bluuebunny/crossref_metadata_2025 huggingface dataset:
Discovery and validation of a 30-gene expression signature to identify prostate cancer patients who are candidates for active surveillance.
Authors: Gerke Travis , Tyekucheva Svitlana , Penney Kathryn , Sweeney Christopher , Lis Rosina , Sesso Howard D. , Nuttall Elizabeth , Loda Massimo , Stampfer Meir J. , Parmigiani Giovanni , Mucci Lorelei A.
Published: February 2017

10

Background: Considerable attention has been devoted to the search for biomarkers of aggressive prostate cancer. While many promising markers have been proposed, it is often unclear whether their ability to risk classify is adequate to reduce overtreatment of indolent cancers. We present and validate a gene expression signature that is highly specific for indolent disease and that, when combined with Gleason, improves upon the prognostic power of Gleason alone. Methods: A 30-gene signature of indolent disease was derived from a case-control sample of men (n=254) from the Health Professionals Follow-Up Study (HPFS) who were followed prospectively from cancer diagnosis for a median of 13.7 years. Cases were defined as men with prostate cancer who experienced a metastatic event or died of cancer during follow-up, while indolent controls survived at least 8 years without metastases. Whole-transcriptome gene expression was quantified from archival formalin-fixed, paraffin-embedded (FFPE) tumor tissue specimens acquired at prostatectomy. Genes were selected by a novel analytic strategy that maximizes a partial area under the curve (pAUC) to accurately identify indolent tumors. We validated the signature in two independent cohorts: the Physicians’ Health Study (PHS; n=150) and a Swedish Watchful Waiting cohort (WW; n=253) with respective median follow-up times of 14.4 and 9.0 years. Results: When compared to a model with Gleason alone, application of the signature to both validation data sets significantly improved prognostic accuracy as measured by pAUC (p=0.003 in PHS and p<0.001 in WW). Performance was particularly strong among men diagnosed with Gleason 7, where unit standard deviation increases in the signature score were associated with odds ratios of indolence of 5.24 (95% CI 2.21-15.75; p<0.001) and 2.37 (95% CI 1.45-4.19; p=0.001) in the PHS and WW cohorts, respectively. Conclusions: We present a signature of indolent prostate cancer that adds prognostic information beyond Gleason and has the potential to guide men to active surveillance and avoid overtreatment. Validation across both treated and untreated cohorts supports the discovery of a robust signature.
Familial risk and heritability of genitourinary cancers in the Nordic Twin Cohorts.
Authors: Mucci Lorelei A. , Hjelmborg Jacob , Penney Kathryn , Skytthe Axel , Harris Jennifer , Adami Hans-Olov , Kaprio Jaakko
Published: February 2017

11

Background: Twin studies estimate familial risk and heritability by leveraging the unique genetic relatedness of twins. We analyzed data from the Nordic Twin Study to investigate the genetic underpinnings of risk of genitourinary cancers. Methods: The cohort included 202,868 monozygotic (MZ) and same-sex dizygotic (DZ) twins from nationwide registries with follow-up via cancer registries. We examined cancers of the prostate, bladder, kidney and testes, and estimated familial risk, risk of a specific cancer in a twin, given that his co-twin was diagnosed with the same cancer, and heritability, the proportion of variation in cancer risk due to genetic differences. Statistical models used time-to-event analyses and accounted for censoring and competing risk of death. Results: During 32 years of follow-up, 5,041 cases of genitourinary cancer were diagnosed. The cumulative incidences in the cohort overall were 10.5% for prostate, 2.2% for bladder, 0.8% for kidney and 0.5% for testes. The strongest familial effects were found for testicular cancer. The familial risks of testicular cancer were 6% for DZ and 14% for MZ twins, i.e. a 12-fold and 28-fold higher risk for DZ and MZ twins, respectively, when their twin was also diagnosed with testicular cancer. Familial risk was also elevated for prostate, bladder, and kidney cancer and showed higher estimates among MZ than DZ twins. Statistically significant estimates of heritability were observed for prostate (57%) and kidney (38%) cancer, while testicular cancer showed evidence of both genetic (37%) and shared environmental (24%) effects. Conclusions: Familial risk estimates provide evidence of significant excess risks for individuals whose siblings develop genitourinary cancers. The higher concordance in MZ vs. DZ twins translated to strong heritability estimates for these malignancies. Results from this study have the potential to be directly translated to clinical practice and genetic counseling, and provide a context for the findings from genome wide association studies.
Primary focal cryosurgery of the prostate: Long-term clinical and biochemical outcomes in a large cohort at a tertiary referral center.
Authors: Pak Jamie Sungmin , Cheetham Philippa J. , Katz Aaron , Wenske Sven
Published: February 2017

