bluuebunny/crossref_metadata_2025 huggingface dataset:
Serum proteomics guided discovery of predictive biomarkers of response to androgen ablation (AA) in prostate cancer.
Authors: Kohli Manish , Oberg Ann L. , Mahoney Douglas W. , Riska Shaun M , Zenka Roman M , Sahasrabudhe Deepak M. , Zhang Sheng
Published: February 2017

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Background: Currently there are no serum predictive markers of response to AA. We used a proteomic based analytic approach to identify candidates.

Methods: Serum from three non-localized prostate cancer cohorts was analyzed. The first included15 paired untreated hormone-sensitive “pre-AA” and 3-month “post-AA” specimens; the second included 10 “early AA failure” (median time to AA failure:11 months) and the third included 10 “late AA failure” specimens (median time to AA failure: 95 months). Proteomic analysis was performed with isobaric mass tags for relative and absolute quanititation (iTRAQ) analyzed by reverse-phase liquid chromatography coupled to tandem mass spectrometry (LC/MS/MS). Differentially expressed candidate proteins were identified by comparisons of (i) paired pre/post-AA proteomes and (ii) post-AA proteome with the combined AA failure cohorts at a False Discovery Rate of 0.2. ELISA assays were used to verify candidate markers in a second stored aliquot of first cohort specimens. This cohort was followed for AA failure. Association of post-AA ELISA levels of candidate markers with time to AA failure was performed using Cox proportional hazards regression, summarized as relative risk (RR) for AA failure.

Results: Median PSA in pre/post-AA first cohort were 3.15 ng/ml and 0.29 ng/ml. Median PSA in the second and third cohorts were 27.3 and 4.3 ng/ml. Between post-AA and AA failure cohorts, 149 proteins were differentially expressed. Between early and late AA failure 98 proteins were differentially expressed; 47 proteins were common in both comparisons. ELISA assays verified expression levels of 2/47 proteins in the first cohort; zinc alpha-2 macroglobulin (ZAG), and Neuropilin-2 (NPL2). Median change in ZAG decreased by 2073.5 ng/ml (post versus pre-AA) while median change in NPL2 levels increased by 2.9 ng/ml. After a median follow-up of 43 months from the post-AA time-point, 4/15 first cohort subjects had failed AA. The RR of AA failure for ZAG levels below the median change was 3.8 (95% CI: 0.4-37) and 3.0 (95% CI: 0.3-29) for NPL2.

Conclusions: A global proteomic analysis identified ZAG and NPL2 as candidate serum predictive markers of AA response which needs further validation.
Identifying cancer mutations in neuroendocrine prostate cancer (NEPC) through massively parallel DNA sequencing of formalin-fixed paraffin-embedded (FFPE) tissue.
Authors: Beltran Himisha , Park Kyung , Tagawa Scott T. , Yelensky Roman , Lipson Doron , Frampton Garrett , Stephens Philip J , Cronin Maureen T. , Nanus David M. , Mosquera Juan Miguel , Rubin Mark A.
Published: February 2017

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Background: NEPC is an aggressive and lethal variant of prostate cancer that most commonly arises from existing prostate adenocarcinoma (PCA). Little is known about the underlying biology of NEPC, as metastases are rarely biopsied. The purpose of this study is to determine the spectrum of somatic mutations in NEPC by using a novel DNA sequencing platform and to evaluate for targetable molecular alterations.

Methods: 44 NEPC and mixed NEPC/PCA were evaluated and 77 high density foci of NEPC, PCA, and benign areas were selected for DNA extraction. Massively parallel sequencing via HiSeq2000 was performed using indexed seq libraries constructed by adapter ligation followed by hybridization with optimized capture probes. Data was processed using publicly available and newly validated software tools to make mutation assignments for base alterations, indels, and CNAs in 182 cancer associated genes and common sites of rearrangement for 15 genes.

Results: 5/8 biopsies and 62/65 (overall 93%) of prostate foci yielded sufficient DNA (>50 ng) for analysis from 40m of FFPE tissue. Average median sequence coverage was 934x. TMPRSS2-ERG fusion was present in 28% of NEPC. Recurrent homozygous deletions involving PTEN and RB1 were seen, and 1 tumor with BRCA2 loss. Several high confidence non-synonymous mutations were identified including TP53 (40%), CTNNB1 (12%), and less frequently mutations involving PTEN, PIK3CA, AR, as well as other novel mutations/fusions. There was high concordance between NEPC and PCA foci in mixed tumors, as well as between primary tumor and metastases. High confidence lesions were validated with exome sequencing and FISH.

Conclusions: This study shows feasibility of an in-depth DNA analysis using FFPE tissue, and even biopsy material. Comprehensive genome sequencing has nominated novel biologic pathways and provides insight into disease progression from PCA to NEPC, as well as potential new drug targets for a tumor that is currently lethal. This is a useful and comprehensive sequencing tool to evaluate tumors such as NEPC and other metastatic tumors, where obtaining tissue is challenging.
Impact of PCA3 on the number of repeat prostate biopsies and sensitivity to detect high-grade cancer in the placebo cohort of the REDUCE study.
Authors: Tombal Bertrand , Andriole Gerald L. , Smets Louis , Stoevelaar Herman
Published: February 2017

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Background: 10-35% of men with a negative initial biopsy (Bx) have prostate cancer (PCa) found on repeat Bx (rBx). Fear of missing significant cancer frequently results in, often negative, rBx. As Bx is associated with pain, anxiety and complications, a better individualization of the decision for rBx to reduce the number of rBx and overdiagnosis of indolent PCa is needed. Recently, we used the RAND Appropriateness Method (RAM) to develop a model for rBx patient selection, based on expert recommendations and including the PROGENSA PCA3 Assay (Tombal B, et al. World J Urol 2011;doi:10.1007/s00345-011-0721-0). PCA3 has been shown to predict the probability that a rBx will be positive and may be indicative of PCa significance (Aubin SMJ, et al. J Urol 2010;184:1947-52). In the current analysis, we tested the expert recommendations model on the placebo cohort of the REDUCE study.

