bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of thalidomide on the TGFβ-1-mediated synthesis of testosterone from DHEA in prostate cancer.
Authors: Sissung Tristan , Kirkland C. Tyler , Reece Kelie M , Arnold Julia T , Figg William Douglas
Published: February 2017

141

Background: TGFβ-1 induces conversion of DHEA to testosterone in prostate cancer stromal cells. We hypothesized that thalidomide would inhibit TGFβ-1-mediated formation of testosterone from DHEA.

Methods: We grew LAPC4 or LNCaP prostate cancer epithelial cells and 6S primary prostate stromal cells in mono-/co-culture with DHEA (100nM) and/or TGFβ-1 (40 or 100pM). Testosterone and PSA concentration in media were ascertained using ELISA and corrected for cell count using CCK8 (%DHEA controls).

Results: TGFβ-1 and DHEA induced a dose-dependent increase in the formation of testosterone over controls (∼5-6 fold; P<0.0001). Thalidomide (100μM) inhibited the formation of testosterone in cocultured cells treated with DHEA and TGFβ-1 (40pM) by 35% (P=0.0008). The thalidomide analogues, CPS49 (10μM) and lenalidomide (10μM) also had activity; CPS49 inhibited testosterone synthesis by 54% (P=0.010) while lenalidomide reduced testosterone by 15% (P=0.011). However, only thalidomide and CPS49 decreased median PSA secretion (40% and 93% respectively; P≤0.031). Other angiogenesis inhibitors (i.e., suramin (10μM) and sorafenib (500pM)) had no effect on testosterone synthesis (P>0.05). Therefore, anti-androgen activity was not a class effect of antiangiogenesis agents. Ketoconazole also did not have activity suggesting that TGFβ-1-induced testosterone synthesis from DHEA evades standard therapies designed to inhibit androgen synthesis enzymes (i.e. CYP3A4 and CYP17 inhibitors). We assessed the phosphorylation status of TGFβ-1 pathway constituents (i.e., SMAD2/3, p38, JNK, and ERK) in cocultured cells treated as above. Thalidomide inhibits the phosphorylation of ERK without affecting total ERK levels; however, neither MEK inhibition (via U0126) nor Raf inhibition (via sorafenib) resulted in anti-androgenic effects in these cells suggesting that the canonical RAF/MEK/ERK pathway is not responsible for the difference in testosterone secretion phenotype.

Conclusions: These results indicate that thalidomide and its analogues have anti-androgen activity and may explain the success of thalidomide and its analogues in clinical treatment of hormone-dependent and castration-resistant prostate cancer.
An analysis to quantify the overall survival (OS) benefit of sipuleucel-T accounting for the crossover in the control arm of the IMPACT study.
Authors: Nabhan Chadi , Gomella Leonard G. , DeVries Todd , Whitmore James Boyd , Frohlich Mark Walter , George Daniel J.
Published: February 2017

144

Background: Sipuleucel-T is an autologous cellular immunotherapy approved for the treatment of asymptomatic or minimally symptomatic metastatic castrate resistant prostate cancer (mCRPC). Our previous analyses on the effect of salvage crossover treatment with a product constructed from previously frozen cells (APC8015F) on OS in the control arms of mCRPC studies of sipuleucel-T suggested a positive treatment effect with salvage therapy (George DJ et al. JCO 2011;29:abstr 139). To quantify how treatment with APC8015F might have impacted the OS of the IMPACT study, we performed an exploratory analysis adjusting for the potential bias that salvage APC8015F might have had in estimating the OS advantage of sipuleucel-T.

Methods: After objective disease progression, patients (pts) in the control arm were offered 3 infusions of APC8015F, an autologous immunotherapy made from cells cryopreserved at the time of control generation. A rank-preserving structural failure time (RPSFT) model, as previously described, was applied to adjust the sipuleucel-T treatment effect.

Results: In the 512-pt IMPACT study, there was a 4.1-month median improvement in OS (25.8 vs 21.7 months) for sipuleucel-T compared to control (HR=0.78; 95% CI: 0.61, 0.98; p=0.032). 109/171 (64%) of control pts received APC8015F; other post-progression interventions were balanced. Median OS was 23.8 months for control pts receiving APC8015F and 11.6 months for control pts not receiving APC8015F. Using the RPSFT model, and assuming APC8015F was equally as effective as sipuleucel-T, the estimate of median OS for control was 18.0 months (HR=0.60, 95% CI: 0.41, 0.95), representing a 7.8-month median improvement in OS in favor of sipuleucel-T. Results from extensions of the RPFST model, where APC8015F is assumed to have less treatment effect than sipuleucel-T, will be presented.

Conclusions: Adjusting for a positive effect of APC8015F in the control arm resulted in a sipuleucel-T OS treatment benefit in the IMPACT study ranging from 4.1 to 7.8 months. These results support a greater treatment effect of sipuleucel-T than reported in the IMPACT study and should be factored into future studies without APC8015F crossover.
Early detection of high-grade prostate cancer using digital rectal examination in men with a normal PSA and risk of death.
Authors: Hattangadi Jona Ashok , Chen Ming-Hui , Sun Leon , D'Amico Anthony Victor
Published: February 2017

147

Background: A digital rectal examination (DRE) is less commonly practiced in the PSA screening era. Whether detection of high-grade prostate cancer (PC) while still clinically localized on DRE can improve survival in men with a normal PSA is unknown.

Methods: From the Surveillance, Epidemiology and End Results database, 166,498 men with PC diagnosed between 2004-2008 were identified. Logistic regression was used to identify factors associated with the occurrence of palpable, PSA-occult (PSA <2.5 ng/ml) and Gleason score (GS) 8-10 PC. Factors examined included age at and year of diagnosis and race. Fine and Grays and Cox multivariable regression were performed to analyze whether these factors, treatment and known prognostic factors were associated with the risk of PC-specific mortality (PCSM) and all-cause mortality (ACM), respectively.

