bluuebunny/crossref_metadata_2025 huggingface dataset:
Durable radiologic and clinical disease stability beyond PSA progression in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone acetate (AA).
Authors: Bianchini Diletta , Sandhu Shahneen Kaur , Mulick Cassidy Amy , Zivi Andrea , Mezynski Janusz , Mukherji Deborah , Pezaro Carmel Jo , Reid Alison Helen , Oommen Nikhil Babu , Olmos David , Omlin Aurelius Gabriel , Sarvadikar Ajit , Thompson Emilda , Hunt Joanne , Sheridan Elizabeth , Attard Gerhardt , De Bono Johann Sebastian
Published: March 2020

4553

Background: AA, a potent oral CYP17A1 inhibitor is approved for treatment of mCRPC with a survival advantage of 4.9 months. In clinical practice, response evaluation remains challenging for pts with mCRPC. CTC conversion from CTC ≥ 5 to CTC < 5 with treatment predicts for improved overall survival in mCRPC. We hypothesized that pts continue to have durable disease stability beyond PSA progression on AA. Methods: Prostate Specific Antigen (PSA) responses, radiological responses and CTC conversion rates were retrospectively analysed in pts treated on AA at our institution. CTCs, PSA and imaging were obtained at predefined time points during these studies. Radiological and PSA progression were defined by standard Prostate Cancer Working Group Criteria II. Clinical progression consisted of worsening disease related pain, skeletal events or declining performance status.Pearson’s chi-squared test and the Kaplan-Meier method were used for this analysis. Results: 141 patients [ECOG Performance Status 0-2; Median Age: 69.7 (range 44.7-87.1); 85 post-docetaxel, 56 pre-docetaxel] received AA. The median duration of clinical and radiological stable disease (SD) was 16.8 months (n=55) and 5.6 months (n=75) in patients with a baseline CTCs count of ≤ 5 cells/7.5mls and ≥ 5 cells/7.5 mls respectively. In the 105 patients with documented PSA progression on AA there was a median 5.7-month delay in detecting radiological and/or clinical progression (95% CI: 4.2, 8.4; range 0.3, 35.6 months). Radiological and clinical SD of ≥ 1 year, ≥ 2 years and ≥ 3 years on AA was observed in 43/141 (30.5%), 21/141 (14.9%) and 12/141 (8.5%) respectively. Conclusions: Radiological and clinical disease stabilization beyond PSA progression is maintained in a high proportion of mCRPC patients treated with AA. Future studies should evaluate whether continued AA treatment beyond PSA and radiological progression can impact outcome.
Abiraterone in patients with metastatic castration-resistant prostate cancer progressing after docetaxel and MDV3100.
Authors: Ileana Ecaterina , Loriot Yohann , Albiges Laurence , Massard Christophe , Blesius Aurore , Di Palma Mario , Escudier Bernard J. , Blanchard Pierre , Bossi Alberto , Fizazi Karim
Published: March 2020

4554

Background: Chemotherapy with docetaxel is the standard first-line treatment in patients with metastatic castration-resistant prostate cancer (mCRPC). In patients progressing after docetaxel, both abiraterone and MDV3100 have yielded improved survival for patients with mCRPC. The efficacy of abiraterone in patients pre-treated with MDV 3100 is unknown. Methods: We investigated abiraterone-prednisone in 24 patients with cancer progression after docetaxel followed by MDV3100. All patients received abiraterone 1000 mg/day plus prednisone 10mg/day. Prostate-specific antigen (PSA) response, symptom response, and time to progression were assessed. Results: Patient characteristics were as follows: median age: 74 years (53-84), median PSA: 108 ng/mL (2-2541), metastatic sites: bone: all 24 patients, liver/lung: 6 patients (25%), and lymph nodes : 9 patients (38%). Five patients (21%) had a PSA decrease on abiraterone-prednisone. Three patients (13%) achieved a PSA response, defined as a decrease of >50% in PSA, confirmed after≥ 4 weeks. The duration of PSA response was 2, 3 and 4.5 months. Six patients (29%) had a symptomatic response on the pain score and analgesic consumption was decreased. Treatment was well tolerated. Abiraterone-prednisone was discontinued in one patient due to edema and hypokaliemia. Conclusions: This study shows preliminary evidence that abiraterone-prednisone yields activity in patients with mCRPC pretreated with docetaxel and MDV3100.
Expression of MET and HGF in bladder cancer tumorigenesis and invasion.
Authors: Sweis Randy F. , Grivas Petros , Pearson Alexander T. , Day Kathleen C. , Day Mark L. , Hussain Maha
Published: March 2020

4573

Background: The human MET gene encodes the hepatocyte growth factor (HGF) tyrosine kinase receptor. Limited studies in human bladder cancer have demonstrated that expression of MET protein is linked with disease progression and survival. We hypothesized that the expression of both MET and its ligand HGF are altered in bladder cancer. Methods: Expression of MET and HGF in human bladder tissues was explored using Oncomine, an online compendium of cancer transcriptome profiles. The largest relevant dataset was identified and contained 157 samples (Sanchez-Carbayo, et al. 2006). Normalized and log2 transformed mRNA expression values for Affymetrix U133 microarray probe sets corresponding to the genes of interest were compiled and averaged for each gene. Mann-Whitney U testing was used to compare means. Nominal and standard least squares logistic regression was used to evaluate the predictive significance of, and relevance of clinicopathologic variables on, gene expression. Statistical analyses were carried out using JMP 9.0.2. Results: Expression of MET and HGF was compared across subsets of normal bladder tissue (n=48), superficial tumors (n=28), and invasive tumors (n = 81). Relative to normal tissue, MET expression was greater in superficial (p = 0.0008) and invasive tumors (p<0.0001). HGF expression was reduced in both invasive and superficial tumors vs. normal tissue (both p< 0.0001), but was higher in invasive vs. superficial tumors (p= 0.0007). In a logistic regression model of tumor samples, both MET and HGF correlated with tumor invasion (model p=0.0003). Interaction between MET and HGF was not significant (p=0.55). Neither MET nor HGF expression was predicted by regression using age, gender, grade, or nodal stage (p=0.16 and 0.27, respectively). Conclusions: Decreased HGF expression and MET over-expression are strongly associated with tumorigenesis and invasion in bladder cancer. The reduction in HGF expression is blunted in invasive vs. superficial tumors, suggesting a potential loss of negative feedback in more aggressive tumors. Expression of both genes could not be predicted by modeling clinicopathologic variables. MET signaling represents a potential therapeutic target in bladder cancer.
Quality of life and late toxicities in germ-cell cancer patients after high-dose chemotherapy.
Authors: Wuendisch Thomas , Naermann Regina , Beyer Joerg , Lorch Anja ,   for the German Testicular Cancer Study Group
Published: March 2020

