bluuebunny/crossref_metadata_2025 huggingface dataset:
AXIN2 and prostate cancer recurrence after radical prostatectomy.
Authors: Hu Brian Robin , Fairey Adrian Stuart , Yang Dongyun , Li Meng , Groshen Susan G. , Stephens Craig , Quinn David I. , Kim Philip , Virk Navneet , Wang Lina , Martin Sue Ellen , Gill Inderbir S , Goldkorn Amir
Published: February 2017

145

Background: Sub-populations of cancer stem cells (CSC) present in prostate cancer (PCa) and other malignancies have been associated with more aggressive characteristics. We investigated whether tumor expression of genes putatively linked to the CSC phenotype is associated with PCa recurrence. Methods: Expression of mRNA from radical prostatectomy specimens in 241 patients (cases 147, control 94) was analyzed by RT-PCR. Univariate analysis and recursive partitioning measured associations between expression of 12 CSC genes and PCa recurrence. Bootstrap internal validation was used to confirm associations. External validation was performed in-silico using the Oncomine microarray data compendium, analyzing differential gene expression in relevant studies. Results: Four genes (AXIN2, p<0.001; CD44A, p=0.036; OCT 4, p=0.017; TACSTD2, p=0.008) were differentially expressed in PCa recurrence. Recursive partitioning analysis identified three genes jointly predictive of disease recurrence (AXIN2, NANOG, CTNNB1; OR 5.1 to 8.5). Bootstrap internal validation identified low AXIN2 expression as the CSC gene most predictive of PCa recurrence. In-silico external validation was performed for AXIN2, identifying one closely-matched cohort. Primary data analysis confirmed the association between low AXIN2 expression with PCa recurrence after prostatectomy (p=0.003). Additional queries of the Oncomine platform correlated low AXIN2 expression to worse disease in PCa: metastatic versus primary (six of seven studies, p=2.6x10-9 to 0.07) and locally-advanced versus low grade (four of seven studies, p= 0.007 to 0.037). Lastly, low AXIN2 expression was associated with worse disease in multiple other cancers (10 of 10 studies, p=7.7x10-6 to 0.007). Conclusions: Low AXIN2 expression was internally and externally validated as predictive of PCa recurrence after radical prostatectomy. In-silico analysis demonstrates low AXIN2 expression is associated with more aggressive disease and worse clinical outcomes in prostate and other cancer cohorts. This novel finding delineates a link between the CSC phenotype and disease prognosis, suggesting AXIN2’s role as a potential biomarker.
Impact of tertiary Gleason pattern 5 on prostate cancer aggressiveness: Lessons from a contemporary single institution radical prostatectomy series.
Authors: Koloff Zachary Benjamin , Hamstra Daniel A. , Wei John Thomas , Montgomery Jeffrey Scott , Tomlins Scott A. , Wu Angela J. , Morgan Todd Matthew , Siddiqui Javed , Paich Kellie , Chinnaiyan Arul M. , Feng Felix Yi-Chung , Weizer Alon Z. , Hollenbeck Brent K. , Kunju Lakshmi Priya , Miller David Christopher , Palapattu Ganesh S. , Mehra Rohit
Published: February 2017

15

Background: This retrospective study was conducted to better evaluate the impact of tertiary Gleason pattern 5 (TP5) on tumor pathological features and biochemical recurrence following radical prostatectomy (RP). Methods: We retrospectively reviewed 1,965 patients who underwent RP for clinically localized prostate cancer; TP5 was reported in 159 cases (8.1%). Men with Gleason score (GS) 7 and GS 8 disease were divided into two subgroups, with and without TP5, and histopathologic features were compared. Multivariate analyses and Kaplan-Meier curves were conducted to assess the impact on TP5 on biochemical-free survival (BFS). Results: Tumors possessing GS 3 + 4 with TP5 were significantly more likely to exhibit extraprostatic extension (EPE) and have a larger tumor diameter (TD) than GS 3 + 4 alone. GS 3 + 4 with TP5 was also associated with positive surgical margins (SM), seminal vesicle involvement (SVI), and higher pre-operative PSA values, but without statistical significance. GS 4 + 3 with TP5 more commonly presented with EPE, positive SM, SVI, and greater TD and PSA than GS 4 + 3 alone, with significance. In multivariate analysis, TP5 was shown to be an independent risk factor for PSA recurrence (Table). Additionally, GS 4 + 3 with TP5 was associated with shorter time to recurrence versus GS 4 + 3 alone. Conclusions: Our results emphasize the importance of high-grade tertiary patterns and suggest that criteria for tertiary pattern reporting in prostate cancer should be standardized. In addition, further studies are needed to evaluate the role of tertiary patterns in prognostic models. [Table: see text]
Effect of a genomic classifier on adjuvant radiation recommendations after prostate cancer surgery.
Authors: Badani Ketan K. , Thompson Darby J. S. , Buerki Christine , Singh Amar
Published: February 2017