Results: Of 166,498, 685 men (0.4%) had palpable, PSA-occult and GS 8 to 10 PC. Median age and PSA at diagnosis in this group were 68 years [IQR: 61-75] and 1.5 ng/ml [IQR: 1-2], respectively. Most (83%) men were white. Both increasing age (adjusted odds ratio (AOR): 1.02 [95% confidence interval (CI) 1.01-1.03]; p<0.0001) and white race (AOR: 1.26 [95% CI 1.03-1.54]; p =0.03) were associated with palpable, Gleason 8 to 10 PC with normal PSA. Significant factors associated with an increased risk of PCSM and ACM in this cohort are shown in the table. For these 685 men, detecting locally advanced as compared to localized PC on DRE was associated with a significantly lower survival (p = 0.0001).

Conclusions: Detecting PSA-occult high-grade PC with DRE while disease remains clinically localized amongst high-risk men (over age 68 and white race) has the potential to improve survival.

[Table: see text]
Prospective determination of long-term toxicity and quality of life (QoL) of patients with prostate cancer after intensity-modulated radiotherapy (IMRT).
Authors: Goineau Aurore , Marchand Virginie , Bourdin Sylvain , Rio Emmanuel , Campion Loic , Lisbona Albert , Mahe Marc-Andre , Supiot Stephane
Published: February 2017

151

Background: To determine prospectively long-term toxicity and quality of life (QoL) of prostate cancer patients after intensity-modulated radiotherapy (IMRT).

Methods: 55 patients with localized prostate adenocarcinoma were treated by IMRT (76 Gy) between February and November 2006. Physicians scored acute and late toxicity using the Common Terminology Criteria for Adverse Events version 3.0. Patients assessed general and prostate-specific QoL before IMRT (baseline) and at 2, 18 and 54 months using European Organization for Research and Treatment of Cancer questionnaires QLQ-C30 and QLQ-PR25.

Results: Median age was 73 years (range 54-80 years). Risk categories were 18% low risk, 60% intermediate risk, and 32% high risk. The incidence of urinary and bowel toxicity immediately after IMRT (n=55) was, respectively, 36.8% and 23.7% (grade 1), 5.3% and 5.3% (grade 2), 2.6% and none (grade 3). At 18 months (n=55), it was 23.7% and 10.3% (grade 1), 26.3% and 13.2% (grade 2) and none and 2.6% (grade 3). At 54 months (n=38), it was, 34.2 and 23.7% (grade 1), 5.3% and 15.8% (grade 2) and 5.3% and none (grade 3). After 54 months, there was a statistically significant worsening of QoL with regards to 11 items among the 19 studied. However, the scores were clinically relevant (decrease > 10 points) only for physical functioning, role functioning, social functioning, fatigue, pain, dyspnea and constipation. No statistical differences were shown between 54 months and baseline for general health, bowel symptom, treatment related symptoms and sexual activity. Concerning urinary symptoms, there was a statistically significant deterioration but not clinically relevant (difference < 10 points).

Conclusions: High-dose IMRT to the prostate with accurate positioning does not induce any clinically relevant deterioration in long-term urinary and gastrointestinal QoL. Deterioration in functioning items may also be related to age and comorbidities. To our knowledge, our study is the only prospective study regarding quality of life following prostate IMRT with a very long follow-up of 54 months.
Palliative radiotherapy for prostate cancer: Outcomes of a weekly schedule of 6 fractions of 5 or 6Gy.
Authors: Tolan Shaun P. , Mbanu Peter , Walshaw Richard C. , Robson Peter , Eswarvee Chinnamani , Ibrahim Azman , Malik Zafar , Littler John , Syndikus Isabel
Published: February 2017

160

Background: In the current era of PSA screening and advances in image guided intensity modulated radiotherapy, not all patients with carcinoma of the prostate (CaP) are suitable for radical radiotherapy (RT). Some patients have locally advanced disease and are unfit for radical RT or have significant local symptoms with coexisting metastatic disease. The outcomes of a weekly palliative RT schedule of 6 x 5 or 6Gy fractions are reported.

Methods: This retrospective analysis identified 80 patients with CaP who received palliative prostate RT between 2003 and 2007. 62 patients received six, weekly fractions of 3D conformal RT and are included in this study. Clinico-pathological data of the cases are presented along with the clinical outcomes and survival data. Median follow up was 16.5 months.

Results: 62 patients (median age 70 yrs), received 30Gy (87%) or 36Gy (10%) in 6 fractions over 6 weeks. Two patients received 27Gy. Gleason score at diagnosis was ≤6, 7, or 8–10 in 21%, 16% and 45% of cases respectively and was associated with a median PSA of 53ng/ml, and T3/4 stage in 59%. The median time from diagnosis to RT was 15.9 months and prior to RT, treatment included hormone therapy (100%), TURP (60%) and chemotherapy (13%). Disease was metastatic in 68% and castrate resistant in 77% of cases. ECOG performance status was 0–1 in 44% and 2–3 in 24%. No patients with PS 4 were treated over 6 weeks. Indications for RT were obstructive urinary symptoms (69%), pain (44%), haematuria (35%), obstructive bowel symptoms (23%), and rectal bleeding (2%). At 3–6 months post-RT the frequency of these symptoms was 27%, 13%, 4%, 17% and 2% respectively. RTOG grade 3 or 4 bladder toxicity was 18% and grade 3 or 4 bowel toxicity was 6%. Median overall survival after RT was 16.0 months and on multivariate analysis lower pre-RT PSA and prior use of chemotherapy were predictive of improved survival.

