bluuebunny/crossref_metadata_2025 huggingface dataset:
Investigating the association of cytoplasmic and nuclear HIF-2 expression with cancer specific survival (CSS) in clear cell renal cell carcinoma.
Authors: Kroeger Nils , Seligson David B. , Signoretti Sabina , Yu Hong , Birkhaeuser Frederic D. , Magyar Clara , Huang Jiaoti , Riss Joseph , Kabbinavar Fairooz F. , Belldegrun Arie S. , Pantuck Allan J.
Published: February 2017

387

Background: Studies support the prognostic importance of HIF-2α for ccRCC. Interestingly, a recent study has implicated HIF-2α as part of a protein translational initiation complex, a cytoplasmic function that goes far beyond its role as a nuclear transcription factor. We hypothesized that both the absolute expression as well as the subcellular localization of HIF-2α would predict clinicopathological features and CSS in ccRCC. Methods: A tissue microarray (TMA) study was conducted on 308 ccRCC patients. Survival differences were investigated with the log rank test and associations with CSS with uni- and multivariate Cox regression analyses. Recursive partition tree analysis was used to identify relevant cutoff values. Results: The median follow-up was 2.29 years (IQR 11.82). The mean percentage of positive cells was 22.45±18.00 and 0.12 ± 0.29 for HIF-2α nuclear (N) and cytoplasmic (C), respectively. High HIF-2α N (cutoff>32%) expression was associated with smaller tumor sizes (p = 0.002) and less advanced Fuhrman grades (p = 0.044). To the contrary, tumors with high HIF-2α C (>0%) more often had lymph node (p = 0.004), distant metastases (p = 0.021), and higher Fuhrman grades (p<0.0001). Univariate analyses showed an association of high HIF-2α N (p = 0.035) with better CSS. This was not found when HIF-2α N was used as a continuous variable (p = 0.067). In contrast, HIF-2α C demonstrated an association with CSS when examined as both a continuous (p < 0.0001) and as a dichotomized variable (p < 0.0001). After adjustment for TNM stage, ECOG PS, and Fuhrman grade, both continuous (p < 0.0001) and dichotomized (p < 0.0001) HIF-2α C variables remained significant predictors of CSS, while neither HIF-2α N variable was retained. The ratio of HIF-2α C/N was the strongest predictor of CSS in multivariate analysis (p = 0.001; HR 4.83 [95% CI: 1.99 – 11.76]). Conclusions: Our investigation suggests an important role for HIF-2α as a cytoplasmic protein translational initiation complex in ccRCC. This novel observation warrants further molecular and genetic studies examining biological pathways that are involved in the tumor promotive properties of HIF-2α in the cytoplasm.
Everolimus for patients with metastatic renal cell carcinoma (mRCC) refractory to anti-VEGF therapy: Preliminary results of a pooled analysis of noninterventional studies.
Authors: Albiges Laurence , Bergmann Lothar , Eymard Jean-Christophe , Schmidinger Manuela , Bamias Aristotelis , Ktiouet Meryem , Fischer Gregor , Xanthaki Despoina , Guderian Gernot
Published: February 2017

392

Background: In RECORD-1, the oral mTOR inhibitoreverolimus significantly improved PFS compared with placebo in patients with mRCC refractory to 1 or 2 prior VEGFr-TKIs. Here, we provide prospective data from European countries on everolimus use in patients with mRCC after failure of anti-VEGF therapy. Methods: To evaluate the safety and efficacy of everolimus in routine clinical practice, data were pooled from 4 prospective, noninterventional studies conducted in Germany, France, Greece, and Austria. Results: Data from the first 6 months of treatment are available for 534 patients. At baseline, median time since diagnosis of first metastasis from RCC was 1.8 years, and 91% of patients were of favorable or intermediate MSKCC risk prognosis. Predominantly clear cell mRCC was evident in 90% of patients, and most patients had prior nephrectomy (89%). Best overall response by investigator assessment was partial response in 13%, stable disease in 56%, and progressive disease in 32%. Overall, 77% of patients experienced ≥1 adverse event (AE) and 22% experienced ≥1 serious AE. AEs occurring in >5% of patients included stomatitis (25%), anemia (13%), asthenia (9%), fatigue (8%), pneumonitis (8%), rash (8%), diarrhea (7%), decreased appetite (7%), hypertriglyceridemia (6%), dyspnea (6%), nausea (6%), and peripheral edema (5%). Serious AEs occurring in >2% of patients included stomatitis (3.4%), general health deterioration (2.2%), anemia (2.1%), dyspnea (2.1%), and pneumonitis (2.1%). Median everolimus duration was 4.8 months. Treatment was discontinued due to disease progression in 50% of patients and AEs in 24% of patients. A similar proportion of patients had Karnofsky performance status ≥70 at baseline (86%) and at end of analysis (80%). Updated data will be available in February 2012. Conclusions: Preliminary results of this pooled analysis of 4 European studies substantiate the safety of everolimus reported in the pivotal RECORD-1 trial and provide evidence for the effectiveness of everolimus in routine use. The results support the use of everolimus as a standard of care for VEGF-refractory patients with mRCC.
Characteristics and clinical outcomes of patients with renal cell carcinoma with sarcomatoid dedifferentiation (sRCC).
Authors: Merrill Megan M. , Wood Christopher G. , Tannir Nizar M. , Slack Rebecca , Babaian Kara , Jonasch Eric , Pagliaro Lance C. , Compton Zachary , Tamboli Pheroze , Sircar Kanishka , Pisters Louis L. , Matin Surena F. , Karam Jose A.
Published: February 2017

