bluuebunny/crossref_metadata_2025 huggingface dataset:
Predicting outcomes in renal cell cancer: The role of single nucleotide polymorphisms (SNPs).
Authors: Garrigos Carmen , Espinosa Marta , Osman Ignacio , Ávila Rainiero , Medina Rafael , Melendez Ricardo , Salinas Ana , Pérez-Valderrama Begoña , Duran Ignacio
Published: September 2018

e16074

Background: Despite major advances in the knowledge of the molecular basis of RCC, prognosis is still defined mostly using clinical and pathological parameters. Moreover, no valid predictive biomarkers exist to help us selecting the best treatment for each patient. The aim of this work is analyzing the expression and determining the prognostic and predictive value of 64 key SNPs in 18 genes related with angiogenesis or metabolism of antiangiogenics in two cohorts of RCC patients (pts) [localized and advanced] RCC treated at our institution. Methods: DNA from formalin fixed paraffin embedded tumor and non-tumor samples from 99 pts with RCC (26 advanced/ 73 localized) was extracted with QiAGEN Kit and amplified with a specific primers pool for every SNP as determined by the manufacturer (Lifetech). Sixty-four SNPs were chosen based on their Minor Allele Frequency by HapMap, linkage disequilibrium by Haploview and information from SNP data base (dSNP) and were studied by TaqMan OpenArray (Lifetech). Statistically significant SNPs were validated in an external cohort by individual assays. The presence of the selected SNPs was correlated with clinical features, disease free survival (DFS), overall survival (OS) and response to treatment (RR). SPSS v20 was utilized for statistical analyses. Results: In pts with localized RCC, 2 SNPs in 2 genes involved in angiogenesis showed a protective effect (VEGFR2: rs2071559, PDGFRA: rs4358459) and others SNPs predicted for worse DFS (VEGFR2: rs10013228, rs1870377, PDGFRA: rs2228230) and shorter OS (VEGFR2: rs2305948, rs10013228; VEGFR3: rs6877011, rs307826) (p < 0.05). In the advanced setting, 6 SNPs in genes related to both angiogenesis and metabolism of antiangiogenics were statistically implicated in OS (IL8: rs2227543, PDGFA: rs9800958, PDGFRB: rs2302273 (p≤0.05)) and RR (VEGFA: rs699947, rs3025010, VEGFB: rs594942 (p < 0.03)). These 14 SNPs are currently being validated in an external cohort of 80 patients with RCC and this data will be presented. Conclusions: These SNPs in genes critical to angiogenesis and metabolism of antiangiogenics might be used as potential prognostic/predictive biomarkers. Prospective validation is ongoing.
Oncological outcomes of positive surgical margins in partial nephrectomy for renal cell carcinoma.
Authors: Nonemacher Henrique T. S. , Cordeiro Mauricio , de Albuquerque George Lins , Galucci Fabio , de Carvalho Paulo Afonso , Borges Leonardo , Guglielmetti Giuliano Betuni , Bastos Diogo Assed , Coelho Rafael , Sarkis Alvaro , Dzik Carlos , Nahas William Carlos
Published: September 2018

e16079

Background: The prognostic significance and optimal management of positive surgical margins following partial nephrectomy remain controversial. The association between positive margin and risk of disease recurrence in patients with clinically localized renal neoplasm undergoing partial nephrectomy was evaluated. Methods: We analyzed the records of 429 patients cases of non-metastatic renal cell carcinoma who underwent partial nephrectomy (PN) at our institution, from 2001 to 2016. Recurrence free-survival was evaluated using Kaplan–Meier method and the log rank test and Cox models adjusting for tumor size, grade, histology, pathological stage, focality and laterality. The relationship between positive margin and risk of relapse was evaluated independently for pathological high risk (Fuhrman grades III-IV) and low risk (Fuhrman grades I-II) groups Results: A positive surgical margin was found in 55 (12.8%) patients. Recurrence developed in 26 (6%) patients during a median follow up of 39 months. A positive margin was associated with an increased risk of relapse on multivariable analysis (HR 3.19, CI 95% 1.21 – 7.61 p=0.02) (Table). In a stratified analysis based on pathological features, a positive surgical margin was significantly associated with a higher risk of recurrence in cases of high risk (HR 13.8, CI 95% 4.19–45.9, p = 0.0005). Conclusions: Positive surgical margins after partial nephrectomy increase the risk of disease recurrence, primarily in patients with high-risk pathological features. [Table: see text]
Metastatic clear cell renal cell carcinoma: Proangiogenic gene expression and outcome on sunitinib.
Authors: Verbiest Annelies , Beuselinck Benoit , Couchy Gabrielle , Job Sylvie , De Reynies Aurelien , Meiller Clément , Albersen Maarten , Verkarre Virginie , Lerut Evelyne , Mejean Arnaud , Patard Jean-Jacques , Laguerre Brigitte , Rioux-Leclercq Nathalie , Schöffski Patrick , Oudard Stephane , Zucman-Rossi Jessica
Published: September 2018

