bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase II trial of neoadjuvant dasatinib (Neo-D) in muscle-invasive urothelial carcinoma of the bladder (miUCB): Hoosier Oncology Group GU07-122 trial.
Authors: Hahn Noah M. , Daneshmand Siamak , Posadas Edwin M. , Koch Michael O. , Bihrle Richard , Foster Richard , Masterson Timothy A. , Cheng Liang , Liu Ziyue , Breen Timothy , Fleming Mark T. , Lance Ray , Ryan Christopher W. , Corless Christopher L. , Galsky Matt D. , Alva Ajjai Shivaram , Mitchell Carmen , Shen Steven S. , Lerner Seth P. , Sonpavde Guru
Published: March 2020

4586

Background: Neoadjuvant chemotherapy (NC) preceding radical cystectomy (RC) is an accepted standard for miUCB patients (pts). Dasatinib (D) is an oral tyrosine kinase inhibitor of Src mediated signaling, and has demonstrated promising preclinical anti-tumor activity, providing a rationale to evaluate Neo-D in human miUCB. Methods: A phase II trial was conducted to assess the safety and biologic activity of Neo-D in miUCB. Key eligibility criteria included: miUCB (T2-T4a, N0, M0), unsuitable or willing to forego platinum-based NC, adequate TURBT tissue available, ECOG PS 0-1, creatinine < 2 x ULN. Pts received D 100 mg po once daily for 28 +/- 7 days followed by RC 8-24 hours after the last dose. The primary endpoint was feasibility defined as > 60% of pts completing therapy without treatment-related dose limiting toxicity (DLT) specified as grade 4 hematologic toxicity, grade 3 non-hematologic toxicity, or any grade 2 toxicity > 14 days. Secondary endpoints included the assessment of biologic activity as assessed by pre- and post-treatment tumor tissue immunohistochemistry analysis of Src, pSrc, EPHA2, pEPHA2, FAK, pFAK, AKT, pAKT, CD31, Ki67, TUNEL. Results: The study completed accrual with enrollment of 25pts. 22 and 24 pts were respectively evaluable for feasibility and toxicity endpoints. Patient demographics included: median age – 62, M/F – 20/5, ECOG PS 0/1 – 19/6. Baseline tumor staging included: T2 – 17, T3 – 7. The study achieved its primary endpoint with 15 pts (68%) completing therapy without treatment related DLT’s. DLT’s included: fatigue (2 pts), DVT/PE, abdominal pain, supraventricular tachycardia, enteric fistula, and hematuria (1 pt each). Frequency of highest observed toxicity on study included: Grade 1 – 13%, Grade 2 – 38%, Grade 3 – 46%, Grade 4 – 4%. Among 22 patients, pathologic stage at RC was T1/Tis in 3 pts (14%), ≥T2 in 19 pts (86%), and node positive in 6 pts (27%). Correlative analyses of pre- and post-treatment tumor Src signaling are ongoing and will be updated at the meeting. Conclusions: Neoadjuvant dasatinib preceding RC is feasible in miUCB patients. Tumor tissue correlative studies may provide directions for further development.
Clinical validation of the 7th AJCC-TNM nodal staging system in lymph node-positive patients undergoing radical cystectomy.
Authors: Skinner Eila C. , Bruins Harman Maxim , Dorin Ryan Paul , Rubino Barbara , Miranda Gus , Cai Jie , Daneshmand Siamak
Published: March 2020

4588

Background: The AJCC TNM staging system for bladder cancer has recently been updated. In the new 7th edition, staging of lymph node (LN) metastases is based on anatomical location instead of size as in the former 6th edition. This study evaluated whether the prognostic value of nodal staging according to the 7th edition is superior to the 6th edition. Methods: Prospectively collected data of patients who underwent radical cystectomy (RC) at a high-volume center between 2002 and 2008 were reviewed. Patients who underwent RC for non-urothelial cancer, received neo-adjuvant therapy or had non-LN metastatic disease at the time of RC were excluded. All patients underwent RC with extended lymphadenectomy up to the inferior mesenteric artery. LNs were submitted in predesignated anatomically defined packets. Detailed data on the number, size and location of LN metastases were recorded. Both the 6th and 7th edition AJCC TNM editions were used to stage LN positive (LN+) disease. Median follow-up time was 2.8 years. Kaplan-Meier analysis was used to estimate overall survival (OS) and recurrence-free survival (RFS). Results: A total of 637 patients were identified of whom 141 patients (22.1%) had LN+ disease. In total, 83 patients (58.9%) received adjuvant chemotherapy. Administration of adjuvant chemotherapy did not differ significantly per N-stage according to both editions. Based on the 6th edition, 31 patients (22.0%) had N1 disease, 105 patients (74.5%) N2 disease and 5 patients (3.5%) N3 disease. Three-year RFS rates for N1, N2 and N3 disease were 51%, 43% and 0% respectively (p = 0.87). Based on the 7th edition, 29 patients (20.6%) had N1 disease, 60 patients (42.6%) N2 disease and 52 patients (36.9%) N3 disease. Three-year RFS rates for N1, N2 and N3 disease were 51%, 42% and 45%, respectively (p = 0.84). Conclusions: Neither the AJCC-TNM 7th edition (location-based) LN staging nor the 6th edition (size-based) staging performed well as a prognostic tool for the patients in this cohort. The new staging system moved a large percent of patients into the N3 category, which did not have a worse prognosis than either the N1 or N2 categories. A better staging system for LN+ bladder cancer patients needs to be developed.
Novel oncogenic function of ATDC in bladder cancer.
Authors: Palmbos Phillip Lee , Wang Lidong , Yang Huibin , Detzler Taylor , Ney Gina , Lotan Yair , Healy Patrick N. , Daignault-Newton Stephanie , Kunju Priya , Kumar Chandan , Ljungman Mats , Liebert Monica , Simeone Diane M.
Published: March 2020