Methods: The RAM expert recommendations were applied to the placebo cohort of the REDUCE study in which 1073 men with a baseline PSA 2.5-10 ng/mL and a prior negative Bx had a PCA3 test before the planned 2-year and 4-year rBx2. For each scenario (with and without PCA3), the number of rBx and the number of missed high-grade (Gleason sum ≥ 7) cancers were assessed.

Results: Data from 1024 subjects were available for analysis. In the scenario without PCA3 consideration (reflecting the experts’ recommendations using PSA, DRE, number of previous negative Bx, prostate volume and life expectancy), 267 (26%) of study-mandated rBx were considered inappropriate and the number of missed high-grade cancers was 14. The scenario including also PCA3 consideration led to a reduction of the number of rBx (656 or 64%), while the number of missed high-grade cancers was decreased to 8. The diagnostic accuracy was superior in the model with PCA3: sensitivity for high-grade cancer was 85% vs. 75%, specificity 67% vs. 26%, positive predictive value PPV 13% vs. 5%, NPV 99% vs. 95%.

Conclusions: Application of RAM expert recommendations for rBx that include the PCA3 Score can reduce the number of rBx for men with an elevated PSA while maintaining the sensitivity to detect high-grade cancer.
Single-fraction high-dose-rate (HDR) brachytherapy boost and hypofractionated radiation for intermediate- and high-risk prostate cancer: A report of toxicity from a single center experience.
Authors: Arthur Claire , Alam Nooreen Sarah , Mandall Paula , Swindell Ric , Elliott P. Anthony , Tran Anna , Livsey Jacqueline E. , Choudhury Ananya , Logue John P. , Wylie James
Published: February 2017

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Background: Single-fraction HDR brachytherapy offers a highly conformal approach to dose escalation for intermediate and high risk prostate cancer and exploits the apparent low α/β ratio of prostate cancer cells. The potential benefit of improving tumour control must be balanced against the heightened risk of toxicity. We assessed and compared toxicity among patients receiving either 12.5 Gy or 15 Gy as a single fraction HDR boost prior to conformal external beam radiotherapy (EBRT).

Methods: Between July 2008 and February 2011, 177 patients received HDR brachytherapy prior to conformal EBRT (37.5 Gy in 15 fractions). 95 patients in the early cohort received 12.5 Gy and 82 patients in the later cohort received 15 Gy. The median patient age at presentation was 67 (range 57 – 77) with a median PSA of 16.0 (range 0.29 – 102), median Gleason score 7 (range 6 – 10), clinical stages T1c to T4 and median baseline IPSS was 8 (range 0 – 27). Prospective patient questionnaires - IPSS, LENT SOMA and EPIC QoL - were completed prior to treatment and at regular intervals following EBRT (6 weeks, 6 monthly thereafter).

Results: Both treatment groups had similar median IPSS values at 6 weeks (12.5 Gy = 10, 15 Gy = 11); there was no significant difference in values throughout follow-up. Mean LENT SOMA scores for bladder/urethra toxicity peaked at 6 weeks (12.5 Gy = 0.6, 15 Gy = 0.72) with no trend towards greater reporting of maximum values of ≥ 2 in the 15 Gy cohort. Rectum/bowel mean LENT SOMA scores peaked at 6 weeks (12.5 Gy = 0.30, 15 Gy = 0.39). Although a greater proportion of 15 Gy patients reported a maximum score of ≥ 2 at 6 weeks and 6 months compared with the 12.5 Gy patients, this returned to pre-treatment levels at 12 months.

Conclusions: We conclude that dose escalation from 12.5 Gy to 15 Gy delivered in a single HDR fraction is not associated with a clinically significant increase in toxicity. We believe that the reported toxicity is acceptable at this level of dose escalation (2 Gy equivalent = 112 Gy, assuming an α/β ratio of 1.5). Ongoing follow-up is required to ascertain tumour control.
Changes in plasma metabolomic profiles during the first 3 months of androgen-deprivation therapy for prostate cancer.
Authors: Saylor Philip James , Karoly Edward D , Smith Matthew Raymond
Published: February 2017

116

Background: Androgen-deprivation therapy (ADT) with a GnRH agonist is the foundational systemic therapy for prostate cancer but causes gain of fat mass, loss of muscle mass, adverse changes in serum lipid profile, and a decline in insulin sensitivity. It is unknown whether ADT causes a broader pattern of metabolic alterations. In order to better characterize the metabolic effects of ADT, we measured changes in plasma metabolomic profile during the first 3 months of ADT.

Methods: Fasting plasma samples were drawn from 36 subjects at baseline and after 3 months (range: 71-112 days) of GnRH agonist therapy. Metabolomic analyses were performed by Metabolon, Inc (Durham, NC). Extracted samples were split into equal parts for analysis on the gas chromatography/mass spectrometry and liquid chromatography/tandem mass spectrometry platforms. Matched pairs t-test was used to identify biochemicals that differed between baseline and month 3.

Results: Of the 504 identified metabolites, 88 changed significantly (p<0.05) from baseline to 3 months. Consistent changes in biochemicals were grouped as follows: (a) Multiple steroids were lower at 3 months, consistent with the effect of therapy on gonadal androgen synthesis. (b) Markers of lipid beta-oxidation (acetyl-carnitines and ketone bodies) and omega-oxidation were lower at 3 months. (c) Two previously-identified biomarkers of insulin resistance (2-hydroxybutyrate and branch chain keto-acid dehydrogenase complex products) were lower at 3 months. (d) Most bile acids and their metabolites were higher during treatment. Cholesterol levels changed very little (1.06 fold change, P = 0.029).