151

Background: Clinical guidelines recommend adjuvant radiation therapy (ART) after radical prostatectomy in men with adverse pathological features. Practice patterns vary on use of ART. This prospective, multi-center study examines the effect of a genomic classifier (GC) on ART recommendations post-prostatectomy. Methods: A prospective, pre-post tumor-board–like survey was conducted to assess urologists’ treatment recommendations for ART as part of a clinical utility study; results are from a pre-specified interim analysis of 11 unique de-identified cases with adverse pathology. All case histories were based on patients treated by at least one of the urologists participating in the study. Patient age, pathological features, and preoperative prostate-specific antigen were presented to the respondents. Presentation of cases was randomized to minimize recall bias. For each case history, physician respondents first were asked to render an ART recommendation without knowledge of the GC findings (pre-GC); they were then asked to render an ART recommendation after GC findings were provided for the same cases (post-GC). Recommendations were made without knowledge of others’ responses. Results: Twelve urologists at 11 US institutions provided 132 adjuvant therapy recommendations. Pre-GC, ART was recommended in 56 (42%) cases. Thirty three percent (95% CI: 25-41%) of recommendations changed following review of GC results. Among pre-GC recommendations for ART, 39% (95% CI: 27-53%; n=22) changed to observation and among pre-GC recommendations for observation, 8% (95% CI: 3%-17%; n=5) changed to ART. Compared to observation, ART was 11.8 times (odds ratio 95% CI: 2.9 - 46.3) more likely to be recommended for cases with high risk GC scores. Adjuvant therapy recommendations were more strongly influenced by GC score (p=0.0006) than any clinical variable (all p>0.33) when both informed recommendations. Conclusions: Additional knowledge of the tumor’s genomic characteristics, as assessed by GC, results in a statistically significant and clinically meaningful change in treatment recommendations in patients indicated for adjuvant radiation therapy by current clinical guidelines.
Proton therapy for prostate cancer: An analysis of rectal toxicity outcomes at University of Florida Proton Therapy Institute (UFPTI).
Authors: Colaco Rovel J. , Hoppe Bradford S. , Henderson Randal H. , Nichols Romaine Charles , Morris Christopher G. , Bryant Curtis , Li Zuofeng , Mendenhall William M. , Mendenhall Nancy Price
Published: February 2017

161

Background: We aimed to characterize gastrointestinal effects of proton therapy (PT) in patients treated for prostate cancer, identify factors associated with rectal bleeding (RB), and compare RB between patients on investigational protocols (IP) versus outcome tracking protocols (OTP). Methods: 1,290 patients treated consecutively with PT between August 2006 and June 2010 were studied. Pre-existing potential risk factors for RB (hemorrhoids, diabetes, aspirin, other anticoagulants) were recorded. Common terminology criteria for adverse events (CTCAE version 4.0) were used to grade toxicity. Median follow up was 3.5 years. Results: The majority (94.6%) of Grade 2 or higher gastrointestinal toxicity (GR2+) events after PT were rectal bleeding. GR1 RB occurred in 390 (30.2%) of patients, including those requiring no prescription intervention (82.6%) and those placed on a vitamin A regimen (16.3%). GR2 RB occurred in 14.7% of patients, including patients requiring prescription rectal suppositories (9.5%), cautery (4.9%), or hyperbaric oxygen (0.3%). Grade 3 (GR3) occurred in 0.8% of patients, including those requiring transfusion (0.6%) or colostomy (0.1%). Multivariate analyses showed that pretreatment daily aspirin (p=0.03), other anticoagulation (p=0.001), and the volume of rectum exposed to radiation dose levels (V70) (<.0001) were associated with an increased risk of Gr2+RB. Patients treated on investigational protocols (IP) had similar toxicity rates as those treated on an outcomes tracking protocol (OTP). Reduced rectal toxicity was noted in latter years of the study, which correlated with changes in treatment technique, pretreatment evaluation, and post-treatment supportive care regimens. Conclusions: PT was associated with low rates of GI toxicity, the most common toxicity being transient RB. GR2+RB is strongly associated with patient use of aspirin, other anti-coagulation and radiation dose volume parameters.
EpCAM expression in lymph node and bone metastases of prostate carcinoma: A pilot study.
Authors: Hoving Hilde , Campos Karen , De Jong Igle
Published: February 2017

165

Background: Correct staging of prostate carcinoma has huge treatment implications since metastasized prostate carcinoma cannot be treated curatively. Nowadays, skeletal scintigraphy is the mainstay for the assessment for bone metastases despite its poor sensitivity. Lymph node metastases can be diagnosed accurately with Computed Tomography. However, the gold standard is a pelvic lymph node dissection. A non-invasive diagnostic modality, that can assess both lymph node and bone metastases simultaneously, is preferred. In this retrospective pilot study expression of epithelial cell adhesion molecule (EpCAM) was investigated in lymph node metastases, normal lymph nodes, and bone metastases of prostate carcinoma. Furthermore, EpCAM expression was correlated to clinicopathological parameters. Methods: Lymph node metastases (n = 22) and matched normal lymph nodes (n = 22) were available in 17 patients who underwent a pelvic lymph node dissection because of suspicion of nodal involvement on CT. Bone metastases (n = 24) were available in 24 patients who underwent surgery to confirm the disease or to treat skeletal related events. Immunohistochemistry was performed to determine EpCAM expression. Two researchers, blinded to clinical data, scored the immunoreactivity according to Allred. Sensitivity and specificity of EpCAM immunoreactivity in lymph node and bone metastases was calculated. Fisher’s Exact Test was used to correlate EpCAM expression to the clinicopathological parameters Gleason score, prior radiotherapy and prior hormonal treatment. Results: Sensitivity and specificity of EpCAM expression was 100% in lymph nodes. In bone metastases sensitivity was 92%. No correlation between EpCAM expression and clinicopathological parameters was found. Conclusions: Molecular imaging of EpCAM is promising for prostate carcinoma staging, due to the high sensitivity and specificity in lymph node metastases and the high sensitivity in bone metastases. Even in poorly differentiated metastases and after hormonal treatment and radiotherapy, EpCAM was expressed.
Perceptions of radiation oncologists and urologists on the type of evidence that informs and changes the clinical practice of prostate cancer.
Authors: Delpe Sophia D , Shah Nilay , Tilburt Jon Charles , Karnes R. Jeffrey , Nguyen Paul Linh , Shuch Brian , Gross Cary , Schulam Peter , Yu James B. , Ziegenfuss Jeanette , Kim Simon
Published: February 2017