4591

Background: Bladder cancer is a common and deadly disease, but the molecular events leading to its initiation and progression are incompletely understood. We recently identified Ataxia-Telangiectasia Group D Associated (ATDC) as a novel oncogene which drives tumor proliferation and invasion in pancreatic carcinoma (Cancer Cell, 2009). In this study, we describe the role of ATDC as an oncogene in bladder cancer. Methods: To further determine the oncogenic role of ATDC, we generated ATDC transgenic (tg) mice in which ATDC expression was driven by a CMV promoter and characterized the resulting tumors. Results: Interestingly, the dominant phenotype in these mice was the development of both non-invasive and invasive urothelial carcinomas (9% and 20% respectively, average age of onset 10-12 months of age). Histologically, these tumors were indistinguishable from human urothelial carcinomas. Gene expression profiling of invasive tumors derived from ATDC tg mice demonstrated a marked overlap with gene signatures of human invasive bladder cancers. ATDC was the 11th most highly up-regulated gene in bladder cancers represented in the Oncomine gene expression database. Analysis of a human bladder cancer tissue microarray (311 samples) by IHC showed elevated expression in 70% (173/252) of muscle-invasive carcinomas, 22% (5/23) of papillary tumors and little or no expression in normal bladder urothelium. ATDC tg mouse bladder tumors demonstrated loss of p53 signaling and down-regulation of PTEN expression, which correlated with ATDC induced methylation of the PTEN promoter by DNMT3A. Furthermore, ATDC knock-down in invasive cancer cell lines resulted in decreased proliferation, invasion and reactivation of p53-mediated signaling and PTEN expression. Conclusions: ATDC is a novel oncogene that is highly expressed in human bladder cancers and is sufficient to drive the development of invasive bladder tumors in tg mice. The mechanism by which ATDC drives bladder cancer formation involves alterations in p53 and PTEN pathways known to be important in bladder tumorigenesis.
Interim results of phase II trial of the cyclin-dependent kinase 4/6 inhibitor PD-0332991 in refractory retinoblastoma protein positive germ cell tumors.
Authors: Vaughn David J. , Gallagher Maryann , Lal Priti , Rosen Mark Alan , Hwang Wei-Ting , Einhorn Lawrence H. , O'Dwyer Peter J.
Published: March 2020

4596

Background: Deregulation of the retinoblastoma pathway in germ cell tumors (GCT) has been well documented. We previously reported that PD-0332991, a selective oral inhibitor of cyclin-dependent kinase 4/6, led to prolonged disease control in 3 patients (pts) with unresectable growing teratoma syndrome (NEJM, 2009). For these reasons, we initiated a phase II trial of PD-0332991 in pts with refractory retinoblastoma protein (Rb) positive (+) GCT. Methods: Pts with incurable refractory GCT that expressed Rb by immunohistochemistry were treated with PD-0332991 125 mg orally daily for 21 days followed by a 7 day break (cycle = 28 days). Tumor assessments were performed every 2 cycles. The primary endpoint was 6-month progression-free survival (PFS) rate. Results: As of 1/12/2012, archived tumors from 36 pts with refractory GCT were stained for Rb and 35 had ≥ 1+ staining. 18 of planned 24 pts have been enrolled and treated. Pt characteristics: 17 male, 1 female; median age, 31 years (range, 17-56); median ECOG performance status, 1 (range, 0-1); median number of prior chemotherapy regimens, 2 (range, 1-6); median number prior surgeries, 3 (range, 1-6). Pt pathology: mature teratoma (MT), 7; teratoma with malignant transformation (TMT), 7; mixed GCT, 2; late relapse (LR), 2. 16 pts are evaluable; 2 pts are too early to evaluate. 5 of 16 evaluable pts achieved 6-month PFS (3 MT, 1 TMT, 1 LR). Median PFS was 2 months (range, 0-17). No objective radiological responses were observed; 7 patients had best response of stable disease by RECIST criteria (3 MT, 3 TMT, 1 LR). Grade 3 toxicity included neutropenia (4 pts), thrombocytopenia (3 pts), anemia (1 pt), mucositis (1 pt). No grade 4 toxicity was seen. Analysis of archival tumor for predictive biomarkers including Rb and p16 expression is being performed. Conclusions: PD-0332991 has resulted in 6-month PFS in pts with refractory Rb + GCT, including pts with incurable teratomas.
Residual tumor resections (RTR) in patients with germ cell tumors (GCT) after salvage chemotherapy.
Authors: Winter Christian , Bingoel Cigdem , Witthuhn Ralf , De Geeter Patrick , Albers Peter
Published: March 2020

4601

Background: Residual tumor resections (RTR) after salvage chemotherapy are of utmost importance due to a much higher rate of vital carcinoma in the residual tumor. A complete RTR may lead to an improved long term survival of such patients (pts). Methods: A retrospective analysis was performed in 197 pts who underwent 209 RTRs in 2 referral centers (2003-2011) with identical surgical technique (2 surgeons). The RTR database was queried for pts who received salvage chemotherapy (conventional salvage chemotherapy (CCT) or high-dose salvage chemotherapy (HDCT)) and a subsequent RTR. Results: Sixty (29%) of all RTRs were performed after salvage chemotherapy. In 31 pts (52%) and 29 pts (48%) a CCT and HDCT was used as salvage regimen, respectively.Vital cancer was found in 48% and 45% of pts with CCT and HDCT. Respectively, vital cancer consisted of germ cell cancer and malignant transformed teratoma in 61% and 39% of the cases. In contrast, the percentage of vital cancer in pts after 1st-line treatment was 30% (p= 0.0365).This comparatively high rate is due to a 55% rate of intermediate/poor prognosis pts in the whole group of 209 RTRs. To date we have evaluated the oncological outcome in 171 of 197 pts with a median follow-up of 23 months (1-227). In 142 pts no relapse was observed, whereas in 29 pts a GCT relapse occured (17%), 7 (4.6%) of all evaluated pts had an “in-field”-relapse. 7 pts died due to tumor progression. The relapse rate in pts with RTR after salvage regime was significantly higher compared to RTR pts after primary chemotherapy (37% vs. 13%, p= 0.0008). The „in-field“-relapse rate in pts with RTR after salvage was only in 3.9%, 2 pts died due to tumor progression. Conclusions: Every second pts with RTR after salvage chemotherapy showed vital cancer in the residual tumor. The relapse rate in pts with RTR after salvage chemotherapy was significantly higher compared to RTR pts after first-line chemotherapy (p=0.0008) but the “infield” relapse rate was similar. A complete resection of all residual lesions after salvage chemotherapy is necessary to potentially improve the long-term disease-free survival. This is especially true for pts with malignant transformed teratoma and restricted options for repeated salvage chemotherapy.
Overall and progression-free survival with everolimus, temsirolimus, or sorafenib as second targeted therapies for metastatic renal cell carcinoma: A retrospective U.S. chart review.
Authors: Yang Hongbo , Wong Michael K.K. , Signorovitch James E. , Wang Xufang , Liu Zhimei , Liu Nathan S. , Qi Zhengyun , George Daniel J.
Published: March 2020