e16085

Background: Clear cell renal cell carcinomas (ccRCC) are hypervascular tumors that respond to vascular endothelial growth factor receptor (VEGFR) inhibitors such as sunitinib. They can be divided into 4 mRNA-expression based subgroups (ccrcc 1-4) with different outcomes on sunitinib. We hypothesized that the expression of proangiogenic genes is predictive for response to sunitinib. Methods: Retrospective series of metastatic ccRCC-patients treated with sunitinib as first line targeted therapy (n = 104). We studied expression of genes involved in angiogenesis and the immune-suppressive microenvironment (qRT-PCR) and mutational status of Von Hippel Lindau and Polybromo (PBRM) 1 (sequencing) on primary tumor samples. Outcome parameters were response rate (Response Evaluation Criteria in Solid Tumors), progression free survival (PFS) and overall survival (OS). Gene expression levels were tested in multivariate analysis (MV) against the IMDC risk criteria, presence of bone metastases and sarcomatoid dedifferentiation ≥25%. Results: Expression of Hypoxia Inducible Factor (HIF) 2A, Platelet Derived Growth Factor Receptor B, VEGFC, VEGFR1 and VEGFR2 was significantly correlated with PFS on MV and expression of HIF1A, HIF2A and VEGFR2 with OS. VEGFR2-expression was also correlated with partial response (p = 0.03) and anti-correlated with early progressive disease (p = 0.008). HIF2A, VEGFA, VEGFR1, VEGFR2 and VEGFR3-expression was higher in ccrcc2-tumors compared to others. Expression of genes involved in angiogenesis and in the immune-suppressive microenvironment was not directly correlated nor anti-correlated. In tumors with a bi-allelic PBRM1-inactivation, HIF2A, VEGFA, VEGFR1 and VEGFR2-expression were higher compared to tumors with 1 or 2 functional PBRM1-alleles. This did not translate in different outcome on sunitinib. Conclusions: Tumoral expression of genes involved in the HIF-VEGF-VEGFR proangiogenic pathway, especially VEGFR2, is associated with favorable outcome on sunitinib in metastatic ccRCC. Expression of these genes was high in the molecular ccrcc2-subgroup, known to be sensitive to sunitinib. These findings could be used for patient selection in future clinical trials.
Prognostication of outcome in men with bone metastatic castration-resistant-prostate-cancer with early rising PSA after initiation of abiraterone acetate.
Authors: Boegemann Martin , Grossmann Phillip , Steinestel Julie , Schlack Katrin , Krabbe Laura Maria , Brücher Benedikt
Published: September 2018

e16514

Background: Abiraterone acetate (AA) prolongs survival in men with mCRPC in the pre- and post chemotherapy setting and is mainly used in asymptomatic men. In the first 12 weeks an early rise of prostate specific antigen (PSA) may occur followed by either delayed decline (PSA-flare) or true progression. Bouncing of alkaline phosphatase (ALP-Bouncing) was shown to be a promising marker for outcome and response during very early AA therapy. This retrospective study was conducted to analyze the capability of ALP-Bouncing to predict overall survival (OS) in men with bone mCRPC (bmCRPC) with rising PSA after initiation of AA therapy. Methods: Men with bmCRPC and rising PSA during early AA therapy were includeded and analyzed. PSA response rate (RR) was monitored according to PCWG2 criteria and assessed 12 weeks after start of AA treatment. PSA-flare vs. no flare and ALP-Bouncing vs. no Bouncing were analyzed using Kaplan-Meyer estimates and uni- and multivariate (UV/MV) cox-regression models. ALP-Bouncing was defined as increase of ALP after the beginning of AA with a subsequent significant decline below baseline during the first 8 weeks of therapy. Results: Forty men were evaluable for analysis: 20 men were chemotherapy naïve, 20 pretreated with docetaxel. The PSA RR was 30%. The median survival for ALP-Bouncing was 20 months (95% confidence interval (95%CI): 4.7-13.3) vs. 9 months (95%CI not distinguishable) for no ALP-bouncing (p = 0.04) and 13 months (95%CI: 8.8-17.2) for PSA-flare vs. 9 months (95%CI 4.4-13-6) for no PSA-flare (p = 0.62). In UV no ALP-bouncing was significantly associated with worse OS (Hazard Ratio (HR): 2.65 (95%CI: 1.0-7.0); p = 0.05). After adjustment for PSA-flare no AP-bouncing remained an independent prognosticator of worse OS (HR: 2.78 (95%CI: 1.0-7.71); p = 0.05). Conclusions: ALP-Bouncing, occurring earlier than delayed PSA-decline, may be a helpful marker to identify patients with subsequent favorable outcome in men with bmCRPC and rising PSA after initiation of AA therapy. These results have to be validated in a prospective trial.
Outcomes of prechemotherapy (pCHT) abiraterone (AA) or enzalutamide (E) for metastatic castration-resistant prostate cancer (mCRPC) after androgen deprivation therapy (ADT) + docetaxel (D) or ADT alone for metastatic hormone sensitive prostate cancer (mHSPC) in a hospital-based registry.
Authors: Francini Edoardo , Gray Kathryn P. , Evan Carolyn , Kaymakcalan Marina D. , Shaw Grace Katherine , Kantoff Philip W. , Taplin Mary-Ellen , Sweeney Christopher
Published: September 2018

e16515

Background: The E3805: CHAARTED trial noted use of D at time of commencing ADT for mHSPC was associated with an improvement in time to CRPC (PSA rise or clinical progression [CP]) or time to CP and resulted in a prolongation of overall survival (OS). Therefore, we postulated that pCHT AA or E maintained activity after ADT+D. Methods: A cohort of CRPC patients (pts) treated with pCHT AA or E for CRPC between 2010 and 2016 was selected from the Dana-Farber Cancer Institute IRB approved database. Patients were grouped by use of D and whether they had prior localized therapy (PLT) or de novo (DN) metastatic disease, at time of ADT start for mHSPC. The analysis endpoints included OS (time to death from all causes) from ADT start, time to AA/E start from ADT start, OS from AA/E start. Kaplan-Meier method estimated the time to events distribution with median (95% CI). Results: Of the 147 pts selected, 134 (91.2%) had previously received ADT alone, while 13 (8.8%) had ADT+D. Once stratified by PLT or DN, the distributions of the 4 groups are 33.3% (ADT/PLT), 57.8% (ADT/DN), 0.7% (ADT+D/PLT), and 8.2% (ADT+D/DN). In the ADT alone group, the median OS with pCHT AA or E for CRPC was approximately 3 years from the AA/E start, regardless of PLT or DN. In the smaller cohort of pts selected for treatment with ADT+D, both the OS from ADT start and from AA/E start were shorter than the ADT alone cohort. However, even in this group with shorter time to AA/E start, the median OS from AA/E start was still 1.5 years despite prior chemotherapy. Conclusions: Within limitations of a hospital-based registry, small sample size for ADT+D and lack of volume of metastases data, pts selected for ADT+D show poorer outcomes but still have an OS of 1.5 yrs from AA/E start. [Table: see text]
Rate of occult metastases in patients (pts) with biochemically-recurrent prostate cancer (BRPC) from a phase 2 trial of sipuleucel-T and androgen deprivation therapy (STAND).
Authors: Kibel Adam S. , Drake Charles G. , Yu Evan Y. , Vogelzang Nicholas J. , Corman John M. , Karsh Lawrence Ivan , Elfiky Aymen , Shore Neal D. , Millard Frederick E. , Chang Nancy N. , Antonarakis Emmanuel S.
Published: September 2018