114

Background: Modern primary focal cryosurgery (PFC) has emerged as a primary therapy option for localized and minimal low-risk prostate cancer (PCa), achieving good local cancer control and survival outcome. The aim of this analysis was to report on the experience of PFC in our tertiary referral center in the management of localized PCa. Methods: We identified a consecutive series of patients that underwent PFC for localized PCa at our institution between 8/2000 and 1/2014. Demographics, PSA levels and Gleason scores before primary treatment and at time of recurrence were assessed; BDFS, OS, and DSS were assessed. BCR was defined by the Phoenix (PD) and Stuttgart Definitions (SD). Results: A total of 126 patients were included in the analysis, with a median follow-up of 40.3 (0.8-116, IQR 41) months. Median age was 73.5 (range 45-92, IQR 9) years. Median initial serum PSA level was 6.0 (1-44.5, IQR 3) ng/ml. Median primary and secondary Gleason score on initial biopsy was 3 (3-5, IQR 1) with a median sum of 6 (6-10, 1), and 15% (2-95%, IQR 0) of biopsy tissue involved with cancer. Median number of biopsy cores was 12 (2-32), with a median of 1 (1-12, IQR 1) core affected by cancer. Median PSA nadir post-treatment was 1.3 (0.1-13.1, IQR 2) ng/ml. According to PD and SD, 24 and 37 patients had BCR after a median of 14.9 (3.4-91.3, IQR 17) and 13.0 (2.9-90.3, IQR 11) months. Overall 4-year-BDFS was 83% and 73% by PD and SD, respectively. 5-year OS and DSS was 95%, and 99.2%. Of patients that met BCR criteria, almost 25% were proven to be negative on biopsy, confirming over-estimation of failures. Patients that recurred had significantly higher initial median PSA levels (8.5 vs. 5.8 ng/ml; p<0.01) and PSA-nadir (2.1 vs. 1.0 ng/ml; p<0.05). Conclusions: Our analysis confirms PFC being a good option with low rate of morbidities for patients with localized PCa, with excellent BDFS and DSS at a long follow-up of 40 months. Controversy exists regarding criteria of BCR-definitions after focal therapies. More stringent definitions, such as the SD, especially in a focal cryosurgery setting, significantly over-estimate failure rates, and prostate biopsy seems to be the only reliable means to assess for recurrence at this point.
Grade 3 or higher morbidity requiring urologic surgical management following curative-intent radiotherapy of localized prostate cancer: Patient characteristics.
Authors: Thorpe Cameron S. , Myers Jeremy B. , Shrieve Dennis C. , Tward Jonathan D.
Published: February 2017

116

Background: Although there are prospective data reporting the incidence of grade 3 morbidity after treatment of prostate cancer (PCA), little has been reported on the specific morbidities, latency period and surgical management of these patients. We retrospectively evaluated the characteristics of patients treated for grade 3 or higher complications at the University of Utah. Methods: We identified patients with PCA from our institutional database who were treated with definitive or postoperative radiation between the years 1995 and 2012 with at least 1 CTCAE defined Grade 3 or higher adverse event (AE). We evaluated the details of surgery and/or radiation, time course to development of AE’s, and procedures performed to manage the AE’s. Descriptive statistics were performed. GI toxicities were not evaluated. Results: There were 208 Grade 3 events reported in 44 patients. Five had a single event, 8 had 2 events, and 31 patients had 3 or more. Following radiotherapy, 21 patients initially presented with a grade 3 toxicity, whereas 12 presented with a grade 1 and 11 presented with a grade 2 that progressed to grade 3. One subject had a grade 4 toxicity. There were 9 subjects who reported baseline grade 1 to 3 toxicity prior to curative-intent treatment. The most common Grade 3 events were: obstruction (100 events), incontinence (40 events) and fistula (21 events). Fourteen patients had surgery and EBRT, and at least 16 patients had HDR brachytherapy. The average latency period to the first grade 3 event was 76.8 months (range 0 to 195 months). Between 2005 and 2010 an average of 531 and 92 patients with PCA were treated with radiation in the state of Utah (SEER) and the University of Utah annually, respectively. Conclusions: Grade 3 or higher urologic morbidity is uncommon following prostate cancer radiation treatment. Combinations of radiation therapies and HDR brachytherapy appear to increase the risk of an adverse event. Outcome studies reporting late toxicity with median follow up of less than 5 years may significantly under-report the incidence.
Young age to predict for transient elevation in PSA after definitive stereotactic body radiation therapy for prostate cancer.
Authors: Blacksburg Seth , Katz Aaron , Witten Matthew R. , Clancey Owen , Haas Jonathan A.
Published: February 2017

118

Background: Stereotactic Body Radiation Therapy (SBRT) is a standard therapeutic option for men with prostate adenocarcinoma. There is a small body of literature characterizing a PSA bump after treatment with SBRT. Despite this, there is a paucity of data addressing rates of transient PSA increase immediately after SBRT treatment and what factors portend for this rare occurrence. This study reports outcomes on initial PSA after SBRT therapy for men who have received definitive SBRT for prostate cancer. Methods: Between May 2006 and February 2014, 921 patients with prostate cancer were treated with SBRT delivered via Cyberknife therapy. The mean age was 67 years old. 68.5% of patients were Caucasian, 17.4% African American, and 14.1% were another ethnicity. Patients were divided into prognostic risk groups with 44.7%, 43.5%, and 11.1% of patients falling in the low, intermediate, and high risk stratifications. Gleason scores were < 6 in 44.4%, 7 in 41.3%, and 8-10 in 14.2%. 37 patients also received supplemental external beam radiation (median dose 4500cGy) and 8.9% of patients received Androgen Deprivation Therapy (ADT) as part of their treatment regimen. Pre-treatment PSA was 0.8 – 205 ng/ml (median 6.1). Results: At 3 months’ follow-up, 2.8% of patients had a PSA elevated above their baseline value. 27.8% of patients age ≤50 (p<.0001) and 8.4% of patients age ≤60 (p=.001) experienced an increased in baseline PSA. African Americans were more likely to experience a transient increase in PSA over Caucasians (7.8% vs. 3.0%, p=.06). Patients treated with fewer beams were also more likely have a temporary rise in PSA (p=.056). Gleason Score, Risk grouping, prostate volume, ADT, and EBRT did not predict for rise on Pearson Chi-Square analysis. On multivariate analysis, only age ≤50 (p<.0001) portended for increased PSA at 3 months’ time. Conclusions: This represents the largest series evaluating elevation of PSA after definitive SBRT for prostate cancer. Temporary rise in baseline PSA after SBRT is rare. Despite that, a significant cohort of younger patients can experience transient elevation. Patient age ≤50 was found to be the only predictor of this otherwise rare occurrence.
Treatment outcomes of radiotherapy versus prostatectomy for localized prostate cancer with Gleason 8 or more on biopsy.
Authors: Baker Christopher , McDonald Andrew M. , Clark Grant , Dulaney Caleb , Yang Eddy Shih-Hsin , Jacob Rojymon , Fiveash John B.
Published: February 2017