4612

Background: Tyrosine kinase inhibitors (TKIs) (sorafenib, sunitinib, pazopanib) and inhibitors of the mammalian target of rapamycin (mTORs) (everolimus, temsirolimus) are used for treating metastatic renal cell carcinoma (mRCC) following initial treatment with a TKI. This study’s objective was to establish the effectiveness of the most commonly used 2nd line treatments based on real-use data. Methods: mRCC patients who received a TKI as their 1st targeted therapy and everolimus, temsirolimus or sorafenib as their 2nd therapy were identified by oncologists (85% in community practice) throughout the US as part of an online chart review study. Baseline characteristics were assessed prior to 2nd targeted therapy, including type and duration of initial TKI, response, histological subtype, performance status, and sites of metastasis. Overall survival (OS) and progression free-survival (PFS) were assessed after initiating 2nd targeted therapy. OS and PFS were compared between treatment groups using Cox proportional hazards models adjusted for baseline characteristics. Results: Charts were reviewed for 233, 178, and 123 mRCC patients receiving everolimus, temsirolimus, and sorafenib after an initial TKI, respectively. Median age was 64 years and 70.4% were male. Prior to initiating a 2nd targeted therapy, 86.0% used sunitinib and 85.9% had disease progression. After adjusting for baseline characteristics, everolimus was associated with significantly prolonged OS compared to temsirolimus (hazard ratio [HR] 0.56; CI 0.40-0.78; p<0.001) and sorafenib (HR 0.65; CI 0.42-0.99; p=0.047). Everolimus was associated with significantly longer PFS compared to temsirolimus (HR 0.73; CI 0.55-0.96; p=0.025), and non-statistically significant longer PFS compared to sorafenib (HR 0.75; CI 0.53-1.07; p=0.110). Results were similar in the subgroup with sunitinib as 1st targeted therapy and the subgroup with progression on 1st TKI. Conclusions: Among mRCC patients with prior TKI treatment, everolimus was associated with significantly prolonged OS and PFS compared to temsirolimus and significantly prolonged OS compared to sorafenib.
Xp11.2 translocations in adult renal cell carcinomas with clear cell and papillary features.
Authors: Chan Susanne M. , Sherman Christopher G. , Gabril Manal Y. , Zbieranowski Ingrid J. , Sugar Linda M. , Yousef George M. , Bjarnason Georg A.
Published: March 2020

4613

Background: Xp11.2 translocation renal cell carcinoma (RCC) is a rare tumor with unpredictable clinical course and prognosis in adults. Recognition of these tumors depends on the identification of a RCC with unique histology, particularly clear cell and papillary (CCP) features. Our objectives were to determine the incidence of Xp11.2 translocations in adult RCCs with clear cell and papillary features, and to characterize the clinicopathological features and prognosis of adult Xp11.2 RCCs. Methods: Slides for 1047 RCCs in adults (1999-2009) were retrieved from multiple institutions. Cases were reviewed histologically in order to detect any degree of clear cell and papillary change. Tissue microarrays were constructed from the clear cell and papillary RCCs as well as 40 non-papillary clear cell, 5 papillary, 3 chromophobe and 2 unclassified RCCs. Immunohistochemistry using TFE3, a marker highly sensitive (97.5%) and specific (99.6%) for Xp11.2 translocations was performed. Four pathologists independently reviewed the TFE3 results. Clinical and pathologic data were also retrieved. Results: Out of 1047 RCCs, 140 (13%) exhibited clear cell and papillary features. Four out of these 140 (3%) were positive for TFE3. All of the non-papillary clear cell, papillary, chromophobe and unclassified RCCs were negative for TFE3. Mean follow up for TFE3+ RCCs was 55 months. Conclusions: Xp11.2 translocation RCCs diagnosed by TFE3 immunohistochemistry were identified in 3% of adult RCCs that had clear cell and papillary changes. These tumors appear to present with smaller tumour size, lower stage and better prognosis in comparison to non-Xp11.2 CCPRCC and clear cell RCCs. In addition to Xp11.2 translocation carcinoma, coexistence of clear cell and papillary features may be present in other subsets of tumors that have yet to be characterized. [Table: see text]
A phase I study of pazopanib (P) combined with bevacizumab (B) in patients with metastatic renal cell carcinoma (mRCC) or other advanced refractory tumors.
Authors: Negrier Sylvie , Pérol David , Bahleda Rastilav , Hollebecque Antoine , Chatelut Etienne , Boyle Helen Jane , Cassier Philippe A , Ferlay Celine , Metzger Severine , Blanc Ellen , Soria Jean-Charles , Escudier Bernard J.
Published: March 2020