e16516

Background: Identifying occult metastases in men with BRPC is critical, as treatment depends on disease state (biochemical recurrence vs oligometastatic disease). It is prudent to investigate pts for metastases, even men with low prostate-specific antigen (PSA) levels, to select appropriate salvage, local or systemic treatments. We evaluated baseline parameters of BRPC pts with occult metastases identified during screening for STAND (phase 2, NCT01431391). Methods: STAND eligibility criteria included prostate cancer primary therapy and PSA doubling time (PSADT) ≤12 months. Pts with metastases were excluded. We compared pts with and without metastases. Results: Of 99 screened pts, 68 entered STAND with non-metastatic BRPC, 11 (11%) failed screening due to metastases and 20 (20%) due to other reasons. In this small sample, no baseline parameters were identified that clearly distinguished between pts with or without metastases. For pts with metastases vs STAND pts, median age was similar (66 vs 65 y); all were Caucasian. Baseline median (range) PSA levels were numerically higher (4.3 [1.7–141.7] vs 2.4 [0.3–47.8] ng/mL) and PSADT values were numerically shorter (3.5 [1.1–7.6] vs 5.1 [1.0–16.4] months) for pts with metastases vs STAND pts, respectively. The proportion of pts with PSA > 10 ng/dL was 29% vs 19%, or PSADT < 6 months was 80% vs 59% for pts with metastases vs STAND pts, respectively. Baseline lactate dehydrogenase, alkaline phosphatase and hemoglobin levels were similar between groups. Conclusions: A substantial proportion (11%) of BRPC pts with presumed non-metastatic disease had undiagnosed occult metastases at low PSA levels. Such pts may benefit from closer monitoring with improved imaging technology, continuous androgen deprivation therapy or potentially docetaxel. While more rigorous screening (even at low PSA levels) may be advantageous, identifying such pts is challenging as their baseline parameters may not differ significantly vs BRPC pts with no metastases. In the future, detection of oligometastatic disease is likely to increase due to more sensitive imaging modalities, thus, the BRPC state will be reduced. Clinical trial information: NCT01431391.
Cabazitaxel in metastatic castrate resistant prostate cancer (mCRPC) in the era of enzalutamide (ENZA) and abiraterone acetate (AA).
Authors: Body Amy , Pranavan Gane , Malik Laeeq
Published: September 2018

e16517

Background: The concurrent development of cabazitaxel, AA, ENZA, and radium-223 has recently increased the number of therapeutic options for mCRPC. Cabazitaxel is currently approved for mCRPC patients who have previously received docetaxel. There are no data on the activity of cabazitaxel in patients who had previously progressed on docetaxel and either ENZA or AA. We examined the efficacy and tolerability of cabazitaxel in patients who progressed on docetaxel and either AA or ENZA. Methods: We searched our databases for all mCRPC patients who had received cabazitaxel up to July 2016. We reviewed medical records to collect information on tolerability, treatment sequencing and treatment outcomes. These data were analysed descriptively using Excel 2010. Results: Of 30 patients screened, only 20 patients received cabazitaxel after progressing on docetaxel and either ENZA or AA. The median age at the time of treatment was 70.8 years. All except one patient had Zubrod performance status (PS) ≥1. All patients had ≥4 sites of metastatic disease, 20% had liver or lung metastases. About 11/20 (55%) individuals had previously received ENZA (median duration 5.8 months) and 12/20 (60%) received AA (median duration 10 months). The median number of cabazitaxel administered was 6 cycles. Only 3/20 (15%) completed 10 cycles. The most common reasons for treatment discontinuation were progressive disease (35.3%) and toxicity (23.5%). The dose of cabazitaxel was reduced at baseline in most patients due to poor PS. PSA response occurred in one-third of patients while stable disease (clinical+radiological) was seen in 40% patients. The median progression free survival (PFS) was 4 months and overall survival measured 4.6 months. About 20% had ≥6 months PFS. After progression, only one-fourth went on to receive further systemic therapy. The most common toxicities were anaemia (100%), neutropenia (65%), fatigue (65%), peripheral neuropathy (35%) and diarrhoea (25%). Conclusions: Within limitations of a small retrospective study, cabazitaxel showed very modest antitumour activity in this cohort of mCRPC patients with significant tumour burden and prior exposure to docetaxel and biological agents.
The effect of corticosteroid (Cs) use during docetaxel (D) treatment on overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Gyergyay Fruzsina , Budai Barna , Biro Krisztina , Kuronya Zsofia , Nagyivanyi Krisztian , Vajdics Timea , Oreskovich Anna , Geczi Lajos
Published: September 2018