120

Background: There have been no prospective randomized controlled trials comparing current treatment options for patients with high-risk localized prostate cancer. This study seeks to compare the biochemical and metastatic outcomes of patients that received definitive radiotherapy (dRT) or radical prostatectomy (RP) for localized prostate cancer with Gleason score ≥ 8 on initial biopsy. Methods: A total of 106 patients met the inclusion criteria of Gleason score ≥ 8 on initial biopsy and biochemical follow-up ≥ 1 year. Seventy-one patients were initially treated with dRT (96% also receiving androgen deprivation therapy) and 35 patients were initially treated with RP (with or without postoperative RT). Our primary endpoint was biochemical failure (BF). For dRT patients, BF was recorded according to the Phoenix Consensus or if extranodal metastasis was diagnosed. For surgical patients, BF was recorded according to American Urological Association guidelines or if extranodal metastasis occurred. If adjuvant/salvage RT was given postoperatively, BF was recorded if PSA ≥ 0.5 on two consecutive measures after completion of RT. Pretreatment characteristics were compared using Pearson Chi-square method and independent samples Mann-Whitney U test. Actuarial rates of BF and metastasis were calculated using the Kaplan-Meier method. Results: Median follow-up for all patients was 5.3 years. There was no statistical difference in clinical T-stage, initial PSA, or months of follow up between patients treated initially with radiotherapy vs. prostatectomy. Patients initially treated with dRT were significantly older than those treated with RP. The dRT group had a lower rate of BF compared to the RP group, p < 0.001. The Kaplan-Meier estimate of BF at 5 years was 7.6% in the dRT group compared to 34.5% in the RP group. Additionally, the Kaplan-Meier estimate of distant metastasis at 10 years was 22.7% in the dRT group compared to 55.9% of the RP group, p = 0.01. Conclusions: For our sample of patients with Gleason score ≥ 8 on initial biopsy, initial treatment with dRT was associated with lower rates of biochemical failure and extranodal metastasis when compared to initial treatment with prostatectomy.
Association of NaF PET/CT findings with PSA and alkaline phosphatase in untreated castration-sensitive prostate cancer.
Authors: Couvillon Anna , Turkbey Baris , Lindenberg Maria Liza , Choyke Peter L. , Martinez Mirna , McKinney Yolanda , Kaushal Aradhana , Citrin Deborah E. , Krauze Andra , McNally Deborah , Giordano Luz , Chun Guinevere , Royce Cheryl , Han Hui , Karzai Fatima , Parnes Howard L. , Pinto Peter A. , Gulley James L. , Dahut William L. , Madan Ravi Amrit
Published: February 2017

122

Background: NaF PET/CT is an emerging imaging technique with potentially high sensitivity in detecting bone metastasis (mets), however, its role in castration-‐sensitive prostate cancer (CSPC) is undefined and it remains unclear which CSPC patients should have NaF PET/CT. Methods: We retrospectively reviewed NaF PET/CT scans done on 45 patients with untreated, high risk CSPC with the goal of determining which disease features were associated with positive findings. Two blinded radiologists reviewed each scan and determined by consensus if findings were negative for metastasis (0% liklihood of mets), possible (50%), probable (75%), or consistent with mets (90%). Prostate specific antigen (PSA) and alkaline phosphatase (AP) values were then evaluated at time of NaF scan when available. Results: Of the 45 patients 2 were Gleason 6, 5 were Gleason 7, 36 were Gleason 8 to 10, 2 unknown. When grouped by findings on NaF PET/CT, there were no substantial differences seen between median PSA or AP values. When patients with both PSA and AP values > median were evaluated, there was no clear association with NaF PET/CT findings. Conclusions: Preliminary findings from this small retrospective analysis suggest that there may be limited associations between PSA and/or AP with findings on NaF PET/CT scan in untreated patients with CSPC. Further analysis in larger cohorts of pts is required. [Table: see text]
Racial variation in positive prostate needle biopsy templates, which include the transition zone.
Authors: Feibus Allison H. , Levy Justin , Moparty Krishnarao , McCaslin Ian R. , Maddox Michael M. , Sartor Oliver , Silberstein Jonathan L.
Published: February 2017

125

Background: Reports have suggested that African Americans (AA) with prostate cancer (PCa) have both increased incidence and increased aggressiveness of tumors located in the transition zone (TZ). Our goal was to evaluate the utility of TZ−directed prostate biopsies in a predominantly AA population at a Veterans Affairs Hospital. Methods: After obtaining IRB approval, we retrospectively reviewed all patients with PCa found on a 14 core biopsy in which 12 needle biopsies were directed at the peripheral zone (PZ) and 2 at the TZ, between January 2010 and June 2014. Location of disease was determined by the results of the biopsy, either PZ alone, TZ alone or both. Aggressiveness of disease was defined by Gleason grade, percent involvement of PCa in any core and NCCN risk-stratification. Self−identified race was recorded for all patients. A series of Mann Whitney U and Chi−square tests were used to compare variables. Results: The total patient cohort consisted of 398 men, in which 277 (70%) were AA. When compared with Caucasian Americans (CA), AA patients had more NCCN intermediate or high risk (50% vs 39%, p = 0.25) PCa. Most patients had PCa limited to the PZ only (n=190) or in both the PZ and TZ (n=191). For 17 patients (4%) PCa was limited to TZ core(s) only, 14 (5%) AA vs 3 (2%) CA (p = 0.24). Of these 17 patients, 14 (82%) had Gleason 6 only disease. Patients with PCa in both the PZ and TZ had higher PSA and PSA density, greater volume of disease, higher-grade lesions and worse NCCN category (all values p <0.01) compared with patients in which the positive biopsy was limited to the PZ. Of these 191 TZ and PZ positive patients, a greater proportion were AA (n=135, 49%) compared to CA (n=56, 46%) (p = 0.48). For patients with PZ and TZ disease, the TZ had the highest-grade in 21 (11%) men, 10% AA and 13% CA (p = 0.67). For most patients (89%), PZ tumor grade was equal to or greater than TZ. Conclusions: TZ−directed prostate needle biopsy cores were rarely the sole location of PCa and when found were usually low grade without clear racial variation. Patients with PCa in both the PZ and TZ had aggressive disease regardless of race although the TZ core resulted in upgrading in a minority of patients. TZ-directed biopsies do not appear to be of greater benefit to AA than CA.
Association of "DNA damage signature" with poor outcome in early prostate cancer.
Authors: Iddawela Mahesh , Pazaro Carmel , Lawrence Mitchell , Furic Luc , Taylor Renea , Risbridger Gail
Published: February 2017