Conclusions: A weekly fractionation schedule of 5 or 6Gy over 6 weeks provides effective palliation, particularly for the symptoms of urinary obstruction, pain and haematuria, and is associated with acceptable toxicity. The prognosis of this group of patients remains poor, but can be improved by the use of chemotherapy if clinically appropriate.
A phase II study evaluating the toxicity and efficacy of single-agent temsorilmus (TEM) in chemotherapy-naive castration-resistant prostate cancer (CRPC): First report of suggested activity.
Authors: Nabhan Chadi , Kruczek Kimberly , Tolzien Kathy , Galvez Angel G. , Lestingi Timothy M.
Published: February 2017

165

Background: PTEN tumor suppressor gene is mutated in CRPC allowing for downstream protein activation including mammalian target of rapamycin (m TOR) leading to tumor cell growth and survival. We investigated TEM; an mTOR inhibitor, in chemotherapy-naïve CRPC patients (pts).

Methods: Eligible pts received TEM at 25 mg weekly until disease progression. Responses were assessed every 8 weeks and toxicity every 4 weeks using CTCAE v.3. Quality of life (QOL) data were collected every cycle using two previously validated scales. Primary end point: Clinical Benefit (CB) [sum of complete response (CR), partial response (PR), and stable disease (SD)]. Secondary end points: Toxicity, time to next treatment (TTNT), time to radiographic and PSA progression (TTP and TTP-PSA respectively), impact on QOL, and overall survival (OS)

Results: To date, 18 pts have been enrolled. Median age was 75 (57–89) with Gleason ≥7 in 14 (77%), and median PSA 211.3 (10.8-1,449). Ten pts (55.5%) had bone and visceral disease. Median time on androgen deprivation therapy (ADT) was 60 months (17–240). Previous therapy included: surgery 3, brachytherapy 3, external radiation 5, ADT 7. All pts were evaluable for toxicity and 16 for response. Six pts (33%) were taken off study without progression (2 withdrew, 3 persitsant thrombocytopenia, 1 non-compliance). Biochemical response data was available for 15 pts (2 not evaluable, 1 refused), of which 4 (26%) had PSA decline and 1 (6%) had >50% drop in PSA. TTP-PSA was 2 months (2-12). Sixteen pts were evaluable by RECIST; 2 PR and 9 SD for a CB of 69% (11 of 16). TTP or event (toxicity that took pts off study was an event) was 3 months (3–10) and TTNT was 4 months (2–11). With a median follow up of 18 months, 8 pts (44%) remain alive for a median OS of 13 months. Most commonly reported grade 3/4 toxicities: Thrombocytopenia (22%), hyperglycemia, hypophosphatemia, and fatigue (17% each), pneumonia and anemia (12% each). TEM did not impact QOL adversely without treatment-related mortality.

Conclusions: TEM has activity in CRPC; some pts have CB without adverse impact on QOL. TEM should be further investigated in combination therapy in CRPC.
Metabolomics and histology on exactly the same ex vivo prostate biopsy.
Authors: Troyer Dean A , Shuster Jeffrey R , Lance Raymond S.
Published: February 2017

166

Background: Histopathology is the standard method for diagnosis and histological grading and staging of cancer. Molecular biomarkers are associated with cancer aggressiveness. One drawback to some molecular studies is that the portion of the tissue to be analyzed is processed in a manner that is destructive to the tissue. We present here a new method for performing analysis of small molecule biomarkers and histology in exactly the same biopsy tissue. The process, molecular Preservation by Extraction and Fixation (mPREF), allows traditional histological examination to be combined with qualitative and quantitative analysis of small molecule biomarkers.

Methods: 18 gauge core biopsies were obtained ex vivo from prostatectomy specimens. One core biopsy/specimen container was immersed in aqueous alcohol. After 12-24 hrs, biopsies were transferred to UMFIX, and the original alcohol retained. Histologic sections of biopsies were stained by routine methods and the immunohistochemical (IHC) stain, PIN4. Small molecular weight molecules in the retained alcohol were examined by a mass spectrometry-based method.

Results: Light Microscopy: Tumor and grade were evaluable and IHC for PIN4 performed well. Metabolomics of Retained Alcohol: From a single core biopsy, 260 named biochemical compounds and their relative concentrations WERE detected. 83 were different between the cancer and non-cancer biopsy extracts (p< .05). 18 of the 20 common amino acids, and a number of long chain fatty acids and phospholipids were increased. Highest fold changes, 4- to 6-fold, were observed in cysteine, dihomo-linoleate, docosapentaenoate, N-acetylaspartate, N-acetylglucosamine, uracil, xanthine, and 1-stearoylglycerophosphoinositol. A sub-set of candidate biomarkers were differentially expressed in pT3 vs pT2 disease.

Conclusions: MPREF allows for both histology and detection of small molecules in exactly the same tissue. The results suggest a higher metabolic state in cancer as compared with non-cancer containing biopsy tissues. Differential expression of small molecules from pT2 vs pT3 disease suggests that quantitative prognostic molecular and histologic data can be obtained from a single core biopsy.
Patterns of second-line chemotherapy for metastatic prostate cancer in the United States.
Authors: Wang Hongwei , Liao Laura , Obi-Tabot Eliot , Sands Robert , Rose Mathieu , Zhang Quanwu
Published: February 2017

169

Background: Patients with prostate cancer progressing from 1st line (1L) docetaxel had limited treatment options available. This study is to evaluate patterns of 2nd line (2L) chemotherapy in US managed care between 2004 and 2010.

Methods: Patients with metastatic prostate cancer (mPC) and treated with docetaxel as 1L chemotherapy after July 1, 2004 were ascertained from the OptumInsight database. We evaluated type and timing of chemotherapy and relationships between patient characteristics, physician specialty, healthcare costs and geographic region 6 months prior to 1L docetaxel and choice of 2L chemotherapy.