4614

Background: Since previous experiments of B with VEGFR tyrosine kinase inhibitors showed overlapping and limiting toxicities, a dose-finding study was designed to explore the safety and feasibility of the combination of a new VEGFR inhibitor P with B, in mRCC treatment-naive patients (pts) or in pts with other advanced refractory solid tumors. Methods: This bicentric trial is conducted with 3+3+3 escalation doses of P + B. The MTD is the highest dosage not expected to cause a dose limiting toxicity (DLT) in more than 2/3, 3/6 or finally 3/9 pts, during the first 8 weeks of treatment. The effect of B on steady-state pharmacokinetic (PK) of P is also investigated. Major inclusion criteria are: ECOG PS ≤1, ALT and AST <=2.5 x ULN, serum creatinine <=1.5 mg/dL or creatinine clearance <=50 mL/mn and absence of uncontrolled hypertension. Results: 15 pts were enrolled with mRCC (n=7), melanoma (n=2), adrenocortical carcinoma (n=1), mesothelioma (n=1), pancreatic cancer (n=1), oesophageal cancer (n=1), bladder cancer (n=1) and seminoma (n=1). Median age is 61 (43-78), 12 pts are male. No DLT were reported at DL1 (P 400 mg/d + B 7.5 mg/kg q2w) (n = 9), or at the first step of DL2 (P 600 mg/d + B 7.5 mg/kg q2) (n=3), but the 3 following nephrectomized pts experienced DLT: a grade 3 transaminitis, a grade 3 pulmonary embolism and a reversible microangiopathic hemolytic anemia. Inclusion of nephrectomized pts was completed, but enrolment of 3 additional non-nephrectomized pts at DL2 was approved by IDSMB in November 2011 and these treatments are ongoing. Preliminary results of PK analysis showed a significantly higher P AUC at steady-state in pts with DLT. Moreover, lower P apparent clearance was observed in nephrectomized pts. Conclusions: The MTD of the combination of P and B is 400 mg/d and 7.5mg/kg respectively, in nephrectomized patients, but is not yet reached in other patients. Unexpected effect of nephrectomy status was observed on P pharmacokinetics.
Outcomes of patients (pts) with metastatic renal cell carcinoma (mRCC) treated with pazopanib after progression on other targeted therapies (TT): A single-institution experience.
Authors: Matrana Marc Ryan , Shetty Aditya V. , Atkinson Bradley J. , Xiao Lianchun , Corn Paul G. , Millikan Randall E. , Jonasch Eric , Tannir Nizar M.
Published: March 2020

4615

Background: Pazopanib is an approved multi-tyrosine kinase inhibitor that prolongs progression-free survival (PFS) compared to placebo in treatment-naive and cytokine-refractory mRCC. Outcomes and safety data on its use after TT are limited. Methods: We retrospectively reviewed pts with mRCC who received salvage pazopanib between 11/09-11/11. Kaplan-Meier method was used to estimate survival outcomes. PFS was calculated from start of pazopanib until progressive disease (PD) or death. Univariable and multivariable Cox proportional hazards models were fitted to evaluate associations of PFS with covariables. Results: 114 consecutive pts met inclusion criteria (median age 62.6 years, 66% males, 83% clear cell). All pts had PD after other TT (median # of prior TT 2, range 1-5; median time on prior TT 23.3 mos). 79% of pts had PD on sunitinib, 39% on sorafenib, 19% on temsirolimus, 59% on everolimus, and 23% on bevacizumab. 25% received prior chemotherapy and 16% received prior cytokines in addition to TT. 87% had prior nephrectomy. 11% had favorable-risk, 68% intermediate-risk, and 21% poor-risk per MSKCC criteria. 85 events (PD or death) occurred. Median OS was 17 mos (95% CI: 10.3-NA). Median PFS was 6.4 mos (95% CI: 4.5-9.5). By multivariable analysis, PFS was associated with male gender (HR=0.433, 95%CI: 0.269-0.696; p=0.0006), # of metastatic sites (HR=1.252; 95%CI: 1.04-1.503; p=0.016), hypertension exacerbation (HR=0.378; CI: 0.175-0.813; p=0.0128) and PS 2+ vs.0-1 (HR=2.067; CI: 1.243-3.437; p=0.0052). 58% discontinued pazopanib due to PD, 12% died of PD on treatment, and 11% discontinued pazopanib due to adverse events (AEs), mostly GI complaints or fatigue. There were no treatment related deaths. Common AEs included: fatigue (44%), diarrhea (29%), nausea/vomiting (15%), anorexia (14%), hypertension exacerbation (11%), hypothyroidism (11%), hand-foot skin reaction (9%), and increase LFTs (4%). 86% of AEs were grade 1/2. Conclusions: In this retrospective study, pazopanib demonstrated efficacy in mRCC following PD with other TT. AEs were mild/moderate and manageable.
Natural history of malignant bone disease in renal cancer: Final results of an Italian bone metastases survey.
Authors: Santini Daniele , Procopio Giuseppe , Porta Camillo , Mazzara Calogero , Barni Sandro , Fontana Andrea , Berruti Alfredo , Berardi Rossana , Vincenzi Bruno , Ortega Cinzia , Ibrahim Toni , Ottaviani Davide , Carteni Giacomo , Lanzetta Gaetano , Virzì Vladimir , Silvestris Nicola , Tanca Francesca Maria , Adamo Vincenzo , Tonini Giuseppe , Bracarda Sergio
Published: March 2020

