bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase II study of dovitinib in first line metastatic or (nonresectable primary) adrenocortical carcinoma (ACC): SOGUG study 2011-03.
Authors: García-Donas Jesús , Polo Susana Hernando , Guix Marta , Climent Duran Miguel Angel , Mendez Vidal Maria Jose , Jiménez Paula , Leon Mateos Luis , Rodriguez-Moreno Juan Francisco , Moreno Fernando , Segura Eduardo , Duran Ignacio , Maciá Sonia , Arranz Arija Jose Angel , Vazquez-Estevez Sergio , Perez Francisco Javier , Lainez Nuria , Castellano Daniel E. ,   Spanish Oncology GenitoUrinary Group (SOGUG)
Published: March 2020

4587

Background: Dovitinib is a novel targeted therapy that inhibits the fribroblast growth factor receptor (FGFR). Preclinical studies have pointed to a major role of this pathway in adrenocortical carcinoma (ACC) thus we aimed to test its clinical efficacy in this tumor. Methods: A phase II proof of concept trial was designed. Since this is an extremely infrequent disease sample size calculation was done taking as a basis the first stage of a two-stage Gehan model. Thus 15 patients needed to be included to show a treatment efficacy of at least 15% (probability of Type I error α = 0.05, power [1 – β] = 0.8). Main inclusion criteria was advanced non-resectable ACC, histologically confirmed, with no prior therapy other than mitotane. Primary endpoint was response rate (RR) by RECIST 1.1 assessed by an independent radiologist. Secondary endpoints included clinical benefit (RR plus stable disease), progression free (PFS) and overall survival (OS). Dovitinib was administered at 500mg daily dose 5 days on 2 days off for 6 months. Continuation of therapy was permitted at physician criteria. Results: From January 2012 to August 2012, 17 patients (5 male and 12 female) have been included in 7 institutions. Median age was 53 years (range 26-72); ECOG was 0-1 in 15 patients, 2 in one patient and N/A in one patient. 77 cycles, defined as one month on treatment, have been administered with dose reductions in 6 (7.8%). Grade 3-4 adverse events deemed as related to the drug were: rash (6%), asthenia (12%), diarrhea (6%), GGT elevation (18%), nausea (6%), hypertriglyceridemia (6%), hypertension (6%), hyperkalemia (6%). 13 patients withdrew treatment because of disease progression and 4 remain on dovitinib. No toxic death was reported. After a median follow-up of 5, 2 months (range 2,27 – 9,7) no objective response has been observed. Median PFS was 1,8 months (CI 95% [ 1,35 -2,25]), median OS has not been reached and clinical benefit has been achieved in 35% of patients with long lasting stable disease (>6 months) in 23%. Conclusions: Though no objective response was observed, a significant number of long lasting stabilizations have been achieved with an acceptable toxicity. These encouraging results merit further study. Clinical trial information: NCT01514526.
Identification of polo-like kinase 1 (PLK1) in aggressive prostate cancer by paradigm analysis.
Authors: Febbo Phillip G. , Goldstein Theodore C. , Baertsch Robert , Youngren Jack , Newton Yulia , Bivol Adrian , Small Eric Jay , Stuart Joshua M.
Published: March 2020

5006

Background: Integrative analysis that combines expression data, copy number variation, sequence, and epigenetic data with thousands of known biological interactions can help identify strong biological associations and novel “genotype to phenotype” associations. Methods: We performed multi-dataset differential expression analysis with Statistical Analysis of Microarrays (SAM) and gene set enrichment analysis (GSEA) across 10 publicly-available PCa microarray datasets to identify genes and pathways differentially expressed between local (n=471) and metastatic (n=220) PCa. We used PARADIGM, an integrated pathway analysis method, on PCa tumor samples with mRNA expression, copy number variation, and TMPRSS2:ERG fusion status data to infer differential fusion gene-related “activities” for pathway features (genes, protein complexes, etc) within a “Superimposed Pathway” representing a comprehensive collection of genetic interactions currently containing 20,314 known interactions among 16,362 concepts representing 6916 proteins, 7345 complexes, 1449 families, 55 RNAs, 15 miRNAs and 582 processes. Results: Out of the 7571 genes tested (those genes having data in two or more studies), the meta-analysis on gene expression revealed 210 (1.8% FDR) positively associated with PCa metastasis and 403 (0.94% FDR) negatively associated genes (threshold was p<0.001, 2-tailed Student’s t-test). GSEA highlighted cell proliferation, cell cycle control, and DNA damage repair pathways with metastatic tumors. The PARADIGM analysis identified a network containing 914 features connected by 1137 edges. PLK1 was identified as both highly expressed in metastatic PCa and as one of the fourteen hubs in the largest (596-feature) sub-network identified by PARADIGM. PLK1 was also associated with high Gleason Sum and recurrent disease in independent local PCa datasets. Conclusions: Using an approach pioneered by members of our SU2C/PCF supported PCa Dream Team, integrated analysis across multiple PCa datasets associates PLK1 activity with aggressive PCa and suggests it may provide a novel treatment target for at least a genetic sub-set of advanced PCa.
Prostate-specific membrane antigen antibody drug conjugate (PSMA ADC): A phase I trial in metastatic castration-resistant prostate cancer (mCRPC) previously treated with a taxane.
Authors: Petrylak Daniel Peter , Kantoff Philip W. , Mega Anthony E. , Vogelzang Nicholas J. , Stephenson Joe , Fleming Mark T. , Stambler Nancy , Petrini Michaela , Blattman Sara , Israel Robert Joseph
Published: March 2020