e16522

Background: Cs are commonly used in the treatment of mCRPC, because of their inhibitory effects on the secretion of ACTH and their palliative effects. Inhibition of ACTH results in downregulation of adrenal androgens. Cs may have a cytotoxic effect on prostate cancer cells, mediated in part by the downregulation of androgen receptors and the activation of glucocorticoid receptor-mediated signaling and downstream antiangiogenic activity. The rationale for adding Cs to D chemotherapy is for the management of symptoms and adverse events rather than for improving responses. D (without Cs) + ADT (androgen-deprivation therapy) vs ADT alone in castration-sensitive prostate cancer has resulted in significant increase in survival (NEJM, 2015). Cs has been reported to adversely influence OS during enzalutamide (NEJM, 2012). In the COU-AA-301 trial Cs use at baseline was an independent prognostic factor in multivariate analysis, but not in a stepwise selection model (JCO, 2013). Methods: We performed a retrospective analysis of 117 mCRPC pts treated with D. All pts had standard Cs premedication before D and 74 pts received prednisone 5 mg po BID, but 43 pts didn’t get continuous Cs therapy. Kaplan-Meier estimates and Cox regression model were used. Results: Pts characteristics were as follows: median age 66 yrs (range 48-81), Gleason score ≤6: 22pts, ≥7: 61pts. (34 NA). Altogether 1015 cycles of D were given, median 8 (range 2-27). Subsequent therapies were as follows: Abiraterone Acetate (AA) (75), Mitoxantrone (46), Xofigo (5), other chemotherapies (7), none (21). Pts receiving Cs had an inferior OS in all subgroups, although none was significant (Table). Only the Gleason score was an independent prognostic factor in multivariate analysis. Conclusions: Our data suggest, that D therapy withouth Cs is at least as effective as the combination. More data is neccesary to support the suspicion of negative influence of Cs on OS. Thus unnecesarry Cs treatment might be ommited. [Table: see text]
Apatinib in combination with hypofractionation radiotherapy in bone metastatic prostate cancer: Results from a pilot, multicenter study.
Authors: Zeng Ming , Zhao Feng , Tian Wei
Published: September 2018

e16523

Background: To study safety and efficacy of apatinib, a vascular endothelial growth factor receptor-2 (VEGF2) inhibitor, in combination with radiotherapy in patients with bone metastatic prostate cancer (BMPC), based on potential synergistic antitumor activities of apatinib and Radiation Therapy (RT). Methods: In a dose escalation study, 18 patients (6/cohort) received apatinib at 250 mg every other day, 250 mg or 500 mg daily. The 250 mg daily cohort was expanded to 19 patients in combination with RT (6 Gy/fraction, 5 fraction in total), comparing with the RT alone cohort with 10 patients. Evaluations included adverse events (AEs), prostate specific antigen (PSA) levels, radiographic evaluation and pain relief. Results: In the dose escalation patients, common apatinib-related AEs (arAEs) were fatigue (11, 61%), anorexia 10, 55%), hand foot syndrome (9, 50%), proteinuria (8, 44%), and HTN (8, 44%). Grade 3 arAEs included HTN, proteinuria, and liver dysfunction. No treatment-related death occurred. In the apatinib plus RT cohort, AEs were increased comparing to either apatinib alone or RT alone; The combination cohort showed improvement in pain control. Conclusions: In BMPC patients, apatinib at less than 500 mg daily dose as mono-therapy had tolerable toxicity, consistent with previous reports in patients with other tumors. Apatinib at dose of 250mg daily combining with RT improved pain control while the overall AEs were manageable. Further studies are needed in large sample size trials. Clinical trial information: NCT02998242.
Is chemical/surgical castration necessary during docetaxel chemotherapy for castration-resistant prostate cancer?
Authors: Watanabe Masahito , Kanao Kent , Muramatsu Hiroyuki , Morinaga Shingo , Kajikawa Keishi , Kobayashi Ikuo , Nishikawa Genya , Kato Yoshiharu , Nakamura Kogenta , Sumitomo Makoto
Published: September 2018

e16530

Background: Docetaxel is the standard treatment for castration-resistant prostate cancer (CRPC). However, the role of chemical/surgical castration during docetaxel chemotherapy is unclear. The purpose of this study was to analyze the impact of castration during docetaxel chemotherapy. Methods: Data from 43 patients diagnosed with CRPC and treated at our institute with docetaxel chemotherapy, from January 2007 to September 2016, were analyzed retrospectively. They were divided into two groups according to the continuation of chemical castration during docetaxel chemotherapy: a continuation group and a discontinued group. Patients’ background data (age and serum prostate-specific antigen [PSA] level), PSA decline, progression-free survival, and overall survival were compared between the two groups. Results: The continuation group included 19 patients, and the discontinued group included 24 patients. Castration included surgical castration (15.8%), use of a luteinizing hormone-releasing hormone (LH-RH) agonist (68.4%), and use of an LH-RH antagonist (15.8%). There were no significant differences in patient age (73.5 years vs. 73.5 years; p = 0.878) and baseline serum PSA levels (14.25 ng/ml vs. 31.1 ng/ml, p = 0.745) between the two groups at the start of chemotherapy. PSA declines of ≥50% were observed in 7/14 patients and in 9/20 patients, respectively. There were no significant differences between the two groups with respect to the median progression-free survival (5.7 months vs. 9.9 months, p = 0.406) and overall survival. (52.1 months vs. 44.1 months, p = 0.776). Conclusions: Continuing chemical/surgical castration during docetaxel chemotherapy did not affect progression and prognosis of CRPC. Our results might suggest that chemical castration is not necessary during docetaxel chemotherapy.
Results of a phase II trial of selinexor, an oral selective inhibitor of nuclear export (SINE), in patients with metastatic castration resistant prostate cancer (mCRPC) refractory to abiraterone or enzalutamide.
Authors: Wei Xiao , Siegel Adam Phillip , Aggarwal Rahul Raj , Lin Amy M. , Friedlander Terence W. , Fong Lawrence , Paraganlija Mirela , Chang Emily , Zhang Li , Ryan Charles J.
Published: September 2018