401

Background: sRCC is an aggressive subset of renal cell carcinomas that is associated with poor prognosis. We describe clinical and pathological characteristics and outcomes of the largest single-institutional cohort of patients with sRCC who underwent nephrectomy. Methods: Data were collected from 1986 to 2011 for patients identified as having sRCC. 221 patients with complete data who underwent a radical or partial nephrectomy and had a sarcomatoid component in the primary kidney tumor were included in the analysis. Clinical and pathologic variables were reviewed and Kaplan-Meier curves were used to compare differences in overall survival. Results: Mean age at diagnosis was 57 years and median tumor size was 11 cm (range 1.5-27.0 cm). 93% of patients were symptomatic at presentation and 96% had an ECOG performance status of 0 or 1. 12 patients had a preoperative biopsy that showed sRCC. 75% of patients were pT3 or higher at time of nephrectomy and 69% presented with metastatic disease. Of these, 11.8% had radiographic evidence of regional nodal involvement alone and 88.2% had distant metastatic disease. The associated epithelial component was clear cell in 72% of the patients, papillary in 12.7% and chromophobe in 3.1%. 29 patients received presurgical systemic therapy, while 161 patients received postoperative systemic therapy. During a median follow-up of 20.5 months, 187 patients (84%) died. Overall survival for the entire cohort at 1 year was 48%. Overall 1-, 2-, and 3-year survival rates for patients with metastatic disease at presentation versus no metastatic disease were 36, 20, and 16% versus 74, 51, and 44% respectively (p < 0.001). Patients with clear cell RCC epithelial component had a survival advantage over those with non-clear cell components with 1-, 2-, and 3-year survival rates of 52, 34, and 31% versus 38, 19, and 12% (p = 0.0057). Conclusions: The majority of patients with sRCC who underwent nephrectomy present with metastatic disease and outcomes are dismal despite surgical intervention and multimodal therapy. Overall survival is better for patients who present without metastatic disease and have clear cell histology at time of nephrectomy.
ER stress protein GRP78 as a therapeutic target combined with antiangiogenic therapy in renal cell carcinoma.
Authors: Han Kyung Seok , Li Na , Raven Peter A. , Li Estelle , Fazli Ladan , Gleave Martin E. , So Alan I.
Published: February 2017