13

Background: Whole genome and matching normal tissue analyses in prostate cancer patients have shown that widespread genomic changes occur in multiple distant regions of the genome simultaneously (Baca et al., Cell. 2013). The inherent genomic instability in prostate cancers causes activation of pathways involved in DNA damage, which could be a prognostic and potentially predictive marker for treatment with agents impacting DNA repair (e.g. PARP inhibitors). Using a published dataset, a “DNA damage signature” was generated to test its role as a potential prognostic marker. Methods: A 10-gene signature was generated, using the top 9 genes (MXD3, ZMYND19, BANF1, TOMM40, UBE2S, SNRPF, RPP21, CDK2AP2 and H2AFX) correlated with H2AFX expression, which is known to be unregulated upon DNA damage. TP53 was added due to its significant role in this pathway. This signature was then assessed in The Cancer Genome Atlas dataset (TCGA, unpublished data at NCI) as a discovery set and then validated in the MSK dataset (Taylor et al., 2010) using mutation, copy number, mRNA and proteomic data. Results: Genes in the signature were altered in 31% (77/246) of patients, by amplification and over expression compared to normal. The most frequent alterations were found in TP53 (15%), MXD3 (7%), BANF1 (7%), UBE28 (7%) and CDK2AF2 (7%). Analysis of protein changes associated with alteration in genomic signature showed upregulation of FOXO3, BCL2L1, BAK1 and PCNA (P<0.05). There were significant correlations between the signature and Gleason score (p=0.0015), PTEN (p=0.003) & RAD51 gene expression (p<0.001), but not with ERG,PSA, PIK3CA or BRCA2. Patients with alterations were associated with poor disease free survival (DFS) (p=0.002). When expression was assessed in the validation set, 73%(62/85) samples showed altered gene signatures and those with alterations also had poor DFS (p=0.003). Conclusions: The DNA damage signature can be used to define a group of patients with poor outcome and has the potential to be used as prognostic marker in treatment decisions in early prostate cancer patients.
Does focal high-intensity focused ultrasound have a role in treating localized prostate cancer in the elderly?
Authors: Guillaumier Stephanie , McCartan Neil , Dickinson Louise , Fatola Yomi , Freeman Alex , Hindley Richard , Emberton Mark , Ahmed Hashim Uddin
Published: February 2017

133

Background: There is an increase in the ageing population leading a significant proportion of men diagnosed with prostate cancer being over 75 years of age. Misconceptions regarding treating the elderly are still rife. The body of evidence that has recently emerged shows that this cohort of patients should be offered the same curative therapies as their counterparts. This study looks at the feasibility of focal HIFU in treating localised prostate cancer in those aged over 75 years of age. Methods: Our independent academic HIFU registry incorporates a total of 60 patients who were diagnosed with low, intermediate and high risk localized adenocarcinoma of the prostate, stage T2a-T3aN0M0 and treated with focal HIFU using Sonablate500, between 2004 and 2014. We divided the patient cohort into those that were treated within the remit of a trial protocol, and those that were not. Results: As biochemical failure is difficult to define, we looked at the medium-term transition rates to redo HIFU, local salvage and systemic therapy. 12% required re-treatment with HIFU. 8% transitioned into local salvage or systemic therapy of which 1 patient had radiotherapy and 4 were subsequently treated with androgen deprivation therapy). The table below outlines the complication rates associated with focal HIFU. Conclusions: Focal HIFU has been shown to be both feasible and effective in the elderly population. It is a safe modality of treatment to use in this patient cohort with a low complication profile. Long-term studies are however necessary. [Table: see text]
Final analysis of COMET-1: Cabozantinib (Cabo) versus prednisone (Pred) in metastatic castration-resistant prostate cancer (mCRPC) patients (pts) previously treated with docetaxel (D) and abiraterone (A) and/or enzalutamide (E).
Authors: Smith Matthew Raymond , De Bono Johann Sebastian , Sternberg Cora N. , Le Moulec Sylvestre , Oudard Stephane , De Giorgi Ugo , Krainer Michael , Bergman Andre M. , Hoelzer Wolfgang , De Wit Ronald , Boegemann Martin , Saad Fred , Cruciani Giorgio , Thiery- Vuillemin Antoine , Feyerabend Susan , Miller Kurt , Ramies David Albert , Hessel Colin , Weitzman Aaron , Fizazi Karim
Published: February 2017