5018

Background: The abundant expression of prostate specific membrane antigen (PSMA) on prostate cancer cells provides a rationale for antibody therapy. PSMA ADC is a fully human antibody to PSMA linked to the microtubule disrupting agent monomethyl auristatin E (MMAE). It binds PSMA and is internalized within the cancer cell where cleavage by lysosomal enzymes release free MMAE, causing cell cycle arrest and apoptosis. A phase 1 dose escalation study of PSMA ADC in taxane-refractory mCRPC has been completed. Methods: Patients with progressive mCRPC following taxane-containing chemotherapy and ECOG status of 0 or 1 were eligible. PSMA ADC was administered by IV infusion Q3W for up to 4 cycles. Safety, pharmacokinetics, PSA, circulating tumor cells (CTC), immunogenicity and clinical progression were assessed. Serum PSMA ADC and total anti-PSMA ADC antibodies were measured by ELISA, and free MMAE was measured by LC/MS/MS.The dosing cohorts ranged from 0.4 mg/kg to 2.8 mg/kg. Subjects who benefitted from PSMA ADC were eligible for treatment in an extension study. Results: 52 subjects were dosed in 9 dose levels. All subjects received prior docetaxel, 6 also received cabazitaxel and 3 subjects also received paclitaxel. PSMA ADC was generally well tolerated with the most commonly seen adverse events being anorexia and fatigue. 16 patients reported peripheral neuropathies, including 3 with grade 3. Dose limiting toxicities (DLT) seen at 2.8 mg/kg were neutropenia (one death) and reversible elevations in liver function tests (LFTs). Antitumor activity was manifested as reductions either in PSA or in CTCs in approximately 50% of patients at ≥ 1.8 mg/kg PSMA ADC. Exposure to PSMA ADC increased with dose and was ~1,000-fold greater than MMAE exposure. There was no accumulation. Conclusion: PSMA ADC in this study was generally well tolerated in subjects with progressive mCRPC, previously treated with taxane. Antitumor activity was seen at doses ≥ 1.8 mg/kg. DLTs were neutropenia and reversible LFT abnormalities. The maximum tolerated dose was determined to be 2.5 mg/kg. A phase 2 trial of PSMA ADC in taxane refractory mCRPC has been initiated at 2.5 mg/kg. Clinical trial information: NCT01414283.
Mortality at 120 days following prostatic biopsy: Analysis of data in the PLCO study.
Authors: Boniol Mathieu , Boyle Peter , Autier Philippe , Perrin Paul
Published: March 2020

5022

Background: With the widespread use of PSA testing for prostate cancer screening in population, more prostate biopsy are being performed and seem set to increase in number. The safety of this diagnostic procedure needs to be ascertained. Only one study evaluated the mortality following prostate biopsy (Gallina et al, Int J Cancer 2008;123:647-52) and reported an increase of 2 deaths per 1,000 biopsies. Our objective was to re-evaluate the risk of death following prostate biopsy in a large, well-conducted randomised trial – the Prostate, Lung, Colorectal and Ovary (PLCO) Study. Methods: We extracted data from the PLCO study on all men participating in the study with a follow-up until 31/12/2009. All biopsies performed since randomisation were included. Cause of death was defined by ICD9 classification. Results: Among 12,300 prostate biopsies, 36 deaths occurred within120 days: 17/8390 in the intervention arm and 19/3910 in the control group. Only 17 deaths had neoplasm listed as the underlying cause of death. Thirty-two deaths out of 9,124 (0.35%) occurred in the positive biopsy group compared to 4 out of 3,176 (0.13%) in the negative biopsy group. In this latest group, this represents 1.3 deaths per 1,000 biopsies. Deaths occurred in all age groups from 55-69 to 70-74, and there was no difference identified in age between study arms (p=0.45) nor between those with a prostate cancer diagnosis and those not (p=0.73). Conclusions: The mortality rate at 120 days following prostate biopsy of 1.3 deaths per 1,000 biopsies, in a population free of cancer, is a serious concern for the computation of benefit risk associated with PSA testing. This figure is in line with the risk reported by Gallina et al (2008) and is now based on a properly monitored population. This prostatic biopsy mortality would occur earlier than any benefit from a screening program and could reverse any potential gain from screening such as recorded in ERSPC study.
Evidence for a field effect in early prostate cancer (PCa): Gene expression profiles in normal-appearing prostate tissue (NT) adjacent to tumor (T) as predictors of clinical outcome.
Authors: Klein Eric A. , Falzarano Sara Moscovita , Zhang Nan , Knezevic Dejan , Maddala Tara , Lawrence H. Jeffrey , Cherbavaz Diana B. , Pelham Robert J. , Millward Carl , Lee Mark , Magi-Galluzzi Cristina
Published: March 2020

5029

Background: We previously identified genes whose expression predicts aggressive PCa (clinical recurrence (cR), prostate cancer death (PCD), adverse pathology) when assessed in histologically heterogeneous tumor foci and in biopsies (Klein ASCO 2012). These results enabled the definition of a multi-gene Genomic Prostate Score (GPS), which has been clinically validated (Cooperberg AUA 2013). There is interest regarding a possible field effect in PCa, i.e. molecular alterations throughout the gland that may influence PCa development. We conducted exploratory analyses to evaluate gene expression, including GPS, in adjacent normal-appearing tissue (NT) for prediction of cR and PCD. Methods: Cohort sampling was used to select 127 patients with and 374 without cR from 2,641 patients treated with RP for T1/T2 PCa. Expression of 732 genes was measured by qRT-PCR separately in T and NT (defined as > 3 mm from T) specimens. GPS (0-100 units) was determined using the genes and algorithm from the validation study. Analysis used Cox proportional hazards models and Storey’s false discovery rate (FDR) control. Results: 410 evaluable patients had paired T and NT. Of the 405 genes which were predictive of outcome in T (FDR < 20%), 289 (71%) showed similar but weaker effects in NT. 47 genes were associated with cR in NT (FDR < 20%), of which 34 also concordantly predicted cR in T (FDR < 20%). GPS assessed in NT significantly predicted time to cR (HR/20 units = 1.8; 95% CI: 1.3-2.4; p< 0.001) and PCD (HR/20 units = 1.9; 95% CI: 1.2-3.0; p = 0.005) but was less predictive than GPS in T (HR/20 units = 4.8 for cR; 95% CI: 3.7-6.2; p < 0.001 and HR/20 units = 6.9 for PCD; 95% CI: 4.4-10.7; p < 0.001). The strongest components of GPS in predicting cR and PCD in NT were stromal response and androgen signaling genes (p < 0.05); proliferation and cellular organization genes did not consistently provide a significant contribution in NT. Conclusions: These data indicate that gene expression profiles, including GPS, can predict outcome in NT, albeit more weakly than in tumor. These findings suggest that there is an underlying field effect associated with the development of aggressive PCa.
Pain analyses from the phase III randomized ALSYMPCA study with radium-223 dichloride (Ra-223) in castration-resistant prostate cancer (CRPC) patients with bone metastases.
Authors: Nilsson Sten , Sartor A. Oliver , Bruland Oyvind S. , Fang Fang , Aksnes Anne-Kirsti , Parker Chris
Published: March 2020