4627

Background: bone metastases (mts) are an emerging clinical problem in renal cancer patients related to survival increase. We report the final data of largest survey never published in literature. Methods: 398 renal cancer patients (pts) with evidence of bone mts, all died at the moment of study inclusion, have been included. Clinico-pathological data, data on survival and Skeletal Related Events (SRE) data and skeletal related therapies have been collected and statistically analyzed. Results: 286 males/112 females; median age: 63 (16-87); pts with bone mts at the moment of renal cancer diagnosis: 31.4%; pts with single bone mts: 31.1%. Type: lytic 77%, mixed: 14.6%, blastic: 7.6 %. Sites: spine (65.8%), pelvis (38.4%), long bones (31.6%), other (18.8%). Median time to bone mts: 8 months (0-288) (all patients); 24 months (1-288) (pts without bone mts at diagnosis). Pts with at least 1 SRE: 71.1%. Types of SREs: pathologic fracture (12.6%), radiotherapy (61.8%), spinal compression (7.6%), bone surgery (14.8%), hypercalcaemia (3.2%). Median number of SRE for patient: 1 (0-4). Median time to first SRE: 2 (0-72), to second SRE: 4 (0-113), to third SRE: 11 (1-108). Median survival after bone mts diagnosis: 12 (1-178). Median survival after first SRE: 10 (0-144). Median survival in pts with at least one SRE: 14 (1-178); median survival in pts without SREs: 9 (0-62). In according with MKSCC criteria median time to skeletal disease was in patients with good prognosis was 24 (0-288), intermediate was 5 (0-180) and poor prognosis was 0 (0-77). A total of 168 pts received zoledronic acid until performance status worsening or death. 162 pts have been analysed as control group. The median time to first SRE in the zoledronic treated pts was 3 mths (0-101) compared with 1 mth (0 - 25) in the control group (p< 0.05). 5 cases of ONJ have been diagnosed. Conclusions: The present survey is the largest descriptive study concerning the natural history of bone disease in renal cancer patients. The effects of biological therpies on bone met will be presented during the meeting.
Hypoxia-inducible factor (HIF) 1α and 2α as predictive markers of outcome to VEGFR tyrosine kinase inhibitors (TKI) in renal cell carcinoma (RCC).
Authors: Saez M.I. , Trigo Perez Jose Manuel , Perez-Rivas L.G. , Perez-Villa L. , Villatoro R. , Montesa A. , Cid J.I. , Leon M. , de Luque V. , Fernandez C. , Quero C. , Pajares B. , Alba E.
Published: March 2020

4630

Background: Relevant biomarkers in RCC are needed to identify appropriate candidates for selected targeted therapies. Mutations in the von Hippel-Lindau (VHL) gene result in the accumulation of HIF and increased expression of proangiogenic factors, including VEGF. Methods: Metastatic clear RCC patients with available baseline tumor samples who received first-line oral VEGFR-TKI were included in this analysis. VHL mutation/hypermethylation status and HIF1α and HIF2α immunohistochemical staining were analyzed from paraffin-embedded tumors. Additionally, a panel of candidate VEGF and VEGFR2 genetic SNPs was determined from peripheral blood samples. HIF was scored as negative or positive based on staining intensity (0-10% and > 10%, respectively). Results were evaluated for associations with clinical outcome. Results: 80 patients were included: 71 evaluable for HIF expression, 63 for VHL status and 52 for SNPs. 73% received treatment with sunitinib and median follow-up was 21.5 months. Unlike VHL status, HIF1 and HIF2 positive expression showed a significant correlation with PFS and OS. HIF1α was also predictive for response rate (RR). On multivariate analysis adjusting for other prognostic factors, HIF1α and HIF2α remained the most significant independent predictive factors for survival (adjusted HR 0.09, 95% CI 0.03-0.28, p < 0.0001 and HR 0.13, 95% CI 0.04-0.37, p < 0.0001; respectively). We did not find any statistically significant differences based on the VEGF and VEGFR2 SNPs analyzed. Conclusions: HIF1α and HIF2α levels represent the most important independent predictive factors of outcome for VEGFR-TKI therapy in metastatic RCC. These findings may contribute to optimize treatment with targeted agents. [Table: see text]
Activity of insulin growth factor-receptor (IGF-1R) antibody cixutumumab combined with the mTOR inhibitor temsirolimus in patients with metastatic refractory adrenocortical carcinoma.
Authors: Naing Aung , LoRusso Patricia , Fu Siqing , Hong David S. , Chen Helen , Doyle L. Austin , Phan Alexandria , Habra Mouhammed Amir , Kurzrock Razelle
Published: March 2020

4639

Background: Adrenocortical carcinoma (ACC) is a rare and aggressive endocrine malignancywithout an available effective systemic chemotherapy. IGF-R2 overexpression leading to the activation of the IGF1R/mTOR pathway is well described in ACC. Cixutumumab, a fully human IgG1 monoclonal antibody directed at insulin growth factor-1 receptor (IGF-1R), was combined with temsirolimus on the basis of preclinical data. Methods: Patientsreceived cixutumumab, 3-6 mg/kg IV weekly, and temsirolimus, 25 mg-37.5 mg IV weekly (4-week cycles), with restaging after 8 weeks. Results: Twenty-six patients were enrolled (13 [50%] men); median age, 47 years; median number of prior therapies, 4. Five patients previously received an IGF-1R inhibitor and one, temsirolimus. The most frequent toxicities, at least possibly drug-related, were grade 1-2 thrombocytopenia (38%), mucositis (58%), hypercholesterolemia (31%), hypertriglyceridemia (35%), and hyperglycemia (31%). Eleven of 26 patients (42%) achieved stable disease (SD) > 6 months (duration range = 6 to 21 months) with 3 of the 11 having received a prior IGF-1R inhibitor. Conclusions: Cixutumumab combined with temsirolimus was well tolerated and more than 40% of patients achieved prolonged SD. This study was supported by R21CA13763301A1 (AN), U01CA62461 (RK), and U01CA62487 (PL).
Inhibition of 3β-hydroxysteroid dehydrogenase by abiraterone: A rationale for increasing drug exposure in castration-resistant prostate cancer.
Authors: Sharifi Nima , Li Rui , Evaul Kristen , Sharma Kamalesh , Auchus Richard J
Published: March 2020

