods: From the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, men with localized PCa diagnosed from 1994-2014 were selected (N = 10, 281). Comorbidity score was determined based on a modified Charlson index. Treatment was classified as curative, either radical prostatectomy (RP) or radiation therapy with curative intent (RT), or non-curative (all other modalities). We used multivariate logistic regression to assess the association of treatment choice with age and comorbidity score (including their interaction), controlling for D’Amico risk group, demographics and diagnosis year. Results: About half (48.3%) of patients had comorbidity score ≥ 1. Most men received curative treatment (75.2%); RT (55.2%) was more common than RP (44.8%). The likelihood of curative treatment decreased with increasing age; odds ratios (OR) for curative treatment were 0.63 (95%CI: 0.52-0.76), 0.36 (95%CI: 0.30-0.43) and 0.13 (95%CI: 0.11-0.16) for men aged 65-69, 70-74 and 75+, respectively, compared to men aged 55-64. Men with a comorbidity score of 2+ (OR = 0.84; 95%CI: 0.74-0.96) were less likely to receive curative treatment than men with a score of 0. Within curative treatment, older age was strongly associated with RT. Compared to men aged 55-64 years, men aged 65-69 years (OR = 2.0; 95% CI: 1.72-2.3), 70-74 years (OR = 5.3; 95% CI: 4.5-6.3), and 75+ years (OR = 25.0; 95% CI: 17-33) were more likely to receive RT than RP. Men with a comorbidity score of 1 (OR = 1.16; 95%CI: 1.03-1.30) or 2+ (OR = 1.92; 95%CI: 1.6-2.3) were also more likely to receive RT. The interaction between age and comorbidity score was not significant. Conclusions: In this cohort, age was a strong independent predictor of treatment choice for localized PCa. Although comorbidity was not a strong predictor of curative treatment, it was associated with receipt of RT.
Tumor contact length used as a biomarker to predict extracapsular extension, lymph node involvement, and biochemical recurrence.
Authors: Viana Públio , Rodrigues Thiana , Mota Davi alves martins , Guglielmetti Giuliano , Bastos Diogo Assed , Fazoli Arnaldo , Nahas William Carlos , Coelho Rafael , Cordeiro Mauricio , Horvat Natally
Published: May 2019

e16588

Background: Prostate cancer (PC) is the cancer most commonly diagnosed in men and the second leading cause of death. Multiparametric magnetic resonance imaging (mpMRI) is the benchmark imaging standard for local staging of PC. Patients with pathological extraprostatic tumor (pEPE) have a worse prognosis than those with confined organ disease with a higher risk of biochemical recurrence (BCR) after radical prostatectomy (RP). These factors, in addition to positive lymph nodes (PLN), are pivotal in the decision-making process regarding treatment. However, the subjective MRI analysis has low sensitivity in the detection of EPE and is plagued by the low interobserver agreement. Tumor contact length (TCL) is an objective parameter of mpMRI defined as the length of prostate cancer in contact with the prostate capsule, which may provide additional information about prostate cancer outcomes. We aimed to evaluate TCL as a predictor of pECE, PLN, and BCR in patients undergoing RP. Methods: In this Institutional Review Board approved single-institution prospective study, we update the follow-up of 148 patients and included 31 new patients, with prostate cancer who underwent prostate MRI before radical prostatectomy from March 2014 to november 2018. TCL was measured using T2-weighted magnetic resonance images.Postoperative prostate-specific antigen (PSA) values were obtained every 3 months in the first year, then biannually and annually thereafter. BCR was defined as PSA≥0.2ng/mL. The exclusion criterion was prior treatment. Results: The median follow-up was 44 months. 76/179 (42,4%) patients had pEPE, 12/179 (6,7%) had pLN, and 29/179 (16,2%) had BCR. TCL values were significantly higher in patients with pathological pECE ( 20,6 mm vs 9,9 mm, p < 0.001). Using a cut-off of 11,9 mm we found area under curve (AUC) of 0,71 to predict pathological ECE, with sensitivity 72,5% and specificity 67,5% . Using a cut-off of 16,5 mm we found AUC of 0,64 to predict BCR, with sensitivity 54,2% and specificity 67,8% and with a cut-off of 21,7 mm the AUC to predict PLN was 0,77, with sensitivity 66,7% and specificity 83,6%. Conclusions: We prospectively demonstrated in our population that TCL values were significantly higher in patients with pEPE , PLN and BCR. If validated, this imaging biomarker may facilitate and inform patient counseling and decision-making.
The internet bias toward nontraditional first line prostate cancer treatments.
Authors: Landau Danny , Landau Alec
Published: May 2019