167

Background: Physicians have a variety of resources available about the treatment of localized prostate cancer. Yet, it is largely unknown what resources and evidence radiation oncologists and urologists commonly use to inform patients and possibly alter clinical practice. In this national survey study, we assessed the types of resources prostate cancer specialists’ use and the level of evidence needed to change treatment recommendations in localized prostate cancer. Methods: From a random sample, 1,422 physicians were sent a mail survey assessing what type of information was used to guide prostate cancer treatment. The survey also queried what level of evidence could alter recommendations. Multivariable logistic regression models were used to identify for differences in physician characteristics for each outcome. Results: Survey response rates were similar for radiation oncologists and urologists (44% vs. 46%; p=0.46). Specialty-specific journals represented the most commonly used resource to inform the clinical practice for radiation oncologists (65%) and urologists (70%). Relative to radiation oncologists, urologists were less likely to utilize medical journals (25% vs. 38.7%, OR: 0.50; p=0.01), cancer journals (21.7% vs. 50.8%, OR: 0.50; p<0.001), but more likely to rely on clinical guidelines (46.3% vs. 37.7%,OR: 1.6; p=0.006). Radiation oncologists and urologists both viewed RCT’s as the most likely source of evidence needed to change treatment recommendations (85% vs. 77%). Conclusions: Both specialties most commonly rely on their specialty-specific journals to inform their clinical practice and view RCT’s as the level of evidence needed to change treatment recommendations for localized prostate cancer. Radiation oncologists embraced greater diversity in literature, while urologists were more likely to use clinical guidelines. Utilizing this information may overcome barriers to the dissemination and adoption of new treatment paradigms for localized prostate cancer.
A population-based study of factors associated with post-prostatectomy radiation therapy utilization.
Authors: Maurice Matthew J. , Zhu Hui , Abouassaly Robert
Published: February 2017

182

Background: Based on level one evidence, adjuvant radiation therapy (aRT) improves cancer control in post-prostatectomy patients with adverse pathologic features. We sought to evaluate its utilization and to identify factors affecting of its use. Methods: Using the National Cancer Database, a joint project of the Commission on Cancer of the American College of Surgeons and the American Cancer Society, we identified men diagnosed with prostate cancer between 2004 and 2011 who were found to have pT3 disease or pT2 disease with positive margins following prostatectomy. We defined aRT as radiation to the prostate and/or pelvis 6 months or less after prostatectomy. We then used univariate and multivariate logistic regression models to assess potential patient and provider predictors of aRT use. Results: We evaluated 103,092 men who had either pT3 disease (81%) or pT2 with positive margins (19%). Of these, we identified 10,043 men (9.7%) who received aRT. Since 2004, there has been a steady decline in aRT usage with time (range, 11.5% to 7.8%). Compared to 2004, patients diagnosed in 2011 were significantly less likely to receive aRT (odds ratio [OR] 0.78, confidence interval [CI] 0.71-0.85, p<0.0001). Higher Gleason score and T stage were strongly associated with positive aRT utilization (p<0.0001), while increasing age was associated with decreased use (p<0.0001). Another strong predictor of aRT uptake was hospital type. Compared to patients treated at community hospitals, patients treated at comprehensive cancer centers or teaching hospitals were significantly less likely to receive aRT (OR 0.63, 0.58-0.68, p<0.0001 or OR 0.42, CI 0.39-0.46, p<0.0001, respectively). Charlson score and hospital location were significantly but weakly associated with aRT. Other demographic variables were not predictive of aRT. Conclusions: Post-prostatectomy aRT use is declining despite clear proof of its benefit. Consistent with the evidence, patients with risk factors for biochemical relapse (i.e. high Gleason score or T3 disease) and younger patients, who are more likely to benefit, are receiving aRT. Surprisingly, aRT use is lower at teaching hospitals, which may reflect higher usage of salvage radiation.
Factors associated with biopsy progression on active surveillance.
Authors: Welty Christopher J , Cowan Janet E. , Nguyen Hao , Shinohara Katsuto , Perez Nannette , Greene Kirsten L , Meng Maxwell V. , Cooperberg Matthew R. , Carroll Peter
Published: February 2017