4600

Background: The number of long term survivors after treatment for relapsed/refractory germ cell cancer (GCC) is increasing but little is known about quality of life (QOL) and late toxicities (LT). Methods: We assessed LT and QOL in GCC patients (pts), treated in a prospective, randomized, multicenter, phase III trial comparing single versus sequential high-dose chemotherapy (HDCT) (Lorch 2007). All 216 pts were asked to complete the European Organization of Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) prior to HDCT, 6 weeks after and yearly thereafter. Results were analyzed according to standard methods (Fayers 2001). In addition pts were contacted at a median of 76 months (range 45-109) after HDCT to obtain information about current social and professional activities as well as LT. Results: Among 216 pts, 92/216 (42%) were alive and without evidence of disease one year after randomization. Median age of pts was 34 years (range 15-56). A median of 4 conventional-dose cisplatin-based treatment cycles had been given prior to HDCT. Questionnaires and response to the survey were evaluable in 86/92 (93%) pts overall and in 59/86 (69%) pts more than 3 years after HDCT. Values for global health status, role functioning and emotional functioning declined during the first year after HDCT, increased in the following years, but did not reach the reference values from large samples of the general population in Norway (Hjermstad 1998). Pts after sequential HDCT scored better in a number of items (e.g. emotional-, cognitive-, social-functioning, fatigue and dyspnoea) in comparison to single HDCT including high-dose cyclophosphamide. Persisting polyneuropathy was reported in 59%, ototoxicity or tinnitus in 56%, erectile dysfunction in 24%, hypertension in 23%, hypercholesterinemia in 17%, diabetes mellitus in 6%, nephrotoxicity in 6%, myocardial infraction in 2% and second cancers in 1% of pts. Overall 82 % of pts were employed, 30% exercised regularly. Conclusions: HDCT has a negative impact on QOL, including social and professional life. Most common late toxicities were ototoxicity and polyneuropathy. Sequential HDCT without cyclophosphamide seems to result in a better outcome in respect to QOL.
Can abdominal ultrasound replace CT scanning in long-term follow-up of male patients with germ cell tumor?
Authors: Gerl Arthur , Hauck Adina , Hentrich Marcus
Published: March 2020

4602

Background: To date, there is no international consensus on how best to follow patients (pts) with GCT after their initial management. In the absence of a generally accepted follow-up schedule the possible benefits of regular CT scanning must be weighed against their cost, potential contrast media reactions and the long term risk of cumulative X-ray exposure. The present study focuses on the role of abdominal ultrasound in the follow-up of males with GCT and raises the question whether CT-scanning may be replaced by abdominal ultrasound. Methods: This retrospective single-center cohort study included 887 GCT pts followed between January 2001 and November 2011. The follow-up schedule was predominately based on abdominal ultrasound performed by the same physician (A.G.). Patterns of recurrence and the long-term outcome were analyzed. Results: 462 of 887 pts (52.1%) had stage I, 258 (29.1%) stage II and 130 (14.7%) stage III disease (not evaluable in 37 pts). The median time between baseline and the most recent follow-up examination was 5.0 years. A total of 14.604 abdominal ultrasound examinations (16.5/pt.), 1170 CT scans (1.32/pt.), and 956 chest X-rays (1.08/pt) were performed. A relapse occurred in 58 pts (6.5%) with 11 of 58 pts experiencing multiple relapses. 34 of 58 relapses (58.6%) were detected in pts with stage I GCT. The sites of relapse included the abdomen (n=42), other sites (n=10), and marker elevation only (n=10). 33 of 42 abdominal relapses (78.6%) were detected by abdominal ultrasound. The median size of abdominal lymph nodes was 25 mm (range, 6 - 67 mm). After a median follow-up of 5 years the GCT specific survival of the entire cohort was 98.4%. Regarding the subgroup of pts with relapse the GCT specific survival was 94.7%. Conclusions: Ultrasound appears to be an appropriate method to detect abdominal recurrences in pts with GCT. However, training and cumulative experience is necessary to detect retroperitoneal recurrences at an early stage. The number of expensive and potentially harmful CT scans may be markedly decreased by abdominal ultrasound.
Evaluation of selective inhibitors of nuclear export (SINE) CRM1 inhibitors for the treatment of renal cell carcinoma (RCC).
Authors: Inoue Hiromi , Kauffman Michael , Shacham Sharon , Landesman Yosef , Weiss Robert H
Published: March 2020