4645

Background: Treatment with abiraterone acetate (abi) increases the survival of men with castration-resistant prostate cancer (CRPC). Resistance to abi invariably occurs, probably due in part to up-regulation of steroidogenic enzymes and/or other mechanisms that sustain the synthesis of dihydrotestosterone (DHT), which raises the possibility of reversing resistance by concomitant inhibition of other required steroidogenic enzymes. The 1,000 mg daily abi dose was selected for the phase III trials despite the absence of dose-limiting toxicities at higher doses. Based on the 3β-hydroxyl, Δ5-structure, we hypothesized that abi also inhibits 3β-hydroxysteroid dehydrogenase/isomerase (3βHSD), which is absolutely required for the intratumoral synthesis of DHT in CRPC, regardless of origins or routes of synthesis. Methods: We tested if abi inhibits recombinant 3βHSD2 activity in vitro or endogenous 3βHSD activity in LNCaP and LAPC4 cells, including conversion of [3H]-dehydroepiandrosterone (DHEA) to androstenedione (AD), androgen receptor (AR) nuclear translocation, expression of AR-responsive genes, and LAPC4 xenograft growth in orchiectomized mice supplemented with DHEA. Results: Abi has a mixed inhibition pattern of 3βHSD2 in vitro, blocks the conversion from DHEA to AD and DHT with an IC50 of < 1 µM in CRPC cell lines, inhibits AR nuclear translocation and expression of TMPRSS2, and decreases CRPC xenograft growth in DHEA-supplemented mice. Conclusions: Abi blocks 3βHSD enzymatic activity, synthesis of AD and DHT, inhibits the AR-response, and suppresses growth of CRPC cells at concentrations that are clinically achievable. Variable abi inhibition of 3βHSD might account in part for the heterogeneous clinical response to abi. More importantly, 3βHSD inhibition with abi might be clinically harnessed to reverse resistance to CYP17A1 inhibition at the standard dose by dose-escalation, or simply by administration with food to increase drug exposure.
Guideline-discordant androgen deprivation therapy (ADT) use in localized prostate cancer (CaP) and cost implications: A population-based study.
Authors: Kuykendal Adam Rea , Hendrix Laura H , Salloum Ramzi George , Godley Paul Alphonso , Chen Ronald C.
Published: March 2020

4647

Background: ADT use in localized CaP has increased overall survival and is recommended by National Comprehensive Cancer Network (NCCN) guidelines in certain clinical situations. However, ADT may cause harm and is without benefit in other situations. Prior studies showed a decline in “inappropriate” ADT use coinciding with Medicare reimbursement changes in 2004-2005. This study examines recent trends in ADT use and quantifies the cost of guideline-discordant ADT. Methods: Patients in the Surveillance Epidemiology and End Results (SEER)-Medicare database diagnosed with non-metastatic CaP between 2004 and 2007, ages 66-80 were included for analysis. PSA, Gleason score and clinical stage were used to define D’Amico risk categories. Logistic regression was used to examine factors associated with guideline-discordant ADT use. Annual direct cost was estimated using the current Medicare reimbursement amount for ADT. Results: Of 24,280 men included, 13% received guideline-discordant ADT. Discordant use declined from 15% in 2004 to 11% in 2007. In low-risk patients, 15% received discordant ADT, mostly due to simultaneous ADT with radiation. Discordant use was seen in 7% of intermediate and 16% of high-risk patients, mostly from ADT monotherapy. African American (AA) (p<.001), older patients (p<.001) and those with more comorbidities (p<.001) were more likely to receive discordant ADT (Table). The estimated annual direct cost to Medicare from discordant ADT is $43,500,000. Conclusions: Approximately one in eight patients received ADT discordant with published guidelines, with AA and elderly patients disproportionately affected. Elimination of discordant use would result in substantial savings in healthcare costs. [Table: see text]
Targeted next-generation sequencing (NGS) of advanced prostate cancer (PCA) using formalin-fixed tissue.
Authors: Beltran Himisha , Yelensky Roman , Frampton Garrett , Park Kyung , Downing Sean , Macdonald Theresa , Lipson Doron , Tagawa Scott T. , Nanus David M. , Stephens Philip , Mosquera Juan Miguel , Cronin Maureen T. , Rubin Mark A.
Published: March 2020

4649

Background: The genomic landscape of advanced PCA is not well characterized, partly due to limited availability of frozen metastatic tissue. This has created a gap in our knowledge of treatment related and potentially targetable genomic alterations. The purpose of this study was to demonstrate feasibility of performing NGS to molecularly characterize advanced PCA using formalin-fixed paraffin embedded (FFPE) tissue. Methods: 25 metastatic CRPC, 4 metastatic hormone naïve PCA, 3 primary localized PCA, and 18 benign matched prostates were evaluated (40mm FFPE tissue per case). High-density foci were captured and sequenced for 3230 exons of 182 cancer-related genes and 37 introns of 14 genes often rearranged in cancer to an average depth of >800x in a CLIA lab (Foundation Medicine). Recurrent mutations, copy number alterations, and fusions were validated using PCR and FISH. Results: In >90% of samples, there was sufficient DNA (≥50 ng) for analysis. Recurrent high confidence cancer alterations in CRPC included: TMPRSS2-ERG fusion (44%), PTEN loss (44%), TP53 mutation (40%), AR mutation (24%), AR gain (24%), RB mutation (28%), MYC gain (12%), and BRCA2 loss (12%). Overall 48% of CRPC harbored AR gene alterations. Additionally, there were mutations in CTNNB1 (12%), ATM (8%) and PIK3CA (4%). Copy number alterations not previously described in PCA included CCND1, CDK4/6 gains and CDKN2A/CDKN2B deletions. Hormone naïve metastatic and high risk localized PCA demonstrated similar frequency of TMPRSS2-ERG gene fusion, BRCA2 deletion, and TP53 mutations as CRPC, but AR alterations and MYC gain were not seen. Conclusions: This study demonstrates feasibility of in-depth, NGS based DNA analysis using FFPE tissue, even biopsy material. Frequent AR alterations in CRPC, mutations associated with disease progression, and potential drug targets were identified. Focused NGS has clinical potential to identify actionable genomic alterations in advanced PCA that can impact patient participation in trials as well as treatment and outcome. Treatment options include PARP inhibitors for patients with BRCA2 and ATM alterations (20% of cases) and PI3K/AKT inhibitors for PIK3CA mutations.
Prevalence of nonmetastatic (M0) prostate cancer (PC) patients on continuous androgen deprivation therapy (ADT) in the United States.
Authors: Cetin Karynsa , Li Shuling , Blaes Anne Hudson , Stryker Scott , Liede Alexander , Arneson Thomas J.
Published: March 2020