Results: Patients (n=1,173) were on average 71 years old at the onset of 1L docetaxel. During a mean follow-up period of 18 months, 38% patients received 2L treatment. Out of the patients received 2L therapy, 32% received mitoxantrone (MITO), 24% with docetaxel rechallenge (RECH), 14% carboplatin (CARB), and 12% paclitaxel (PAC), plus 11% on combo therapy. An examination of the 2L treatment groups showed that during the 6 months prior to 1L docetaxel, the RECH group (n=101) was older (73yrs), had fewer hospital admissions (12%), lower comorbidity burden (Charlson Comorbidity Index (CCI)=7.4), lower total healthcare costs ($10,083), and 78% patients seeing an oncologist; relative to MITO group (n=143) with 70 years of age, 16% hospital admissions, CCI of 7.5, total healthcare costs of $12,074, and 80% seeing an oncologist. The combo group (n=52) was 66 years old, with 19% hospital admissions, CCI of 8, total healthcare costs of $20, 505, and 92% seeing an oncologist. Median time to MITO from the start of 1L docetaxel was 184 days, 309 days to RECH and 223 days to combo therapy. Midwest (36%) and West (37%) were more frequently using MITO than Northeast (26%) and South (31%), while RECH was more frequently used in Northeast.

Conclusions: Patients with mPC in US were most frequently treated with MITO or RECH as 2L chemotherapy after 1L docetaxel. MITO was also given sooner than RECH, hence a valid comparator for comparative effectiveness evaluation on new 2L therapy. Rechallenge with docetaxel increased with time and was given to patients with lower disease burden and healthcare costs than the MITO or Combo group.
Prediction of survival in patients with metastatic prostate cancer by single nucleotide polymorphisms of cancer-associated genes.
Authors: Inoue Takamitsu , Tsuchiya Norihiko , Matsui Shigeyuki , Kamba Tomomi , Mitsuzuka Koji , Hatakeyama Shingo , Horikawa Yohei , Ohyama Chikara , Saito Seiichi , Arai Yoichi , Ogawa Osamu , Habuchi Tomonori
Published: February 2017

177

Background: Individual genetic variations may have a significant influence on the survival of metastatic prostate cancer (PCa) patients. We aimed to identify target genes and their variations involved in the survival of PCa patients using a single nucleotide polymorphism (SNP) panel.

Methods: A total of 185 PCa patients with bone metastasis at initial diagnosis were analyzed. Each patient was genotyped using a Cancer SNP panel that contained 1421 SNPs in 408 cancer-related genes. SNPs associated with the survival were screened by log rank test. A prognostic scoring index using selected SNPs was developed by incorporating the difference in their effect sizes to classify high-risk and low-risk groups and its predictive accuracy was assessed.

Results: Fourteen SNPs in six genes, XRCC4, PSM1, GATA3, IL13, CASP8, and IGF1, were identified to have statistically significant association with the cancer-specific survival. The cancer-specific survivals of patients grouped according to the number of risk genotypes of 6 SNPs selected from the 14 SNPs differed significantly (0-1 vs 2-3 vs 4-6 risk genotypes, P = 7.20×10−8). The predictive model using the 14 SNPs showed a statistically significant cross-validated accuracy in predicting the groups at high and low risk groups for poor survival (P = 0.0050). The high-risk group was independently associated with the survival in a multivariate analysis that included conventional clinicopathological variables (P = 0.0060).

Conclusions: Using a panel of the SNPs, the prediction of the survival and optimization of the individualized treatment for patients with advanced PCa may be possible.
Predictive biomarkers in circulating tumor cells (CTC) from patients with castration-resistant prostate cancer (CRPC) through genomic analysis.
Authors: Danila Daniel Costin , Anand Aseem , Yao Jianchao , Gierszewska Magdalena , Kramer Melissa , Muller Stephanie , Fleisher Martin , McCombie William R. , Scher Howard I.
Published: February 2017

179

Background: Although designed to retain activity against known androgen receptor (AR) mutants, it is predicted that new MDV3100-resistant mutations may predict for sensitivity to the drug in clinic. To predict for tumor sensitivity to treatment with novel AR targeted therapies, we explored the frequency of mutation detection and copy number alteration in CTC isolated from patients with CRPC enrolled on a trial with MDV3100.

Methods: We used fluorescence-activated cell sorting (FACS) methodology to enrich EpCAM+, CD45−, DAPI− cells. For mutation detection and genomic copy number alteration in CTC in low number of cancer cells found in clinical samples, we optimized next-gen deep sequencing by Illumina.

Results: In patients with progressive CRPC, >10 or >50 EpCAM+ events (EPE) were isolated by FACS in 88% or 58% of patients, in whom 32% and 10% had unfavorable (>5 cells/7.5 ml) CTC counts using CellSearch. EPE, expressing prostate-specific mRNAs, provide sufficient high quality DNA for genomic sequencing and copy number analysis. Adequate coverage was obtained from as few 50 EPE, with a recovery rate of 89% from FACS sorted samples. The detection threshold of a mutation was established at 1:4 alleles. To further expand genomic profiling in CTC, we optimized Nimblegen exome mutation detection by deep sequencing on HiSeq PE101. Our initial analysis established the polymorphism frequency detection thresholds in heterogeneous cell populations, and confirmed the sequencing coverage. Somatic missense mutations in AR, APC and TP53 found in CTC but not in paired WBC were confirmed by Sanger sequencing. In parallel, copy number alterations in CTC are studied.