4634

Background: For the ~30% of patients who present with RCC at the metastatic stage, multi-kinase inhibitors have been used with moderate success: progression-free survival remains at only one to two years, and thus it is imperative to discover novel therapeutic approaches for metastatic disease. We asked whether (1) SINE inhibitors of chromosome region maintenance protein 1 (CRM1) attenuate key cell cycle regulatory and apoptotic molecules and whether these compounds exert salutary effects in a human RCC xenograft mouse model. Methods: Four RCC cell lines (ACHN, Caki-1, 786-O, and A498) with distinct genotypes, and primary normal human kidney (NHK) cell lines, were used in this study. The cells were treated with the chemically related SINE CRM1 inhibitors KPT-185 or 251 and MTT assays were performed. In addition, cell cycle analyses, immunofluorescence for p53 and p21, and immunoblotting for CRM1, p53, p21, p27, and p-MDM2 were performed for all cell lines. RCC mice with Caki-1 xenografts were treated with vehicle, the orally-available CRM1 inhibitor KPT-251, or sorafenib for 26 days. Tumor volume was measured over several days. Results: Both KPT185 and 251 specifically reduced CRM1 protein levels in RCC cells. KPT-185 caused dose-dependent cytotoxicity in RCC cells, which was greater than sorafenib in RCC cell lines but less in NHK cells, suggesting a possible clinical advantage of KPT-185 over sorafenib. By FACS analysis, we showed that KPT-185 arrests the cell cycle in both G2/M and G1, and increased the sub-G0 cell population. KPT-185 and 251 both increased p53 and p21 in RCC cells, and KPT-185 confined these proteins to the nucleus. In vivo, KPT-251 inhibited Caki-1 xenografts in mice compared to both vehicle and sorafenib without obvious systemic adverse effects. Conclusions: We introduce a completely novel therapeutic approach to the treatment of RCC based on inhibition of the nuclear export of key cell cycle regulatory proteins. Inhibition of CRM1 leads to forced nuclear retention, and thereby activation, of several key p53-pathway proteins, leading to cell cycle arrest and apoptosis in RCC cell lines in vitro and tumor growth inhibition in vivo.
Genetic polymorphisms’ influence in outcome of metastatic renal cell cancer patients treated with VEGF-targeted agents.
Authors: Schutz Fabio Augusto Barros , Gray Kathryn P. , Pomerantz Mark M , Atkins Michael B. , Hirsch Michelle S. , McDermott David F. , Lampron Megan , Percy Andrew , Lee Gwo-Shu Mary , Rosenberg Jonathan E. , Signoretti Sabina , Kantoff Philip W. , Freedman Matthew , Choueiri Toni K.
Published: March 2020

4635

Background: Single nucleotide polymorphisms (SNP) in critical signaling pathways may impact the outcome of metastatic renal cell cancer (mRCC) patients (pts) treated with VEGF targeted agents. Methods: Germline DNA was extracted from 263 pts of European-American ancestry enrolled in a prospective protocol with full baseline and follow up clinical data. A total of 113 common SNPs within select genes involved in RCC pathogenesis, angiogenesis and drugs metabolism were genotyped and associations sought with clinical outcome. The primary endpoint was progression free survival (PFS), defined as time from VEGF targeted therapy to progression or death. Cox model tested for the association between SNPs with PFS in univariate and multivariate model that adjusted for age, gender, type of VEGF inhibitor and MSKCC risk score. The false discovery rate (pFDR) was used to control for the number of tests performed. Results: The median follow-up time was 51.6 months (mo), 81% of pts had progression or death events. All patients were treated with an approved VEGF targeted agent (bevacizumab, sunitinib, sorafenib or pazopanib). Fifty three percent (140/263) of pts were treated with sunitinib. Two SNPs, one in HIF2α and one in VEGFR2, showed a significant association with the risk of progression. Compared to the dominant genotype (frequency 83%, median PFS 10.1mo), the VEGFR2 rs2305948 variant genotype (frequency 17%) showed a superior PFS (median 19.2mo) corresponded to an adjusted hazard ratio (HR) of 0.56 (95%CI: 0.37-0.84; p=0.005). Similarly and compared to the dominant genotype (frequency 94%, median PFS 10.6mo), the HIF2α rs11687512 variant genotype (frequency 6%) had a superior PFS (median 26.5mo) with an adjusted HR of 0.33 (95%CI 0.16-0.68; p=0.002). The analysis adjusted for age, gender, type of VEGF targeted therapy (Sunitinib vs. others) and MSKCC risk score. False discovery rate was <20% with both SNPs. Conclusions: Inherited variants may influence the PFS of pts with mRCC treated with VEGF targeted agents. Validation of these findings in an independent cohort is required. If validated, these results could help identifying subset of pts that are more likely to remain progression free on treatment.
Epidermal growth factor receptor (EGFR) expression and KRAS mutations in penile squamous cell carcinoma: Analysis of potential application of anti-EGFR monoclonal antibodies.
Authors: Gou Hongfeng , Liu Jiyan , Li Xiang , Qiu Meng , Cheng Ke , Bi Feng , Xu Feng
Published: March 2020

4638

Background: Penile squamous cell carcinoma (SCC) is a rare cancer with poor prognosis and limited response to conventional chemotherapy. Anti-EGFR monoclonal antibodies (mAbs) have exhibited significant anti-tumor activities in several cancers such as colorectal carcinoma, head and neck cancer. KRAS mutations are linked to a poor response to mAbs and may thereby result in resistance to anti-EGFR agents. This study was aimed to examine EGFR expression and KRAS, BRAF mutations in penile SCC and to analyze the potential application of anti-EGFR monoclonal antibodies (mAbs) for this disease. Methods: Totally 150 penile SCC specimens from patients undergone surgical resection were included. EGFR expression was evaluated by immunohistochemistry. KRAS mutations at codons 12 and 13, and the BRAF mutation at codon 600 were analyzed on DNA isolated from formalin fixed paraffin embedded tissues by direct genomic sequencing. Results: EGFR expression was positive in all specimens, and its overexpression rate was 92%. We failed to observe a significant correlation between EGFR expression and tumor grade or lymph node metastases. The detection of KRAS and BRAF mutations analysis were performed in 94 and 83 tumor tissues, respectively. KRAS mutation was detected in only one sample and no patient was found to harbor BRAF V600E point mutation. Conclusions: We found the overexpression of EGFR and the absence of KRAS and BRAF mutations in penile SCC. This suggests that anti-EGFR mAbs may be potentially considerable therapeutic agents in penile SCC.
Baseline covariates impacting overall survival (OS) in a phase III study of men with bone metastases from castration-resistant prostate cancer.
Authors: Fizazi Karim , Massard Christophe , Smith Matthew Raymond , Rader Michael E. , Brown Janet Elizabeth , Milecki Piotr , Shore Neal D. , Oudard Stephane , Karsh Lawrence Ivan , Carducci Michael Anthony , Damião Ronaldo , Wang Huei , Goessl Carsten Dietrich
Published: March 2020