19

Background: Active surveillance (AS) is a treatment strategy for prostate cancer (CaP) involving monitoring of men diagnosed with low-risk CaP to reduce overtreatment. We report factors associated with disease progression while on AS in a large, single institution cohort. Methods: We retrospectively reviewed the data of men enrolled in the University of California at San Francisco (UCSF) AS cohort between 1990 and 2012. Strict eligibility criteria were prostate-specific antigen (PSA) less than 10ng/ml, Stage less than cT3, Gleason grade 6 or less, 33% or less of biopsy cores positive, and 50% or less of any single biopsy core positive. Men who did not meet these criteria but elected AS were followed as well. Surveillance consisted of quarterly PSA testing, reimaging with TRUS at provider discretion, and annual prostate biopsy. Biopsy progression was defined as upgrade to at least Gleason 7 or increase in volume more than 33% cores. Factors associated with progression while on active surveillance were determined through multivariate Cox proportional hazards regression. Results: Of 1,009 men enrolled in AS at UCSF, 758 men have consented to participate in research to date and have been followed on AS for a median of 57 months. Of these, 518 (68%) met strict criteria for AS while 240 (32%) did not. The median number of repeat biopsies was three (IQR 2-4). At 5 years after diagnosis, 53% were progression-free and 40% of patients received local therapy. Overall survival was 94% among those not AS eligible and 100% among those AS eligible at 5 years. There were no CaP-related deaths. In multivariate analysis, only PSA density (PSAD) and later year of diagnosis were positively associated with the risk of both biopsy progression (HR 1.62, 95% CI 1.36-1.92, p<0.01 and HR 1.17, 95% CI 1.10-1.25, p<0.01, respectively) and receiving treatment (HR 1.39, 95% CI 1.20-1.60, p<0.01 and HR 1.18, 95% CI 1.14-1.23, p<0.01, respectively). White race was associated with receiving treatment (HR 1.92, 95% CI 1.35-2.74, p<0.01) but not with disease progression. Conclusions: The majority of men who enrolled in this active surveillance cohort remained on AS after a median follow up of 57 months. While higher PSAD was associated with biopsy progression, additional predictive tools would improve selection and counseling of men for AS.
Bother following stereotactic body radiation therapy for clinically localized prostate cancer.
Authors: Bhattasali Onita , Chen Leonard , Park Jee-Won , Kim Joy S. , Yung Thomas M. , Collins Brian Timothy , Suy Simeng , Lynch John , Dritschilo Anatoly , Collins Sean P.
Published: February 2017

195

Background: Stereotactic body radiation therapy (SBRT) delivers high doses of radiation while minimizing radiation to adjacent normal tissues. Large fraction sizes may increase the risk of functional decrements. However, treatment-related bother may be more important to a patient than treatment-related dysfunction. Methods: Between August 2007 and July 2011, 228 hormone-naïve patients with clinically localized prostate cancer were treated with 35-36.25 Gy SBRT delivered using the CyberKnife Radiosurgical System (Accuray) in five fractions. Patients completed the validated Expanded Prostate Cancer Index Composite (EPIC)-26 questionnaire at baseline, one month post-treatment, every three months the first year, then every six months. EPIC scores for bother range from 0 to 100 with lower values representing increased interference or annoyance caused by limitations in function. Results: Two hundred twenty eight patients at a median age of 69 (range, age 44 to 90) received SBRT with a minimum follow-up of 24 months. Urinary bother increased transiently first at one month and again at 12 months before returning to pre-treatment scores at two years: 80.2 (baseline); 68.2 (one month); 79.8 (three months); 78.3 (six months); 74.5 (nine months); 71.1 (12 months); 75.8 (18 months); 78.3 (24 months). Bowel bother followed a similar pattern but with a more protracted late-stage decline: 91.4 (baseline); 76.0 (one month); 87.8 (three months); 88.4 (six months); 85.8 (nine months); 85.7 (12 months); 87.8 (18 months); 90.1 (24 months). Sexual bother progressively worsened over two years: 65.9 (baseline); 64.8 (three months); 63.0 (six months); 63.2 (12 months); 59.0 (18 months); 58.4 (24 months). Conclusions: SBRT for clinically localized prostate cancer was well tolerated. Treatment-related bother was comparable to conventionally fractionated radiation therapy and brachytherapy. Transient late increases in urinary and bowel bother were observed at one year. Sexual bother steadily increased during the first two years following treatment.
Circadian dysrhythm and advanced prostate cancer.
Authors: Mucci Lorelei A. , Markt Sarah , Sigurdardottir Lara , Lockley Steven W. , Fall Katja , Stampfer Meir J. , Gudnason Vilmundur , Kraft Peter , Rider Jennifer R , Czeisler Charles A , Valdimarsdottir Unnur Anna
Published: February 2017

199

Background: The circadian rhythm regulates diverse biologic pathways including tumor oncogenes, metabolism, and cell proliferation. Dysregulation of the circadian rhythm arises from faulty input signals such as exposure to light at night, variability in core circadian rhythm genes, and variation in outputs that regulate circadian behavior including melatonin. There is compelling biologic rationale, but little human data, on circadian dysrhythm and advanced prostate cancer. Methods: We undertook an integrative molecular epidemiology study of circadian dysrhythm and advanced prostate cancer among men in the Icelandic AGES-Reykjavik cohort and the U.S. Health Professionals Follow-up Study, which allowed integration of questionnaire data, biorepositories, and long-term follow-up. We characterized circadian dysrhythm using complimentary approaches: information on sleep problems from questionnaires, prediagnostic melatonin (6-sulfatoxymelatonin) measured on first morning void urine samples, and genetic variation across twelve circadian clock genes. We used multivariable regression models to estimate relative risks (RR) and 95% confidence intervals (CI) of associations with advanced prostate cancer, adjusted for potential confounders. Results: Twenty percent of men reported sleep problems. Men who had trouble falling asleep (RR = 2.1; 95% CI 0.7-6.2) and staying asleep (RR=3.2, 95% CI 1.1-9.7) had an increased risk of developing advanced prostate cancer. Men with sleep problems had significantly lower melatonin levels compared to those without. Low melatonin levels were associated with a statistically significant 4-fold higher risk of advanced prostate cancer compared to those with high levels (95% CI: 1.25-10.0). Variant alleles in two SNPs in cryptochrome (CRY1), involved in generating and maintaining circadian rhythms, were significantly associated with risk of advanced prostate cancer in both cohorts, with a gene-level p-value<0.01. Conclusions: Our results suggest there are multiple nodes in the circadian rhythm that are associated with an increased risk of advanced prostate cancer. As such, there is the potential for complimentary strategies to target circadian disruption and reduce the risk of advanced prostate cancer.
Response to androgen signaling (AS)-directed therapy after treatment with abiraterone acetate (AA) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): Post hoc analysis of study COU-AA-302.
Authors: Smith Matthew R. , Matheny Shannon , Saad Fred , Rathkopf Dana E. , Mulders Peter F.A. , De Bono Johann Sebastian , Small Eric Jay , Shore Neal D. , Fizazi Karim , Kheoh Thian San , Li Jinhui , Todd Mary Beth , Griffin Thomas W. , Yu Margaret K. , Ryan Charles J.
Published: February 2017