428

Background: Antiangiogenic therapy deprives oxygen and nutrition from the tumor. These stresses cause unfolded proteins in tumor cells. Glucose regulated protein 78 (GRP78) binds to unfolded proteins and its subsequent activation suppresses global mRNA translation to protect cells from excessive unfolded proteins. We investigated a potential role of GRP78 as a combined therapeutic target in renal cell carcinoma treated with antiangiogenic therapy. Methods: Renal cell carcinoma cells (Caki-1, Caki-2, UMRC-3, and UMRC-6) were used to investigate the effect of GRP78 knockdown, which was performed by small interfering RNA. Caki-1 xenografts were developed and treated with sunitinib 40mg/kg/day to evaluate in vivo expression of GRP78 during antiangiogenic therapy. Caki-1 cells stably overexpressing GRP78 were developed to investigate the role of GRP78 in cancer cell. Hypoxic stress was induced by 1% hypoxia chamber and hypoglycaemic stress was induced by glucose-free media. Downstream signalling pathways of GRP78 were evaluated by Western blots. Results: In vitro hypoxia and/or glucose deprivation induced GRP78 upregulation in Caki-1 cells. GRP78 was also induced in Caki-1 xenografts treated by sunitinib. Overexpression of GRP78 increased tumor proliferation in hypoxic and/or hypoglycemic stresses by activating PERK/eIF2α pathway and protected tumor cells from stress-induced apoptosis. Knockdown of GRP78 using small interference RNA inhibited cancer cell survival and induced apoptosis in renal cell carcinoma cells in vitro. GRP78 knockdown also sensitized renal cell carcinoma cells to ER stress-induced apoptosis and hypoxic and hypoplycemic stress-induces apoptosis. Conclusions: Antiangiogenic therapy induces ER stress by depriving oxygen and glucose from renal cell carcinoma. ER protein GRP78 has a critical role in protecting renal cell carcinoma cells from hypoxic and hypoglycemic stress induced by antiangiogenic therapy. Knockdown of GRP78 sensitizes RCC cells to apoptotic cell death from anti-angiogenic stresses. Our results suggest that GRP78 is a novel therapeutic target in renal cell carcinoma management.
Nanoscale proteomic profiling to define diagnostic signatures and biomarkers of therapeutic activity in patients with RCC.
Authors: Fan Alice C. , Leppert John , Liliental Joanna E. , Xu Liwen , Thong Alan E. , Yost Christine , Yaghi Alia , Brooks James D. , Harshman Lauren Christine , Sabatti Chiara , Srinivas Sandy , Felsher Dean W.
Published: February 2017

432

Background: Novel agents that inhibit kinases in the hypoxia and MTOR pathways can achieve response rates of 30-60% in renal cell carcinoma (RCC); however, protein biomarkers to diagnose RCC and guide treatment have not been identified. Methods: We developed the use of two high-throughput, nanoscale immunoassays to profile hypoxia and downstream signaling in clinical specimens from patients with RCC. These automated technologies minimize errors due to manual variability, and make 96 independent measurements per overnight experiment. We used size-based protein separation (Sally Instrument, Protein Simple) to quantify proteins using antibody-specific detection, normalized to loading control. Next, we used a nano-immunoassay with charge-based separation (NIA, Nanopro1000 Instrument, Protein Simple) to distinguish multiple charged modifications of individual proteins, and measure relative ratios of individual unphosphorylated and phosphorylated isoforms. Results: We first optimized assays for proteins in MAPK, PI3K and STAT pathways, and loading controls, to analyze frozen surgical specimens and ex-vivo fine needle aspirates (FNA’s) performed immediately following nephrectomy. We analyzed more than 200 FNA’s from solid tumors, comparing RCC with paired adjacent non-tumor tissue, and other epithelial malignancies. Basal MAPK signaling of tumors varied across 3 logs of expression. Unique to NIA, we analyzed percent phosphorylation and resolved differences in single phosphorylations. Subtle differences in basal MAPK signaling between tumor calls and adjacent non-tumor tissue can distinguish RCC from other malignancies. Lastly, we prospectively collected and analyzed blood peripheral mononuclear cells from 20 RCC patients before and during treatment with standard targeted therapies. Kinase inhibitors can preferentially inhibit or activate specific protein phospho-isoforms. Conclusions: Our studies demonstrate that rapid and quantitative nanoproteomic profiling in very small amounts of clinical specimen may accelerate translational studies for novel diagnostic and predictive biomarkers.
Prediction of systemic spread independent of local extension or nodal disease by venous tumor thrombus in renal cell carcinoma.
Authors: Aboumohamed Ahmed , Digiorgio Lorenzo , Mehedint Diana , Attwood Kristopher , Schwaab Thomas
Published: February 2017