4642

Background: Prognostic models of OS in men with metastatic castrate-resistant prostate cancer (M+CRPC), have been limited. Here we present an analysis of baseline covariates associated with OS from an international phase 3 study that demonstrated superiority of denosumab over zoledronic acid for prevention of skeletal-related events (SRE) in this population (Fizazi et al., Lancet 2011;377:813-822). Methods: Patients had confirmed bone metastases (BM) from CRPC (a rising PSA despite castrate testosterone levels) and no prior bone anti-resorptive therapy. Proportional hazards modeling with various selection strategies was used to assess the prognostic significance of baseline covariates in multivariate analyses. Study-specified factors (previous SRE [Y vs N], PSA level [<10 vs ≥10 ng /mL]) and additional variables (Cook et al., Clin Cancer Res 2006;12:3361-3367; Halabi et al., J Clin Oncol 2003;21:1232-1237; Halabi et al., J Clin Oncol 2008;26:2544-2549) were explored. As no difference in OS was observed between treatment arms, analyses were performed using the pooled overall patient population. Results: Analyses included all randomized subjects with available baseline covariate data (n=1745). At the primary analysis date (median study duration 12.2 months), OS was 51%. Various selection strategies produced consistent results. In multivariate analysis, bone-specific alkaline phosphatase (BAP) ≥146 μg/L (p<0.0001) and corrected urinary N-telopeptide (uNTx) >50 nmol/mmol (p=0.0008) were associated with shorter OS, as were prior SRE (p=0.0002), PSA ≥10 ng /mL (p<0.0001), visceral metastases (p=0.0002), greater time from either diagnosis to first BM or first BM to randomization (p<0.0001 for both), ECOG performance status 2 vs. 0/1 (p=0.017), BPI-SF pain score >4 (p<0.0001), age (p=0.008), alkaline phosphatase >143 U/L (p<0.0001), and hemoglobin ≤128 g/L (p<0.0001). Conclusions: Besides known factors previously associated with OS in men with CRPC (Halabi et al., 2003), we show that bone-associated covariates (pain, prior SRE, BAP, and uNTx) are also important and independent prognostic factors for OS.
Correlation of increased eosinophil count following sipuleucel-T treatment with outcome in patients (pts) with metastatic castrate-resistant prostate cancer (mCRPC).
Authors: McNeel Douglas G. , Lin Daniel W. , Gardner Thomas , Sheikh Nadeem A. , Whitmore James Boyd , Sims Robert Brownell , Dreicer Robert
Published: March 2020

4650

Background: Sipuleucel-T is the first autologous cellular immunotherapy approved for asymptomatic or minimally symptomatic mCRPC. In the IMPACT trial, pts treated with sipuleucel-T had transient increases in eosinophil counts compared with control. In this retrospective analysis, we assess potential correlations between eosinophilia, overall survival (OS), prostate cancer-specific survival (PCSS) and immune response following sipuleucel-T. Methods: Data from three phase III trials (D9901, D9902A, and IMPACT) were pooled. The analysis included CBCs performed at baseline and wks 2–34. Eosinophilia was defined as either >ULN (with normal baseline), or a max change from baseline within the top quartile, at any time between wks 2–16. Results: Increased eosinophil counts were seen in sipuleucel-T pts by wk 6, decreasing to near baseline by wk 14; eosinophil counts in control pts were stable. Of 377 sipuleucel-T pts eligible for analysis, 105 (27.9%) had eosinophilia. Baseline disease characteristics associated with eosinophilia were indicative of better prognosis (i.e., longer Halabi predicted survival [p=0.007], lower PSA [P=0.033], higher Hgb [p<0.001], and no prior docetaxel [p=0.012]). In univariate analyses, eosinophilia correlated with improved OS (HR=0.75; 95%CI: 0.56–1.01; p=0.057) and PCSS (HR=0.71; 95%CI: 0.53–0.97; p=0.031); trends persisted after adjusting for Halabi. The magnitude of eosinophilia positively correlated with antigen-specific humoral responses (p ≤0.039 for wks 6, 14 and 26) and elevations in the cytokines at wk 6 (IL2 [p=0.011], IL5 [p=0.038] and TARC [p=0.001]). AEs occurring more frequently (p<0.05) in pts with eosinophilia were infusion-related: pyrexia (33.3 v 21.3%) and nausea (19.0 v 10.7%). No cases of hypereosinophilic syndrome were reported. Conclusions: Increases in eosinophils after sipuleucel-T correlated with improved OS and PCSS. Large increases in eosinophil counts were associated with humoral responses and Th2-type cytokine production. Further studies of eosinophilia as a biomarker for sipuleucel-T response, particularly in earlier disease settings, are of interest.
Comparing the ability of clinicians and a nomogram model at predicting future 99mTc-bone scan (BS) positivity in patients (pts) with rising prostate-specific antigen (PSA) following radical prostatectomy (RP) for prostate cancer (PCa).
Authors: Kattan Michael W. , Yu Changhong , Stephenson Andrew J. , Sartor A. Oliver , Tombal Bertrand
Published: March 2020