e16594

Background: Despite relegation to relapsed localized disease per National Comprehensive Cancer Guidelines, we have noticed upticks in cryotherapy and High-intensity focused ultrasound (HIFU) as initial therapy for prostate cancer in Orlando. We believe internet advertisements play a role in this. When directly questioned, patients confirm our belief. We conducted internet searches to analyze the information available to patients. Methods: Utilizing common search engines, Google and Bing, searches were conducted using the terms “cryotherapy prostate cancer” and “HIFU”. The first three pages of general results and sponsored results were broken into categories. The categories include verified information (VI) properly describing the therapies and their indications, advertisement for traditional care (TC) centers, centers that promote nontraditional care (NTC), or information that is unclassifiable/ misleading (other). A final search was done for “alternative prostate cancer treatments”. The results that mentioned HIFU or cryotherapy were counted manually. Results: Cryotherapy Google general search In total, unverified information or advertisements for centers practicing outside of traditional norms were represented in: General search combined: 26/82: 32% Sponsored searches: 54/75: 73% The general search term “alternative prostate cancer” search including HIFU or Cryotherapy General Search: 3/55 (0.05%) Sponsored Search: 8/39 (21%). Conclusions: Using general search terms, it seems that there is a wealth of information that can influence a patient’s decision making on prostate cancer treatment. While there is more information promoting HIFU/ cryotherapy on sponsored searches, general searches have potential for misunderstanding and abuse in nearly a third of cases.[Table: see text][Table: see text][Table: see text][Table: see text][Table: see text][Table: see text][Table: see text][Table: see text]
Prognostic impact of tristetraprolin (TTP) and PTEN loss and assessment of associated immune infiltrates in localized prostate cancer (PrCa).
Authors: Hamid Anis , Werner Lillian , Huang Ying , Vicier Cecile , Morel Katherine , Ellis Leigh , Sweeney Christopher
Published: May 2019

e16601

Background: We previously showed that loss of PTEN by quantitative multiplex immunofluorescence (qIF) is associated with relapse after prostatectomy. Low expression of TTP, which modulates the NF-kB pathway and inflammation, is prognostic for lethal PrCa after surgery. We also showed, with this assay, that low CD8+ density is a poor prognostic marker. We hypothesized that co-loss of these independent cell signaling regulators leads to poorer outcomes, and low TTP is associated with a modified tumor immune microenvironment. Methods: qIF was performed on tissue microarrays from a cohort treated by radical prostatectomy (N = 128). PTEN and TTP expression intensity was measured continuously at a cell-by-cell level and summarized per patient using binary thresholds. Immune marker (CD3, CD8, PD-L1, PD-1, FOXP3) density (positive cells/area) was evaluated in glands and stroma. Median time to biochemical recurrence (BCR) and metastasis (MFS) was estimated using Kaplan Meier method and log rank test summarized associations between expression and time to event outcomes. Wilcoxon test assessed the association of biomarker status and immune marker density. Results: Of 128 patients with a median follow-up of 14.6 years, 67 (52%) had BCR. 102 had staining for PTEN, 103 for TTP and 86 for both. Key findings are detailed in Table. PTEN and TTP co-loss was associated with the shortest time to BCR and worst MFS. TTP-low tumors had an immune infiltrate deplete of CD8 (p = 0.0004) and PD-1 (p = 0.0001) expressing cells. No significant differences in immune markers were noted by PTEN status. Conclusions: Co-loss of regulators of inflammation and cell cycling is associated with incremental risk of relapse in localized PrCa. Loss of TTP is associated with a diminished effector T cell infiltrate and may be a modifier towards a ‘cold’ PrCa immune microenvironment. Table: Clinical outcomes by biomarker status [Table: see text]
Effect of pectasol-c modified citrus pectin (P-MCP) treatment (tx) on PSA dynamics in non- metastatic biochemically relapsed prostate cancer (BRPC) patients (pts): Primary outcome analysis of a prospective phase II study.
Authors: Keizman Daniel , Frenkel Moshe A. , Peer Avivit , Rosenbaum Eli , Margel David , Sarid David , Neiman Victoria , Leibovitch Ilan , Sternberg Itay Aharon , Boursi Ben , Gottfried Maya , Dresler Hadas , Eliaz Isaac
Published: May 2019