e16533

Background: Patients (pts) with abiraterone (abi) or enza (enza) refractory mCRPC typically have limited treatment options. Selinexor is a first in class SINE that specifically inhibits the nuclear export protein Exportin-1 (XPO-1) which is overexpressed in prostate cancer (PCa), leading to cytoplasmic mislocalization of tumor suppressor proteins. In preclinical models of PCa, selinexor reduced tumor growth and decreased the incidence of bone metastasis. Methods: Eligibility criteria included progressive mCRPC with primary or acquired resistance to abi, enza, or their combination. Prior chemotherapy for mCRPC was not allowed. All pts must have > 1 bone metastasis. The primary objective was radiographic progression free survival (rPFS). Results: Fourteen pts were enrolled between Oct 2014 and Oct 2016. The median age was 72 years (range 56-79) and median baseline PSA was 73.8 ng/mL (range 12.8-686.9). Eleven pts (79%) had both prior abi and enza. The initial selinexor dose was 65 mg/m2 on Day 1 (D1) and Day 3 (D3) weekly. For toxicity concerns, after the first 2 pts, dose was reduced to 60 mg on D1 and D3 for the first 3 wks followed by a 1-wk rest period (28-day cycle). All pts received ondansetron and olanzapine to prevent nausea and anorexia. The median treatment duration was 3 cycles (range 1-12), and median follow-up was 4 months. One pt (7.1%) had > 50% PSA decline, 5 pts (35.7%) had > 30% PSA decline, and 7 pts (50%) had any PSA decline. Of 10 pts evaluable, 9 pts had stable disease as best radiographic response, and 1 pt had progressive disease on the first radiographic evaluation. The median rPFS was 3.6 months (95% CI 2.1-not reached). The most common AEs of any severity were anorexia (86%), nausea (64%), weight loss (50%), fatigue (50%), thrombocytopenia (50%), anemia (36%), and vomiting (36%). Grade 3/4 AEs included nausea (14%), vomiting (14%), anemia (14%), anorexia (7%), weight loss (7%), thrombocytopenia (7%) and neutropenia (7%). Conclusions: Selinexor demonstrated limited clinical activity in mCRPC. Toxicity, in particular anorexia and weight loss, hinders further development in this pt population. Clinical trial information: NCT02215161.
Treatment outcomes in men with metastatic castration-resistant prostate cancer (mCRPC) and cardiovascular disorders or diabetes: The Prostate Cancer Registry.
Authors: Lumen Nicolaas , Chowdhury Simon , Birtle Alison J. , Bjartell Anders , Costa Luis , Feyerabend Susan , Galli Luca , Kalinka-Warzocha Ewa , Kramer Gero , Maroto Pablo , Matveev Vsevolod B , Paiss Thomas , Pisconti Salvatore , Spaeth Dominique , Veiga Francisco Gomez , Antoni Laurent , Klumper Edwin , Wapenaar Robert , Thoret-Bauchet Florence , Lee Emma
Published: September 2018

e16537

Background: The Prostate Cancer Registry is a prospective study of >3000 men with mCRPC in routine care. These patients (pts) have a high level of comorbidities which are often underrepresented in RCTs. Methods: Data were collected from pts with mCRPC irrespective of treatment (tx). Outcomes in pts with comorbidities were assessed. Results: At study entry, 16.6% of pts had a cardiac disorder, 9.7% hypertension only, 17.7% diabetes. Characteristics, first txs and outcomes are shown in the table below. Conclusions: In this real-life setting, AAP, ENZ, or DOC tx was feasible in pts with cardiac disorders, hypertension or diabetes; proportions treated with each drug were similar to the overall mCRPC population. Regardless of tx PFS was shorter than TTP, which may reflect the impact of pts’ comorbidities in real life. Pts with cardiac disorders had poorer outcomes vs the overall population. Clinical trial information: NCT02236637. [Table: see text]
Costs of skeletal-related events (SREs) in patients with metastatic castrate-resistant prostate cancer (mCRPC) treated with oral therapies.
Authors: Engel-Nitz Nicole , Behl Ajay S. , Blauer-Peterson Cori , Li Sophia S , Dawson Nancy Ann
Published: September 2018

e16539

Background: SREs are associated with increased mortality and costs for mCRPC patients. The impact of mCRPC oral therapies on SREs is not well understood in the real world. This study examined the occurrence of and health care costs associated with SREs among mCRPC patients treated with abiraterone acetate + prednisone (ABI) or enzalutamide (ENZ). Methods: A retrospective study of a large national health claims database identified patients initiated on ABI or ENZ from 9/2012- 6/2015. Patients included had: ≥1 claim with prostate cancer diagnosis (ICD-9-CM 185.x) from 6 mo. pre- to 30 days post-index; ≥6 mo. pre- + ≥3 mo. post-index health plan enrollment. Index was date initiated on first oral therapy (ABI/ENZ). SREs (spinal cord compression, radiation to bone, pathological fracture, bone surgery) were assessed and health care cost calculated for patients with/without SREs in baseline/follow-up. Descriptive analyses and Cox proportional hazards examined SREs; generalized linear models assessed costs. Models adjusted for ABI/ENZ, age, region, baseline comorbidities, bone/brain/visceral metastases, docetaxel, and statin use. Results: The table below summarizes unadjusted results. Total all-cause per patient per month (PPPM) costs of 1,516 patients were highest for those with follow-up SREs. A significant difference in cost exists when comparing across all groups. Among patients without baseline SREs, adjusted analysis found greater hazards of follow-up SREs for baseline bone metastases (HR: 1.62, P = 0.003), baseline visceral metastases (HR: 1.68, P < 0.001), prior docetaxel (HR: 1.46, P = 0.004), and ENZ (vs. ABI) as first treatment (HR: 1.35, P = 0.013). Patients with follow-up SREs (with/without baseline SREs) had 19% higher adjusted costs compared to those without baseline or follow-up SREs (P < 0.001 each). Conclusions: SREs were common among mCRPC patients and associated with a significant financial burden. [Table: see text]
Pathogen identification in prostate cancer biopsies using transcriptome sequencing.
Authors: Shah Carisa M , Bareja Rohan , Elemento Olivier
Published: September 2018