4652

Background: Nomograms that assist clinicians in predicting which PCa pts have a high risk of developing M1 disease have been developed, but clinicians still tend to use their own judgment of risk when managing individual pts. This is the first study to compare the ability of clinicians vs a nomogram at predicting future BS positivity in pts with PCa. Only androgen deprivation therapy- (ADT-) naive post-RP pts were considered, as there are currently no nomograms for predicting M1 disease in pts receiving ADT. The Slovin nomogram (Slovin et al. Clin Cancer Res 2005; 11: 8669-8673) was chosen based on considerations of the numbers of pts analyzed and the follow-up intervals used in its development. Methods: During an advisory board in June 2011, 24 PCa experts were given details of 25 ADT-naive post-RP PCa pts with biochemical recurrence who were randomly selected from the Cleveland Clinic Database of 759 pts. The predicted 1-yr from today probability of freedom from metastasis was generated using the Slovin nomogram and estimated by the clinicians. The predictive accuracy was quantified using the concordance index (C-index). Results: All pts were Caucasian and median age was 62 yrs. Median PSA level at biochemical recurrence was 1.2 ng/mL and PSADT varied between 1.3 and 11.7 months. The data used for each of the pts was acquired between 4 and 133 months after the RP procedure. Eight pts had a positive BS within 1 yr. Considerable variation between the clinicians’ predictions for each pt was observed. The nomogram gave a higher C-index compared to the clinicians (0.812 and 0.628, respectively; p=0.003). The clinicians typically overestimated the risk of developing M1 disease. The nomogram outperformed all of the clinicians (C-index range: 0.47 to 0.75). Urologists predictions were superior to those of oncologists (p=0.048). Conclusions: The Slovin nomogram was more accurate than expert clinicians in predicting 1-yr BS positivity. We suggest nomograms should become an integral part of the clinical decision process in the PCa setting.
A phase II study of KX2-391, an oral inhibitor of Src kinase and tubulin polymerization, in men with bone-metastatic castration-resistant prostate cancer (CRPC): A PCCTC trial.
Authors: Antonarakis Emmanuel S. , Heath Elisabeth I. , Posadas Edwin M. , Harrison Michael Roger , Bruce Justine Yang , Yu Evan Y. , Cho Steve Y. , Wilding Gregory E. , Fetterly Gerald J. , Hangauer David G. , Kwan Min-Fun Rudolf , Dyster Lyn M. , Carducci Michael Anthony ,   Prostate Cancer Clinical Trials Consortium (PCCTC)
Published: March 2020

4654

Background: KX2-391 is an oral small molecule inhibitor of Src kinase and tubulin polymerization. In phase 1 trials, PSA declines were seen in men with advanced prostate cancer. Methods: A single-arm phase 2 study of KX2-391 in 31 men with chemo-naïve bone-metastatic CRPC was conducted at 5 PCCTC sites. Men received oral KX2-391 (40 mg BID) until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS) at 24 wk (progression = clinical/radiographic progression or death, but not rising PSA; PCWG2 criteria); a 50% success rate was predefined as clinically significant. Secondary endpoints were PSA progression-free survival (PPFS) at 24 wk (PSA progression = 25% PSA rise above nadir; PCWG2 criteria); median PFS; median PPFS; and max PSA decline. Exploratory outcomes included PK studies, CTC enumeration, and analysis of markers of bone resorption (urinary N-telopeptide [uNTx]; C-telopeptide [CTx]) and formation (bone alk phos [BAP]; osteocalcin). Results: The trial closed early after accrual of 31 men, due to a prespecified futility rule. In all, 26/31 men were evaluable for the primary endpoint; efficacy results are shown below. Also, 2/11 men (18%) with unfavorable (≥5) CTCs at baseline converted to favorable (<5) CTC counts on study, and 18/19 men (95%) with baseline favorable CTC counts maintained them. The proportion of men with declines in bone turnover markers was 32% (8/25) for uNTx, 21% (6/29) for CTx, 10% (3/29) for BAP, and 25% (7/28) for osteocalcin. In PK studies, median Cmax was 61 (range 16–129) ng/mL, and AUC was 156 (35–348) ng*hr/mL. Common toxicities (≥10%) included LFT elevations, leukopenia, thrombocytopenia, fatigue, nausea and constipation. Conclusions: KX2-391 dosed at 40 mg BID lacks antitumor activity in men with CRPC, but modulates bone turnover markers in some men. Because a Cmax of >142 ng/mL is required for tubulin polymerization inhibition, higher once-daily dosing will be used in future trials. [Table: see text]
Results of telomerase activity measurements from live circulating tumor cells captured on a slot microfilter in a phase III SWOG-coordinated prostate cancer trial (S0421).
Authors: Goldkorn Amir , Ely Benjamin , Quinn David I. , Tangen Catherine M. , Tai Yu-Chong , Twardowski Przemyslaw , Van Veldhuizen Peter J. , Agarwal Neeraj , Carducci Michael Anthony , Monk J. P. , Garzotto Mark , Mack Philip C. , Lara Primo , Higano Celestia S. , Hussain Maha , Vogelzang Nicholas J. , Cote Richard J , Thompson Ian Murchie ,   Southwest Oncology Group
Published: March 2020