Conclusions: Somatic mutations detected in CTC isolated from patients with CRPC can serve as predictive markers of tumor sensitivity to targeted therapies. We established standard operating procedures for specimen processing, and confirmed the sequencing coverage and polymorphism detection thresholds in heterogeneous cell population. Currently we are proceeding to clinical samples to study the associations between specific molecular alterations in CTC as predictive markers of sensitivity and clinical outcomes.
Immune responses in prostate tumor tissue following neoadjuvant sipuleucel-T in patients with localized prostate cancer.
Authors: Fong Lawrence , Weinberg Vivian K. , Corman John M , Amling Christopher L , Stephenson Robert A , Formaker Carl , Chan Stephen E , Simko Jeffrey , Sims Robert Brownell , Carroll Peter , Small Eric Jay
Published: February 2017

181

Background: Sipuleucel-T is an FDA-approved autologous cellular therapy that has been demonstrated to prolong overall survival in patients with asymptomatic or minimally symptomatic metastatic castrate resistant prostate cancer (mCRPC). To better understand the immunologic effects of sipuleucel-T, an open-label Phase 2 study (P07‐1; NCT00715104 ) of sipuleucel-T prior to radical prostatectomy (RP) was undertaken in patients with localized prostate cancer.

Methods: Patients received 3 infusions of sipuleucel-T at approximately 2-week intervals, beginning 6–7 weeks prior to RP. Prostate biopsies (pre-treatment) and tissue from RP (post-treatment) were assessed for the presence of lymphocytes by immunohistochemistry (IHC).

Results: The median age of the 42 enrolled patients was 61 years, and all had an ECOG performance status of 0. Thirty-eight patients received all 3 pre-RP infusions of sipuleucel-T. To date, tissue IHC analysis has been completed in 19 patients. Treatment-related AEs were manageable and reversible. Sipuleucel-T did not appear to impact surgery, as judged by operative complications, procedure time, and estimated blood loss. Frequent events that occurred ≤1 day after infusion (>10% of patients) were fatigue, headache, and myalgia. Significant increases (>2‐fold) in CD3+ and CD4+ T cells populations were observed at the tumor rim (where benign and malignant glands interface), compared with the pre-treatment biopsy (ANOVA post hoc Newman-Keuls test: p=0.0002, 0.0002, respectively). CD8+ T cells or CD56+ cells were not significantly increased at the tumor rim compared with benign biopsy regions.

Conclusions: Neoadjuvant sipuleucel-T treatment appears to result in an increased frequency of T cells in prostate cancer tissue at the rim between the benign and malignant glands. These data suggest that sipuleucel-T may modulate the presence of lymphocytes at the prostate tumor site. Work is ongoing to more fully characterize the immune response within the prostate tumor tissue and in the peripheral blood.
Pain control and delay in time to skeletal-related events (SREs) in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone acetate (AA): Long-term follow-up.
Authors: Basch Ethan M. , De Bono Johann Sebastian , Scher Howard I. , Molina Arturo , Sternberg Cora N. , Fizazi Karim , North Scott A. , Chi Kim N. , Jones Robert J. , Goodman Oscar B. , Mainwaring Paul N. , Farr Amanda M. , Rothman Margaret , Hao Yanni , Liu Cameron S. , Kheoh Thian San , Haqq Christopher M. , Efstathiou Eleni , Logothetis Christopher
Published: February 2017

183

Background: In study COU-AA-301, the androgen biosynthesis inhibitor AA significantly increased overall survival in mCRPC post-docetaxel (D) in both interim and updated analyses at 552 and 775 events, respectively. Interim data also showed a significant benefit of AA on patient (pt) reported pain. We present long-term outcomes of the effect of AA on pain and SREs.

Methods: In this international randomized double blind study of AA (1 g QD) + prednisone (P) (5 mg BID) vs placebo + P in mCRPC post-D, pain was assessed at baseline and each treatment cycle until treatment discontinuation using the BPI-SF questionnaire. Palliation/progression of pain intensity (P-INT) and pain interference (P-INF) were evaluated using a priori definitions. P-INT palliation was defined as ≥ 30% improvement in pt reported “worst pain in last 24 h” (on 0-10 numerical rating scale) durable for ≥ 28 d without increased analgesic use (by WHO criteria) in eligible pts (those with significant baseline pain). Conversely, P-INT progression was defined as ≥ 30% deterioration, or increased analgesic use, over ≥ 28 d.

Results: 797 pts were randomized to AA + P, 398 to placebo + P. Median follow-up was 20.2 mos. Median time to SRE was 25.0 mos (AA + P) vs 20.3 mos (placebo + P), p = 0.0001. Pain data were available for most patients; the cumulative amount of missing data ranged from 5% at Cycle 1 to 7% at Cycle 20. AA + P improved P-INT outcomes (Table); P-INF benefits were similar and also highly significant.

Conclusions: Benefits of AA + P observed in the interim analysis, including superior and more durable pain relief and delay of pain progression and SREs, were maintained with longer follow-up. Additional analyses of the potential relationships between pain/SREs and other outcomes, as well as of prednisone’s effect on pain palliation in the control arm, are ongoing.

[Table: see text]
Biochemical, pathologic, toxicity, and quality-of-life outcomes in a five-fraction hypofractionated accelerated radiotherapy treatment using standard linear accelerators and gold seed fiducials.
Authors: Loblaw D. Andrew , Cheung Patrick , Tang Colin I , Quon Harvey Charles , Pang Geordi , Morton Gerard , Mamedov Alexandre , D'Alimonte Laura , Deabreu Andrea , Tirona Romeo , Jain Suneil
Published: February 2017

186

Background: Biological dose escalation through hypofractionated image-guided radiotherapy (H-IGRT) holds the promise of improved patient outcomes, system capacity but decreased cost. In 2006 we initiated a prospective trial of H-IGRT of patients with low risk localized prostate cancer. In this report, we report the toxicities, quality of life (QOL), biochemical and pathologic outcomes of this cohort with more mature follow-up.