e16609

Background: 30% of pts with localized PC will have a biochemical relapse post local tx. Their optimal tx remains elusive. While androgen deprivation therapy is effective in reducing PSA level, its long-term benefit remain undefined, and it is associated with significant toxicities. Thus, evaluation of new non-toxic compounds in this pt population is warranted. P-MCP is a competitive inhibitor of galectin-3, a carbohydrate-binding protein, known to be involved in cancer pathogenesis. Pre-clinical data suggest that P-MCP is active in PC, and in two previous smaller clinical trials in biochemically relapsed prostate cancer (BRPC) pts, a PSA response/stabilization rate of 57%-75% was noted. In the present study, we aimed to evaluate the safety and PSA dynamics of P-MCP tx in BRPC pts. Methods: non-castrate non-metastatic BRPC pts were enrolled in a prospective phase 2 study of oral P-MCP tx, at 4.8 grams X 3/day for 6 months (mos). Eligible pts had 3 consecutive rise of PSA, without any tx in the previous 3 mos, a normal level of serum testosterone, and negative scans. The primary outcome was the rate of pts without disease progression (DP) (clinically, biochemically with stabilization/decrease of PSA or improvement of PSA doubling time = PSADT, and radiologically) at 6 mos. A Sample size of ≥ 50 pts provided 85% power to assess a decrease in DP rate from 80% (natural history) to 40% (P-MCP tx) at 6 mos. Pts that did not progress at 6 mos, were treated for subsequent 12 mos (secondary outcome of long term effect). Herein we report the results of the primary outcome analysis. Results: 53 pts were enrolled. Median age was 74 years. Tx of the primary tumor consisted of surgery in 13% (n = 7), radiation in 60% (n = 32), and both in 26% (n = 14). No pt had tx related grade 3/4 toxicity. One pt withdrew his consent after 1 mos. At present, 46 pts completed 6 mos of tx, and were analyzed for the primary outcome. Among them, 20% (n = 9) had grade 1 toxicity (all gas and bloating ). The primary outcome was met in 76% (n = 35), that did not progress at 6 mos of tx. Of these, 59% (n = 27) had a stabilization/decrease of PSA, 70% (n = 32) had an improvement (increase) of PSADT, and all had no metastases on scans at 6 mos. DP at 6 mos was noted in 24% (n = 11: PSA only in 20%, n = 9; PSA and scans in 4%, n = 2). Full cohort data (additional 6 pts that will complete 6 mos of tx) will be available by June 2019. Conclusions: The present study suggests the safety and potential benefit of P-MCP tx on progression of BRPC. Clinical trial information: NCT01681823.
Influence of the new FIGO classification for cervical cancer on patients’ survival: Retrospective analysis of 265 histologically confirmed cases with FIGO stages Ia to IIb.
Authors: de Gregorio Nikolaus , De Gregorio Amelie , Ebner Florian , Schochter Fabienne , Friedl Thomas W. P. , Huober Jens Bodo , Janni Wolfgang , Widschwendter Peter
Published: May 2019