139

Background: Cabo inhibits tyrosine kinases including MET and VEGFRs. In a phase 2 study in mCRPC pts, Cabo was associated with improvements in bone scans, pain, measurable disease, and circulating tumor cells. COMET-1 compared the effects of Cabo versus Pred on overall survival (OS) in men with progressive mCRPC and prior D and A and/or E. Methods: In this randomized, double-blind, controlled phase 3 study (NCT01605227), pts with mCRPC and prior D and A and/or E were randomized 2:1 to receive Cabo (60 mg qd) or Pred (5 mg bid). Pts were stratified by prior treatment with cabazitaxel, ECOG status, and presence of moderate to severe pain. The primary endpoint was OS. The study was designed to observe 578 deaths to provide 90% power to detect a hazard ratio (HR) of 0.75. A secondary endpoint was bone scan response at Week 12 (BSR) determined by central independent radiology committee, defined as a ≥30% decrease in the bone scan lesion area compared to baseline. Exploratory endpoints include PFS and OS subgroup analyses. Results: 1,028 pts were randomized between Jul 2012 and Nov 2013. In the final analysis after 614 deaths, the estimated median OS was 11.0 months for Cabo vs 9.8 months for Pred (HR 0.90; 95% CI: 0.0.76-1.06; P = 0.212). The secondary endpoint of BSR was 41% for Cabo vs 3% for Pred (P <0.001). Median PFS per investigator was 5.5 months for Cabo vs 2.8 months for Pred (HR 0.50; P <0.001). For 191 pts with visceral disease median OS was 7.1 months for Cabo vs 4.8 months for Pred (HR 0.65; P = 0.0215). 371 (54.4%) and 233 (67.3%) pts received salvage therapy in the Cabo and Pred arms, respectively. Subsequent cabazitaxel and/or D was reported in 107 (15.7%) and 104 (30.1%) Cabo and Pred pts, respectively. Serious adverse events of pulmonary embolism, nausea, dehydration and fatigue were more frequent with Cabo. Conclusions: Compared to prednisone, Cabo improved BSR and PFS but did not significantly increase OS. The improvement in OS was greatest in the subset of patients with visceral metastases. The activity and safety profile of Cabo was similar to that observed in phase 2 studies in mCRPC. Clinical trial information: NCT01605227.
A phase 2 study of prostate specific membrane antigen antibody drug conjugate (PSMA ADC) in patients (pts) with progressive metastatic castration-resistant prostate cancer (mCRPC) following abiraterone and/or enzalutamide (abi/enz).
Authors: Petrylak Daniel Peter , Vogelzang Nicholas J. , Chatta Gurkamal S. , Fleming Mark T. , Smith David C. , Appleman Leonard Joseph , Hussain Arif , Modiano Manuel , Singh Parminder , Tagawa Scott T. , Gore Ira , McClay Edward Francis , Mega Anthony E. , Sartor A. Oliver , Somer Bradley G. , Wadlow Raymond Couric , Shore Neal D. , Stambler Nancy , DiPippo Vincent A. , Israel Robert Joseph
Published: February 2017

144

Background: PSMA is a validated target that is overexpressed selectively on prostate cancer cells. PSMA ADC is a fully human IgG1 antibody conjugated to the microtubule disrupting agent MMAE which binds to PSMA-positive cells, inducing cytotoxicity. A phase 1 study showed activity and tolerability at doses from 1.8-2.5 mg/kg. We have enrolled 119 mCRPC pts who progressed following abi/enz in a phase 2 trial of PSMA ADC. Methods: mCRPC pts (83 taxane experienced (TE) and 36 chemo-naïve (CN)) were administered PSMA ADC 2.5 or 2.3 mg/kg IV Q3 wk for up to 8 cycles. 95% of pts received prior abi and/or enz treatment. Safety, antitumor activity (including PSA, CTCs, and tumor imaging) and exploratory biomarkers were assessed. Results: In all treated pts, PSA declines of ≥30% and ≥50% were 30% and 14%, respectively (n=113); CTC counts showed a decline of ≥50% in 78% of pts and conversion from ≥5 to <5 cells/7.5 ml blood in 47% (n=77) at any time during the study. For 2.3 mg/kg pts (n=82), corresponding PSA declines were 35% and 17%; CTC declines of ≥50% were seen in 81% and conversions in 46% (n=54). For CN pts, PSA declines of ≥30% and ≥50% were 31% and 20% (n=35); CTC declines of ≥50% were seen in 89% and conversion in 53% (n=19). Radiologic response by RECIST in 31 pts with measurable target lesions: PR in 4 pts, SD in 19 pts, and PD in 8 pts. Efficacy responses were associated with: low neuroendocrine serum markers (low CgA, low NSE, and high PSA), high PSMA expression (CTCs or tumor tissue). The most common treatment-related AEs ≥CTCAE grade 3 were neutropenia (TE: 25%; CN: 22%), fatigue (20%; 8%), electrolyte imbalance (16%; 11%), anemia (10%; 8%), and neuropathy (8%; 8%). Grade 1-2 neuropathy occurred in 40% (TE) and 50% (CN) of pts. Two 2.5 mg/kg pts (n=34) and one 2.3 mg/kg pt (n=85) died of sepsis. 2.3 mg/kg was better tolerated than 2.5 mg/kg. Conclusions: PSMA ADC was active in abi/enz refractory mCRPC pts. Clinically significant AEs included neutropenia and neuropathy. CTC conversions/reductions, PSA declines, and radiologic evidence of antitumor activity were seen in CN as well as heavily pretreated pts. Clinical trial information: NCT01695044.
A comprehensive molecular characterization of aggressive variant prostate cancer (PC).
Authors: Aparicio Ana , Shen Li , Tapia Elsa Li Ning , Lu Jing-Fang , Chen Hsiang-Chun , Zhang Jiexin , Wu Guanglin , Wang Xuemei , Troncoso Patricia , Broom Bradley McIntosh , Baggerly Keith A. , Logothetis Christopher , Maity Sankar N.
Published: February 2017