Conclusions: Unbiased metabolomic analyses on fasting plasma samples from men receiving GnRH agonist therapy revealed expected, unexpected, and novel results. Steroid levels fell, consistent with the effects of ADT. Biomarkers of lipid metabolism and insulin resistance also fell, unexpected results given that ADT has previously been shown to decrease insulin sensitivity. Finally, we observed evidence of increased levels of bile acids and bile acid metabolites. Further investigation of this novel finding is warranted.
Impact of statin therapy on PSA kinetics during active surveillance of prostate cancer.
Authors: Rogers William , Rothschild Daniel , Bylund Jason R. , Venkatesh Ramakrishna , Demos Jon , Strup Stephen E. , Preston David , Crispen Paul L.
Published: February 2017

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Background: Statin therapy has been associated with decreased serum PSA levels in men undergoing prostate cancer screening, lower rate of adverse pathologic features in radical prostatectomy specimens and decreased risk of biochemical recurrence following prostatectomy. Here we evaluate the impact of statin therapy on PSA kinetics during active surveillance of prostate cancer.

Methods: A retrospective review of patients diagnosed with prostate cancer at our institution between the years 2000 and 2009 was performed. Patients undergoing at least 12 months of active surveillance were identified. PSA velocity and percentage change in PSA per year were compared between patients receiving and not receiving statin therapy during active surveillance. Subgroup analysis was performed on low risk patients (prebiopsy PSA <10, Gleason score <6, <cT2).

Results: We identified 81 patients meeting our inclusion criteria, 43% (35/81) were on statin therapy during active surveillance. Prebiopsy PSA was significantly lower in patients receiving statin therapy (6.0 ng/ml) compared to controls (8.3 ng/ml), p = 0.005. There was no difference in duration of active surveillance, PSA velocity, and percentage change in PSA per year based on statin use in all patients. When evaluating the 41 low risk patients, 54% (22/41) were on statin therapy. Prebiopsy PSA was lower in low risk patients receiving statin therapy (4.9 ng/ml) compared to controls (6.4 ng/ml), p= 0.055. PSA velocity was significantly lower in low risk patients (0.02 ng/ml/year) compared to low risk controls (0.89 ng/ml/year), p=0.024. Percentage change in PSA per year was significantly lower in low risk patients receiving statin therapy (-1.7%/year) compared to low risk controls (11.6%/year), p=0.05. The percentage of low risk patients receiving definitive therapy following a period of active surveillance on statin therapy was 9% (2/22)compared to 26% (5/19) in controls, p = 0.14.

Conclusions: PSA kinetics during active surveillance appear to be significantly altered by statin therapy in low risk patients. Further evaluation of the impact of statin therapy on PSA kinetics and clinical outcomes of men undergoing active surveillance for prostate cancer are warranted.
MR spectroscopy compared with DW-MRI and DCE-MRI at 3-tesla for the noninvasive prediction of short-term radiation response for patients with localized prostate cancer.
Authors: Crehange Gilles , Maingon Philippe , Gauthier Mélanie , Cochet Alexandre , Martin Etienne , Mirjolet-Didelot Céline , Cormier Luc , Bonnetain Franck , Vignon Nicolas , Brunotte Francois , Walker Paul M
Published: February 2017

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Background: PSA is not appropriate for assessing early radiation response for patients treated with and without hormones for prostate cancer. New biomarkers using multiparametric functional MR could be of value. To investigate the benefits of multiparametric functional MR for predicting radiation response during the first year after radiation therapy in prostate cancer patients.

Methods: Between 01/2008 and 04/2010, 34 patients with a localized prostate cancer (T1-T3, N0) were prospectively enrolled in the ERIS trial. All patients underwent high dose IMRT with or without long term adjuvant hormonal therapy and were prospectively followed with MR spectroscopy, diffusion-weighted MRI and dynamic contrast-enhanced MRI at 3-Tesla without endorectal coil every 3 months up to 1 year. Patients were followed with DRE, PSA level every 3 months and with sextant-biopsy at 6 and 12 months following radiation. Choline and Citrate levels on MRS, apparent diffusion coefficient on DW-MRI and the slope of the contrast uptake on DCE-MRI were measured in the central gland and in the peripheral zone every 3 months over 12 months and compared with PSA nadir at 12 months (≤0.5 ng/mL vs. >0.5 ng/mL).

Results: Cho, Cit and SCU significantly decreased over time whereas ADC remained stable. For the entire prostate at 3 months, the mean Cho level was higher in patients with PSA level >0.5 ng/mL at 1 year (10.1±3.0 vs. 6.6±2.5, p= 0.004). Similarly, Cit level was higher at 3 months for patients with PSA level > 0.5 ng/mL at 1 year (15.4±7.9 vs. 8.5±9.9, p= 0.0065). Neither ADC value nor contrast enhancement evaluated at each time interval was correlated with PSA at 1 year.

Conclusions: Low Cho and Cit levels evaluated at 3 months are new markers for early success in prostate cancer patients treated with exclusive radiation therapy.
Calcium metabolism in patients with castration-resistant prostate cancer: Development of a quantitative urinary assay for extent of bone metastasis.
Authors: Pai Ashok P. , Hillegonds Darren , Lara Primo , Pan Chong-xian , Shelton David
Published: February 2017

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Background: In patients with metastatic castration-resistant prostate cancer (CRPC), the degree of perturbation from normal bone turnover provides a strong indication of risk for disease progression, skeletal complications and death. Biomarkers of bone cell function and bone collagen degradation provide an integrated index of the underlying disease for patients with bony metastases, but available bone markers are not precise or accurate. In this study, patients with CRPC with bony metastases will consume a single oral calcium-41 dose and the pharmacokinetics of this will be measured over an 18 month period. Participants will also be assessed clinically for time to progression, skeletal related events and death.