e17006

Background: End of 2018 a new FIGO Classification for cervical cancer was published, mainly revising stage Ib and introducing a new stage IIIc, which includes irrespectively of tumor size and local spread all patients with lymph node metastasis. Methods: We retrospectively analyzed all cases of cervical cancer stage I to IIb who underwent surgery as primary treatment at our institution from 2000 until 2016 and therefore had a histological confirmation of tumor stage. We reclassified all histologies according to the new FIGO classification and calculated outcome parameters according to the new stage. Results: Out of 265 patients, 146 (55%) patients were reclassified into a higher FIGO stage. Most changes appeared within stage Ib and from any stage to stage IIIc1. Kaplan Meier curves for new stages showed a significant difference for stages I vs. II vs. III (log rank test, p < 0.001). Overall, patients that were upstaged had a significant worse PFS (p = 0.012) and OS (p = 0.008) than patients whose stage did not change. Similar observations were made within sub-stages, when node-positive Ib or IIb tumors were upstaged to IIIc tumors. Conclusions: The new FIGO classification for cervical cancer reflects the strong impact of lymph node metastases on survival and is a clear improvement compared to the old FIGO classification with regard to risk stratification.
Trends in opioid use in patients undergoing primary surgery for cervical cancer.
Authors: Tucker Katherine , Farnan Laura , Bensen Jeannette T , Doherty Irene , Gehrig Paola A.
Published: May 2019

e17014

Background: In response to the opioid epidemic, restrictions on prescribing opioids for pain management may result in unintended consequences for patients with cancer-related pain. Factors that place women at higher risk for opioid misuse include age, insurance status, tobacco use and a diagnosis of cervical cancer. Our objective was to describe describe patterns of opioid use and prescribing practices over time. Methods: We performed a retrospective study of patients diagnosed with cervix cancer enrolled in our institution’s Health Registry/Cancer Survivorship Cohort from 5/2010-3/2017. The dataset included demographics, clinicopathologic data, reported opioid use (prior, during and after treatment) and prescription history from the EMR after IRB approval. This preliminary analysis included frequencies, cross-tabulations, and measures of distributional characteristics. Results: Of the 122 patients identified, 94 had surgery. Mean age at diagnosis was 44.7 yrs and BMI was 29.13. Eighteen (19.1%) patients had an opioid use history. Given changes in EMR documentation in 2014, 37 were excluded as assessment of opioid use and prescriptions was limited to only MD documentation. While there was no pre-defined protocol change, post-operative opioid prescribing practices changed in late 2014. From 5/2014-11/2014, 17 patients underwent surgery with 88% receiving prescriptions for 40 tablets of an opioid. From 12/2014-12/2016, 40 patients underwent surgery with 27.5% receiving prescriptions for 40 tablets of an opioid and 65% receiving 20-30 tablets. Prior to 12/2014, 1/16 patients (6.3%) required additional opioids postoperatively with no documented complication compared to 9/40 patients (22.5%) after 12/2014. In this group, most frequent prescriptions were coming from the patient’s gynecologic oncologist and/or a primary care provider. Conclusions: We saw a small increase in additional opioids after the routine number prescribed declined. However, this comprised a minority of patients. Monitoring of the opioid needs and use among women with cervix cancer will aid in the development of clinically-tailored guidelines to replace the current reactionary restrictions on treatment for all patients.
Cervical cancer outcomes after chemoradiation and brachytherapy in New York City comparing public versus private hospitals.
Authors: Berger Amnon Asher , Ishaq Omar , Curtin John Patrick , Pothuri Bhavana , Kehoe Siobhan Marie , Schiff Peter B. , Boyd Leslie R. , Lymberis Stella C.
Published: May 2019