149

Background: Unusually aggressive PC behavior is linked to small cell carcinoma (SCC) morphology. We observed SCC clinical features in association with morphologically heterogeneous PC and, in a prospective clinical trial (NCT00514540), also with chemotherapy responsiveness. Our previous studies in patient derived xenografts (PDX) revealed a distinct molecular profile for SCC. Here we sought to support the hypothesis that clinically defined aggressive variant PCs also share relevant biology with SCC. Methods: 59 PC samples, and 8 PDX, from 42 men registered to NCT00514540 were stained for RB, p53, AR, NKX3-1, ASCL1, AURKA, UBE2C and Ki67. Labeling indices (LI) were calculated as the ratio of positive epithelial cells to total of epithelial cells, at 200x. We determined copy number alterations (CNA) by Onco Scan® in 36 of 59 samples and 8 PDX lines. We used Western Blot and qRT-PCR to expand pathway analyses and their associations in PDX models. Results: Donor patients were similar to non-donor patients except for higher ECOG PS and LDH values. Strong positive correlations between nuclear AR (AR-N) and NKX3.1, AR-N and RB, AR-N and nuclear AURKA (AURKA-N), NKX3.1 and RB, p53 and nuclear UBE2C (UBE2C-N), Ki67 and UBE2C-N, Ki67 and cytoplasmic UBE2C (UBE2C-C) as well as a strong negative correlation between NKX3.1 and Ki 67 were observed. Frequent copy number losses were found for PTEN (largely gene-specific) and RB1 (often associated with regional-CNA). Gene-specific AURKA amplifications were not observed. Only RB1 CNA showed a positive correlation with its LI. Samples were segregated by quantity of CNA. PDX models shared these features and showed that only AR-negative tumors expressed pro-neural transcription factors, albeit heterogeneously. Conclusions: Our results support the hypothesis that clinically defined aggressive variant PC (including SCC and non-SCC morphologies) are characterized by frequent Rb, p53 and PTEN alterations, aberrant expression of mitotic, neural development and AR-signaling pathways, and high rates of CNA. Ongoing studies will confirm whether these molecular features distinguish this variant from the more common bone-homing, bone-forming, AR-driven adenocarcinomas of the prostate.
Cautionary tale of active surveillance in intermediate-risk patients: Overall and cause-specific survival in the Sunnybrook experience.
Authors: Musunuru Hima Bindu , Klotz Laurence , Vespirini Danny , Zhang Liying , Mamedov Alexandre , Sethukavalan Perakaa , Jethava Vibhuti , Yamamoto Toshihiro , Jain Suneil , Loblaw D. Andrew
Published: February 2017

163

Background: To document the long-term outcomes of intermediate risk (IR) prostate cancer patients managed on active surveillance (AS) protocol in a single institute. Methods: Patients(pts) with PSA >10ng/ml or Gleason score 7 or clinical stage T2b/2c were identified from a prospectively collected database of 945 patients managed on AS between 1995 and 2013. Intervention was offered to those pts with a PSA doubling time of < 3 years, Gleason score or clinical progression.Overall survival (OS), cause-specific survival (CSS) for IR and low risk (LR) pts were analyzed as well as metastasis free survival (MFS) and treatment-free survival (TFS) for IR pts. Results: 237 (23.9%) pts had IR disease, with a median follow up of 6.9 years (IQR 3.89, 10.85) .708 pts had LR cancer with a median follow up of 6.4 years (IQR 3.76, 9.03). 61.2% of the IR cohort was older than 70 years. 86 IR pts (36.3%) received treatment (mainly radiation). The median treatment free interval for IR pts was 12.3 years (range 10.1 - 19.8). 33 IR patients developed biochemical failure and 17 developed metastatic disease [11 IR pts(4.6%) and 6 LR pts(0.8%)].The 10 and 15year OS was 68.4% and 50.3% for IR pts;83.6% and 68.8% for LR pts (p value <0.0001).Similarly 10 and 15 year CSS was 95.5% and 88.5% for IR ; 98.2% and 96.3% for LR pts (p value=0.006).The hazard ratio for IR pts versus LR pts was 2.08 for OS and 3.75 for CSS.IR pts had 3.75 times higher chance of dying from prostate cancer when compared to LR pts (Table). 10 year MFS and TFS were 92.1% (87.4-97.1%) and 58.5% (51.6-66.4%) in the IR cohort. Survival outcomes did not vary according to the year of patient enrollment. Conclusions: AS for intermediate risk prostate has significantly lower OS and CSS compared to low risk patients and therefore extreme caution should be exercised if it were to be implemented in intermediate risk patients. [Table: see text]
Molecular characterization of heterogeneity in circulating tumor cells (CTCs) and tumor samples of metastatic castration-resistant prostate cancer (mCRPC) patients: The multicenter PETRUS program.
Authors: Massard Christophe , Oulhen Marianne , Le Moulec Sylvestre , Loriot Yohann , Auger Nathalie , Beuzeboc Philippe , Albiges Laurence , Culine Stephane , Oudard Stephane , Hennequin Christophe , Vielh Philippe , Farace Françoise , Fizazi Karim
Published: February 2017

165

Background: In order to optimize molecular screening in advanced prostate cancer patients, we implemented a prospective molecular triage trial PETRUS (NCT01786031), based on molecular characterization of fresh tumor biopsies and circulating tumor cells (CTCs) in patients with mCRPC. The primary objective was to investigate the feasibility of prospectively performing molecular profiling of CRPC patients. Methods: A tumor biopsy from a metastatic and tumor primary site, along with blood samples specimen were collected from patients, and both frozen and FFPE samples were obtained. CTCs were detected using two methods, CellSearch and filtration (ISET, isolation by Size of Epithelial Tumor cells) combined to four-color immunofluorescent staining. Results: From December 2012 and March 2014, 51 CRPC patients with metastases accessible for biospy were included in 5 centres in France. Tumor biospy were successful (≥ 50% tumor cells) in 36/51 pts (72%). CTCs with different phenotypes were detected by CellSearch and ISET combined to four-color immunofluorescent staining in 28 (51%) pts. FISH AR and ERG was successful in only 54% and 32% of metastasis biopsies and primitive tumors respectively, most likely due to the absence of tumor cells or overfixation. The ISET platform was able to detect CTCs clusters, CTCs expressing epithelial and vimentin markers. AR amplification and ERG rearrangement analyses showed high level of heterogeneity with evidence of multiple CRPC iCTC subpopulation. A high level of heterogeneity between CTCs, metastasis biopsies and primitive tumors was observed for ERG rearrangement and AR amplification status. Conclusions: Our results demonstrate that CTCs could be an alternative source for surrogate molecular marker assessment in mCRPC, but neither approach could truly reflect the extreme heterogeneity observed in CTCs from mCRPC. Our preliminary results suggest also the operational feasibility of metastatic tumor biopsy: high interest for patients, significant yield of tumor biopsies and ad hoc molecular analysis. Clinical trial information: NCT01786031.
A genomic classifier to identify men with adverse pathology post radical prostatectomy who benefit from adjuvant radiation therapy.
Authors: Den Robert Benjamin , Yousefi Kasra , Trabulsi Edouard John , Abdollah Firas , Choeurng Voleak , Feng Felix Yi-Chung , Dicker Adam , Lallas Costas D. , Gomella Leonard G. , Davicioni Elai , Karnes R. Jeffrey
Published: February 2017