5038

Background: Bone metastases (mets), present in > 90% of patients (pts) with CRPC, may cause severe pain. In a phase 2 dose-response study with a single injection of Ra-223, pain response was seen in up to 71% of CRPC pts with painful bone mets (Nilsson 2012). In the phase 3 ALSYMPCA study, which included 921 CRPC pts with bone mets randomized 2:1 to receive 6 injections of Ra-223 (50 kBq/kg IV) q4wk or matching placebo (Ra-223, n = 614; placebo, n = 307), Ra-223 significantly improved overall survival vs placebo (median 14.9 vs 11.3 mo; HR = 0.695) and was well tolerated. Post hoc analyses of pain parameters in ALSYMPCA are presented. Methods: The Cox proportional hazards model was used to analyze time to initial opioid use and time to EBRT. Pts with no opioid use at baseline were included in the pain analyses. All pts were included in the analysis for the prespecified endpoint time to EBRT. Concomitant opioid use was recorded from first study drug injection to 12 weeks after last injection. Pain-related QOL was analyzed based on the sum of 4 questions within FACT-P prostate cancer subscale (PCS) (Cella 2009) using ANCOVA. Results: Baseline pain characteristics were similar between the treatment groups (approximately 55% of pts had moderate to severe pain and opioid use based on WHO ladder for cancer pain). Time to EBRT was significantly longer with Ra-223 vs placebo (HR = 0.670; 95% CI, 0.525-0.854). Despite a longer observation time, fewer Ra-223 pts (50%) than placebo pts (62%) reported bone pain as an AE. At baseline, 269 Ra-223 pts and 139 placebo pts did not use opioids. Median time to initial opioid use was significantly longer in the Ra-223 group, with a risk reduction of 38%, compared to placebo (HR = 0.621; 95% CI, 0.456-0.846). Fewer Ra-223 pts (36%) than placebo pts (50%) required opioids for pain relief. The QOL pain score indicated reduced pain for Ra-223 pts relative to placebo pts at week 16 (P = 0.001). Ra-223 pts had significant pain reduction relative to baseline at weeks 16 (P < 0.001 ) and 24 (P = 0.001). Conclusions: These results provide consistent evidence that, in addition to prolonging survival, Ra-223 reduces pain and opioid use in CRPC pts with bone mets. Clinical trial information: NCT00699751.
A randomized phase II study of cediranib (CED) alone versus CED plus dasatinib (DAS) in patients (pts) with castration-resistant prostate cancer (CRPC).
Authors: Spreafico Anna , Chi Kim N. , Sridhar Srikala S. , Smith David C , Carducci Michael Anthony , Kavsak Peter , Wong Tracy S , Wang Lisa , Ivy S. Percy , Mukherjee Som Dave , Kollmannsberger Christian K. , Hotte Sebastien J.
Published: March 2020

5039

Background: Activation of the Vascular Endothelial Growth Factor Receptor (VEGFR) and the oncogenic Src pathway has been implicated in the development of CRPC in preclinical models. CED and DAS are multi-kinase inhibitors targeting VEGFR and Src respectively. Phase II studies of CED (Karakunnel et al ASCO 2009) and DAS (Yu et al Urology 2011) in CRPC have shown single agent activity. Methods: Docetaxel-preteated CRPC pts were randomized to arm A: CED alone (20 mg/day) vs arm B: CED (20 mg/day) plus DAS (100 mg/day) given orally on 4-week cycles. Primary endpoint was 12 week progression-free survival (PFS) as per the Prostate Cancer Clinical Trials Working Group (PCWG2). Patient reported outcomes were evaluated using Functional Assessment of Cancer Therapy-Prostate (FACT-P) and Present Pain Intensity (PPI) scales. Correlative studies of bone turnover markers (BTM), including bone alkaline phosphate (BAP) and serum beta-C telopeptide (B-CTx) were serially assayed. Results: 22 patients, 11 per arm, were enrolled. Baseline demographics were similar in both arms. Median number of cycles = 4 in arm A (range 1-12) and 2 in arm B (range 1-9). Twelve-week PFS was 73 % in arm A vs 18 % in arm B (p = 0.03). Median PFS in months (arm A vs B) was: 5.2 vs 2.6 (95% CI: 1.9-6.5 vs 1.4-not reached). Most common grade 3 toxicities were hypertension, anemia and thrombocytopenia in arm A and hypertension, diarrhea and fatigue in arm B. One treatment-related death (retroperitoneal hemorrhage) was seen in arm A. FACT-P and PPI scores did not significantly change in either arm. No correlation between BTM and PFS was seen in both arms A and B. Conclusions: Although limited by small numbers, this randomized study showed that the combination of VEGFR and Src targeted therapy did not result in improved efficacy and may be associated with a worse outcome than VEGFR targeted therapy alone in pts with CRPC. Clinical trial information: NCT01260688.
Use of bone scans during initial prostate cancer (CaP) workup, downstream procedures, and associated Medicare costs.
Authors: Falchook Aaron David , Salloum Ramzi George , Hendrix Laura H. , Chen Ronald C.
Published: March 2020