21

Background: In study COU-AA-302 of men with mCRPC and no prior chemotherapy, AA plus prednisone (hereafter AA) significantly increased radiographic progression-free survival. There is limited information about response to subsequent AS-directed therapies following AA. In this post hoc analysis of pts who received AA during study COU-AA-302, we evaluated clinical response to subsequent AA or enzalutamide (ENZ). Methods: In COU-AA-302, 546 pts were randomized and received AA. Subsequent response and discontinuation data from 88 pts receiving AS-directed therapy after study were collected retrospectively, source verified, and entered into the database. Median time to prostate-specific antigen (PSA) progression with 95% confidence intervals was estimated using the Kaplan-Meier method. Results: As of May 2013, following AA on study, 55 pts received subsequent AA and 33 received subsequent ENZ. 69% (38/55) of pts in the AA then AA group and 67% (22/33) pts in the AA then ENZ group received intervening chemotherapy. Baseline patient characteristics were similar across both groups and to the overall COU-AA-302 population. Median (range) exposure to subsequent therapy was 4 (1-20) months for AA and 5 (1-12) months for ENZ. Response to subsequent AA or ENZ is summarized in the Table. Conclusions: In this post hoc analysis, pts previously treated with AA experienced modest clinical response on subsequent treatment with either AA or ENZ. These data support further studies of subsequent AS-targeted drugs following treatment with AA for mCRPC. Clinical trial information: NCT00887198. [Table: see text]
Whole pelvic irradiation for prostate cancer patients with a biochemical relapse following radical prostatectomy: The era of robot-assisted minimally invasive surgery.
Authors: Kim Jae-Sung , Kang Hyun-Cheol , Byun Seok-Soo , Lee Sang Eun
Published: February 2017

210

Background: We hypothesized that the addition of whole pelvic radiotherapy (WPRT) might improve biochemical outcome in salvage radiotherapy (RT) for biochemical failure (BCF), especially in patients with postoperative high-risk features after radical prostatectomy (RP) being good candidates beneficial from WPRT. Methods: From August 2004 to April 2012, 180 patients who experienced BCF after RP were treated with salvage RT. The primary end point was the biochemical relapse-free survival (bRFS) defined as no prostate-specific antigen (PSA) failure and no additional salvage treatments. Patients were stratified into theee groups; prostate bed radiotherapy (PBRT) alone (n = 52), PBRT with hormone (n = 85), and WPRT with hormone (n = 43). The effects of WPRT combined with hormone was measured in the high-risk patients defined as pN1 stage or inadequate pelvic lymph node dissection (harvested lymph nodes number of less than four). Toxicity from treatment was recorded when genitourinary or gastrointestinal (GI) events occurred. Results: The median follow-up was 43 months (8 to 103 months). The independent predictors for poor bRFS were time to PSA failure less than or equal to 1 year, PSA at salvage greater than 1 ng/mL, PSA doubling time less than 6 months, and PBRT alone group. The risk of BCF after salvage RT was significantly higher in PBRT alone group in comparison to that of WPRT with hormone group (hazard ratio [HR], 3.9; 95% CI, 1.8-8.3, p <0.001), but the outcomes of PBRT with hormone was not statistically different from that of WPRT with hormone (p = 0.67). The advantage of WPRT and hormone over PBRT alone was only observed in the high-risk patients (HR, 5.7; 95% CI, 1.8-17.7, p = 0.003), and not in other patients (HR, 3.2; 95% CI, 0.7-14.9. p = 0.14). Patient treated with WPRT had more greater than or equal to grade 2 late GI toxicity than those having PBRT (17% vs. 5%, p= 0.01). Conclusions: Patients with postoperative high risk features could benefit from WPRT and hormone therapy for postoperative BCF. The additional toxicity by WPRT and long-term outcomes warrant further investigations.
Spironolactone: A selective androgen receptor modulator in castration-resistant prostate cancer.
Authors: Barthelemy Philippe , Erdmann Eva , Duclos Brigitte , Bergerat Jean Pierre , Kurtz Jean-Emmanuel , Ceraline Jocelyn
Published: February 2017

212

Background: Spironolactone is an effective drug to treat arterial hypertension as well as fluid retention and hypokalemia. Recently, some data suggested that spironolactone might induce progression in castration-resistant prostate cancer (CRPC) patients treated by abiraterone acetate, a recently approved selective CYP17 inhibitor. Nevertheless, no biological data are available to explain these clinical observations. The purpose of this study was to identify the potential underlying molecular mechanism. Methods: Effect of spironolactone with or without Abiraterone acetate (AA) on androgen receptor (AR) was assessed on LNCaP cells in this study. We performed a yeast-based functional assay with different levels of spironolactone with and without AA. The nuclear localization and activation of androgen receptor (AR) were detected by immunofluorescence and luciferase assays. Results: Results from the yeast-based functional assay show that the wild type androgen receptor is activated by high concentrations of spironolactone in an androgen-depleted environment. Moreover, spironolactone-induced AR transcriptional activity is downregulated by different AR antagonists as well as high concentrations of AA. These results suggest that spironolactone is possibly a potential AR modulator. Luciferase reporter assays showed that AR transcriptional activity in LNCaP cells was upregulated by spironolactone as well. Finally, AR immunoreactivity was almost nuclear in spironolactone-exposed cells. Taken together, these results suggest that spironolactone is a selective androgen receptor modulator. Conclusions: Spironolactone is a selective androgen receptor modulator and should be used with caution in routine practice in patient with metastatic prostate cancer treated by hormonotherapy especially AA.
The PROFILE feasibility study: Genetic prostate cancer risk stratification for targeted screening.
Authors: Mikropoulos Christos , Castro Elena , Bancroft Elizabeth , Page Elizabeth , Taylor Natalie , Dadaev Tokhir , Kote-Jarai Zsofia , Antoniou Antonis C. , DeSouza Nandita , Keating Diana , Saunders Edward , Easton Doug , Borley Nigel , Ahmed Mahbubl , Lee Andrew , Eeles Ros A.
Published: February 2017