435

Background: Renal cell carcinoma (RCC) venous extension is a challenging condition. Its prognostic significance is not well established. We investigated possible prognostic correlations between venous extension in RCC, with its various levels, and local extension, lymphatic spread and systemic metastasis; and its impact on progression free survival (PFS) and overall survival (OS). Methods: We analyzed an IRB-approved prospectively-maintained kidney cancer database at Roswell Park Cancer Institute. Patients with venous involvement were identified, classified according to the highest cephalic venous thrombus extension into 3 groups; group 1, renal vein; group 2, infrahepatic; group 3, subdiaphragmatic. Preoperative, postoperative, and pathologic factors were recorded. Patient characteristics were compared between groups using Kruskal-Wallis and Chi-Square tests for quantitative and categorical variables respectively. Results: 711 patients underwent nephrectomy for RCC between 2004 and 2011. Out of 63 patients with RCC and venous tumor thrombus, 55 patients were analyzed in this study who underwent radical nephrectomy and venous thrombectomy. Median age was 63 years and median follow-up was 18.7 months. 37 patients were group 1, 10 were group 2, and 8 were group 3. 1 and 3 year PFS were 66% and 38.5% respectively, and 1 and 3 year OS were 74.2% and 47.4% respectively. There were no statistically significant differences in OS or PFS between different groups. Among several factors examined, venous extension was associated with increased risk of distant metastasis, and that risk did not increase with higher cephalic venous extension (p = 0.011). When patients were categorized by local extension and nodal disease spread, there was no statistically significant association with venous tumor extension (p =0.24 and 0.35 respectively), though they were independently associated with distant spread (p = 0.002 and 0.013 respectively) and OS (p =0.005 and0.03 respectively). Conclusions: Venous tumor extension alone can serve as an independent predictor of distant metastasis in patients with RCC. Our analysis suggests that cephalic venous thrombus extension does not impact patient survival.
The risk of proteinuria with the angiogenesis inhibitor axitinib in patients with cancer.
Authors: Kuei Andrew , Wu Shenhong
Published: February 2017

439

Background: The use of axitinib, a potent inhibitor of the vascular endothelial growth factor receptor (VEGFR), is associated with proteinuria, which may cause morbidity and treatment interruptions in cancer patients. We performed a systematic review and meta-analysis of published clinical trials to assess the overall risk of severe proteinuria when treated with axitinib. Methods: Potentially relevant studies were identified by searching databases from PubMed and abstracts presented at the American Society of Clinical Oncology annual meetings until June 2012. Eligible studies included prospective clinical trials in cancer patients treated with axitinib containing data on all-grade and/or high-grade proteinuria. Summary incidence, relative risk (RR), and 95% confidence interval (CI) were calculated using the fixed- or random-effects models. Results: A total of 1,671 patients with advanced renal cell carcinoma (RCC) and other solid tumors from 9 studies were included for analysis. The overall incidence of all-grade proteinuria with axitinib was 22.7% (95% CI: 10.4-42.6%). There was no significant difference between RCC and non-RCC patients (p = 0.45), although the incidence in RCC patients was higher (30.0%, 95% CI: 8.4-66.7 vs. 17.5%, 95% CI: 7.4-36.3%). The overall incidence of high-grade (grade 3 or 4) proteinuria with axitinib was 3.8% (95% CI: 2.6-5.7%). In comparison with a control (gemcitabine), axitinib significantly increased the incidence of high-grade proteinuria (3.3%, 95% CI: 1.6-6.5% vs. 0.1%, 95% CI: 0-2.3%; p=0.031). When compared to sorafenib, another angiovsgenesis inhibitor, axitinib has elevated risk of proteinuria but without statistical significance (RR=1.48 for all-grade, 95% CI: 0.92-2.38, p = 0.10; RR=1.81 for high-grade, 95% CI: 0.68-4.85, p = 0.24). Conclusions: There was a significant risk of high-grade proteinuria associated with the use of axitinib in cancer patients. Adequate monitoring and appropriate use of axitinib is recommended to reduce renal complications.
Patient and physician perspective on published therapy management recommendations for TKI-treated patients with a focus on sunitinib: The TheMaPaC project (Therapy Management Patient Consensus).
Authors: Eberhardt-Wetherington Berit , Gall Valerie , Lang Melanie , Schmidinger Manuela , Gruenwald Viktor , Claussen Christina , Wartenberg Markus , Niedtner Rainer , Kalanovic Daniel
Published: February 2017