5040

Background: Bone scans are not recommended in the routine workup for patients with apparent low and intermediate risk CaP. We quantified the use of bone scans in low and intermediate risk patients, uses of other imaging and procedures after the bone scan, and costs to Medicare. Methods: Patients in the Surveillance Epidemiology and End Results (SEER)-Medicare database diagnosed with CaP from 2004 to 2007 were included. PSA, Gleason score and clinical T stage were used to define D’Amico risk categories. Patients with metastatic disease were included because the decision to order a staging bone scan for patients with apparent low and intermediate risk cancers occurs before knowledge about metastasis. We report use of bone scans from the date of diagnosis to the earlier of treatment or 12 months. In patients who received bone scans, we report use of X-ray, CT, MRI, and bone biopsy following bone scan to the earlier of treatment or 12 months. Cost was estimated using Medicare reimbursement rates. Results: 28% and 47% of patients with apparent low- and intermediate-risk prostate cancer received a bone scan (Table); <1% of these patients were found to have metastatic disease after work-up. A high proportion of patients had other imaging studies or biopsies after bone scan. For low and intermediate risk patients, the combined cost to Medicare of bone scan, X-ray, and bone biopsy as part of initial workup is estimated at $11,000,000 per year. The cost from CT and MRI after bone scan costs Medicare approximately $15,400,000 per year. Conclusions: Overuse of bone scans is common in workup of apparent low and intermediate risk CaP, even with an almost 0% risk of metastatic disease. X-rays, bone biopsies, and perhaps additional scans such as CT and MRI may result from bone scan findings, which are mostly false positives for these patients. These unnecessary procedures are costly to Medicare. [Table: see text]
Value of cell cycle progression (CCP) score to predict biochemical recurrence and definitive post-surgical pathology.
Authors: Schlomm Thorsten , Sangale Zaina , Lanchbury Jerry S. , Gutin Alexander , Reid Julia E. , Graefen Markus , Haese Alexander , Tennstedt Pierre , Steurer Stefan , Sauter Guido , Stone Steven
Published: March 2020

5043

Background: Prostate cancer (PCA) has a highly variable natural history and better tools are needed to more appropriately match treatment to a patient’s risk of progression. A prognostic mRNA expression signature composed of genes involved in cell cycle progression (CCP) has been previously developed. Here, we tested the utility of this signature to predict biochemical recurrence (BCR) and definitive post-surgical pathological stage. Methods: The eligible patient population was treated for PCA by radical prostatectomy at a single high volume center (2005-2006). We randomly selected 390 patients for the study. From each patient we prepared a ‘simulated biopsy’ by removing a tissue cylinder (0.6mm) from the post-surgical FFPE block containing the largest tumor foci. 249 patients remained eligible for analysis after excluding patients for either insufficient tumor in the biopsy, poor quality molecular data, or receiving neoadjuvant therapy. The median follow-up time for patients who did not recur was 60.8 months. 46 patients experienced BCR. CCP scores were generated as in previous studies. Cox PH models and logistic regression were used to evaluate CCP associations with outcome. Results: The CCP signature was a highly significant univariate predictor of BCR (HR=2.03; 95%CI: 1.48-2.79; p=3.1x10-5). After adjusting for clinical parameters including biopsy Gleason and PSA, the hazard ratio for CCP score remained significant (HR=1.6; 95%CI: 1.15-2.24; p=0.0068). In a multivariate model including PSA, biopsy Gleason, and clinical stage, CCP score was also an independent predictor of pathological stage (pT2 vs. pT3, p=0.029). In this analysis, PSA was the most predictive variable, but CCP score and clinical stage also provided important and non-redundant information. Conclusions: The CCP score has predicted PCA outcomes in multiple patient cohorts and different clinical settings. In this study, we have extended the demonstrated clinical utility to a modern patient cohort from Europe, and for the first time, provided evidence that the score can be used to predict definitive post-surgical tumor stage. The CCP expression score is an emerging and important component in evaluating PCA prognosis.
ASP9521, a novel, selective, orally bioavailable AKR1C3 (type 5, 17ß-hydroxysteroid dehydrogenase) inhibitor: In vitro and in vivo characterization.
Authors: Kikuchi Aya , Enjo Kentaro , Furutani Takashi , Azami Hidenori , Nimi Tatsuya , Kuromitsu Sadao , Kamiyma Yoshiteru
Published: March 2020

5046

Background: Aldo–keto reductase 1C3 (AKR1C3), also known as type 5, 17β-hydroxysteroid dehydrogenase, is reported to be highly expressed in human normal prostate and prostate cancer (PC) and the expression increases along with increasing malignancy or grade of PC. Since AKR1C3 converts the adrenal androgen, androstenedione (AD) into testosterone (T), combination with a GnRH analogue and AKR1C3 inhibitor would be expected to provide total androgen blockade in the treatment of castration-resistant prostate cancer (CRPC). We obtained a lead compound having a non-steroidal scaffold by high throughput screening (HTS) approaches for targeting enzyme activity of AKR1C3. After optimization of the lead compound, we found ASP9521 as a potent, selective, and orally bioavailable AKR1C3 inhibitor. Methods: The inhibitory effect of ASP9521 on enzymatic conversion from AD to T by AKR1C3 was evaluated in vitro, and in CWR22R xenograft models. Effect of PSA production and proliferation on LNCaP cells stably expressing AKR1C3 was examined. Pharmacokinetics in various animals were also investigated. Results: ASP9521 showed potent inhibitory effect on enzymatic conversion from AD to T by both human AKR1C3 and cynomolgus monkey homologues in a concentration-dependent manner, with IC50 values of 11 and 49 nmol/L, respectively ASP9521 suppressed both AD-dependent PSA production and cell proliferation in LNCaP cells exogenously expressing AKR1C3 in vitro. The bioavailability of ASP9521after oral administration of 1mg/kg were 30% and 78% in rat and dog, respectively. Furthermore, ASP9521 single oral administration of 3 mg/kg suppressed AD-induced intratumoral T production in CWR22R xenografted castrate nude mice, and this inhibitory effect was maintained for 24 h. In addition, ASP9521 was rapidly eliminated from plasma after oral administration while its intratumoral concentration remained high in tumors expressing AKR1C3. Conclusions: These preclinical in vitro and in vivo data are consistent with a potent inhibition of 17β-hydroxysteroid dehydrogenase. The results suggest that ASP9521 should be investigated further to elucidate its role as treatment for PC.
A phase I dose-escalation trial of AEZS-108 in taxane- and castration-resistant prostate cancer (CRPC).
Authors: Pinski Jacek K. , Schally Andrew V. , Tsao-Wei Denice D , Dorff Tanya B. , Groshen Susan G. , Xiong Shigang , Quinn David I. , Tai Yu-Chong , Engel Juergen , Liu Stephen V.
Published: March 2020