22

Background: Prostate cancer (PC) screening is controversial and a better assessment of individualized PC risk is needed. Several single nucleotide polymorphisms (SNPs) conferring a cumulative risk of PC have been identified. We have explored the potential role of genetic markers for targeted screening in a population with increased risk of PC due to family history (FH). Methods: PROFILE was developed as a pilot study to determine the feasibility of targeted PC screening using prostatic biopsy (PB) and its association with specific genetic profiles in men with FH. We also evaluated the role of PSA and Diffusion Weighted MRI (DW-MRI) as screening tools. One hundred sixteen men age 40 to 69 with FH of PC were enrolled between October 2009 and December 2012. Cumulative SNP risk scores were calculated by summing 59 risk alleles for each locus using the weighted effect (log-additive model). DW-MRI was performed in 50 patients. Participants were asked to undergo a 10 core PB regardless of baseline PSA. Results: Median age 53 (40 to 69) and median PSA was 1.15. One hundred and two men accepted to undergo a PB as primary PC screening. Twenty-three tumours were found (22.5% of biopsies) as well as seven men diagnosed with atypical small acinar proliferation (ASAP) (6.8%) and eight men with high-grade prostatic intraepithelial neoplasia (HG-PIN) (7.8%). In total 37.1% received an abnormal result. Out of the diagnosed PC 41% were intermediate or high risk and requiring treatment, which compares with 24% in general population screening. The predictive performance of DW-MRI, PSA, genetic model and genetic model plus PSA measured by AUC were: 0.85, 0.73, 0.57 and 0.74, respectively. The genetic model performed best in men with a normal PSA of <3(AUC 0.63). Analyses of a 78 SNP profile from the recent COGS results are underway. Conclusions: Ourresults indicate that PB is acceptable for PC screening in men with FH of PC. The significant AUC for DW-MRI would warrant a larger study. The incidence of ASAP is higher in this group than the general population.The SNP risk score was more predictive in men with PSA less than three where PB would not normally be undertaken, therefore an expanded study to investigate the role of genetic profiling in directing PB in PC screening is indicated.
Exploration of alternative digit ratios as a predictor of prostate cancer aggressiveness.
Authors: Stolten Michael , Ledet Elisa , Dotiwala Aryeneesh , Luk Eric , Sartor A. Oliver , Wood Byron
Published: February 2017

231

Background: During gestation, development of the prostate is dependent on a functional androgen receptor and the presence of dihydrotestosterone. Prenatal androgen exposure has been correlated with a range of diseases including prostate cancer (PCa). Historically, the ratio of the second to the fourth digit (2D:4D) has been linked to prenatal androgen levels; however, the use of alternate finger ratios have been shown to be a greater indicator of prenatal androgen exposure compared to the traditional 2D:4D ratio. Studies have shown that the distal fingertip extent of the second digit (2T:2D) was also associated with prenatal androgens. This study aims to use alternative digit ratio measurements to determine aggressiveness of PCa. Our hypothesis is that alternative digit ratios are more sensitive to prenatal androgen levels, and a better predictor of disease than the traditional 2D:4D ratio. Methods: Digital measurements were made from hand scans of PCa patients. All fingers on the right hand were measured from the basal crease to the fingertip as well as the distal fingertip extent of the second digit. Race, family history (FH) (first degree relatives with PCa), and age at diagnosis were recorded. These clinical covariates were then compared to the finger length ratios which were dichotomized based on the median values and analyzed for possible correlations. Results: Hand measurements were taken on 350 Caucasian (CA) and 100 African American (AA) PCa patients. AA men were more likely to have a smaller 2D:3D (P < 0.0001) and 2D:4D digit ratio (P < 0.0001), and larger 3D:5D (P = 0.0002) and 4D:5D (P = 0.0125) when compared to CA men. AA men with a smaller 2T:2D ratio were younger at the time of diagnosis (P = 0.0446). Additionally, AA men with a larger 2D:5D ratio were more likely to have a FH of PCa (P= 0.0238). Conclusions: Alternative finger length ratios show strong differences between AA and CA men. In AA men, alternative digit ratios are associated with age of PCa diagnosis and FH of PCa. These hypothesis generating results require validation in a larger cohort, but may provide insight to the underlying racial disparity observed in PCa. Finger length may represent a unique, non-invasive predictor of PCa, specifically age of onset and FH in AA men.
Compliance of subjects using electronic patient-reported outcomes (ePRO) in multinational prostate trials.
Authors: Dallabrida Susan M.
Published: February 2017