Methods: A phase I/II study in which patients with T1-2b, Gleason≤6, and PSA≤10 ng/ml prostate cancer received 35 Gy in 5 fractions, once a week over 29 days. No patients received hormone therapy. Treatment was delivered with intensity modulated radiotherapy (IMRT) on standard linear accelerators, with daily image guidance using gold seed fiducials, and a 4 mm CTV-PTV margin. CTCAE v3.0 and RTOG late morbidity scores were used to assess acute and late toxicities, respectively. QOL was assessed by the Expanded Prostate Cancer Index Composite (EPIC). Biochemical control (BC) was defined by the Phoenix definition, adjusted for benign bounce.

Results: As of September 2011, 83 patients have completed treatment with a median follow-up of 42 months (range 12–60 months). Median age was 67y (42 – 82y). 78 patients (92%) were T1a-c; all had Gleason 6 cancers; median PSA was 5.3 (0.8 – 9.9 ng/ml). 82 (99%) had BC; the remaining patient had a negative biopsy and a history of chronic prostatitis. The median PSA on last visit was 0.69 ng/ml (.02 – 2.6 ng/ml). Of 59 patients who have had a biopsy to date, 2 (3%) were positive but both are under BC. The following toxicities were observed: acute grade 3+: 0% GI, 1% GU, 0% fatigue; late grade 3+: 1% GI, 1% GU. Median transformed QOL scores at baseline (0.5 SD) and 36mo follow-up are: urinary – 95% (4.1), 93%; bowel – 96% (4.8), 96%; sexual – 65% (13.7), 51%; and hormonal – 95% (5.3), 95%.

Conclusions: This novel technique employing standard linear accelerators to deliver an extreme hypofractionated schedule of radiotherapy is feasible, well tolerated and shows excellent pathologic and biochemical control. A randomized study versus standard fractionation should be performed.
Physical activity and prostate gene expression in men with low-risk prostate cancer.
Authors: Magbanua Mark Jesus Mendoza , Richman Erin L , Sosa Eduardo V , Jones Lee , Simko Jeffrey , Shinohara Katsuto , Haqq Christopher M. , Carroll Peter , Chan June M.
Published: February 2017

189

Background: Physical activity (PA), in particular longer duration or higher intensity, may reduce the risk of PCa progression and PCa-specific mortality in men diagnosed with clinically localized PCa. However, the molecular mechanism(s) by which PA exerts its protective effect in the prostate remains unknown. We examined the correlation of PA and gene expression patterns in men with low risk prostate cancer who elected to undergo active surveillance.

Methods: Morphologically normal prostate tissue was obtained from men who subsequently participated in a clinical trial focused on nutritional supplements (previously published microarray dataset #GSE27140). Of the original sample (n=84), 70 completed a brief PA questionnaire and were dichotomized based usual PA [e.g. any vigorous PA (yes/no), 3+ h/wk vigorous PA (yes/no)]. Differential expression and pathway (gene set) analyses between groups were performed using Significance Analysis of Microarrays. Genes and gene sets with a false discovery rate ≤0.10 and 0.20 were considered significant, respectively.

Results: Gene expression analysis detected 184 significant genes that were differentially expressed between men who performed vigorous PA for 3+ h/wk (n=23) and those who did not (n= 47). Up-regulated genes included the known tumor suppressors, BRCA1 and BRCA2. Furthermore, pathway analysis revealed that cell cycle and DNA repair pathways were positively modulated in men who participated in 3+h/wk vigorous PA vs. not. Consistent with the data on vigorous PA and clinical outcomes in men with PCa, the duration of vigorous PA was important; there were no significant genes detected when comparing men who participated in any vigorous PA to men who did none.

Conclusions: Prostate gene expression and pathway analyses revealed candidate genes and in vivo pathways that may be modulated by participating in 3+ h/wk of vigorous PA. These data provide mechanistic insight into how 3+ h/wk of vigorous PA may offer PCa-specific benefits. Furthermore, understanding the molecular mechanisms by which such PA affects normal prostate gene expression may aid the development of strategies to prevent or delay PCa progression.
The influence of physician densities and patient characteristics on the decision to treat prostate cancer patients with varying clinical benefit.
Authors: Yu James B. , Aneja Sanjay , Makarov Danil V. , Roberts Kenneth B , Gross Cary P.
Published: February 2017

19

Background: Our study investigates whether regional variations in physician densities or patient populations influence the decision to treat patients with prostate cancer.

Methods: Data from the NCI Surveillance, Epidemiology, and End Results (SEER) database was combined with the health system factors from the Area Resource File for Health Service Areas (HSA). Patients treated from 2004-2007 with low likelihood of benefit from treatment (Gleason 6, PSA <10.0, stage T1cN0M0, and age >75) or high likelihood of benefit (Gleason 8-10 or PSA >20.0 or stage T3N0M0, aged <60) were analyzed. Health system factors analyzed were; radiation oncologist, urologist, and primary care provider densities, % unemployment, and % with at least a high school education. Patient factors analyzed included race and marital status. A logistic regression model was built to test the association between variables and attempted curative therapy (radical prostatectomy, EBRT, and/or brachytherapy).

Results: For the 2630 pts with the lowest likelihood of benefit, 56.1% underwent some form of attempted curative therapy. White pts and those residing in HSAs with better-educated populations were less likely to be treated, whereas married pts (OR 0.69 [SE 0.07, p<.001]) were more likely to receive treatment. For the 3207 pts with the highest likelihood of clinical benefit from treatment, 91.1% underwent curative therapy as first initial treatment. Being married was again associated with a higher odds of curative therapy (OR 1.68 [SE 0.22], p<.001) whereas being black was associated with a lower odds (OR 0.43 [SE 0.16], p=.02). Both radiation oncologist density and urologist density were not found to influence receipt of treatment in either group.