445

Background: Optimizing outcomes in RCC or GIST patients (pts) receiving TKI (e.g. sunitinib ([U]) involves therapy management as a key component. Reduction/elimination of adverse events (AEs) by prevention/early intervention may improve quality of life and enable adequate duration of therapy. Published recommendations (RECs) for AE management are heterogeneous and often rely on hypothetical considerations or limited evidence. A collaborative effort of physicians, patients, and Pfizer addresses these issues. An initial analysis of a patient survey on real-life validity of RECs in 27 TKI-treated pts was shown at ASCO 2012 (abstr. 99588). We report an updated combined analysis with an expert survey in 23 physicians experienced in SU use for RCC and GIST. Methods: RECs for AE management in pts receiving SU or other VEGFR-TKIs were retrieved from the literature since 2006 and listed in a questionnaire (QU). For the patient survey, RECs were converted into patient-friendly language, RECs requiring physician intervention/decision were excluded. Pts rated RECs in 5 categories (positive/negative experience [self/others]; no information). Experts rated the RECs according to strength of their consent and own experiences. Results: 27 pts had evaluable QUs. Pts were on SU for 16 months (median). On average, 49% of RECs were rated positive; 44% based on individual experience. 20 RECs were rated positively by >80% of pts. Pts had most positive experiences with RECs concerning pt/physician communication on AEs, care/protection of feet and skin, food preference, hydration, and fatigue. Pts had a preference for RECs with low interference in daily life. RECs rated positive by >80% of pts were supported by most experts. Several RECs supported by most experts were unknown to many pts, including dermatological interventions, dietary counselling, and self-perception. Conclusions: To our knowledge, this is the first patient and expert survey on validity and practicability of published AE management RECs. The data identify useful consensual RECs from real-life perspective. TKI therapy management may be improved by enhanced pt education.
Sunitinib (SU) plus extended courses of irradiated allogeneic lymphocytes (IAL) for patients with metastatic renal cell carcinoma (RCC).
Authors: Stein Mark N. , Huzzy Lien , Anand Monica , Jeyamohan Chandrika , Mayer Tina M. , DiPaola Robert S. , Gharibo Mecide Meric , Strair Roger
Published: February 2017

464

Background: Treatment of patients with RCC using IAL from a haploidentical donor (sibling/parent), without prior conditioning of the recipient, induced tumor regressions in 3/13 patients with minimal toxicity (Strair J Clin Onc 2003:3785). Responses were not detected until after 2-3 courses, consistent with an immunologic mechanism. We hypothesize that combining the angiogenesis inhibitor SU with IAL will improve outcomes given the potential immune stimulatory benefit of VEGF inhibition and the benefit from preventing clinical progression prior to the development of an immune response in patients with rapid disease progression. Single agent SU has a median PFS of 11mos and response rate of 31%. Methods: Eligible pts with measurable metastatic clear cell RCC, no prior systemic therapy, adequate organ function, no CNS met, and a suitable donor (≥2/6 HLA A, B, DR match, CMV-, HIV-, HepB/C-) received SU 50mg/day in a 4 wk on/2wk off schedule with IAL administration commencing at the start of cycle number 2 of SU. IAL was given once every 8-16 weeks. The primary objective of the study is to determine the PFS of the combination of SU and IAL in 35 patients for 80% power to detect an increase in median PFS from 11 to 18 months. Results: A pre-planned futility analysis was performed. To date 9 pts (7M/2F), median age 63 (range 49-74) have been treated with 29 cycles of DLI. Median number of DLI/pt 2(1-7). 5 pts discontinued DLI due to disease progression, 4 due to loss of donor availability. Median time to disease progression was 41 weeks (range 12-180 weeks), with 4 pts on study for >80 weeks. Response rate (CR+PR): 44% (1/9 CR, 3/9 PR, 2/9 SD, 3/9 PD). DLI was well tolerated with G2 fever in 1pt and G1 fever in 5 pts as the only DLI related AEs. SU related AE lead to SU dose reduction in 8/9 pts. Conclusions: Co-administration of SU and IAL is feasible and safe with no significant IAL related toxicity. Further study accrual is required to determine if SU plus IAL is superior to single agent SU. Clinical trial information: NCT00853125.
Classification of oncocytic papillary renal cell carcinoma.
Authors: Culp Stephen Hembree , Mo Yunchuan Delores , Diolombi Mairo , Cathro Helen P
Published: February 2017