e17018

Background: In the US, cervical cancer (CC) disproportionately impacts minorities and women with insufficient access to care. In our department, patients (pts) with advanced CC referred from a public hospital (PbH) and a private hospital (PrH) are treated with the same integrated team of physicians. We sought to determine whether referral source affects outcome post definitive chemoradiation (CRT) and brachytherapy (BT) for CC pts. Methods: An IRB approved retrospective review was conducted for pts diagnosed with CC and treated with definitive CRT. All pts were treated with external beam RT and chemotherapy followed by intracavitary BT boost (median 7 Gy x 4 fractions) delivered via two insertions of intracavitary BT two weeks apart with image-guided CT/MR delineation. Disease free survival (DFS) and overall survival (OS) were analyzed with the Kaplan-Meier method. Multivariate Cox hazards analysis was run to identify the effects of covariates, using R v3.5.1. Results: Between 7/2009 and 9/2017, 106 pts were diagnosed with FIGO stage IA(1), IB(22), IIA(10), IIB(46), IIIA(3), IIIB(24) and IVA(2) CC. 81 (76.4%) pts were diagnosed and received chemotherapy and operative insertion at PbH, 25 (23.6%) at PrH. Median age was 54 years (y), range (28-83). At median follow-up of 32.2 months (3.8-110.2), local control was 82%. 5-y DFS and OS was 62.4% and 84.2%. 19.8% pts were diagnosed at age 65 or greater. PbH pts were diagnosed at a younger median age of 52.4y (28.1-77.7) compared to 59.8y (30-83) at PrH (P = 0.03). PbH vs PrH pts were more likely to present at earlier stages I/II (79% vs 56%), than stages III/IV (21% vs 44%), p = 0.04 and have better outcomes; PbH vs PrH DFS was 65.0% vs 54.5% (P = 0.1), while OS was 89.3% vs 54.9% (P = 0.01). In Cox multivariate analysis, only stage at diagnosis was a significant independent predictor of survival (P = 0.006). Conclusions: Our data suggests that patients referred from a public hospital do not have worse outcomes when treated by a centralized multidisciplinary team. PrH pts presented at older age, more advanced stage and had worse OS than PbH pts. Twenty percent of pts diagnosed with advanced CC were above age 65, highlighting the need for continued screening.
Cervical carcinomas that overexpress human trophoblast cell-surface marker (Trop-2) are highly sensitive to the antibody-drug conjugate sacituzumab govitecan.
Authors: Zeybek Burak , Manzano Aranzazu , Bianchi Anna , Bonazzoli Elena , Buza Natalia , Lopez Salvatore , Perrone Emanuele , Manara Paula , Bellone Stefania , Zammataro Luca , Santin Alessandro
Published: May 2019