5062

Background: The receptor for luteinizing hormone releasing hormone (LHRH-R) is highly expressed on CRPC cells and is a potential therapeutic target. AEZS-108 is an LHRH-cytotoxic hybrid that covalently couples an LHRH agonist with doxorubicin. We report the completed Phase I trial of AEZS-108 in men with taxane-resistant CRPC. We explored visualization of AEZS-108 internalization into circulating tumor cells (CTCs) exploiting the auto-fluorescence of doxorubicin and also tested LHRH-R expression on CTCs. Methods: This was a dose escalation Phase I trial in men with taxane-resistant CRPC to confirm the dose established in a phase I trial in women. Standard 3+3 design was used with planned expansion at the MTD to ensure 6 patients received 2+ courses without DLT. Eligibility criteria included progression of disease despite prior LHRH agonist and taxane therapy. Patients received AEZS-108 every 21 days until progression or unacceptable toxicity. The primary endpoint was safety. CTCs were captured with a novel slot microfilter and identified by PSA and DAPI staining. AEZS-108 internalization was visualized by fluorescence microscopy. Results: Eighteen men with a median of 2 prior chemotherapy regimens (range 1-5) and a median PSA of 106.4 ng/mL (range 8.4-1624.0) enrolled from November 2010 to August 2012. The dose was escalated from 160 mg/m2 to 210 mg/m2 then to 267 mg/m2. There were 2 DLTs in the 7 men receiving 267 mg/m2 (grade 4 neutropenia), prompting de-escalation to 210 mg/m2 where 1 of 8 men experienced a DLT (grade 4 neutropenic fever), establishing 210 mg/m2 as the MTD. Significant non-hematologic toxicities included a case of grade 3 nausea. No cardiotoxicity was seen on serial evaluation and 6 patients completed 6 cycles. Internalization of AEZS-108 was consistently visualized in CTCs 1-3 hours after dosing. Maximal PSA response was stable or decreased in 8 of 18 men. Conclusions: The MTD of AEZS-108 in men with taxane-resistant CRPC is 210 mg/m2, which is below the MTD reported in women with refractory endometrial, ovarian and breast cancer. The activity of AEZS-108 was promising in this heavily pretreated population. The Phase II portion is currently accruing. Clinical trial information: NCT01240629.
Efficacy and safety of radium-223 dichloride (Ra-223) in castration-resistant prostate cancer (CRPC) patients with bone metastases who did or did not receive prior docetaxel (D) in the phase III ALSYMPCA trial.
Authors: Vogelzang Nicholas J. , Helle Svein Inge , Johannessen Dag Clement , O'Sullivan Joe M. , Garcia-Vargas Jose E. , O'Bryan-Tear C. Gillies , Shan Minghua , Parker Chris
Published: March 2020

5068

Background: Ra-223, a first-in-class α-emitter, significantly improved median overall survival (OS) by 3.6 mo vs placebo (Pbo) in CRPC patients (pts) with bone metastases (mets) receiving best standard of care (BSoC) in the ALSYMPCA study (HR = 0.695; 95% CI, 0.581-0.832; p = 0.00007), and had a highly favorable safety profile in the updated ALSYMPCA analysis (Parker et al. ASCO 2012). This predefined subgroup analysis assessed efficacy and safety of Ra-223 in pts who did or did not receive prior D (pD). Methods: Eligible pts had progressive, symptomatic CRPC with ≥ 2 bone mets; had no known visceral mets; were receiving BSoC; and had received pD, or were unfit for or declined D (npD). Pts were randomized 2:1 to 6 injections of Ra-223 (50 kBq/kg IV) q4wk or matching Pbo and stratified by prior D use, baseline alkaline phosphatase level, and current bisphosphonate use. Survival data were compared using a log-rank test. Results: 395/921 (43%) randomized pts had npD (Ra-223, n = 262; Pbo, n = 133); 526/921 (57%) received pD (Ra-223, n = 352; Pbo, n = 174). Median ages were 74 y (npD) and 69 y (pD). In pts with npD, median OS was 16.1 mo in the Ra-223 group vs 11.5 mo in the Pbo group (HR = 0.745; 95% CI, 0.562-0.987; p = 0.039). In pts with pD, median OS was 14.4 mo vs 11.3 mo in the Ra-223 and Pbo groups, respectively (HR = 0.710; 95% CI, 0.565-0.891; p = 0.003). Overall, there was a low incidence of myelosuppression. Incidences of neutropenia and thrombocytopenia were higher in pts with pD vs pts with npD. Conclusions: Ra-223 significantly prolonged OS and had a highly favorable safety profile in CRPC pts with bone mets, regardless of whether they had pD or npD. pD pts had a slightly increased rate of grade 3 and 4 bone marrow suppression with Ra-223. Clinical trial information: NCT00699751. [Table: see text]
Denosumab and zoledronic acid treatment in patients with genitourinary cancers and bone metastases.
Authors: Costa Luis , Fizazi Karim , Saad Fred , Brown Janet Elizabeth , Von Moos Roger , Oudard Stephane , Sternberg Cora N. , Ganju Vinod , Miller Kurt , Wang Huei , Maniar Tapan , Braun Ada
Published: March 2020