4663

Background: Analysis of circulating tumor cells (CTC) is a promising biomarker strategy in advanced prostate cancer, and telomerase activity (TA) is a recognized cancer marker. To test whether CTC TA is prognostic for survival (OS), we developed a novel Parylene-C slot microfilter capable of capturing live CTC and used it to measure CTC TA as part of a Phase III SWOG-coordinated therapeutic trial in metastatic castration resistant prostate cancer (S0421). Methods: Blood samples were drawn into EDTA tubes and shipped overnight to a central processing site. After Ficoll centrifugation, low constant pressure was used to pass the mononuclear cell layer through two slot microfilters in series as published previously (filter1 captures CTC + background white blood cells; filter2 captures only background white blood cells). Filter-trapped cells were lysed in CHAPS buffer and assayed for TA using qPCR-based telomeric repeat amplification. In parallel, CTC were enumerated using CellSearch (J&J). Cox regression was used to evaluate the association between baseline (pre-treatment) TA and OS overall, and within subgroups characterized by good prognosis (<5) vs. poor prognosis (>=5) baseline CTC counts. CART regression was used to explore potential prognostic subgroups based on baseline PSA, CTC, and TA cutpoints. Results: Samples were obtained from 263 patients. While no association was observed between TA and OS overall, in patients with baseline CTC >=5 (108 of 263 or 41% of patients), TAfilter2 – TAfilter1 representing high CTC TA relative to background blood cells was associated with a hazard ratio (HR) of 1.14 (95% CI 1.05-1.23, p<0.001) for OS after adjusting for risk factors and remained significant when also adjusting for CTC: HR 1.14 (95% CI 1.04-1.23; p=0.005). Exploratory CART regression assessing baseline PSA, CTC, and TA identified risk groups based only on CTC and TA values. Conclusions: Baseline TA from CTC live-captured on a new slot microfilter is the first CTC biomarker shown to be prognostic of OS in men with CTC counts >=5 in a prospective clinical trial. CTC TA may be useful for further identifying prognostic groups in this population.
Long-term follow-up of a randomized trial comparing conventional paclitaxel and carboplatin with dose-dense weekly paclitaxel and carboplatin in women with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer: JGOG 3016 trial.
Authors: Katsumata Noriyuki , Yasuda Makoto , Isonishi Seiji , Michimae Hirofumi , Kimura Eizo , Aoki Daisuke , Jobo Toshiko , Kodama Shoji , Terauchi Fumitoshi , Tsuda Hiroshi , Sugiyama Toru , Ochiai Kazunori ,   Japanese Gynecologic Oncology Group
Published: March 2020

5003

Background: The primary analysis of the JGOG3016 trial (Lancet 2009, 374:1331) showed that dose-dense weekly administration with paclitaxel and carboplatin (dd-TC) demonstrated statistically significant efficiency over tri-weekly administration withTC (c-TC) as first-line chemotherapy in patients with stage II-IV epithelial ovarian, fallopian tube or primary peritoneal cancer. We report the long-term follow-up results on progression-free survival (PFS) and overall survival (OS). Methods: Patients with stage II to IV ovarian cancer were randomly assigned to receive c-TC (carboplatin AUC 6 and paclitaxel 180 mg/m2 on day 1) or dd-TC (carboplatin AUC 6 on day 1 and paclitaxel 80 mg/m2 on day 1, 8, 15). The treatments were repeated every 3 weeks for six cycles; in responding patients, additional three cycles were administered. Results: The analysis included eligible 631 patients. At 6.4 years of median follow-up, there continues to be a highly statistically significant improvement in median PFS in favor of the dd-TC group compared with the c-TC group (28.1 vs. 17.5 months, hazard ratio [HR] 0.75, 95% CI, 0.62-0.91; P=0.0037). Median survival has not yet been reached in the dd-TC group, and OS at 5 years was higher in the dd-TC group than the c-TC group (58.6% vs. 51.0%, HR 0.79, 95% CI, 0.63-0.99; P =0.0448). Conclusions: The dd-TC improves long-term PFS and OS in patients with advanced epithelial ovarian cancer.
Impact of metformin use on risk of recurrence in high-grade endometrial cancers.
Authors: Ko Emily Meichun , Franasiak Jason , Clark Leslie Horn , Gehrig Paola A. , Bae-Jump Victoria Lin
Published: March 2020

5009

Background: Obesity and diabetes (DM) have been linked to increased recurrence rates and worse survival in endometrial cancer. Metformin is widely used as the first line treatment for type II DM. Recent epidemiological evidence suggests that metformin may lower cancer risk and reduce cancer-related deaths among DM patients. However, no studies have assessed the effect of metformin use on endometrial cancer outcomes. Methods: A retrospective cohort analysis was conducted of all grade 3 endometrial cancer patients with DM at a single institution from 2005-2010. Clinical-pathologic data was abstracted, including metformin, insulin, sulfonamide and thiazolidinedione use at the time of cancer diagnosis. Statistical analysis were performed using summary statistics and multivariate cox analysis, with two tailed p-values <0.05 considered significant. Results: 55/329 patients with grade 3 cancer had DM. Mean age was 68.3 (sd 8.4), and BMI 35.7 (sd 9.4). Stage distribution consisted of 58.2% stage I, 7.3% stage II, 27.3% stage III, and 7.3% stage IV. Histology included 41.8% endometrioid, and 58.2% serous or clear cell. 56.4% of diabetics used metformin and 43.6% did not. Mean follow-up was 21.6 months (sd 15.0). After adjusting for BMI, myometrial invasion, stage, histology, adjuvant treatment, and non-metformin DM medications, metformin use was significantly associated with decreased cancer recurrence (HR 0.06, 95CI 0.01, 0.40; p<0.004). Conclusions: Metformin use was associated with a decreased risk of recurrence in high-grade endometrial cancer, suggesting that it may have a role as adjuvant and maintenance therapy for this obesity-driven disease. [Table: see text]
Adjuvant therapy with zoledronic acid (AZURE-BIG 01/04): The influence of menopausal status and age on treatment effects.
Authors: Marshall Helen , Gregory Walter , Bell Richard , Cameron David A. , Dodwell David John , Keane Maccon M. , Gil Gil Miguel J. , Davies Claire , Coleman Robert Edward ,   AZURE Investigators
Published: March 2020