Conclusions: Radiation oncologist and urologist densities do not seem to influence the decision to treat prostate cancer at the regional level, whereas marital status is a significant predictor of attempted treatment. Though health system factors may influence the receipt of proper therapy, a patient’s decision-to receive treatment is potentially more influenced by his interpersonal relationships.
VT-464: A novel, selective inhibitor of P450c17(CYP17)-17,20 lyase for castration-refractory prostate cancer (CRPC).
Authors: Eisner Joel Robert , Abbott David H , Bird Ian M , Rafferty Stephen W , Moore William R , Schotzinger Robert J
Published: February 2017

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Background: CYP17 is a single protein with two distinct enzyme activities, 17 α-hydroxylase (hydroxylase) and 17,20-lyase (lyase). Reduction of extragonadal androgen production through CYP17 inhibition is a validated CRPC treatment paradigm. While treatment with the recently-approved CYP17 inhibitor, abiraterone acetate (AA), increases overall survival in post-docetaxel CRPC patients (de Bono et al, N Engl J Med 2011; 364:1995–2005), it is also associated with cortisol (F) suppression and increased steroid concentrations up-stream of CYP17 hydroxylase. The clinical candidate VT-464 is an oral, non-steroidal, lyase-selective CYP17 inhibitor. The study objectives were to compare VT-464 to abiraterone in regards to in vitro selectivity and to compare VT-464 to AA in regards to in vivo primate endocrine response.

Methods: Human CYP17 hydroxylase and lyase IC50 values were determined for VT-464 and abiraterone in vitro. Plasma progesterone (P), F, and testosterone (T) responses were measured 0-24 hours after single subcutaneous doses of AA (12.5 mg/kg), VT-464 (6.25 and 12.5 mg/kg), or vehicle in adult, castrate, male rhesus monkeys.

Results: Human lyase and hydroxylase IC50 values were 69nM and 670nM for VT-464 and 15nM and 2.5nM for abiraterone, respectively. AA and both dose levels of VT-464 produced a similar overall reduction in plasma T, compared to vehicle (p ≤ 0.009). AA treatment resulted in an elevated plasma P (peak increase >9,000%; p ≤ 0.05), compared to both VT-464 treatments and vehicle. F was not affected by either VT-464 dose, whereas AA resulted in F suppression (p ≤ 0.005) compared to vehicle.

Conclusions: VT-464 was 10-fold more selective for human CYP17 lyase vs. hydroxylase inhibition. This selectivity was associated with androgen suppression, but not increases of up-stream steroids or F suppression in male monkeys. In contrast, abiraterone was 6-fold more selective for hydroxylase vs. lyase inhibition resulting in associations with increased up-stream steroids and F suppression in AA-treated male monkeys, consistent with clinical observations in CRPC. VT-464 may thus provide a more lyase-selective alternative to AA for extra-gonadal androgen suppression in CRPC.
Efficacy of docetaxel and prednisone in men with metastatic castration-resistant prostate cancer (mCRPC) exposed to prior ketoconazole (KC).
Authors: Pond Gregory Russell , Armstrong Andrew J. , Wood Brian A. , Leopold Lance Howard , Galsky Matt D. , Sonpavde Guru
Published: February 2017

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Background: The efficacy of docetaxel following exposure to androgen synthesis inhibitors such as KC or abiraterone acetate (AA) is unknown. Given the emerging use of pre-docetaxel AA and docetaxel’s inhibition of androgen signaling, we retrospectively evaluated the efficacy of every 3 week docetaxel with prednisone (DP) in mCRPC previously exposed to KC as compared to KC-naïve patients.

Methods: A randomized phase II trial of men with mCRPC treated with DP+AT-101 (bcl-2 inhibitor) vs. DP+placebo was analyzed (stratified for pain and performance status). Both arms were combined for analysis as no significant differences were seen. Overall survival [OS], progression-free survival [PFS], objective response [ORR], pain and PSA response rates were estimated with and without prior KC.

Results: Of 220 evaluable men, 40 (18.2%) received prior KC (median duration=2.0 months, maximum=31.1 months). These 40 men had less visceral disease (15% vs 28%), more prior radiotherapy (70% vs 51%), and increased prior radiological (38% vs 21%) or bone scan progression (55% vs 41%). Efficacy outcomes were not statistically different (table). After adjusting for baseline stratum and treatment group, prior KC did not appear to significantly change OS with DP-based therapy (HR 1.34, 95%CI: 0.86–2.09, p=0.20).

Conclusions: Similar outcomes were observed in mCRPC treated with DP-based therapy with or without prior KC. Given the marginally inferior survival with prior KC, evaluation of docetaxel outcomes following AA is of clinical importance, given its more potent CYP17 inhibition.

[Table: see text]
The influence of daily localization during treatment of prostate cancer on acute toxicity.
Authors: Rossi Peter john , Cooper Sherrie , Jani Ashesh B.
Published: February 2017

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Background: Various localization techniques are used in clinical practice but little comparative effectivess data exists. The purpose of this investigation is to assess the impact of daily localization (L) of the prostate on toxicity during definitive treatment of prostate cancer with intensity modulated radiotherapy (IMRT).

Methods: This study details an IRB approved retrospective review of three cohorts of patients treated for prostate cancer utilizing IMRT and different L technologies at four academic hospitals. Patients were treated with no technique (N), gold markers (G), or electromagnetic beacons [Calypso] (C) for daily L. Acute genitourinary (GU) and gastrointestinal (GI) toxicity was assessed according to RTOG toxicity criteria; toxicity rates between the groups were compared using the chi-square test. Ordered logit regression of all major demographic (age, race), disease (PSA, Gleason grade, and T-stage) and treatment (hormones, pelvic nodal treatment, total dose, and prior TURP) characteristics on GU and on GI toxicity were performed.