5079

Background: Phase III trial results showed that denosumab is superior to zoledronic acid (ZA) in preventing skeletal-related events (SREs) in patients with cancer and metastatic bone disease (Lipton et al; 2012, Eur J Cancer). Genitourinary (GU) cancers are some of the most commonly diagnosed cancers worldwide. We now compare the efficacy and safety of denosumab (DMAb) or ZA in a subgroup analysis of patients with GU cancers enrolled in the pivotal phase III trials. Methods: Patients were randomized 1:1 to receive DMAb (120 mg, SC) or ZA (4 mg, IV, adjusted for renal function) every 4 weeks. Daily calcium and vitamin D supplements were strongly recommended. Time to 1st on-study SRE, using a Cox proportional hazards model, time to 1st and subsequent on-study SRE, using the Anderson-Gill model, and safety were evaluated for the GU subgroup in an ad hoc analysis. Results: 2,128 patients (1,052 DMAb; 1,076 ZA) had GU cancers (prostate = 1,901, renal = 155, bladder = 63, and transitional cell = 9). DMAb significantly delayed the time to 1st on-study SRE by 4.0 months compared with ZA (20.7 months vs 16.7 months) in patients with GU cancers (Table). DMAb also significantly delayed the time to 1st and subsequent on-study SRE. Time to disease progression and overall survival were similar between treatment groups. Adverse events (AEs) and serious AEs were reported by similar percentages of patients in both groups (AEs: 96.9% denosumab, 96.8% ZA; serious AEs: 62.8% denosumab, 60.2% ZA). 14.6% of DMAb pts and 15.9% of ZA pts had a renal AE. Hypocalcemia was reported for 12.9% of DMAb patients and 6.2% of ZA patients. There was no significant difference in the incidence of positively adjudicated osteonecrosis of the jaw between the DMAb (2.2%) and ZA (1.6%) groups (p=0.34). Conclusions: Among patients with GU cancers and metastatic bone disease, DMAb was superior to ZA in preventing SREs. Clinical trial information: NCT00330759 and NCT00321620. [Table: see text]
Sera cytokine levels to predict survival in men with progressive castration-resistant prostate cancer.
Authors: Subudhi Sumit Kumar , Heller Glenn , Danila Daniel Costin , Anand Aseem , Lacuna Kristine Peregrino , Samoila Aliaksandra , Fleisher Martin , Scher Howard I.
Published: March 2020

5083

Background: Serum cytokines have been proposed as immunologic biomarkers of clinical responses based on their role in tumor biology. Recently, two whole blood mRNA signatures, which included immunomodulatory gene transcripts, were found to be predictive of survival in CRPC. This study explores serum cytokines, measured with analytically valid assays, as prognostic biomarkers in CRCP. Methods: Serum was collected from 75 progressive CRPC patients treated at MSKCC. A panel of 10 cytokines (M-CSF, IFN-γ, TNF-α, IL-1 β, IL-4, IL-5, IL-6, IL-10, IL-12 and IL-13) was measured in a CLIA-certified laboratory by clinically validated ELISAs. To create a risk group classification based on the 10 cytokines, a regression tree methodology was used with the intent to maximize the survival differences between risk groups. In addition to the cytokine risk groups, PSA, LDH, albumin, hemoglobin and CTC enumeration were also independently prognostic. The Cox model was developed to determine the factors that jointly predicted survival. The concordance probability estimate (CPE) was used to determine the discriminatory power of this model. Results: Among the 10 cytokines, M-CSF (stimulates monocytes and macrophages) and IL-10 (suppresses T-cell-mediated anti-tumor responses), were most predictive of overall survival in a 3 risk-group model. The relative risk for log CTC was 1.78 (95% CI 1.43 – 2.21). The combination of the cytokine risk groups and CTC enumeration provided the best discriminatory power for predicting survival, yielding a discrimination index measured by the CPE equal to 0.77 (se = 0.03). Conclusions: A risk group classification, based on two serum cytokines, M-CSF and IL-10, and log CTC measured by analytically valid assays, predicted survival in patients with progressive CRPC. These cytokines may reflect the biology within the tumor microenvironment, and may also serve as biomarker for clinical benefit. Independent validation in a similar cohort of patients is ongoing. [Table: see text]
Phase II trial of single-agent ganetespib (STA-9090), a heat shock protein 90 (Hsp90) inhibitor in heavily pretreated patients with metastatic castration-resistant prostate cancer (mCRPC) post docetaxel-based chemotherapy: Results of a Prostate Cancer Clinical Trials Consortium (PCCTC) study.
Authors: Heath Elisabeth I. , Stein Mark N. , Vaishampayan Ulka N. , Antonarakis Emmanuel S. , Liu Glenn , Sheng Shijie , Farrow Katherine , Smith Daryn W. , Heilbrun Lance K.
Published: March 2020