4659

Background: ADT is the cornerstone treatment of metastatic PC, but the nature and extent of its use in the M0 setting is less well-described. We sought to estimate the current prevalence of M0 PC patients actively receiving continuous ADT (≥6 months) in the US. Methods: Two point-prevalent cohorts on 12/31/2008 with continuous insurance coverage in 2008 were assembled: men aged 45-64 years (yrs) enrolled in commercial health plans (MarketScan) and men aged ≥67 yrs enrolled in fee-for-service (FFS) Medicare (Medicare 5% sample). Among those with evidence of PC and no evidence of metastases, we selected men who had continuous exposure to gonadotropin-releasing hormone agonists during at least the last 6 months of 2008 or received bilateral orchiectomy prior to 7/1/2008. The number of prevalent ADT users was extrapolated to the entire national commercially insured population aged 45-64 yrs and to the entire Medicare FFS population aged ≥65 yrs using person-level weights. Applying age-specific prevalence estimates to the US Census population on 12/31/2008, we estimated the number of prevalent ADT users in the total US male population aged ≥45 yrs. Results: An estimated 11,935 (95% confidence interval [CI]: 11,310-12,561) commercially insured men aged 45-64 yrs and 115,468 (95% CI: 112,304-118,633) Medicare FFS men aged ≥65 yrs were M0 PC patients actively receiving continuous ADT for ≥6 months on 12/31/2008. Extrapolated to the total US male population aged ≥45 yrs, this estimate was 188,916 (95% CI: 184,104-193,727). Age-specific prevalence (N [95% CI]) on 12/31/2008 is presented in the table. Conclusions: We projected nearly 190,000 US men with M0 PC were actively receiving continuous ADT for ≥6 months at the end of 2008, and the vast majority (91%) of these men were aged ≥65 yrs. Additional work will address timing of initiation, duration, and other aspects of ADT use in this large population of M0 PC patients. [Table: see text]
A first-in-human phase I imaging study using hyperpolarized 1c-13 pyruvate (h-Py) in patients (pts) with localized prostate cancer (l-PCa).
Authors: Harzstark Andrea Lynne , Weinberg Vivian K. , Grycz Krystyna , Hurd Ralph E. , Ardenkjaer-Larsen Jan Henrik , Murray Jonathan , Chen Albert , Ferrone Marcus , Park Ilwoo , Reed Galen , Munster Pamela N. , Small Eric Jay , Carvajal Lucas E. , VanCriekinge Mark E. , Larson Peder E. , Chang Jose , Bok Robert A. , Nelson Sarah J. , Vigneron Daniel B. , Kurhanewicz John V.
Published: March 2020

4660

Background: Preclinical studies demonstrated that the conversion of h-Py to hyperpolarized 13C lactate (h-lac) is detectable on MRI-spectroscopy and is a useful marker of differentiation in PCa. H-Py MRI provides more than 10,000-fold enhancement in signal to noise ratio (SNR), allowing for rapid detection of metabolic alterations in vivo. Hyperpolarized compounds have not been previously studied in man. Methods: Pts with biopsy-proven untreated l-PCa were enrolled in a phase I study of h-Py MRI. Following a modified 3+3 design, 6 pts were enrolled at each dose level (0.14, 0.28 and 0.43 mL/Kg): 3 to monitor kinetics of h-Py, and 3 to evaluate the spatial distribution of metabolism in PCa and normal prostate (nl-P). An expansion cohort of 15 pts explored the biological variability of metabolism. A dynamic nuclear polarization (DNP) system, the first human system anywhere, generated and delivered 230 mM sterile h-Py. IV injection of h-Py was followed by imaging with a 3T MR scanner with custom transmit and receive coils. Monitoring included EKG, vital signs, and laboratory testing. Results: 31 pts were imaged. 23 pts had Gleason (G) 6, 6 pts G7, and 2 pts G8 PCa. Median age was 63 years (range 45-75); median PSA was 5.9 ng/mL (1.88-20.2). No dose limiting toxicities or >grade (gr) 2 toxicity was observed. Toxicity included: gr 1dysgeusia (6 pts), gr 1 hypokalemia, gr 1 hypocalcemia, gr 1 dizziness, and gr 2 diarrhea (1 pt each). Median time from dissolution of the agent to delivery into patients was 66 seconds (43-88). Signals from h-Py and h-Lac were seen in PCa and nl-P at all doses; 0.43 mL/Kg showed the best SNR and discrimination between PCa and nl-P and was therefore established as the phase II dose. There appeared to be an association between h-Lac levels and PCa grade. Conclusions: H-py metabolic imaging has minimal toxicity and provides the ability to discriminate Ca from nl-P based on increased levels of h-lac. The correlation with grade and changes with therapy require further study.
Response to ketoconazole (keto) or docetaxel (D) following clinical progression on abiraterone acetate (AA) in castrate-resistant prostate cancer (CRPC).
Authors: Aggarwal Rahul Raj , Formaker Carl , Small Eric Jay , Molina Arturo , Ryan Charles J.
Published: March 2020