e16545

Background: Tumor biopsies may frequently be associated with microbial species due to proximity with microbial communities or due to contamination during tissue processing. We examined sequencing data from tumor biopsies to explore the tumor-associated microbiome in prostate cancer. Methods: Patients were enrolled in a prospective Precision Medicine study to evaluate genomic alterations based on freshly obtained tissue biopsies. Total RNA was prepared for RNA sequencing using the standard Illumina mRNA sample preparation protocol. Paired-end RNA-sequencing at read lengths of 50 or 51 bp was performed with the HiSeq 2000 (Illumina). A total of ~268 million paired-end reads were generated, corresponding to 27 billion bases. Kraken and FusionCatcher were used to identify the metagenome that maps to microbial species. R was used to analyze the microbial pathogens and to create a heatmap of microbial abundance. We focused our analysis on prostate cancer. Results: From 1/30/2013 to 12/16/15, 83 patients with urothelial cancers were identified, of which 32 patients with prostate cancer (n = 23 from primary tumor, n = 9 metastatic prostate cancer) were sequenced. Of the 9 metastatic samples, 5 were metastatic prostate cancer to bone, 4 were other metastases. A giant cell tumor of bone was used as a control. The metagenome was identified and mapped to the Kraken pathogen database. 43 unique pathogens characterized the microbiome associated with prostate cancer, including Streptomyces species, Acinetobacter baumannii, Enterobacteriaceae, and Corynebacterium species. The most prevalent species in prostate cancer bone metastases were also the most prevalent in primary prostate tumors. Prostate cancer bone metastases clustered separately from the primary prostate cancer samples, the other metastases, and primary bone cancer. Conclusions: We have identified a putative microbiome signature associated with prostate cancer. Prostate cancer bone metastases appear to cluster separately from prostate cancer, suggesting a non-random association with microbial communities. Ongoing work is looking to (1) validate microbial association using orthogonal analyses and (2) determine the exact origin of the signature.
Detection of HRD gene mutations and copy number changes in cfDNA from prostate cancer patients.
Authors: Raymond Chris , Hernandez Jenny , Brobey Reynolds , Wang Yue , Potts Kristy , Garg Kavita , Lim Lee , DiPasquo Dan , Li Mark , Dehghani Mehdi , Amato Robert J.
Published: September 2018

e16546

Background: Recent genomic surveys of prostate cancer have identified somatic mutations in metastatic castration-resistant prostate cancer (mCRPC). In this study, we examined mCRPC patients for AR aberrations and mutations in the HRD (homologous recombination DNA-repair) pathway which may confer platinum or PARP inhibitor sensitivity. Methods: A novel targeted-hybrid-capture NGS assay capable of identifying deleterious mutations, copy number amplification and gene copy loss, was applied to circulating, cell-free DNA (cfDNA) extracted from plasma samples from 20 mCRPC patients. Samples were collected between 3/2010 – 10/2015 and stored at -20C. The gene panel used in the assay included AR and several genes in the HRD pathway — ATM, BARD1, BRCA1, BRCA2, BRIP1, CDK12, CHEK2, FANCA, HDAC2, NBN, PALB2, and RAD51. Sequencing libraries created with the cfDNA extracted from 2.8-4 mLs of plasma had an average unique read coverage depth of 2282 genome equivalents (range 445 – 5136, median 2181). Results: Somatic variations were observed in 17 of the 20 samples analyzed. Copy number variation (CNV) was observed in 11 samples. AR amplification, linked to resistance to abiraterone and enzalutamide, was observed in 30% (6) of samples. Canonical AR ligand binding domain mutations, such as T787A and L702H were also detected. ATM, BRCA1, BRCA2, HDAC2, and FANCA gene deletions were also detected, as well as frameshift, nonsense, and other deleterious mutations in HRD genes. Significant CNV in multiple genes was observed in at least 5 patient samples. Mutations were detected across the entire collection date range, speaking to the robustness of cfDNA. Conclusions: Non-invasive tumor mCRPC genotyping appears to be feasible. The ability to detect HRD gene alterations suggests cfDNA testing may be suitable for the detection of HRD pathway defects and overall genome instability.
Computer extracted nuclear features from tumor and benign regions of Feulgen and H&E images to help predict recurrence in prostate cancer patients following radical prostatectomy.
Authors: Gawlik Anna , Lee George , Feldman Michael D , Zhu Guangjing , Veltri Robert W. , Madabhushi Anant
Published: September 2018

e16556

Background: Following radical prostatectomy, around 30% of prostate cancer (PCa) patients experience biochemical recurrence (BCR). H&E highlights nuclear morphology and Feulgen reflects nuclear DNA content, a feature linked to PCa presence and aggressiveness. In this work we sought to explore whether computer extracted measurements of tumor morphology and tumor adjacent benign regions on H&E and Feulgen tissue images could predict BCR. Methods: We used 108 patients (59 BCR and 49 non-recurrence (NR)) and each patient had 242 QH features calculated from both the tumor and benign region of stained TMA core images. Feature selection was performed on a training set (30 BCR, 24 NR) to select the 10 most discriminating tumor and tumor adjacent benign features of each stain. A random forest classifier was trained with features so identified and validated on a test set (29 BCR, 25 NR) to predict BCR. Predictions were displayed using Kaplan-Meier analysis and area under the ROC curve (AUC). Results: The most discriminating feature from the tumor regions of the H&E stain was Fourier descriptors of nuclear shape and from the Feulgen stain was texture intensity while from the benign regions it was invariant moments of nuclear shape and texture contrast energy. Combining the significant features from tumor and tumor adjacent benign regions from H&E and Feulgen resulted in the highest accuracy and a statistically significant difference (p < 0.05) via a log-rank test (Table 1). Gleason score did not show statistically significant differences and had the lowest AUC. Conclusions: Combining nuclear morphology and DNA related features of the tumor and tumor adjacent benign regions enabled accurate prediction of BCR. With additional multi-site validation, the combined H&E + Feulgen classifier could allow better risk stratification and post-surgical patient management. [Table: see text]
Accounting for improved prostate cancer mortality outcomes in Haitian men: A histological analysis.
Authors: Thoreson Nick , Rand Alexander , Sarita-Reyes Carmen , Soliman Mahmoud , Li Lei , Qureshi Muhammad M. , Gignac Gretchen , Hirsch Ariel
Published: September 2018