Methods: Patients with metastatic castration-resistant prostate cancer and bony metastatses, as diagnosed via bone scintigraphy, who were on bisphosphonates were enrolled into the study. 12 consenting research subjects consumed a single 1.2 microgram 41Ca tracer dose and provided 30-250mL urine specimens (single voids) after dose on day 1 (6h after dosing), days 7, 14, 28, 42, 60, and monthly thereafter. Isotope ratios were measured via accelerator mass spectrometry.

Results: Urinary 41Ca/Ca was significantly and inversely associated with increased skeletal tumor burdens suggesting that development of an isotopic urine test for bone metastasis extent is feasible, providing a non-invasive and quantitative measure of disease extent. A calculation of the area under the curve of the measurements between day zero and 14 were inversely correlated with disease extent at baseline. Clinical deterioration with worsening bony disease was associated with a significant decrease in the urinary 41Ca/Ca value. We are currently assessing correlations between bone turnover and outcomes such as therapy effectiveness, disease progression, skeletal related events and death.

Conclusions: This work is the first direct measurement of long-term calcium metabolism in advanced prostate cancer, providing a basic scientific complement to cellular and collagen-based measures of bone formation and resorption rates as well as a correlation to clinically relevant outcomes.
Exclusive image-guided IMRT versus radical prostatectomy followed by postoperative IMRT for localized prostate cancer: A matched-pair analysis based on risk groups.
Authors: Azelie Caroline , Gauthier Mélanie , Mirjolet-Didelot Céline , Cormier Luc , Martin Etienne , Peignaux-Casasnovas Karine , Truc Gilles , Maingon Philippe , Crehange Gilles
Published: February 2017

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Background: To investigate whether patients treated for a localized prostate cancer require prior radical prostatectomy followed by postoperative radiotherapy or exclusive radiotherapy, in the modern era of image-guided IMRT.

Methods: One hundred and seventy-eight patients with localized prostate cancer were referred for daily on-line exclusive image-guided IMRT (IG-IMRT), while 69 patients were referred for postoperative IMRT without image guidance after radical prostatectomy (RP+IMRT). The patients were matched in a 1:1 ratio according to their baseline risk group before any treatment. Late toxicity was scored using the CTV v3.0 scale. Biochemical failure was defined as a postoperative PSA ≥ 0.1 ng/mL followed by 1 consecutive rise in PSA for the postoperative group of patients and by the Phoenix definition (nadir+2 ng/mL) for the group of patients treated with exclusive radiotherapy.

Results: A total of 98 patients were matched (49:49). Thirty patients had a low-risk (30.6%), 62 patients an intermediate risk (63.3%) and 6 patients a high risk (6.1%). In the RP+IMRT group, the median PSA value before radiotherapy in the RP+IMRT group was 0.28 ng/mL [undetectable-6.99]. The median radiation dose in the IG-IMRT group was 77.4Gy [73.0-79.8 Gy] whereas it was 66.0 Gy [31.4-70.3 Gy] in the RP+IMRT group. The duration of the hormones was similar in both groups (p= 0.438). From the start of any treatment, the median follow-up was 56.6 months (95% CI = [49.6-61.2], range [18.2-115.1]. No patients had late gastrointestinal grade ≥ 2 toxicity in the IG-IMRT group vs. 4% in the RP+IMRT group. Forty-two percent of the patients in both groups had late grade ≥ 2 genitourinary toxicity. The 5-year freedom from biochemical failure rates in the IG-IMRT group and in the RP+IMRT groups were 93.1% [80.0-97.8] and 76.5% [58.3-87.5], respectively (p= 0.031).

Conclusions: Patients with localized prostate cancer treated with IG-IMRT had a better oncological outcome than patients treated with RP+IMRT. Further improvements in postoperative IMRT using image guidance and dose escalation need to be evaluated to determine whether it could eventually be superior to IG-IMRT.
The effect of acute and chronic exposure to acetaldehyde—a mutagenic metabolite of dietary ethanol—on prostate cancer cells: A potential source of race disparity disfavoring black men.
Authors: Banez Lionel Lloyds , Davidson Anthony Kyle , Etienne Wiguins , Allott Emma H , Calloway Elizabeth Ellen , Inman Brant Allen
Published: February 2017

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Background: We recently reported that the ADH1B*3 allele, which is specific to African Americans (AA), when combined with ethanol intake may constitute a gene-environment interaction leading to elevated prostate cancer (CaP) and potentially aggressive CaP risk among AA men possibly through intra-prostatic acetaldehyde accumulation. Indeed, studies have shown microsomes from rat ventral prostates biotransform ethanol to acetaldehyde that further metabolizes into oxidative stress-inducing acetyl radicals. In addition, acetaldehyde has been previously shown to enhance proliferation of colon cancer cells. Whether acetaldehyde has the same effect on CaP is unknown.

Methods: We subjected DU-145 CaP cells to varying concentrations of acetaldehyde using acute and chronic models of exposure and measured tumor proliferation using MTS assay. Proliferation was measured over 4 days of acetaldehyde treatment in acute and after 2 weeks of treatment in chronic exposure experiments. All experiments were conducted in triplicate. Results were expressed as mean values for each treatment referenced to untreated cells. Doubling times were calculated using least squares fitting exponential regression.