e17028

Background: Recurrent disseminated cervical cancer is a discouraging clinical entity with 1-year survival rates between 10-15%, and development of novel, effective treatments remains an unmet medical need. We investigated the preclinical efficacy of IMMU-132 (sacituzumab govitecan), an antibody-drug conjugate (ADC) comprised of a humanized anti-trophoblast-cell-surface-antigen (Trop-2) antibody (hRS7), conjugated with a hydrolysable linker to the active metabolite of irinotecan (SN-38), against Trop-2 positive primary cervical cancer cell lines and mouse xenografts. Methods: Trop-2 expression was evaluated in 151 cervical tumors and 5 primary tumor cell lines by immunohistochemistry, real-time polymerase chain reaction (RT-PCR) and flow cytometry. Cervical cancer cell viability against IMMU-132, non-targeting control ADC, and naked antibody (hRS7 IgG) was evaluated using flow-cytometry-based assays after 48-72 hours of incubation at a concentration of 0.05, 0.5, 1, 2, 4, and 10 nM of each agent. In vivo antitumor activity was tested in xenograft models with 3+ Trop-2 expression. Results: Out of 151 cervical tumors, 123 were squamous cell carcinoma (SCC), 26 were adenosquamous/adenocarcinoma, 1 was neuroendocrine carcinoma, and 1 was clear cell carcinoma. Strong diffuse staining was seen in 61% (75/123) of SCCs, and 92% (24/26) of adenocarcinoma/adenosquamous cancers. The neuroendocrine carcinoma was also strongly positive, while there was no staining in the clear cell carcinoma. Four out of five (80%) primary cervical cancer cell lines evaluated overexpressed Trop-2 as determined by RT-PCR and flow cytometry. Trop-2 positive cell lines showed high sensitivity to IMMU-132 in vitro, with IC50-values in the range of 0.18 to 0.26 nM ( P= 0.02). In contrast, a Trop-2 negative cervical cell line was highly resistant to the ADC with similar IC50 for IMMU-132 and control ADC. In xenografts, twice-weekly intravenous administration of IMMU-132 for three weeks demonstrated significant tumor growth inhibition compared to controls ( P≤0.001). Overall survival was significantly increased in mice treated with IMMU-132 ( P= 0.014) when compared to naked antibody and ADC-control groups. Conclusions: Sacituzumab govitecan may represent a novel class of active drugs for cervical cancers overexpressing Trop-2. Clinical trials are warranted.
Glucocorticoid receptor expression in Müllerian carcinosarcomas.
Authors: Steiner Meghan , Veneris Jennifer Taylor , Lastra Ricardo , Weroha S. John , Hou Xiaonan , Maurer Matthew John , Heinzen Ethan P. , Oberg Ann L. , Fleming Gini F. , Conzen Suzanne D.
Published: May 2019

e17038

Background: Carcinosarcomas (CS) are aggressive gynecologic malignancies defined by a biphasic tumor histology of carcinomatous and sarcomatous components. High expression of glucocorticoid receptor (GR) is associated with aggressive tumor biology in triple-negative breast, ovarian, and endometrial cancers. GR activation results in transcriptional regulation of epithelial-mesenchymal transition (EMT) genes. Therefore, we hypothesized that the sarcomatous component of Müllerian CS may be associated with relatively higher GR expression compared to the carcinomatous portion. Methods: Müllerian CSs from the University of Chicago tissue bank diagnosed from 5/19/2009  8/25/2014 were identified and pathology confirmed (RL). In addition, we evaluated GR expression in a mouse PDX CS model. Immunohistochemical expression of nuclear estrogen (ER), progesterone (PR), androgen (AR), and GR was quantified using the H-score. Scores between the sarcomatous and carcinomatous components were compared using a paired t-test. Results: Mean GR H-score was relatively higher in the sarcomatous vs carcinomatous component, overall (144.44 vs 38.89, P = 0.0014). Mean H-score also differed between sarcomatous and carcinomatous components for ER (3.06 vs 63.06, P = 0.016), PR (1.67 vs 47.22, P = 0.004), and AR (0 vs 2.78, P = 0.056). The significantly higher sarcomatous GR expression was replicated in IHC evaluation of the mouse PDX model. Conclusions: GR expression is significantly higher in the sarcomatous than the carcinomatous component of Müllerian CS, while ER, PR, and AR expression is significantly lower. Recent data suggest that an EMT gene signature is more prominently expressed in the sarcomatous versus carcinomatous component. We hypothesize that GR expression and activity may mediate EMT gene expression and represent a therapeutic target for CS. [Table: see text]
Selective and nonselective GR antagonists in combination with chemotherapy in ovarian cancer PDX models.
Authors: Veneris Jennifer Taylor , Hou Xiaonan , Weroha S. John , Heinzen Ethan P. , Maurer Matthew John , Oberg Ann L. , Conzen Suzanne D. , Fleming Gini F.
Published: May 2019