e16557

Background: In a previous wide-ranging study on the outcomes of prostate cancer patients at a safety-net hospital, we discovered significantly improved mortality outcomes for Haitian Creole prostate cancer patients compared to all other languages spoken, including black English speakers, with p = 0.017 [Rand, AE, et al., Clin Genitourin Cancer. (6):455-60 (2014)]. In order to assess any molecular indications that could be contributing to this finding, we performed a histological analysis of prostate cancer specimens, comparing black English-speaking patients to Haitian Creole patients. Methods: We sampled prostatectomies from 34 black English-speaking patients and 38 black Haitian Creole-speaking patients, taken between December 2011 and June 2015. In addition to primary and secondary Gleason scores, extraprostatic extension (EPE), seminal vesicle invasion (SVI), lymphovascular invasion (LVI), and perineural invasion (PNI), we observed any small amounts of grade 5 tissue present for the tertiary Gleason score. Finally, we analyzed the presence of acute and chronic inflammation and inflammatory severity. A chi square analysis was used to compare the categories between the Haitian and non-Haitian sets, with a probability less than 0.05 considered statistically significant. Results: While the null hypothesis was confirmed for primary, secondary, and total Gleason scores, 23.7% of the Haitian samples had a tertiary Gleason score of 5, compared to only 6.3% of non-Haitian samples (p = 0.046). The two populations exhibited similar rates of EPE (p = 0.719), SVI (p = 0.884), and PNI (p = 0.597), with no LVI apparent in any sample. No significant trends were noted in acute vs. chronic inflammation (p = 0.402) or severity of inflammation (p = 0.601). Conclusions: Samples taken from Haitian Creole-speaking patients had a significantly higher rate of grade 5 tertiary Gleason tissue than the non-Haitian patient samples. The presence of a tertiary Gleason score indicates a higher risk of metastasis, yet the Haitian samples do not reveal a greater rate of extraprostatic invasion. Further studies investigating underlying health factors among Haitian patients might be useful in accounting for improved patient outcomes.
Computer extracted features of gland morphology on H&E surgically resected tissue images as predictive of biochemical recurrence and rate of expression in African American compared to Caucasian American men.
Authors: Leo Patrick , Janaki Nafiseh , Thawani Rajat , Elliott Robin , Gupta Sanjay , Shih Natalie , Feldman Michael D , Madabhushi Anant
Published: September 2018

e16559

Background: Prostate cancer (PCa) is 1.7 times more prevalent and 2.3 times more lethal in African American (AA) men than in Caucasian American (CA) men. Additionally there is a higher incidence (when controlling for relative population size) of more aggressive PCa in the AA compared to the CA population which has led a number of groups to investigate whether there are molecular differences in the disease phenotype between the two groups. In this work we investigate whether computer extracted features of glandular morphology from digitized pathology images of surgical specimens identified as predictive of biochemical recurrence are also differentially expressed between AA and CA patients. Methods: Two cohorts were gathered. Cohort 1 (C1) contained digitized whole mount Gleason 7 radical prostatectomy specimens (RPS) from 72 patients (46 CA, 26 AA). Cohort 2 (C2) comprising quarter and whole mount RPS from 145 patients (135 CA, 10 AA), who either had biochemical recurrence in 5 years (47) or did not (98). A pathologist annotated each image in both cohorts for a representative cancerous region. Glands were automatically segmented and 216 features describing gland arrangement, shape, and disorder were extracted from every image. Features were tested for significance by Wilcoxon rank sum test at p < .05. Results: 8 features of gland morphology were significantly different between AA and CA groups and also predictive of biochemical recurrence (Table). Conclusions: We identified 8 computer extracted features of gland morphology that were both differentially expressed between AA and CA men and predictive of biochemical recurrence, suggesting that there are histomorphometric differences in prostate cancer appearance between AA and CA men. [Table: see text]
First-in-human phase 1 PET study of CTT1057, a novel 18F-labeled imaging agent targeting prostate specific membrane antigen (PSMA) in prostate cancer.
Authors: Aggarwal Rahul Raj , Behr Spencer , Seo Youngho , Gao Kenneth , Rahanfar Vahid , Slater Jim , Blecha Joseph , Langton-Webster Beatrice , Berkman Clifford , Vanbrocklin Henry
Published: September 2018