Results: In the acute exposure model, proliferation of DU-145 cells was inhibited by 150 uM acetaldehyde by 28% while 1,500uM and higher concentrations resulted in complete inhibition of proliferation. After chronic exposure to acetaldehyde, proliferation of DU-145 cells was inhibited by 500 uM acetaldehyde by 19%. In contrast, chronic exposure with 1,000 uM acetaldehyde resulted in increased proliferation by 9% and shortened tumor doubling time.

Conclusions: Acute exposure to acetaldehyde resulted in inhibition of CaP cellular proliferation. Chronic exposure to high acetaldehyde concentrations promoted tumor proliferation likely through selection for more robust CaP cells that survive the repeated chemical insult. Our results suggest that chronic acetaldehyde exposure of existent CaP may potentially promote disease aggressiveness. Uncovering mechanisms for enhanced CaP cell proliferation by acetaldehyde are warranted.
A gene expression signature to predict high-grade prostate cancer response to oxaliplatin.
Authors: Pourquier Philippe , Puyo Stephane , Richaud Pierre , Robert Jacques , Houede Nadine
Published: February 2017

150

Background: Prostate cancer (PCa) is one of the leading causes of death from cancer in men. High Gleason grade prostate cancers are characterized by aggressive tumors with poorly differentiated cells and a high metastatic potential. They are often refractory to chemical castration but still treated with hormone therapy to which docetaxel or cabazitaxel are added when they become resistant to the anti-androgen. Despite many clinical trials with other chemotherapeutic agents, response rates remain low. Moreover, none of these trials took into account the tumor grade.

Methods: We used an in silico approach to screen for drug candidates that could be used as an alternative to taxanes, based on a 86 genes signature which could distinguish between low-grade and high-grade tumors. We extracted from the NCI60 panel databases the expression profiles of the 86 genes across 60 human tumor cell lines and the corresponding in vitro cytotoxicity data of 152 drugs and looked for correlation between their expression level and cell sensitivity to each of these drugs.

Results: Among the 86 genes, we identified 9 genes (PCCB, SHMT2, DPM1, RHOT2, RPL13, CD59, EIF4AI, CDKN2C, JUN) for which expression levels across the 60 cell lines was significantly correlated (p< 0.05) to oxaliplatin but not to cisplatin sensitivity. This signature was validated at the functional level since repression of each of these genes conferred a significant change in the sensitivity of PCa cell lines to oxaliplatin but not cisplatin.

Conclusions: Our results provide a proof of concept that gene expression signature specific from high grade PCa could be used for the identification of alternative therapies to taxanes. They could also be used to select patients for further clinical trials and as predictive markers of response to these drugs, which represents a further step forward towards personalized therapy of PCa.
The impact of neoadjuvant weekly ixabepilone for high-risk prostate cancer: A phase I/II clinical trial.
Authors: Layton Jodi Lyn , Plette Angela Marie , Renzulli Joseph F. , Miller E. Bradley , Safran Howard , Mega Anthony E.
Published: February 2017

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Background: Potential benefits of neoadjuvant chemotherapy are tumor downstaging and treatment of micrometastatic disease. A prior study using docetaxel yielded no pathologic complete responses and concerns for increased operative morbidity. In Phase II studies, ixabepilone has promising activity in metastatic prostate cancer. Our study is a Phase I/II clinical trial evaluating neoadjuvant, weekly ixabepilone in men with high-risk prostate cancer opting for radical prostatectomy.

Methods: Men with high risk prostate cancer defined as either Gleason 8-10, cT3 disease, high volume Gleason 4+3 and a palpable nodule or a PSA>20 ng/ml were eligible. Men received weekly ixabepilone 16-20/m2 for 12-16 weeks prior to surgery. Fifteen men underwent robotic prostatectomy; one patient who had an open prostatectomy. Initial PSA response, post-operative PSA values, pathology, and evaluation of adverse events were recorded.

Results: We enrolled 16 men with a mean follow-up of 15.25 months at time of review. All had pretreatment Gleason scores of 4+3 or higher. With neoadjuvant treatment, PSA values decreased in 14/16 men (mean 46.8%); increased in 2/16 men. None reached an undetectable pre-operative PSA. Nine men experienced an adverse event requiring dose modification or cessation of chemotherapy (neuropathy or allergic reaction). Only 5/16 men completed planned treatment. Mean operative time, EBL, and hospital stay were 189 minutes, 184mL, and1.5 days, respectively; all consistent with institutional and national norms. Post surgery 15/16 (94%) had pT3 disease, 8/16 (50%) had a positive surgical margin and 2/16 (12.5%) had positive regional lymph nodes. There were no pathologic complete responses. Only 1/16 (6.25%) had a biochemical relapse.

Conclusions: While a PSA response is achieved, there is substantial toxicity with neoadjuvant weekly ixabepilone. Men were able to undergo prostatectomy without increased morbidity after neoadjuvant therapy. Extracapsular extension and positive surgical margins remained common in this population with high-risk disease. Assessment of biochemical recurrence rates and time to treatment failure will require longer, planned follow-up.
Impact of 36 months of androgen-deprivation therapy (ADT) on physical function and quality of life (QOL) in men with nonmetastatic prostate cancer.
Authors: Alibhai Shabbir M.H. , Breunis Henriette , Timilshina Narhari , Tomlinson George A. , Duff Canning Sarah , Fleshner Neil Eric , Krahn Murray , Tannock Ian , Warde Padraig Richard , Naglie Gary
Published: February 2017

16

Background: Use of ADT has been shown to adversely affect physical function and QOL within 3 months of initiation; declines persist at 12 months. Few studies have examined physical function with ongoing ADT use beyond 12 months.