5085

Background: Hsp90 is a molecular chaperone required for the proper folding and activation of numerous client proteins and is critical to cell survival and proliferation. Ganetespib (G), a synthetic small molecule that binds to the ATP pocket in the N-terminus of Hsp90 causes the degradation of cellular proteins and ultimately death of cancer cells dependent on these proteins. G displays potent anticancer activity in prostate cancer cells. Methods: Eligible patients were ≥ 18 yrs old with ECOG performance status ≤ 2. Adequate hepatic, renal, and bone marrow function was required. Patients were treated with G 200 mg/m2 intravenously once weekly for 3 consecutive weeks followed by 1 off-week. The primary objective was to evaluate the 6-month progression-free survival (PFS). Secondary endpoints included overall safety and tolerability of G and overall survival. Exploratory markers including maspin, cytokeratins 8 and 18, and HDAC1 were obtained pre, during, and post G treatment. We sought ≥ 4 patients with ≥ 6 months PFS (a success) in Stage 1 of a 2-stage near-optimal Simon design. Results: 18 patients were enrolled at 4 institutions. The patients’ median age was 68 (range 51-82), 13 were Caucasian, 4 were African American, and 1 was Asian. Median PSA was 210.7 ng/mL (range 25.9 – 3,489 ng/mL). One patient never started therapy. Among the 17 treated patients, the median number of cycles was 2 (range 1-5). The most frequent Grade 3 toxicities were diarrhea (3 patients), fatigue (3), and dehydration (3). Prior therapy included abiraterone (8), sipuleucel-T (4), and other targeted therapy (4). With < 4 successes in Stage 1, the trial was terminated early. Median PFS was 1.9 months (90% CI: 1.7 – 2.7 months); median OS was 10.2 months (90% CI: 2.3 – 18.3 months). Exploratory markers have been evaluated and will be presented. Conclusions: Our study represents the first clinical trial of G in treating mCRPC patients. As a single agent therapy, G did not prolong PFS. Combination therapy is a consideration to improve therapeutic efficacy. Clinical trial information: NCT01270880.
Phase II randomized study of the EGFR, HER2, HER3 signaling inhibitor AZD8931 in combination with anastrozole (A) in women with endocrine therapy (ET) naive advanced breast cancer (MINT).
Authors: Johnston Stephen R. D. , Basik Mark , Hegg Roberto , Lausoontornsiri Wirote , Grzeda Lukasz , Clemons Mark , Dreosti Lydia Mary , Ghiorghiu Serban , Mann Helen , Landers Donal , Stuart Mary , Cristofanilli Massimo
Published: March 2020

531

Background: Preclinical data suggest a key role for EGFR inhibition in delaying acquired resistance to ET in ER+ breast cancer (BC). Retrospective analyses of 2 Phase II studies suggested adding gefitinib to ET delayed PFS in ET naive (ETN) BC. This randomized, double-blind, placebo-controlled multi-center study (NCT01151215) was conducted to prospectively test the hypothesis that adding AZD8931, an inhibitor of EGFR, HER2 and HER3 signaling, to A would be beneficial in delaying endocrine resistance in an advanced ETN BC population. Methods: Post-menopausal women with ER+ and/or PR+, ETN, HER2-negative, advanced BC were randomized (1:1:1) to receive A (1 mg od) plus AZD8931 20 or 40 mg bd or placebo (P). The primary endpoint was PFS (ITT population). Data presented are from an interim analysis (data cutoff 31 Aug 2012; 39% pts had a progression event). Results: Between Jun 2010 and Jun 2012, 359 pts (median age 61 years) were randomized to A combined with AZD8931 20 mg (n=118), 40 mg (n=120) or P (n=121). At the interim analysis, median PFS in the AZD8931 20 mg, 40 mg and P arms was 10.9, 13.8 and 14.0 months, respectively; PFS HR (95% CI) for AZD8931 20 mg:P was 1.37 (0.91–2.06, P=0.135) and for AZD8931 40 mg:P was 1.16 (0.77–1.75, P=0.485). Deaths were reported for 20 (17%), 16 (13%) and 12 pts (10%) in the AZD8931 20 mg, 40 mg and P arms, respectively. Grade ≥3 AEs were reported for 22 (19%), 44 (37%) and 18 (15%) pts in the AZD8931 20 mg, 40 mg, and P arms, respectively, the most frequent being rash (0% vs 8% vs 2%), acneiform dermatitis (0% vs 7% vs 0%) and hypertension (3% vs 3% vs 2%). Serious AEs were reported for 12%, 14% and 9% pts in the AZD8931 20 mg, 40 mg and P arms, respectively, and discontinuation (of AZD8931 or P) due to an AE in 5%, 8% and 2% pts, respectively. Conclusions: Co-blockade of EGFR, HER2, HER3 in combination with aromatase inhibition does not appear to delay endocrine resistance to ETN BC. Based on the low probability of demonstrating superior efficacy with addition of AZD8931 to A and the overall risk/benefit, the study was closed at the recommendation of the IDMC and pts discontinued AZD8931. Clinical trial information: NCT01151215.
Single nucleotide polymorphisms to predict for neoadjuvant chemotherapy in breast cancer according to estrogen receptor (ER) status.
Authors: Pannier Diane , Dumont Aurelie , Tresch Emmanuelle , Chen Jinying , Ducoulombier Agnes , Revillion Francoise , Bonneterre Jacques , Peyrat Jean-Philippe
Published: March 2020

544

Background: Neoadjuvant chemotherapy (NCT) using anthracyclines and taxanes is a standard treatment for locally advanced breast cancer and pathologic complete response (pCR) is a major prognostic factor for survival. Gene polymorphisms have been identified as modulators of chemotherapy response. Our study investigated constitutional variants of genes associated with a change in the response to neoadjuvant chemotherapy using taxanes and/or anthracyclines in patients with breast adenocarcinoma. Methods: From November 2007 to January 2012, 118 women with breast adenocarcinoma histologically proven, with no Her2 surexpression, receiving or having received a neoadjuvant chemotherapy with taxanes and/or anthracyclines were included in the study. NCT associated 3 FEC100 then 3 Docetaxel every 21 days. Genotyping of 46 SNPs was performed on germline DNA using real time PCR. pCR was correlated to clinical characteristics and genotypes using univariate logistic regression. Results: 21.2% had a pCR according to Sataloff classification. pCR is increased in SBRIII (p=0.009), estrogen receptor negative (p=0.005) and triple negative (p=0.006) tumors. 7 SNP are significantly associated with pCR in ER+ breast tumors (pCR=13.5%). Among these SNP, pCR is increased for patients carrying almost one G allele for SLCO1B3-rs11045585 (pCR=28.6%; p=0.032), for homozygotes GG for SHTM1-rs1979277 (pCR=24.3%, p=0.006) and for homozygotes CC for CYP1B1-rs1056836 (pCR=25.7%; p=0.003). Moreover, 4 SNPs are significantly associated with pCR in ER- breast tumors: ERCC1-rs11615 (carriers of almost one C allele: pCR=50%; p=0.030), CD24-rs52812045 (Homozygotes CC pCR=56.3%, p=0.033), CYP2B6-rs2279343(carriers of one or two G allele: pCR=52.6%; p=0.046) and GSTP1-rs1695 (carriers of one or two G allele: pCR=48%; p=0.050). Conclusions: Besides ER status, polymorphisms could be useful markers to predict response to anthracyclines/taxanes NCT in breast cancer. Furthermore, this work is the first describing ERCC1-rs11615, SLCO1B3-rs11045585 and SHTM1-rs1979277 as new potential genetic markers for NCT in breast cancer. (The first 3 authors contributed equally to this work.)
Clinical significance of ERβ mRNA expression in ERα-negative and triple-negative breast cancers.
Authors: Kim Young Choi , Kim Hadong , Kim Tae-Hoon
Published: March 2020