Results: One hundred fifty four men who received definitive dose escalated IMRT (no brachytherapy or post-prostatectomy patients) for prostate cancer from 2006 to 2010 and were included (G: n=47; C: n=47; N: n=60). The cohorts were balanced except race (higher percentage of African Americans in the N group, due to hospital demographics) and higher grade and use of pelvic nodal treatment (which were more common in the G and C groups). Bladder V40 and V70 were higher in the N group (45.4%/24.3%) compared to C (27.9%/12.3%) and G (37.4%/18.4%) groups; however, rectal V40 and V70 were similar among all 3 groups. Toxicity results are shown in the Table; as shown the C and G groups had lower GU toxicity (p <0.001) respectively compared to the N group; no significant differences in GI toxicity were seen among the 3 groups. Ordered logit regression showed only daily L (p=0.041) reached significance in lowering GU toxicity, and only pelvic RT use (p =0.008) reached significance in increasing GI toxicity.

Conclusions: In patients treated with IMRT, daily L was associated with lower acute GU toxicity but not acute GI toxicity.
A randomized phase II study of bicalutamide (BIC) followed by placebo or gamma secretase inhibitor RO4929097 (RO492) in men with rising PSA.
Authors: Stein Mark N. , DiPaola Robert S. , Mayer Tina M. , Jeyamohan Chandrika , Metzger Dorinda , Anand Monica , Ivy S. Percy ,   Prostate Cancer Clinical Trials Consortium
Published: February 2017

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Background: Notch signaling is a key determinant of cell fate. RO492 is a selective γ-secretase inhibitor blocking cleavage of Notch. We hypothesize that anti-androgen therapy will lead to an enriched population of basal prostate cancer stem cells. Targeting Notch following anti-androgen treatment will lead to delay in re-growth of mature luminal PC cells. We are using a novel double blind, placebo controlled randomized discontinuation design to treat men with rising PSA. A non-castrating anti-androgen (BIC) was used to induce initial tumor regression

Methods: Pts with rising PSA after primary therapy for PC, and no radiographic evidence of disease were enrolled in this ongoing study. All pts received BIC 50mg/day for 16 weeks (induction phase). Pts achieving a >50% (modified from 80% decrease after the first 8 pts) decrease in PSA were randomized to placebo or RO492 20mg orally 3 days on/ 4 days off per week (randomization phase). Primary endpoint is PSA progression (increase in PSA by 50% over nadir with minimum PSA rise of 2ng/mL) during randomization phase. Pts meeting primary endpoint could receive 12 months of RO492 and BIC (combination phase). Serum is collected for evaluation of soluble markers of gamma secretase inhibition. 29 pts/arm in randomization phase gives 90% power to detect a decrease in1 yr PFS from 80% to 45% with 5% alpha.

Results: We report on the first 16 patients that have enrolled. Median pretreatment PSA was 6.3ng/ml (0.35 to 34). 9 of 16 pts on the induction phase came off study due to PSA progression, although 5 of 9 pts would have been randomized using the 50% PSA response criteria. 6 pts have been randomized to RO492 or placebo (1 pt not yet randomized) and 2 pts have proceeded to combination phase. Median PSA decrease during induction phase in 6 pts who went on to randomization was 86% (69–97). Overall decline in PSA in induction phase was 67% (7.3-99%). Placebo/RO492 has been well tolerated with 1 pt experiencing g1 fatigue, and 1 pt experiencing g1 nausea in the combination phase. 8/16 pts had g1 breast tenderness with BIC.

Conclusions: In this ongoing randomized phase II trial, BIC decreased PSA by >50% in 12/16 pts. Placebo/RO492 is well tolerated. Enrollment continues with analysis of plasma correlates to be compared to clinical results.
Effect of a therapeutic sphingosine 1-phosphate antibody on intratumoral hypoxia and standard chemotherapy in a preclinical model of prostate cancer.
Authors: Cuvillier Olivier , Ader Isabelle , Bouquerel Pierre , Sabbadini Roger Allen , Malavaud Bernard
Published: February 2017

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Background: Hypoxia promotes vascularization, metastasis and resistance to treatments. The activation of HIF-1α is identified as the master mechanism of adaptation to hypoxia. We recently identified the sphingosine kinase 1/sphingosine 1- phosphate (SphK1/S1P) pathway as a new modulator of HIF-1α activity under hypoxia in multiple cancer cell models (Ader et al, Cancer Res, 2008). S1P elicits proliferation, survival, or angiogenesis, and is believed to exert most of its actions as a ligand for a family of specific GPCRs to elicit paracrine or autocrine signaling. We have suggested that inhibiting SphK1/S1P signaling, which is upregulated under hypoxia, may normalize the microenvironment and increase sensitivity to chemotherapy, in the broader concept of «normalization of tumor vessels» as tumor oxygenation is known to enhance response to chemotherapy (Ader et al., Cancer Res, 2009).

Methods: Quantitation of hypoxia and angiogenesis, and treatment efficacy using an orthotopic (o.t) xenograft model of fluorescent HRPC cells.

Results: We provide in vitro evidence that inhibiting the S1P exogenous signaling, through pharmacological inhibition of its receptors or by taking advantage of a monoclonal antibody neutralizing S1P, blocks HIF-1α accumulation and its activity in prostate cancer cells under hypoxia. Second, using an o.t model of prostate cancer, we show that an anti-S1P antibody inhibits intratumoral hypoxia, modifies vessel architecture and improves tumor perfusion within 5 days of treatment. Third, we demonstrate that an anti-S1P strategy sensitizes to docetaxel, the ’gold standard’ treatment for HRPC. A 5-day anti-S1P antibody pretreatment markedly sensitizes to docetaxel in an o.t. PC-3/GFP model established in nude mice. The combination anti-S1P antibody together with docetaxel was not only accompanied by a smaller primary tumor volume compared to docetaxel alone, but also significantly reduced the occurrence and number of metastases.

Conclusions: These data establish the proof-of-concept that blocking the exogenous action of S1P reduces intratumoral hypoxia and sensitizes to chemotherapy in prostate cancer animal model.