Methods: In this extension of our prior study, men age 50 or older with non-metastatic prostate cancer (PC) who were on continuous ADT were followed along with two control groups (PC, no ADT; healthy controls) matched on age, education, and baseline function. Physical function was assessed with the 6-minute walk test (6MWT), grip strength, and the Timed Up and Go (TUG) test, representing endurance, upper extremity strength, and lower extremity strength, respectively. Aggregate physical and mental QOL were measured with the Medical Outcomes Study SF-36. Assessments were done at baseline and at 3, 6, 12, 18, 24, 30, and 36 months. Mixed effects regression models were used, adjusting for age, baseline function, and other covariates.

Results: 87 patients on ADT, 86 PC controls, and 86 healthy controls were enrolled (mean age 69.4 y, range 50-87). At baseline, all three groups were similar in age and physical function (all ANOVA p>0.05) and most subjects were otherwise quite healthy. 6MWT distance improved in both control groups but remained unchanged in ADT users (p=0.0379). Grip strength declined sharply in the ADT group by 3 months and remained stable up to 36 months (p<0.001), whereas both control groups were stable over time. There was a slight worsening of TUG scores in the ADT group over 36 months (p=0.0003) but were unchanged in both control groups (p>0.10). Aggregate physical QOL continued to decline in ADT users over time (p=0.0002) but remained stable in both control groups over 36 months, whereas aggregate mental QOL was stable in all groups over time. Most declines were evident within 3-6 months of ADT initiation.

Conclusions: Initial declines with continuous ADT use in both physical function and aggregate physical QOL persist for 36 months but generally did not decline further beyond one year despite ongoing ADT use. Early exercise interventions and/or intermittent ADT use may improve these outcomes.
A phase I/II study of adenovirus-mediated reduced expression in immortalized cells (REIC/DKK-3) gene therapy for prostate cancer: An interim report.
Authors: Sasaki Katsumi , Nasu Yasutomo , Watanabe Masami , Kaku Haruki , Tanimoto Ryuta , Kanbara Daiki , Watanabe Toyohiko , Yanai Hiroyuki , Kumon Hiromi
Published: February 2017

161

Background: A new cancer therapeutic gene; REIC/Dkk-3 was found in Okayama university in 2000. In vivo experiments have demonstrated outstanding cancer-selective apoptosis effects and anti-cancer immunoactivity against various types of malignant tumors. With these positive experimental results, a phase I/II study of adenovirus-mediated REIC/Dkk-3 gene therapy for prostate cancer was initiated from January 2011 in Okayama university hospital.

Methods: Two major inclusion criteria category were set up; A: A recurrence of prostate cancer following definitive endocrine therapy with/without metastasis, B: A localized prostate cancer which was considered high risk of recurrences following radical surgery according to a nomogram reported by Kattan et al. Replication-defective adenovirus vector expressing REIC/Dkk-3 (Ad-REIC) was injected directly into the prostate (or metastatic lesion in patients who received prostatectomy) in escalating doses from 1.0×1010 to 1.0×1012 viral particle (vp). Each patient in category A received total of 2 times viral injections every 4 weeks. Patients in category B also received total of 2 times viral injections every 2 weeks, then received radical prostatectomy 6 weeks after second viral injection.

Results: Three patients in category A, and 9 patients in category B were entered the present study. No significant side effects were observed. In category B, signs of immunological responses in surgically removed specimens (apoptosis induction of cancer cells in TUNEL staining and infiltration of CD8 positive cells (CTL) in immunohistochemical staining) were observed in second dose. These responses were remarkably observed in the third dose.

Conclusions: This initial and preliminary report suggests the favorable safety profile and positive clinical responses in a clinical trial of Ad-REIC gene therapy for prostate cancer.
Phase I trial of metronomic cyclophosphamide (CTX) and lenalidomide (LEN) in patients with castration-resistant prostate cancer (CRPC).
Authors: Wang Jue , McGuire Timothy R. , Schwarz James K. , Meza Jane L , E Talmadge James E
Published: February 2017

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Background: Angiogenesis and suboptimal antitumor immune response are important in the progression of CRPC. Both LEN and metronomic CTX have known anti-angiogenic and immunomodulatory activities. A phase I study of a novel combination of metronomic CTX with LEN in patients with CRPC who have failed prior docetaxel therapy was initiated to assess safety and effects on potential biomarkers.

Methods: CTX was given 50 mg PO QD(day 1-28) and LEN 10-25 mg PO QD(day 1-21) on a 28 day cycle. Dose limiting toxicity was defined as any treatment-related grade 4 hematologic event or grade 3 / 4 non-hematologic event during cycles one. Quantification of circulating tumor cells (CTC), plasma cytokines, analgesic consumption and quality of life assessments were performed. Measurement of Treg and MDSCs were performed in some patients.

Results: 17 patients with CRPC have been enrolled in L0-4; all patients are evaluable for toxicity. Patient characteristics include: ECOG performance status 0/1= 4/13; median age=77 (range 50–86); median PSA=36.7 (range 1.36–2287). Dose level 1 (CTX 50 mg/d, LEN 10 mg/d) was expanded to 6 patients after one out of three initial patients was removed from the study for Gr 3 gastrointestinal bleeding (in cycle 1). Dose level 1 (CTX 25 mg/d, LEN 10 mg/d) had no DLT’s. The maximum tolerated dose has not yet been reached. Other Grade 3/4 toxicities observed after cycle 1 included grade 3 pain (N=1), grade 3 neutropenia (N=4), grade 3 thrombocytopenia (N=2), grade 4 neutropenia (N=2). Most frequent grade 1 and 2 toxicities included anemia, fatigue, neutropenia, and hypocalcemia. Overall, 9 of 14 patients (64%) have experienced a reduction in PSA. One patient had partial response after one cycle. Stable disease was documented in 5 of 14 (36%) evaluable patients. Two inflammatory cytokines, IL-6 (N = 19; r = 0.64; p = 0.0035) and IL-8 (N = 9; r = 0.86; p = 0.0028), were found to significantly correlated with PSA.