545

Background: Previously at the 2012 ASCO meeting, we reported significant ERβ mRNA expression in ERα-negative (ERα-) and triple negative breast cancers (TNBC). In this study, we analyzed its clinical outcome and correlation with other clinical parameters. Methods: A total of 141 cases consisted of 69 ERα- BC including 41 TNBC and 72 ERα+ BC were obtained from patients aged 29 to 97 years old between 2003 and 2010. Treatments included surgery, hormone, chemo- or radiotherapy, or any combinations. The follow-up period ranged from 1 to 132 months. ERβ mRNA was analyzed from formalin-fixed tumor tissues by RT-PCR. ERα, PR, Her-2, Ki-67, AIB-1, NFk/p65, p-c-jun, Ki-67, TIF-2, SRC-1, CK5/6 and p53 were tested by immunohistochemistry. The correlation was deemed significant if p value less than 0.05 from Chi-square. Overall survival (SVR) was defined from the date of diagnosis to last follow-up or death attributed to BC and was analyzed by the Kaplan-Meier curves and Wilcoxon rank sum. Results: Single or combination of ERβ isoform(s) was highly expressed in both ERα- and TNBC and ERβ2 was the most frequent (48.8%) and ERβ5, the least (30.2%). In contrast, ERβ5 was the most frequent in ERα+BC. Presence of all or any ERβ isoform was associated with significantly higher SVR in all cases, and in TNBC (ERβ total, Wilcoxon p = 0.0177, ERβ2, p= 0.0329), and also with negative LN (p< 0.0001). ERβ2 and ERβ5 were expressed in 63.2% and 30 %, respectively, in 20 patients died in 1 to 60 months. Over expression of AIB-1, NF-kB/p65 and TIF-2 was associated with ERβ1 and ERβ2 (p<0.05). Ki-67 + cells were mostly ERβ + BC than ERα+. ERα mRNA expression was up-regulated, and ERβ,down- regulated, with the ERα: ERβ+ ratio of 3-1000:1. There was no association between ERβ expression and the stage, age, tumor size, and postmenopausal status. Conclusions: Specific ERβ isoform appears to be a significant discriminating factor for SVR and negative node. ERβ2 is the predominant isoform in ERα- but ERβ5 in ERα+BC, suggesting a distinct role of ERβ isoform in ERα- and ERα+BC. ERβ isoform may be a selective therapeutic target in this cohort. ERβ+/ Ki-67+cells appear to be a sub-population of BC arising from basal-myoepithelial cells in this cohort.
Post-surgical highly sensitive C-reactive protein (hsCRP) and prognosis in early stage in breast cancer (BC).
Authors: Tibau Martorell Ariadna , Goodwin Pamela Jean , Ennis Marguerite
Published: March 2020

550

Background: Obesity, commonly associated with inflammation, is associated with poor prognosis in BC. Previous research suggests CRP, an obesity-associated marker of systemic inflammation, may mediate the adverse prognostic effects of obesity and be associated with fatigue. We examined the association of hsCRP with obesity-related factors, fatigue and distant disease-free and overall survival (DDFS, OS) in an early BC cohort. Methods: 501 non-diabetic women with T1-3, N0-1, M0 BC diagnosed 1989-96 provided fasting blood (mean 7.7 ± 4.3 weeks after surgery, prior to systemic therapy, stored at -80°C) which was analyzed for hsCRP (Roche Elecsys immunochemistry). 359 women also completed the EORTC QLQ-C30 (mean 8 ± 3.9 weeks post-surgery). Women were followed prospectively to 2007. Data were analyzed using Spearman's rank correlation coefficients (r) and Cox models. Results: Mean age was 50.5 ± 9.7 years; 282/159/24/36 subjects had T1/T2/T3/TX cancers; 350 were N0; 306 had ER+ and 278 PgR+ cancers (HER2 was not performed); 76/208/142 cancers were grade 1/2/3; adjuvant treatment involved radiation (369 subjects), chemotherapy (196), tamoxifen (107). Median hsCRP was 0.9 mg/L (25th/75th percentiles: 0.4/2.4 mg/L). hsCRP was correlated (all p < 0.0001) with age (r = 0.25), Body Mass Index (BMI, r = 0.6), insulin (r = 0.44), Homeostasis Model Assessment (r = 0.45) and leptin (r = 0.54), but not with EORTC fatigue (r = 0.02), T or N stage, grade or ER/PgR status (any + vs. both -). Median follow-up was 12 years. hsCRP was not associated with DDFS or OS in univariate analyses (Q4 vs. Q1 HR 1.03, 95% CI 0.69-1.52, p = 0.9 and HR 1.27, 95% CI 0.86-1.86, p = 0.24 respectively) or multivariate analyses adjusting for age, T, N, grade, ER/PgR status, treatment (HR 1.02, 95% CI 0.66-1.59, p = 0.93 and HR 1.17, 95% CI 0.76-1.81, p = 0.48 respectively). Conclusions: hsCRP (measured post-op, prior to systemic therapy) was associated with age, BMI and obesity associated physiologic factors; it was not associated with fatigue, DDFS or OS. Funded by The Breast Cancer Research Foundation (New York), The Canadian Cancer Society Research Institute (formerly The Canadian Breast Cancer Research Initiative).