467

Background: Over the past decade, genitourinary pathologists have increasingly recognized an oncocytic variant of papillary renal cell carcinoma (PRC) that can complicate classification as Type 1 or Type 2 PRC. The International Society of Urological Pathology recently proposed reclassifying oncocytic papillary renal cell carcinoma (OPRC) as a separate subtype. We set out to test the validity of separating oncocytic tumors from other PRC. Methods: 70 consecutive cases of PRC with sufficient tissue for analysis were reviewed from patients undergoing surgery at The University of Virginia (1992 to 2007). All cases were classified by type, including those with oncocytic features. Histologic, clinical, and outcomes data were analyzed based on type and the presence of oncocytic features. Results: A total of 15 (21.4%) tumors displayed oncocytic differentiation, the majority of which were Type 2 tumors (11 or 73.3%) (p < 0.001). The male to female ratio of OPRC cases was nearly 1:1 in contrast to a significant male bias historically seen in PRC. The presence of oncocytic features was significantly associated with higher Fuhrman grade (p < 0.001) and no OPRC tumors were multifocal as opposed to 13 (23.6%) of non-OPRC tumors. At a median follow-up of 79.9 months for the entire cohort, 5-yr disease specific survival (DSS) for OPRC patients was 79.0% which was intermediate between patients with Type 1 (93.4%) and Type 2 (44.4%) tumors. By Cox proportional hazards regression analysis, DSS of OPRC patients was significantly better than Type 2 patients (HR 0.12; 95% CI 0.03, 0.52, p = 0.004), but tended to be worse than Type 1 patients (HR 2.58; 95% CI 0.78, 8.50, p = 0.12). Conclusions: We report the largest cohort of OPRC patients to date. Patients with OPRC demonstrate a survival rate intermediate between that of patients with non-oncocytic Type 1 and Type 2 PRC. Though the majority of OPRC tumors were classified as Type 2 PRC, oncocytic features complicate histomorphologic typing. Therefore, classification of OPRC separately would clarify typing of PRC and improve the validity of Fuhrman nuclear grading for PRC. Our results support separation of OPRC from Type 1 and Type 2 PRC, based on both histomorphologic typing and patient survival.
Outcomes of sunitinib therapy in patients (pts) with metastatic renal cell carcinoma (mRCC) with poor risk features.
Authors: Barroso-Sousa Romualdo , Munhoz Rodrigo Ramella , Fonseca Leonardo Gomes , Fede Angelo Bezerra de Sousa , Linck Rudinei Diogo Marques , Moniz Camila Motta Venchiarutti , Mak Milena Perez , Souza Ciro Eduardo , Hoff Paulo M. , Dzik Carlos
Published: February 2017

476

Background: Temsirolimus is perceived as the standard of care in pts with mRCC with poor risk features. However, sunitinib (Su) is commonly used in this setting. In this study, we assessed the use of Su in an unselected mRCC population. Methods: Retrospective analysis of 51 pts with mRCC and ≥ 3 poor prognosis features, as determined in the Advanced Renal Cell Carcinoma (ARCC) trial, treated with Su between January 2006 and July 2012. Primary outcome was overall survival (OS). Clinical and laboratory parameters were evaluated, as well as Su-related adverse events (AE). Median time to treatment failure (mTTF) and OS were estimated by Kaplan–Meier methods. On exploratory grounds, univariate, and multivariate analysis using Cox regression model was performed to determine possible prognostic variables. Results: Median age was 60 years (26-89). Most had clear cell histology (98%), 19% prior systemic treatment, and 51% prior nephrectomy. 64%, 15%, and 4% had 4, 5, and 6 adverse prognosis factors respectively. 88% had diagnosis to treatment intervals < 1 year and 45% had KPS scores of < 80. A median of 2 cycles (0–12) were administered. 63% received standard regimen of Su (50 mg/d 4 wk on/2 wk off). Reasons for discontinuation were disease progression (63%) and adverse events (21%). Most grade ≥ 3 AE were fatigue (14%), neutropenia (8%), and stomatitis (8%). 17%, 25%, and 14% developed hypothyroidism, hand-foot syndrome (HFS), and hypertension, respectively. Two therapy-related deaths were observed (one febrile neutropenia and one intracranial hemorrhage). Estimated mTTF and mOS of this cohort were 2.4 and 6.6 months, respectively. Multivariate analysis revealed that in a model adjusted for type of Su regimen, KPS, presence of brain metastasis, and occurrence of HFS, only Su-associated hypothyroidism was significantly associated with survival (respectively, odds ratio [OR] = 0.23; 95% CI = 0.07-0.68). Conclusions: Pts with mRCC with poor risk features treated with Su have an OS, TTF and rates of therapy discontinuation due to AE comparable to clinical trial subsets of similar pts. Our data suggest that the development of hypothyroidism in this setting might be useful as a predictor of OS, and this finding should be further investigated.
Effect of PSA-tricom, a pox-viral vaccine in prostate cancer (PCa), on tumor growth rates within 80 days after initiation in nonmetastatic PCa.
Authors: Gulley James L. , Madan Ravi Amrit , Stein Wilfred Donald , Wilkerson Julia , Dahut William L. , Heery Christopher Ryan , Schlom Jeffrey , Wilding George , DiPaola Robert S.
Published: February 2017