232

Background: Patient Reported Outcomes (PRO) and electronic PRO (ePRO) are increasingly becoming an important aspect of cancer clinical trials and patient care, especially with regard to measuring drug efficacy, patient quality of life and drug safety. Subject compliance with completion of PRO/ePRO assessments is an important component for obtaining accurate and high-quality data when conducting clinical trials. It has been hypothesized that patient health status, length of time in a trial and country of origin, may affect compliance. Methods: To address this hypothesis, an operational analysis was conducted to assess oncology subject completion compliance of PRO reports using an electronic tablet to determine its suitability and performance in use. Toward this objective, the compliance of prostate cancer patients in completing three electronic questionnaires that were administered at clinic visits was evaluated. Subjects were asked to complete the Brief Pain Inventory – Short Form (BPI-SF) at every clinic visit. At some clinic visits, subjects were asked to additionally complete the Functional Assessment of Cancer Therapy – Prostate (FACT-P) and the Euro Quality of Life 5 Dimensions (EQ-5D). Questionnaires were completed electronically on the tablet. Percent completion was calculated as the number of questionnaires completed divided by the number of questionnaires expected, based on attended clinic visits compiled for this review and the administration schedule for the questionnaires. Results: This review draws on the experience of over 1,000 subjects from 21 countries, and describes the individual and overall compliance with the expected questionnaire completion, the variance between subsequent visits, and compliance by country. Conclusions: The collection of ePRO using a clinic-based tablet yielded a highly complete data set in prostate cancer subjects demonstrating that this is an effective and feasible approach for recording symptoms and quality of life assessments.
Meaningful survival after cabazitaxel in patients with metastatic castration-resistant prostate cancer (mCRPC): The Spanish experience.
Authors: Gonzalez Maeso Iria , Castellano Daniel E. , Campos Balea Begona , Esteban Emilio , Pérez Arnillas Quionia , Villalobos Leon M. Laura , Munarriz Javier , Rubio Gustavo , Cumplido Buron Jose David , Garcia Sanchez Jose , Martin Almudena , Garcia-Bueno Jose Maria , Reyes Garcia Ana , Perez-Valderrama Begoña , Anido Herranz Urbano , Bellmunt Joaquim
Published: February 2017

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Background: New emerging therapies for metastatic castration resistant prostate cancer (mCRPC), such as cabazitaxel (CBZ), have prompted the need to identify appropriate patients (pts) for each specific treatment. We describe preliminary data on the experience with CBZ in patients (pts) with mCRPC in Spain. Methods: Medical records from docetaxel-resistant mCRPC pts receiving CBZ at 15 centers in Spain were reviewed retrospectively. Baseline characteristics, PSA response, overall survival (OS), radiographic progression-free survival (rPFS), and toxicity were collected. Results: Data from 79 consecutive pts (median age 70) were reviewed: Eastern Cooperative Oncology Group (ECOG) zero to one (87.3%), Gleason score of 7 to 10 (87.1%), visceral involvement (24.1%), pain (74.7%), and radiological progression (68.4%) at CBZ initiation. Median duration of response to first-line androgen deprivation therapy was 20.8 months (mo). Most pts received less than or equal to two hormonal lines (72.2%) and only one docetaxel line (74.7%) before CBZ. Thirty-five (44.3%) pts had progressed on docetaxel. Progression less than six mo or greater than six mo after last docetaxel treatment was observed in 23 (29.1%) and 21 (26.6%) pts, respectively. New hormonal agents (abiraterone or enzalutamide) were given before CBZ in 2.5% of pts and after CBZ in 17.7%. Pts received a median of seven cycles (range 2 to 22) of CBZ. CBZ dose-reductions or -delays for any cause occurred in eight (10.1%) and 20 (25.3%) pts, respectively. Prophylactic G-CSF was given in 32 (40.5%) pts. A PSA decrease of greater than or equal to 50% and greater than or equal to 30% was reached in 41.2% and 48.6% of pts treated with CBZ. Median OS from first CBZ cycle was 16.2 [CI: 10.4;-] mo and median clinical and/or radiographic progression-free survival (rPFS) was 9.9 mo [CI: 7.4; 13.1]. Fourteen (17.7%) pts experienced at least one grade greater than or equal to 3 treatment-related AE, the most common being neutropenia (n=4), febrile neutropenia (n=2), asthenia (n=4), and diarrhoea (n=2). No grade greater than or equal to 3 peripheral neuropathy was reported. An analysis of factors predicting outcome will be presented. Conclusions: CBZ administered in real-life practice and in the adequate treatment setting in Spain is associated with meaningful PFS and OS and an acceptable safety profile. Dose delays and reductions were low. Prophylactic G-CSF use in 4 out of 10 pts may have contributed to these good results.
Experience with artificial urinary sphincter implantation in men who underwent prior pelvic radiation therapy for prostate cancer.
Authors: Jhavar Sameer G. , Bird Erin , Swanson Gregory P.
Published: February 2017