4664

Background: Patients (pts) with CRPC treated with keto often experience a rise in serum adrenal androgen levels upon progression and may subsequently respond to more potent adrenal suppression with AA. In contrast, pts treated with AA do not have a rise in serum androgen levels upon progression, and thus may not respond to further androgen synthesis inhibition with keto but require other treatment modalities such as chemotherapy instead. The goal of this analysis is to report the outcomes of pts with CRPC progressing on AA subsequently treated with either keto or D. Methods: Pts with chemotherapy-naïve CRPC were treated on previously reported phase 1 and 2 trials of AA, with doses ranging from 250 to 1000 mg/day. Subsequent treatment following progression on AA was per individual investigator discretion, including treatment with either keto or D. Results: To date, following disease progression on AA, 6 and 14 pts have been subsequently treated with either keto or D respectively. Of the 14 pts treated with D, 11 (79%) had exposure to keto prior to AA. The keto- and D-treated cohorts were similar with respect to other baseline factors, including prior response to AA (4/6 (67%) pts with > 50% PSA decline on AA in keto cohort; 10/14 (71%) pts in D cohort); though pts treated with D were more likely to require opioid analgesics (0 pts in keto cohort; 7 (50%) in D). For pts treated with keto, none experienced a decline in PSA, improvement in bone scan, or an objective response; all had disease progression by 12 weeks. In contrast, for pts treated with D, 10 (71%) had a decline in PSA; 6 (43%) with a > 50% maximum PSA decline. Of 6 pts with measurable disease, 2 (33%) had an objective response. The median time to progression for the D cohort was 129 days (range 60 – 294). Conclusions: Although the cohort size is small, and post-AA therapy was not randomized, these data provide preliminary support for the hypothesis that CRPC progressing on AA is cross-resistant to further androgen synthesis inhibition with keto. Contrary to other reports, prior treatment with AA does not appear to decrease the likelihood of subsequent response to D, but this observation requires prospective validation.
African American race to predict for earlier failure of active surveillance: Results from the Duke Prostate Center.
Authors: Bassett Mitchell , Abern Michael , Banez Lionel Lloyds , Ferrandino Michael , Robertson Cary N. , Inman Brant Allen , Polascik Thomas , Freedland Stephen J. , Walther Philip John , Moul Judd W.
Published: March 2020

4670

Background: As concerns mount regarding overtreatment and over-diagnosis of prostate cancer (CaP), active surveillance (AS) is increasingly utilized in low risk patients. While African-American (AA) race is associated with adverse outcomes after prostatectomy, its effect on patients managed with AS is not known. Methods: A retrospective review identified 222 patients managed with AS at the Duke Prostate Center from January 2005 to September 2011. All men had CaP diagnosed on biopsy performed at our center, and elected AS over treatment. Failure was defined as progression to treatment. In men who failed AS, the reasons for failure, follow-up PSA and biopsy characteristics were analyzed. The primary outcome - time from diagnosis to failure of AS for a reason other than patient choice - was analyzed with univariable and multivariable Cox proportional hazards models. Results: In our AS cohort, 73% are Caucasian and 23% AA. Median follow-up is 25.4 months. Age, household income, BMI, PSA, clinical stage, family history, prostate volume, number of cores with cancer, and Gleason grade on initial biopsy did not differ by race. The number of biopsies and PSA tests performed on AS did not differ by race. A higher proportion of AA men tended to fail from biopsy progression (72.7% vs. 63.8%) while a lower proportion failed by choice (9.1% vs. 14.9%) compared to Caucasians (p = 0.114). AA men had a significantly shorter time to failure (HR 1.74, p = 0.045) compared to Caucasians. There was a trend toward increased Gleason grade 8 or higher cancer on follow-up biopsy in AA compared to Caucasian men (10% vs. 2.5%, p = 0.08). AA race remained a predictor (HR 1.76, p = 0.058) of failure on multivariable analysis, as did initial PSA (HR 1.90, p = 0.031) and number of cores with cancer on initial biopsy (HR 1.29, p = 0.013). Conclusions: AA race was associated with higher risk for failure of AS. There was a trend toward AA men failing due to biopsy progression and with higher grade cancer. Additional follow-up is necessary to determine how this affects the long term outcomes of these men.
Activity of oral VT-464, a selective CYP17-lyase inhibitor, in the LNCaP prostate cancer xenograft.
Authors: Figg William Douglas , Spencer Shawn D. , Pisle Stephen T , Pressler Heather M , Troutman Sarah M , Eisner Joel Robert , Rafferty Stephen W , Schotzinger Robert J , Moore William R
Published: March 2020

4671

Background: With the FDA approval of abiraterone acetate, inhibition of CYP17 (17α hydroxylase/C17, 20-lyase) is now a validated approach to the treatment of castration-resistant prostate cancer. VT-464 is a novel, selective CYP17-lyase inhibitor with decreased activity against CYP17 hydroxylase (less mineralcocorticoid and glucocorticoid effects). The study objectives were to observe the effects of VT-464 in a prostate cancer xenograft model and to compare its activity to abiraterone acetate and surgical castration. Methods: SCID mice were implanted subcutaneously with LNCaP cells. When tumors reached 100 mm3, mice were randomized to receive vehicle (0.5% CMC in saline, 5 mL/kg), VT-464 at 15, 50, or 100 mg/kg p.o. b.i.d. A second cohort of LNCaP tumor-bearing mice received vehicle, surgical castration, or VT-464, or abiraterone acetate at 100 mg/kg p.o. b.i.d. for 28 days. Terminal blood and tumor concentrations were analyzed on day 28, four hours after the last dose. Results: In the first LNCaP xenograft cohort, percent growth inhibition (± S.E.) of 9.6 (±15.6), 38.5 (±12.4), and 73.9 (±13.2) was observed on day 21 of treatment for VT-464 doses of 15, 50, and 100 mg/kg, respectively. Growth reduction at 100 mg/kg was statistically significant compared to vehicle control from day 7 to 28. VT-464 was well tolerated with insignificant weight loss at all doses. In the second cohort, VT-464-treated (100 mg/kg) mice had significantly reduced tumor volumes on day 28 compared to control and abiraterone acetate (p<0.05, p<0.01, respectively). Reduction in tumor volumes were similar between VT-464-treated (100 mg/kg) and castrate animals. Plasma and tumor analyses revealed much greater plasma and tumor exposure of VT-464 compared to abiraterone acetate. Conclusions: VT-464 exhibited dose-dependent growth inhibition with significantly reduced tumor volumes at the highest dose compared to abiraterone acetate. The activity in VT-464-treated animals was similar to that of castrate animals. These preclinical results show promising activity of VT-464 in the treatment of prostate cancer.