e17039

Background: Treatment strategies are needed for platinum-resistant recurrent ovarian cancer. Glucocorticoid receptor (GR) is associated with poor prognosis in ovarian cancer. GR signaling inhibits chemotherapy-induced cell death via transcriptional regulation of anti-apoptotic proteins. Non-selective (mifepristone) and selective GR antagonists (Relacorilant, Corcept Therapeutics) are under clinical development (eg. NCT02046421, NCT03776812). We hypothesized that GR antagonism would improve chemotherapy sensitivity in ovarian cancer patient-derived xenograft (PDX) models. Methods: Five PDX models were selected based on GR expression above median RNA seq levels. Tissues were transplanted into 300 female SCID-Bg mice at the Mayo Clinic. Once tumor diameter reached 0.2 cm, mice were randomized into treatment arms (2-25 mice per arm) and treated intraperitoneal (i.p): control (9% saline, CTL) on day 0 (D0), 1, 7, 8, 14, 15, 21, 22; mifepristone (MIF), 15 mg/kg D0, 1, 7, 8, 14, 15, 21, 22; relacorilant (134), 20 mg/kg D0, 1, 7, 8, 14, 15, 21, 22; carboplatin (CBDCA) at the MTD, 51 mg/kg D1, 8, 15, 22; CBDCA + MIF; CBDCA + 134. Tumor area was measured by ultrasound weekly (D0-D28), and the ratio calculated relative to D0. Tumor growth curves were compared between arms for each PDX via a linear mixed effects regression test of coincident curves. Time to progression was also evaluated and will be presented. Results: In 1/5 models (PH160), CBDCA + MIF significantly suppressed tumor growth compared to CBDCA alone (p < 0.05, Table 1). Addition of 134 to CBDCA did not suppress tumor growth compared to CBDCA alone in any model. In the 2 models with no difference of CBDCA versus CTL (PH160, PH454), addition of a GR antagonist to CBDCA suppressed tumor growth versus CTL. Conclusions: Addition of GR antagonists can improve response to chemotherapy. Work is ongoing to identify the GR transcriptional network, tumor, and host characteristics which predict responses to GR antagonists. [Table: see text]
Neoadjuvant chemotherapy in advanced epithelial ovarian cancer: An institutional experience.
Authors: Jain Kavitha , Chaturvedi Arun , Misra Sanjeev , Kumar Vijay , Gupta Sameer , Lakshmanan Manikandan , Garg Sudeep
Published: May 2019

e17044

Background: Epithelial ovarian cancer is the second most common gynecological malignancy among Indian women. Primary debulking surgery remains the standard of care in advanced operable ovarian cancer patients, but is associated with morbidity. Neoadjuvant chemotherapy followed by delayed primary cytoreductive surgery maybe a better treatment strategy in advanced ovarian cancer. We present our experience of neoadjuvant chemotherapy in advanced ovarian cancer with special emphasis on treatment outcomes. Methods: A retrospective analysis of advanced epithelial ovarian carcinoma (Stage IIIc and IV) patients treated at the Department of Surgical Oncology at King George’s Medical University, Lucknow between 2012 and 2017 was done. Results: A total of 151 patients with advanced ovarian carcinoma were treated during this period. Median age at diagnosis was 46 years. Among these patients, 137 underwent surgery, of which 59.1% were optimally cytoreduced. Papillary serous adenocarcinoma was the most common histological subtype (76.1%). Recurrence was seen in 79.3% patients, with a median time to recurrence 17 months (range 6.5 - 39 months). They were managed with second line chemotherapy and surgery. Median overall survival in this study for optimally cytoreduced stage III patients was 39 months and 18 months for optimally cytoreduced stage IV patients. Median progression free survival for stage III was 12 months and stage IV was 6 months. Conclusions: Neoadjuvant chemotherapy facilitates surgery in advanced ovarian cancer and helps in assessing chemotherapy responsiveness. It provides an opportunity to modify systemic treatment if there no response to therapy or disease progression.