168

Background: The optimal timing of postoperative radiotherapy following radical prostatectomy (post-RP RT) is unclear. We hypothesized that a genomic classifier (GC) would provide prognostic and predictive insight into the development of clinical metastases in men receiving post-RP RT and inform decision-making. Methods: GC scores were calculated from 188 patients with pT3 or margin positive PCa, who received post-RP RT at Thomas Jefferson University and Mayo Clinic, between 1990 and 2009. The primary endpoint was clinical metastasis. Prognostic accuracy of the models were tested using c-index and decision curve analysis. Cox regression tested the relationship between GC and metastasis. Results: The cumulative incidence of metastasis at 5 years post-RT was 0%, 9%, and 29% for low, average, and high GC scores, respectively (p=0.002). In multivariable analysis, GC and pre-RP PSA were independent predictors of metastasis (both p<0.01). Within the low GC score (<0.4), there were no differences in the cumulative incidence of metastasis comparing those who received adjuvant or salvage RT (p=0.79). However, for patients with higher GC scores (≥0.4) cumulative incidence of metastasis at 5-year was 6% vs. 23% for patients treated with adjuvant vs. salvage RT (p<0.01). Conclusions: In patients treated with post-RP RT, GC is prognostic for the development of clinical metastasis beyond routine clinical/pathologic features. Though preliminary, patients with low GC are best treated with salvage radiation, while those with high GC benefit from adjuvant therapy. These findings provide the first rationale selection of timing of post-RP RT.
Quantitative bone scan lesion area as an early surrogate outcome measure indicative of overall survival in metastatic castration-resistant prostate cancer.
Authors: Brown Matthew S. , Kim Hyun J. , Chu Gregory H. , Allen-Auerbach Martin , Fischer Cheryce , Levine Benjamin , Gupta Pawan , Schiepers Christiaan , Goldin Jonathan
Published: February 2017

179

Background: Bone Scan Lesion Area (BSLA) is a biomarker that can be computed semi-automatically from whole-body scintigraphic imaging as a measure of overall bone tumor burden. Initial development and validation, including correlation with outcomes, was performed in trial cohorts from a single drug treatment with controls in subjects with metastatic castrate-resistant prostate cancer (CRPC). A 30% increase/decrease in BSLA was defined as progression/response on bone scan. We hypothesize that, when applied to an independent treatment trial cohort with a different mechanism of drug action, baseline BSLA and Week 12 change post-treatment are predictive of a subject's overall survival. Methods: From an anonymized imaging research database a cohort of 198 CRPC subjects was identified who enrolled in a treatment trial (127 treated, 71 placebo). This cohort was independent of those used for biomarker development and initial validation, and involved a different mechanism of drug action. Subjects underwent standard of care whole-body bone scintigraphy with 99mTc-Methyl diphosphonate (99mTc-MDP). BSLA was calculated at baseline and response at Week 12. Multivariate Cox regression was used to test whether (1) baseline BSLA, and (2) early changes in BSLA (12 weeks post treatment) were predictive of overall survival. Results: BSLA < 2000 mm2 at baseline was a prognostic factor (HR=0.6; p=0.003) and predictive of longer survival (HR=0.4; p<0.001). Subjects without PD by BSLA at Week 12 had significantly longer survival than subjects with PD: median 170 days vs. 186 days in the placebo group and 260 days vs. 392 days in the treatment group. The overall survival rates between non-PD and PD subjects were statistically different (HR=0.64, p=0.007). Conclusions: BSLA is calculated semi-automatically from bone scans and provides a quantitative and objective treatment response assessment. Baseline BSLA and early changes post treatment were found to be predictive of overall survival in patients with metastatic castration-resistant prostate cancer. BSLA has now been demonstrated to be an early surrogate outcome for overall survival in different drug treatments.
Real-world use of epic for clinical practice (EPIC-CP) to assess patient-reported prostate cancer quality of life in the clinical setting.
Authors: Chang Peter , Carneiro Arie , Dovirak Ostap , Taylor Kimberly , Crociani Catrina , Sanda Martin G. , Percy Andrew , McAnally Kyle , Wagner Andrew A
Published: February 2017