502

Background: The AZURE trial evaluated the use of zoledronic acid (ZOL) in addition to standard adjuvant therapy in patients with stage II/III breast cancer. Although analysis of the primary endpoint in the total study population showed no significant effects on disease outcomes, pre-specified subgroup analyses identified significant benefit in both invasive disease-free survival (IDFS) and overall survival (OS) in women >5years postmenopause (Coleman et al. NESM. 2011;365:1396–1405). Here we evaluate the treatment modifying effects of both menopausal status and age. Methods: 3360 patients were randomized to receive standard (neo) adjuvant systemic therapy +/- ZOL 4mg iv every 3-4 weeks for 6 doses, then at reduced frequency to complete 5 years treatment. Results: ZOL had no overall effect on IDFS or OS at a median follow-up of 59 months. Pre-specified subgroup analyses showed significant heterogeneity of treatment effect (chi21 =7.91; p=.0049) on IDFS between those who were >5 years post-menopause (n=1041; adjusted HR= 0.75; 95% CI 0.59-0.96, p=0.02) and all other (pre, peri and unknown status) menopausal groups (n=2318; adjusted HR= 1.15; 95% CI 0.97-1.36, p=0.11). The treatment interaction between the two menopausal groups was related to differences in first extra-skeletal IDFS events (chi21 = 14.00, p=0.0002), rather than first recurrence in bone (chi21 = 0.14, p=0.70). In women aged <40, a significant worsening in extra-skeletal IDFS events was seen (HR = 1.68; 95% CI = 1.14-2.47, p=.008). Although the ZOL effect on IDFS improved by age from a negative effect in younger patients (<40) to a beneficial effect for those aged 54 and over (chi21(trend) = 5.96, p=0.015, using Cox model analysis to test for an interaction effect between age, menopausal status and treatment for IDFS (using age 55 as a cut-off) showed that the age effect is reversed by menopausal status, with this model providing a significantly better fit (chi22 = 22.8, p=.00001) than the aforementioned linear model. Conclusions: These results suggest menopausal status is more informative than age in the selection of patients for treatment with ZOL. In women aged <40, ZOL may increase extra-skeletal recurrence.
Use of chemotherapy (CT) in BRCA1/2-deficient ovarian cancer (BDOC) patients (pts) with poly-ADP-ribose polymerase inhibitor (PARPi) resistance: A multi-institutional study.
Authors: Ang Joo Ern , Gourley Charlie , High Hilda Anne , Shapira-Frommer Ronnie , Powell C. Bethan , Castonguay Vincent , De Greve Jacques , Yap Timothy Anthony , Fong Peter C.C. , Olmos David , Banerjee Susana N. , Chen Lee-may , Friedlander Michael , Kaufman Bella , Oza Amit M. , De Bono Johann Sebastian , Gore Martin Eric , Kaye Stanley B.
Published: March 2020

5022

Background: Emerging clinical data point to the clinical utility of PARPi in BDOC. However, the impact of PARPi exposure on the prospects of response to further CT remains unclear. In our previous single centre study, we provided the first clinical data relating to the use of post-PARPi CT (JCO 2010: 28(15S), A5041). Our aim here was to re-examine this issue in a larger multi-institutional population. Methods: We included pts with advanced BDOC who received CT, having progressed on ≥200 mg bd olaparib. Pt, tumor and treatment characteristics and clinical outcomes were documented. Relationships between post-PARPi CT overall survival (OS) and other variables were explored using Cox regression. Results: We collected data on 75 pts (median age 51 y [range 31-77], BRCA1:BRCA2 54:21, mean 3 previous lines of CT [95% CI 2.5-3.4], pre-PARPi platinum (Plt) resistance rate 49% and olaparib RECIST-response rate [RR] 39% [95% CI 28-50]). Following olaparib, most pts received Plt alone or in combination with taxane (Tx) or liposomal doxorubicin (PLD). Weekly Plt was used in 36% of all Plt-treated pts, mainly in combination with weekly Tx. Overall RECIST and CA125 (GCIG) RRs were 38% and 48%, respectively; these responses occurred independently of PARPi response or pre-PARPi Plt sensitivity (all p>.1). The median progression free survival and OS of RECIST responders were 7.9 m (95% CI 5.8-10.9) and 10.5 m (95% CI 1.4-19.6), respectively. In all pts, the median OS from the start of post-PARPi CT was 7.9 m (95% CI 5.7-10.1) while that from diagnosis was 64.9 m (95% CI 52.9-76.9). Factors associated with improved OS on post-PARPi CT in the MVA included best olaparib response of non-disease progression (p=.003, HR 0.28), optimal initial debulking (p=.01, HR 0.36) and pre-PARPi Plt sensitivity (p=.05, HR 0.46). Conclusions: These data indicate potential for meaningful responses to CT in BDOC pts with PARPi resistance. Analysis to identify molecular predictors of response is ongoing. [Table: see text]
Topotecan plus carboplatin versus standard therapy with paclitaxel plus carboplatin (PC) or gemcitabin plus carboplatin (GC) or carboplatin plus pegylated doxorubicin (PLDC): A randomized phase III trial of the NOGGO-AGO-Germany-AGO Austria and GEICO-GCIG intergroup study (HECTOR).
Authors: Sehouli Jalid , Meier Werner , Wimberger Pauline , Chekerov Radoslav , Belau Antje , Mahner Sven , Kurzeder Christian , Hilpert Felix , Klare Peter , Doerfel Steffen , Strauss Hans-Georg , Canzler Ulrich , Marth Christian , Reinthaller Alexander , Petru Edgar , Richter Rolf , Rubio Maria Jesus , Bover Isabel , Gonzalez-Martin Antonio , Harter Philipp
Published: March 2020

5031

Background: We present the efficacy data from a phase III study of topotecan (T) plus carboplatin (C) versus standard therapy with paclitaxel plus carboplatin (PC) or gemcitabine plus carboplatin (GC) or carboplatin plus pegylated doxorubicin (PLDC). Methods: From 02/07 to 12/09, 590 pts were screened and 550 pts were randomized to either T (0.75mg/m²/d1-3/q21d) + C (AUC 5/d1/q21d) or to standard therapy with CP or GC or PLDC based on patient preference. Progression free survival at 1 year was defined as primary endpoint. Results: Median number of cycles was 6 (range 0-9) in both arms. Most patients preferred GC (78%) in the standard therapy arm.. Best Response (CR+PR) was 73.1% (95%CI) and 75.1% (95%CI) for the CA. Median follow-up was 18 (0-52) months for TC and 20 (0-48) months for standard therapy. TC failed to show any advantage regarding 1-yr.-PFS or OAS. Conclusions: The combination of topotecan plus carboplatin failed to improve PFS or OAS in platinum sensitive relapsed ovarian cancer. In addition, carboplatin plus gemcitabine was well tolerated with lower rates of severe and long-lasting (neuropathy) toxicities compared to paclitaxel-carboplatin. [Table: see text]
Randomized, phase III study of carboplatin plus paclitaxel for 8 cycles (CP8) versus carboplatin x 8 cycles plus paclitaxel x 4 cycles (C8P4) in advanced ovarian, fallopian, or primary peritoneal carcinoma.
Authors: Bamias Aristotelis , Timotheadou Eleni , Aravantinos Gerasimos , Pectasides Dimitrios G. , Papadimitriou Christos A. , Klouvas George , Xanthakis Ioannis , Eleftheraki Anastasia G , Soupos Nikolaos , Makatsoris Thomas , Rodolakis Alexandros , Vlachos George , Pentheroudakis George E. , Papanikolaou Alexandros , Tsiatas Marinos , Antsaklis Aris , Fountzilas George , Dimopoulos Meletios A.
Published: March 2020