57

Background: Our understanding of immunotherapies for prostate cancer (PSA-TRICOM, sipuleucel-T, ipilimumab) is incomplete in that such therapies have improved overall survival (OS) without changes in time to progression (TTP) in randomized trials. In an effort to better understand this discrepancy, we evaluated data from studies of PSA-TRICOM. A pox viral vaccine expressing PSA and 3 T-cell co-stimulatory molecules, PSA-TRICOM has demonstrated PSA-specific immune responses and evidence of clinical activity that supported initiation of a currently accruing Phase III trial. An analysis of NCI PCa trials (including a PSA-TRICOM trial) suggests that immune therapies may eventually slow the growth rate (GR) of tumors, leading to unaltered short term TTP, yet improved OS (Stein et al. Clin Can Res. 2011). Methods: PSA-TRICOM was administered to 50 hormone-naïve patients (pts.) with non-metastatic, castration naive PCa in a multi-center trial (ECOG 9802). Pts were treated every 4 weeks for 3 months, then every 12 weeks (preliminary data previously reported, DiPaola, RS et al. ASCO GU 2009). PSA values were used to calculate tumor GR within the first 100 days of treatment. (Pts were given no additional therapies during this time.) As previously described, a two-phase mathematical equation yielded concomitant PSA GR and regression rate constants.(Stein et. al., 2011) Results: See Table. Conclusions: These data suggest that PSA-TRICOM can alter GR significantly within 3 months. If confirmed in future trials, it could explain why vaccines have demonstrated improved OS without improved TTP. A slowing of the GR may not lead to substantial differences in short term TTP, but may enhance OS in the long term. This concept will be evaluated in an international Phase III trial of PSA-TRICOM in minimally symptomatic, metastatic castration-resistant PCa that is currently recruiting pts. Clinical trial information: NCT00108732. [Table: see text]
Modulation of soluble c-Met, bone turnover markers, angiogenic factors, and c-Met in men with mCRPC treated with cabozantinib.
Authors: Corn Paul G. , Varkaris Andreas , Li Ning Tapia Elsa M. , Araujo John C. , Aparicio Ana , Tu Shi-Ming , Zurita Amado J. , Efstathiou Eleni , Qiao Wei , Wen Sijin , Gallick Gary E. , Logothetis Christopher
Published: February 2017

58

Background: Cabozantinib (cabo) is a multi-TKI against c-Met and VEGFR2. Cabo elicits striking changes in bone scans (BS), reductions in soft-tissue mets, and improves bone pain in mCRPC. This unique response is unlinked from PSA and suggests that targets of Cabo reside in the bone microenvironment. To explore the underlying mechanisms of Cabo activity, we examined changes in soluble c-Met, angiogenic factors, bone specific alkaline phosphatase (BAP), and tumor specific c-Met signaling in men on Cabo. Methods: A phase II cohort of docetaxel pretreated men with mCRPC received Cabo. Response was assessed q6 wks by BS and CT scan. Blood and trans-iliac bone marrow biopsies (BMs) were collected pretreatment and at wk 6. Soluble c-Met was measured by ELISA, angiogenic factors by multiplex immunoassay, and tumor c-Met/phospho c-Met expression by IHC. Results: 21 patients with bony mets were evaluated; 38% also had soft tissue mets. 13/21 (62%) pts experienced an improvement (PRs + CRs) in BS and 2/8 (25%) achieved a PR in soft tissue mets. 12/20 (60%) pts had reductions in BAP on therapy (median reduction 48.5%). VEGFR2 levels decreased in response to therapy (p<0.0001) and VEGF levels increased (p<0.085). Soluble c-Met levels increased on therapy (p<0.009). Pretreatment BMs containing >5% tumor involvement (median 80%) were evaluable for 10 patients, 9 of whom also had a 6 wk BM. High intensity, tumor-specific expression of c-Met was detectable in 8/10 (80%) of pretreatment tumors (median involvement 60%) and increased in 4/9 (45%) pts at 6 wks (median increase 30%). Activated phospho c-Met was detectable in 9/10 (90%) of pretreatment tumors (median involvement 80%) and decreased in 5/9 (56%) pts (median reduction 30%) at 6 wks. Conclusions: The results of our study suggest that changes in soluble markers of c-Met, bone turnover, and angiogenesis are linked to Cabo activity. Analyses of BMs demonstrate high c-Met activation in pretreatment mets and suggest Cabo-mediated inhibition at 6 wks. These data support the hypothesis that c-Met contributes to “driver” signaling networks in mCRPC and suggest that biomarkers of stromal cell function should be prioritized for further study.
Impact of on-study corticosteroid use on efficacy and safety in the phase III AFFIRM study of enzalutamide (ENZA), an androgen receptor inhibitor.
Authors: Scher Howard I. , Fizazi Karim , Saad Fred , Chi Kim N. , Taplin Mary-Ellen , Sternberg Cora N. , Armstrong Andrew J. , Hirmand Mohammad , Forer David , De Bono Johann Sebastian
Published: February 2017