Conclusions: The combination of metronomic CTX and LEN can be safely administered. Preliminary clinical activity was observed in this heavily-pretreated patient population. Enrollment to this study continues and clinical and biomarker studies are ongoing.
Safety of abiraterone acetate (AA) in castration-resistant prostate cancer (CRPC) patients with concomitant cardiovascular disease.
Authors: Procopio Giuseppe , Verzoni Elena , Testa Isabella , Biasoni Davide , Torelli Tullio , Nicolai Nicola , Salvioni Roberto , Valdagni Riccardo
Published: February 2017

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Background: Abiraterone acetate (AA) is an inhibitor of extragonadal androgen biosynthesis that prolongs overall survival in CRPC patients who have received a chemotherapy including docetaxel. The most common adverse events related to AA therapy were fluid retention, hypertension, hypokaliemia and cardiac disorders. No safety data are available in patients with concomitant cardiac disease.

Methods: Metastatic CRPC patients were enrolled in this prospective study if they were also suffering from a concomitant controlled cardiovascular disease. AA 1000 mg per day and prednisone 5 mg bid were administered orally until grade 3-4 adverse events (AE) or disease progression. The primary endpoint was the safety profile while the secondary endpoints were progression-free survival and PSA response.

Results: From April to September 2011, 33 CRPC patients with concomitant cardiovascular disorders have been treated with AA. Main patients characteristics were: median age 71 years (range 57–81); baseline mean PSA value 40 ng/ml (6.32-995); the most common sites of disease were bone (27 pts, 81%), lung (11 pts, 33%) and liver (5 pts, 15%). All patients were previously challenged with at least 2 lines of hormone therapy and 1 chemotherapy regimen including docetaxel. The most common pre-existing cardiac disorders were hypertension 22 (66%), arrhythmias 4 (12%), cardiac ischemia 3 (9%) and conduction irregularity 2 (4%). Additionally 9 patients (27%) had metabolic disorders including dislipidemy and hyperglicemia. AA was feasible without inducing grade 3-4 AE nor treatment modification. The most common grade 1-2 AE were asthenia (27%), hypertension (18%) and fluid retention (28%). After a median time of treatment of 4 months (range 2–7 months) no dose modifications due to toxicity were required. No efficacy data are still available.

Conclusions: Treatment with AA was feasible and well tolerated also in patients suffering from cardiac comorbidities and risk factors for cardiovascular disease.
Personal preferences and treatment choice in an intervention trial of men newly diagnosed with localized prostate cancer.
Authors: Bosco Jaclyn Lee Fong , Halpenny Barbara , Berry Donna Lynn
Published: February 2017

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Background: Men diagnosed with localized prostate cancer (LPC) can choose from multiple treatment regimens and are faced with a decision in which medical factors and personal preferences are important. The Personal Patient Profile-Prostate (P3P) is a computerized decision aid for men with LPC that focuses on personal preferences. We determined the proportion of men with LPC who chose a concordant treatment approach by 6-months with self-reported, influential side effects by intervention or control group, and evaluated whether the intervention (versus control) group was more likely to choose a concordant treatment.

Methods: English or Spanish-speaking men diagnosed with LPC (2007–2009) from four US cities were enrolled into a randomized trial and followed at 1- and 6-months via mailed or online questionnaire. Men were randomized to receive the P3P intervention or standard education plus links to reputable websites (control group). We classified concordance as men who were (a) concerned with urinary incontinence and/or erectile dysfunction and chose radiotherapy, (b) concerned with bowel dysfunction and chose prostatectomy, (c) concerned with all three side effects and chose watchful waiting, or (d) not concerned with any side effect and chose any treatment. We calculated the proportion of concordance by group. Using logistic regression, we calculated odds ratios (OR) and 95% confidence intervals (CI) for the association between the P3P intervention and concordance.

Results: Of 448 men, most were <65 years, non-Hispanic white, and had multiple physician consultations prior to study enrollment. Only 43% of the sample chose a concordant treatment given concerns about potential side effects. There was no significant difference in concordance between the intervention (43%) and control (42%) group (OR=1.1; 95%CI=0.73, 1.7).

Conclusions: The P3P intervention was not associated with concordance between potential side effects and treatment choice. Information and/or physician consultation immediately after diagnosis was likely to influence decisions despite concerns about side effects. The intervention may be more effective before the first treatment options consultation.
Heavy ethanol intake and elevated prostate cancer risk among men with previous negative biopsies in the REDUCE trial.
Authors: Banez Lionel Lloyds , Hoyo Cathrine , Gerber Leah , Moreira Daniel M. , McKeever Madeline G , Andriole Gerald L. , Freedland Stephen J.
Published: February 2017

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Background: Whether ethanol intake contributes to prostate cancer (CaP) risk is debated. Although ethanol was found to contribute to increased CaP risk in the Prostate Cancer Prevention Trial, whether ethanol intake impacts CaP risk among men with previous negative biopsies has not been previously assessed. We therefore examined the relationship between ethanol consumption and CaP risk in the REDUCE trial and further sought to determine whether ethanol intake modifies the effect of dutasteride in reducing CaP risk.