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Background: To assess outcomes after artificial urinary sphincter implantation in men who received prior pelvic radiation therapy. Methods: Between 1997 and 2012, 107 patients were identified from the Scott and White Hospital database who underwent artificial urinary sphincter implantation for urinary incontinence after prostate cancer treatment. Of these 17 were excluded for lack of follow-up data. Of the remaining 90 patients, 59 patients underwent prior surgery alone (group 1), 25 underwent prior surgery followed by pelvic radiation therapy (group 2); and 6 patients underwent prior radiation therapy alone. Results: Average ages at sphincter implantation were 69 yrs. (range 54 - 82), 73 yrs. (range 63 - 81), and 70 yrs. (range 60 - 80) respectively for groups 1, 2 and 3. Social continence rates were 80% (47/59) for group 1, 72% (18/25) for Group 2 and 50% (3/6) for group 3 at an average follow-up of 6 yrs. (range 0 - 17), 4 yrs. (range 1 - 12) and 3 yrs. (range 0 - 6) respectively. Average time between surgery and sphincter implantation was 5 yrs. (range 1-27) in group 1. Average time between radiation and sphincter implantation was 7 yrs. (range 1 - 18) and 6 yrs. (range 1 - 17) in Groups 2 and 3. Re-operation rates were 42% (25/59); 48% (12/25); and 50% (3/6) in groups 1, 2, and 3, respectively. In men who were incontinent at last follow-up, the average time between pelvic radiation and sphincter placement was relatively shorter as compared to those who were continent [5 yrs. (range 1 -11) vs. 7 yrs. (range 1 - 18) in Group 2; and 4 yrs. (range 1 -5) vs.10 yrs. (range 4 - 17) in group 3]. The rates of erosions were 10/59 (17%); 4/25 (16%); and 0/6 (0%) in groups 1, 2, and 3, respectively. The rates of infection were 5/59 (8%), 0/25 (0%), and 2/6 (33%) in groups 1, 2, and 3, respectively. Conclusions: Our experience with artificial urinary sphincter in men who underwent prior pelvic radiation therapy is comparable to that reported in the literature. Our results identify factors associated with worse continence after artificial urinary sphincter in men who underwent prior pelvic radiation therapy.
Isoflavones in Japanese and Caucasian men with prostate cancer in Hawaii.
Authors: Fukagai Takashi , Akaza Hideyuki , Ogawa Yoshio , Carlile Robert , Namiki Thomas , Lederer John Leslie , Maskarinec Gertraud , Tsuji Hirokazu , Moriyama Kaoru , Fujimoto Kiyohide , Hirao Yoshihiko , Namiki Mikio
Published: February 2017

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Background: Recently, several studies have reported that soy isoflavones and the ability to produce Equol, an active derivative of soy isoflavone, may play a role in the suppression of prostate cancer. An Equol-producing bacterium, Slackia sp. strain NATTS has been identified in stool cultures. To further investigate this relationship, we evaluated Japanese-Americans (JA) and whites (W) in Hawaii, with and without prostate cancer, with regards to dietary soy intake, serum isoflavone levels, and the presence of stool NATTS. Methods: The serum levels of Daidzein, Genistein, Glysitein, Dihydrodaidzein (DHD), Equol, o-desmethylangolensin (o-DMA) and total isoflavone was determined in 65 JA (34 patients with prostate cancer , 31 controls) and 68 W (34 patients with prostate cancer , 34 controls) subjects. The control group consisted of age matched cancer-free male subjects. To evaluate Equol producing ability, we assessed the presence of NATTS in stool samples. All subjects completed a lifetime dietary soy consumption survey. Results: The serum level of Genistein and o-DMA were significantly higher in JA (Genistein: W 21.5±54.0, JA 61.8±150.9, p=0.04; o-DMA: W 0, JA 2.0±7.9, p=0.04). Daizein level trended higher in JA (W 13.9±34.7, JA 33.3±84.0, p=0.09). Glysitein level was significantly higher in W (W 35.7±10.4, JA 30.7±15.5, p=0.03). No differences were noted in DHD and Equol levels between W and JA. Total isoflavone level trended higher in JA (W 76.3±104.9, JA 135.1±245.6, p=0.07). There were no differences in serum isoflavone level between prostate cancer patients and controls for both JA and W. Only 10 of 120 stool samples were positive for NATTS (8.6%), a rate much lower than seen in Japan. JA showed higher intake of soy than W. Conclusions: The high soy consumption and isoflavone levels in JA may be related to the observed lower incidence of prostate cancer relative to W in Hawaii. The near absence of equal producers in Hawaii JA may contribute to their higher incidence of prostate cancer compared to Japan based Japanese. These results suggest that both soy isoflavone levels and Equol production may be inversely associated with prostate cancer incidence.
Consideration of height-based rather than weight-based dosing as a more appropriate method of treating with radium-223.
Authors: Longo Thomas Andrew , McDonald Matthew , Mehr Samuel H. , Nordquist Luke T.
Published: February 2017

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Background: Radium 223 is approved for use in patients with symptomatic bone metastasis from castrate resistant prostate cancer, and no known visceral metastatic disease. It is currently dosed in a weight based fashion, however it is only active in the skeleton, and it is distributed primarily to the bone. A more rational dosing regimen may be based off a patient’s height, and the highest safe dose has yet to be determined. Our study looks at the safety profile of radium 223 in the context of a height based dosing regimen. Methods: This is a retrospective, observational study of all patients receiving radium 223 at the Urology Cancer Center. The patients were dosed at 50 kilobecquerels per kilogram as prescribed in the product insert. The dose each patient received was then recalculated based upon the patient’s height. The medical record was then examined for side effects. Results: As of September 2013 total of 30 discreet patients have received a total of 58 doses at our site since radium 223 was approved. The lowest dose received based on height was 17.39 kBq/cm and the highest dose was 40.7 kBq/cm with an average dose of 27.4 kBq/cm. There were eight grade 1 toxicities. The side effect profile did not show any trends across the different levels of dosing regarding the number or grade of toxicity with a greater number occurring below the median dose. Six of the eight men with significant GI distress have had prior radiation. Conclusions: A height based dosing regimen may be more appropriate for a drug designed to treat only the skeleton. In our population, we administered a wide variety of doses when administered by height. Higher doses appear to be well tolerated, and the optimal dose has yet to be determined. We propose future studies with height-based dosing escalation to look at the safety and efficacy.