5033

Background: The combination of carboplatin/paclitaxel represents the standard 1st-line chemotherapy in advanced OC, FC, and PPC. The optimal duration of paclitaxel treatment has not been defined, while its use is associated with cumulative neurotoxicity in about 50% of patients, which becomes long-term in 15-20% of cases. We, therefore, designed a randomized study to investigate the effect of administering 4 instead of 8 cycles of paclitaxel in the combination carboplatin/paclitaxel on efficacy and tolerability of this treatment. Methods: Patients with FIGO stages IIC-IV OC, FC, PPC were included. Carboplatin AUC 6 and paclitaxel at 175 mg/m2 were used. Both agents were administered for 8 cycles in the CP8 arm, while paclitaxel was administered only for 4 cycles in the C8P4. The study was powered to detect a ± 15% difference in survival rate to a baseline rate of 50 % at the 3-year time point. Results: 389 pts were randomized (2/2004-1/2008) and 380 were eligible for analysis (CP8: 192, C8P4:188). The distribution (CP8 vs C8P4) of baseline characteristics were: stage III: 78% vs. 76%; IV: 12% vs. 15%, residual disease 0 cm: 25% vs. 22%, ECOG PS 0: 68% vs. 64%, serous carcinomas: 79% vs. 68%, tumor grade III: 56% vs. 63%. During a median follow up of 72.3 months 231 patients (111 [58%] in CP8 arm and 120 [64%] in the C8P4 arm) have died. Median PFS was significantly shorter in the C8P4 arm (21.41 vs. 16.46 months, HR [95% CI]: 1.36 [1.07-1.71], Wald’s p=0.011), while OS was similar between the two arms (53.41 vs. 46.59 months, HR [95% CI]: 1.18 [0.91-1.53], Wald’s p=0.211). Lower grade 3 or 4 neurotoxicity (1.9% vs. 10.8%, p< 0.001) but higher myelotoxicity (neutropenia 38.8% vs. 28.8%, p=0.031; thrombocytopenia 20% vs. 8.3%, p=0.004) was observed in the C8P4 arm. Conclusions: Lowering the total number of cycles of paclitaxel in 1st-line chemotherapy of advanced OC, FC, PPC resulted in similar OS but shorter median PFS and is not recommended in this setting. The reduction of neurotoxicity by limiting the total paclitaxel cycles to 4 is achieved at the expense of higher myelotoxicity.
13-gene signature to predict rapid development of brain metastases in patients with HER2-positive advanced breast cancer.
Authors: Duchnowska Renata , Jassem Jacek , Goswami Chirayu Pankaj , Gokmen-Polar Yesim , Li Lang , Thorat Mangesh A. , Flores Natasha , Hua Emily , Woditschka Stephan , Palmieri Diane , Steinberg Seth M. , Biernat Wojciech , Sosinska-Mielcarek Katarzyna , Szostakiewicz Barbara , Czartoryska-Arlukowicz Bogumila , Radecka Barbara , Tomasevic Zorica , Sledge George W. , Steeg Patricia Schriver , Badve Sunil S. ,   Polish Brain Metastasis Consortium
Published: March 2020

505

Background: Brain metastases (BM) of breast cancer constitute an important part of therapeutic failures and are associated with severe morbidity and mortality. The risk of BM is particularly high in HER2+ advanced breast cancer pts. We earlier developed in this group a 13-gene signature strongly predicting for rapid development of BM (J Clin Oncol 2008; 26: 45s). Now, we validated these results in an independent group of pts and on culture model system. Methods: Discovery group included 87 samples analyzed using cDNA synthesis, annealing, selection, extension, ligation and array hybridization (DASL). Independent validation group included 75 samples analyzed using quantitative reverse-transcriptase PCR. 3D culture validation model system used immortal, non-tumorigenic human MCF10A breast epithelial cells with and without ectopic expression of HER-2 and RAD51, a DNA double strand break repair gene (one of the three genes of this group overexpressed in 13-gene signature). The number and morphology of breast acini were scored using indirect immunoflourescence and confocal microscopy. Results: Median brain metastasis-free survival (BMFS) in the discovery group for ‘high’ vs. ‘low’ expression signature tumors was 36 months and 66 months, respectively (P=0.0068), and in the validation group 54 and 86 months, respectively (P=0.032). Short BMFS was also associated with ER-negativity; BMFS in the cohort of ‘high’ 13-gene signature and ER- tumors vs. other 3 groups was 31 months and 66 months in discovery group, and 41 and 77 months in validation group (P<0.0001 and P=0.02, respectively). Overexpression of RAD51 in MCF-10A breast cells altered their three-dimensional acinar morphology and increased the percentage of invasive structures by 6.5 fold, both in the presence and absence of HER2 overexpression. Conclusions: 13-gene signature and ER-negativity predict rapid development of BM in HER+ advanced breast cancer pts. RAD51 may promote aggressiveness in breast epithelial cells. These data may be useful in the design of BM preventive trials and may prompt new treatment strategies.