Methods: This is secondary analyses using data from 6,729 men who had at least one on-study biopsy while participating in the REDUCE trial. Ethanol intake, which was expressed as units (½ pint of beer or 1 glass of wine, etc.) per week, was analyzed as a continuous and three-tiered categorical variable [non-drinker, moderate (≤7 units/week), heavy-drinker (>7 units/week)]. Risks for overall and high-grade (Gleason ≥7 vs. Gleason<7 CaP or biopsy negative) CaP were evaluated using logistic regression adjusting for clinical parameters including dutasteride intake. Test for interaction was used to determine whether the association between dutasteride and CaP risk is influenced by ethanol.

Results: Forty-nine percent were moderate-drinkers and 26% were heavy-drinkers. On a continuum, increased ethanol intake was significantly associated with elevated risk for overall (p=0.035) and high-grade CaP (p=0.048). Compared to non-drinkers, heavy drinkers were at increased risk for overall (OR 1.21; 95% CI 1.02-1.43; p=0.03) and high-grade CaP (OR 1.34; 95% CI 1.01-1.78; p=0.04). Risks for overall (p=0.55) and high-grade CaP (p=0.21) were comparable between moderate- and non-drinkers. Dutasteride reduced overall CaP risk (OR 0.73; p<0.001) and ethanol intake did not modify the effect of dutasteride on CaP incidence (p-interaction=0.64).

Conclusions: Among low-risk men with at least one prior negative prostate biopsy, heavy ethanol intake is associated with increased risk for overall and high-grade CaP. In contrast to CaP prevention with finasteride, which appears to be inhibited by heavy ethanol intake, consumption of ethanol does not negatively impact CaP prevention with dutasteride.
Impact of androgen deprivation therapy (ADT) on bone mineral density (BMD) over 3 years in men with nonmetastatic prostate cancer.
Authors: Alibhai Shabbir M.H. , Mohamedali Hassanabbas Z. , Panju Abbas H. , Timilshina Narhari , Breunis Henriette , Duff Canning Sarah , Fleshner Neil Eric , Krahn Murray , Naglie Gary , Tannock Ian , Tomlinson George A. , Warde Padraig Richard , Cheung Angela M
Published: February 2017

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Background: Decreased BMD is a common side effect of ADT, leading to increased fracture risk. Although loss of BMD appears to be greatest within the first 12 months of starting ADT, few data on BMD changes exist beyond 12 months, and other risk factors for bone loss in men on ADT are not well-characterized.

Methods: Men age 50+ with non-metastatic prostate cancer and starting continuous ADT were enrolled in a prospective longitudinal study. BMD was determined by dual-energy x-ray absorptiometry at baseline and yearly for 3 years. A matched control group of men with prostate cancer but not on ADT was also enrolled. Medication use was recorded at each visit. Multivariable regression analyses were done to examine predictors of BMD loss.

Results: 80 ADT users and 80 controls were enrolled (mean age 69.4 y); 49.7% had osteopenia and 4.6% had osteoporosis at baseline. ADT was associated with significant losses in lumbar spine BMD in year 1 compared to controls (p=0.004) and trends towards greater declines at femoral neck and total hip sites. Changes in year 2 and 3 were much smaller and not statistically different from controls (Table). Vitamin D use but not calcium use was associated with improved BMD at the lumbar spine in year 1 (+5.77%, p=0.006) with positive trends at other sites (+2.19% femoral neck, +1.76% total hip) primarily in year 1. Age was not associated with changes in BMD.

Conclusions: Losses in BMD with ADT use are greatest at the lumbar spine and in the first year compared to years 2 and 3 and are independent of age. Vitamin D appears to be protective particularly in the first year of ADT use.

[Table: see text]
Response to ketoconazole (keto) or docetaxel (D) following clinical progression on abiraterone acetate (AA) in castrate-resistant prostate cancer (CRPC).
Authors: Aggarwal Rahul Raj , Formaker Carl , Small Eric Jay , Molina Arturo , Ryan Charles J.
Published: February 2017

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Background: Patients (pts) with CRPC treated with keto often experience a rise in serum adrenal androgen levels upon progression and may subsequently respond to more potent adrenal suppression with AA. In contrast, pts treated with AA do not have a rise in serum androgen levels upon progression, and thus may not respond to further androgen synthesis inhibition with keto but require other treatment modalities such as chemotherapy instead. The goal of this analysis is to report the outcomes of pts with CRPC progressing on AA subsequently treated with either keto or D.

Methods: Pts with chemotherapy-naïve CRPC were treated on previously reported phase 1 and 2 trials of AA, with doses ranging from 250 to 1000 mg/day. Subsequent treatment following progression on AA was per individual investigator discretion, including treatment with either keto or D.

Results: To date, following disease progression on AA, 6 and 14 pts have been subsequently treated with either keto or D respectively. Of the 14 pts treated with D, 11 (79%) had exposure to keto prior to AA. The keto- and D-treated cohorts were similar with respect to other baseline factors, including prior response to AA (4/6 (67%) pts with > 50% PSA decline on AA in keto cohort; 10/14 (71%) pts in D cohort); though pts treated with D were more likely to require opioid analgesics (0 pts in keto cohort; 7 (50%) in D). For pts treated with keto, none experienced a decline in PSA, improvement in bone scan, or an objective response; all had disease progression by 12 weeks. In contrast, for pts treated with D, 10 (71%) had a decline in PSA; 6 (43%) with a > 50% maximum PSA decline. Of 6 pts with measurable disease, 2 (33%) had an objective response. The median time to progression for the D cohort was 129 days (range 60 – 294).

Conclusions: Although the cohort size is small, and post-AA therapy was not randomized, these data provide preliminary support for the hypothesis that CRPC progressing on AA is cross-resistant to further androgen synthesis inhibition with keto. Contrary to other reports, prior treatment with AA does not appear to decrease the likelihood of subsequent response to D, but this observation requires prospective validation.