18

Background: Prostate cancer practitioners tend to underestimate patients’ treatment-related side effects. We developed the Expanded Prostate Cancer Index Composite for Clinical Practice (EPIC-CP) to facilitate patient-reported health-related quality of life (HRQOL) assessment at the point-of-care (Chang P et al, J Urol Sep 2011). We sought to demonstrate the feasibility of EPIC-CP use in routine clinical care, and to compare longitudinal patient-reported and practitioner-reported prostate cancer outcomes. Methods: We reviewed practitioner- and patient-reported HRQOL outcomes in 482 patients who underwent radical prostatectomy at our institution from 2010 to 2014. All EPIC-CP questionnaires were administered and interpreted without research personnel. Practitioner-reported outcomes were assessed using chart review. We used the paired t-test and Wilcoxon signed-rank test to compare pre- and post-treatment EPIC-CP domain scores, and Fisher’s exact test to compare patient-reported and practitioner-reported outcomes. We considered p-values < 0.05 statistically significant. Results: 708 total EPIC-CP questionnaires were completed. Mean urinary incontinence domain scores increased (worsened) significantly from baseline (0.6±0.2) to 3 (3.1±2.3) and 6 months (2.2±2.1) post-treatment, but were not statistically changed from baseline at 12 months (1.6±1.7). Patient-reported incontinence pad-free rates using EPIC-CP at 3, 6, and 12 months were 47%, 76%, and 78%, respectively, which were consistent with practitioner-reported rates. Mean sexual domain scores were significantly worse at 12 months (5.9±3.3) compared to baseline (2.4±2.8). Practitioners significantly overestimated the rate of functional erections compared to patients’ EPIC-CP-reported rates at 3 months (18% vs 12%, p < 0.05) and 12 months (45% vs 23%, p < 0.05). Bowel and vitality/hormonal scores were unchanged, and urinary irritation/obstruction scores improved after surgery. Conclusions: EPIC-CP is feasible to use in the routine clinical care of prostate cancer patients, and can help practitioners more accurately assess patients’ post-treatment symptom severity.
External beam radiation therapy (EBRT) use and safety with radium-223 dichloride (Ra-223) in patients (pts) with castration-resistant prostate cancer (CRPC) and symptomatic bone metastases (mets) from the ALSYMPCA trial.
Authors: Finkelstein Steven E. , Michalski Jeff M. , O'Sullivan Joe M. , Parker Chris , Garcia-Vargas Jose E. , Sartor A. Oliver
Published: February 2017

182

Background: In ALSYMPCA, Ra-223, a first-in-class α-emitter, improved overall survival and delayed time to first symptomatic skeletal event vs placebo (pbo). This post hoc analysis evaluated safety and efficacy of Ra-223 plus EBRT. Methods: Pts had symptomatic (recent EBRT for bone pain or any regular analgesic use) CRPC with ≥ 2 bone and no visceral mets; best standard of care; and prior docetaxel (pD) or were unfit for or declined docetaxel (no pD). Pts were stratified by pD use (yes/no), baseline total alkaline phosphatase level (tALP; < 220 U/L or ≥ 220 U/L), and current bisphosphonate (bp) use (yes/no) and randomized 2:1 to 6 Ra-223 injections (50 kBq/kg IV q 4 wk) or pbo. EBRT for bone pain was permitted within 12 weeks prior to randomization and during study. Baseline pain by prior EBRT, time to first on-study EBRT use for bone pain, and adverse events (AEs) by concomitant EBRT (cEBRT) were analyzed. Results: Pts with no prior EBRT had less pain at baseline; a WHO pain score ≤ 1 (no opioid use) was present in 46% (355/724) of pts with no prior EBRT vs 36% (53/147) of pts with prior EBRT. Ra-223 vs pbo significantly reduced EBRT use in the overall population (HR = 0.67, P = 0.001) and in pts with ≤ 20 bone mets (HR = 0.49, P < 0.001), current bp use (HR = 0.47, P = 0.004), tALP < 220 U/L (HR = 0.66, P = 0.008), and no pD (HR = 0.65, P = 0.038). At 6 months, the percentage of Ra-223 pts requiring EBRT was similar for prior and no prior EBRT subgroups (24% vs 20%), increasing at 12 months (38% vs 29%). cEBRT did not affect Ra-223 safety, and myelosuppression was low (Table). Conclusions: cEBRT did not adversely affect Ra-223 hematologic safety. Ra-223 significantly reduced risk of EBRT use. In Ra-223 pts, prior EBRT did not appear to affect later EBRT use. Clinical trial information: NCT00699751. [Table: see text]
Association of changes in measurable disease by RECIST with survival in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Sonpavde Guru , Pond Gregory Russell , Templeton Arnoud J. , Petrylak Daniel Peter , Tombal Bertrand F. , Rosenthal Mark , Tannock Ian
Published: February 2017

186

Background: In men with mCRPC receiving chemotherapy, measurable disease response by World Health Organization criteria has been demonstrated to be prognostic for overall survival (OS). We aimed to explore the association of changes in measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) with OS. Methods: Data from the control arm (n=612) of the phase III VENICE trial receiving docetaxel plus prednisone combined with placebo were available. Data on baseline clinical and laboratory variables were obtained in addition to outcome measures: best RECIST 1.0 response, PSA response and OS. Cox proportional hazards regression was used to evaluate the prognostic ability of RECIST-defined changes for OS using a 90-day landmark analysis. Results: 363 of 612 patients (59.3%) had measurable lesions, of whom 296 were evaluable for landmark analysis. 28 (9.5%) had progressive disease (PD) prior to day 90, while 58 (19.6%) had unconfirmed partial response (PR), i.e. declines ≥30% of the sum of diameters of target lesions. Median OS beyond day 90 for men with PR, stable disease (SD), and PD was 28.3, 23.3, 11.4 months, respectively (P < 0.001). In a multivariable analysis adjusting for pain, PCWG-2 subtype, type of progression (PSA vs. other), Gleason Score (≤ 7 vs. > 7), PSA, derived neutrophil-lymphocyte ratio, ECOG performance status and alkaline phosphatase, the hazard ratio (HR) for OS for patients with PR was 0.64 (95% CI 0.42 – 0.99, P = 0.045) compared to those without PR, and 1.78 (95% CI 1.07 – 2.95, P = 0.026) for those with PD compared to those without PD. PD remained significant (HR = 1.85, 95% CI 1.10 – 3.12, P = 0.020) after adjusting for PSA changes, but PR (P = 0.14) did not. Conclusions: In men with mCRPC receiving first-line docetaxel-based chemotherapy PR and PD by RECIST 1.0 within 90 days were associated with longer or shorter OS, respectively. Given the more frequent detection of measurable disease with current imaging, the accrual of patients with measurable tumors in phase II trials to assess RECIST changes may provide an objective signal of efficacy of new drugs.