e16562

Background: Urea-based 68Ga-PSMA PET is increasingly being utilized for diagnostic purposes in prostate cancer; however high tracer uptake within the salivary gland and kidney may be dose-limiting upon translation to radiotherapy. We developed a novel 18F labeled agent, CTT1057, a PSMA inhibitor based on a phosphoramidate scaffold with nanomolar and irreversible binding affinity to PSMA and robust internalization, and performed a first-in-human imaging study. Methods: Patients (pts) with metastatic castration resistant prostate cancer (mCRPC) were eligible. 10 mCi (370 MBq) of CTT1057 was injected and whole body PET/MR imaging (SIGNA PET/MR, GE) was performed 60 min post-injection. SUVmean in normal organs was recorded by drawing a 1 cm3 volume-of-interest. SUVmax was determined for each PSMA-avid metastasis. 10 randomly selected, consecutive 68Ga-PSMA PET scans from an independent cohort were used for descriptive comparison. Results: 5 pts with mCRPC were enrolled, with average age of 66 years (range 35–85) and median PSA of 12.2 (range 0.73 – 157.7). 55 PSMA-avid metastases were seen, including 37 osseous (average SUVmax = 8.1 ± 4.4), 15 lymph node (SUVmax = 11.0 ± 6.1), and 3 pulmonary (SUVmax = 3.2 ± 0.6). 31 (83%) and 12 (32%) of the PSMA-avid osseous lesions were visible on CT and bone scan, respectively. The mean short axis diameter of PSMA-avid lymph nodes was 0.7 ± 0.4 cm. Tumor-to-background ratios (liver, muscle, blood pool) were 2.8 ± 2.3, 14.9 ± 11.6, and 3.2 ± 2.4, respectively. SUVmean in salivary gland and kidney were 3.6 ± 0.4 and 9.1 ± 0.8 for CTT1057 and 15.8 ± 2.7 and 35.9 ± 9.6 for 68Ga-PSMA, respectively. No tracer-related adverse events were observed and radiation dose estimates for organs and whole-body effective dose were within acceptable limits. Conclusions: 18F-labeled CTT1057 targeting PSMA, detected mCRPC lesions in the soft tissue and bone at greater sensitivity than conventional imaging. CTT1057 distribution of uptake was similar to urea-based PSMA imaging, with preliminary evidence of lower uptake in the salivary gland and kidney. Further clinical studies of the CTT1057 backbone as a diagnostic and therapeutic agent in mCRPC are warranted. Clinical trial information: NCT02916537.
SM88 in non-metastatic rising PSA-recurrent prostate cancer.
Authors: Del Priore Giuseppe , Sokol Gerald H. , Chen Wen-Tien , Tsao Che-Kai , Hoffman Steve
Published: September 2018

e16567

Background: SM88 is a novel combination of substituted amino acid ( AA) and repurposed agents with non-toxic activity in a variety of cancers including prostate (PC). Non-metastatic biochemically recurrent PC (nmPC) is ideal for such a well-tolerated, non-androgen based treatment. We present biomarker activity including CTCs (circulating tumor cells) after completion of the Ib dose escalating pharmacokinetic portion of the SM88 development plan. Methods: Planned analysis of an ongoing prospective Phase Ib/II open label study of nmPC (PCWG3 definition). Subject 1 received the 1stdose level of AA, and others received 2x dose. All subjects also received a combination of low dose re-purposed CYP3a4 inducer, oxidative stress catalyst, and mTOR inhibitor. Results: Four subjects completed at least 1 cycle (28d) with all PK sampling as prespecified. Median age was 73(70-80); all had prior ADT that was discontinued 3-6 yrs earlier, and either had curative intent prostatectomy (n = 2) or RT (n = 2); Testosterone level was castrate in one after prior RT. CTCs fell (p < 0.01) to undetectable (n = 1) or by > 25% (n = 3) (see table) while PSA remained stable (PCWG3 criteria). Preliminary LDH, neutrophil/lymphocyte ratio (N:L), urinary NTx, bone specific AlkPhos (bAP) trends are in the table below. There were no drug related serious adverse events (2 grade: 1- pigmentation, 1- vasomotor). EORTC-QLQ30 and PR25 scores were either improved or stable. Conclusions: Treatment with SM88 in patients with nmPC in the completed phase Ib cohort was associated with CTC reduction, and stable biomarker trends including PSA and LDH. There was no significant toxicity or adverse patient reported outcomes. Based on these results, the dose escalation was stopped at the second level and a cohort expansion phase II initiated. A phase III RCT is planned for confirmation of these results. Clinical trial information: NCT02796898. [Table: see text]
Analysis of racial differences in histologic subtype and survival in renal cell carcinoma at an urban academic cancer center.
Authors: Wong Kevin , Shusterman Michael , Gartrell Benjamin Adam
Published: September 2018

e16571

Background: Black patientswithrenal cell carcinoma (RCC) have a unique distribution of histological subtypes and historic worse survival compared to white patients. Little is known about RCC in Hispanics. We investigated histologic and survival differences between racial groups treated for RCC at the Montefiore-Einstein Cancer Center (MECC) in Bronx, NY. Methods: We included via the Cancer Registry 1010 patients who underwent RCC resection at MECC between 2000 and 2015. Demographics, clinical characteristics and pathology reports were collected. Logistic regression and Cox proportional hazards models were built to evaluate the association of histology and survival with clinically and statistically significant risk factors in Non-Hispanic White (NHW), Non-Hispanic Black (NHB), and Hispanic (H) patients. Results: 233 patients were NHW (23.1%), 383 NHB (37.9%), 174 H (17.2%), and 220 other race (21.8%). Median age was 61 (range 22, 91). 58% were male. Histology was 529 (52%) clear cell (CC), 255 (25%) papillary (P), 100 (10%) chromophobe, and 126 (12.5%) other. P was more common in NHB (60.5%) compared to NHW (17%) and less common in H (6.3%) patients (P < 0.0001). On multivariate logistic analysis, patients with P vs. CC were more likely to be NHB (OR 5.06; 95% CI 2.92, 8.76; P < 0.0001) and less likely to have a body mass index > 30 (BMI, OR 0.49; 95% CI 0.32, 0.76, P = 0.001) adjusting for age, race, gender, hypertension (HTN), and end stage renal disease (ESRD). Adjusting for above covariates there were no significant differences for C vs. CC. There was no difference in disease free survival (DFS) for NHB vs. NHW (HR 0.93; 95% CI 0.44, 1.94; P = 0.841) or H vs. NHW (HR 1.29; 95% CI 0.62, 2.71; P = 0.495) patients adjusting for age, gender, histology, ESRD, and BMI. There was no difference in overall survival (OS) for NHB vs. NHW (HR 0.97; 95% CI 0.57, 1.65; P = 0.908) or H vs. NHW (HR 1.37; 95% CI 0.79, 2.38; P = 0.256) patients adjusting for the same covariates. Conclusions: In this cohort of patients with RCC, P histology and lower BMI were significantly associated with NHB race. Unlike historic cohorts there was no significant difference in DFS or OS in NHB compared to NHW patients.