6

Background: ENZA increased median overall survival (OS) by 4.8 mo (P <0.001, HR 0.63) vs placebo (PBO) in metastatic castration-resistant prostate cancer (mCRPC) patients (pts) post-docetaxel in AFFIRM (HI Scher et al, NEJM 2012). Corticosteroids (CS) can activate AR signaling in nonclinical models (J Richards, Can Res 2012). In a multivariate model of AFFIRM data baseline CS use was associated with reduced OS (HI Scher et al. ESMO 2012 abstract 899PD). The impact of CS use during study treatment in AFFIRM was evaluated to test if concomitant CS use is also associated with inferior outcomes. Methods: Pts were randomized 2:1 to ENZA 160 mg/d or PBO. Pts were allowed but not required to take CS. OS was the primary endpoint. In a post-hoc analysis On-study CS use was defined as oral CS user for ≥ 1 day on study. Results: On study CS use was 48% in ENZA and 45% in PBO pts. Prognostic factors were slightly better in the no CS group compared to the CS group. Use of CS regardless of treatment was associated median OS of 11.5 mo (95% CI: 10.5, 13.0) for CS pts vs median OS NM (NM, NM) for no CS pts (HR=0.40; 95% CI: 0.33, 0.48). ENZA was consistently superior to PBO for OS, radiographic progression free survival (rPFS) and time to PSA progression (TTPP), regardless of CS use (Table). Pts on CS had higher rates of grade 3 - 4 adverse events (AE) compared to no CS pts: 63.3% vs 34.4% respectively. Conclusions: In this post-hoc analysis, on study CS use was associated with reduced OS and higher rates of grade 3 -4 AEs in mCRPC pts post-docetaxel. While CS pts had worse outcomes, ENZA was consistently superior to PBO regardless of on study CS use. The inferior outcomes in CS pts may be due to unmeasured confounders or the biologic properties of CS use itself. Clinical trial information: NCT00974311. [Table: see text]
Enzalutamide in combination with docetaxel in men with prostate cancer (PC): Preliminary results from a phase I study.
Authors: Fleming Mark T. , Rathkopf Dana E. , Gibbons Jackie , Peterson Amy C. , Hannah Alison , Forer David , Scher Howard I. , Morris Michael J.
Published: February 2017

63

Background: Enzalutamide (ENZA), a novel oral androgen receptor (AR) inhibitor, inhibits AR signaling via inhibition of androgen binding to the AR, AR nuclear translocation, and nuclear AR-DNA binding. ENZA demonstrated a survival benefit in men with metastatic castration-resistant prostate cancer (mCRPC) who had received prior docetaxel (Scher et al, NEJM 2012; 367:1187). A Phase III study in men with progressive chemotherapy-naïve disease (PREVAIL), is ongoing. Docetaxel (DOC) is the current standard first-line chemotherapy for mCRPC. CYP3A4, which plays a role in DOC clearance, is induced by ENZA. Patients (pts) eligible to receive DOC may benefit from continued AR inhibition with ENZA, provided the combination is well tolerated with no unacceptable drug-drug interactions. Methods: This study evaluated the safety and pharmacokinetics (PK) of DOC co-administered with ENZA in men with mCRPC on androgen deprivation therapy. Pts received DOC (75 mg/m2) by 1-h infusion every 3 weeks, with corticosteroids. ENZA (160 mg/d) was started 24 h after the first DOC infusion. Plasma PK samples were collected for 24 h after Cycle (C) 1 and C2 DOC infusions to enable within-subject comparisons of DOC PK ± ENZA. A sample size of 18 pts able to receive ≥ 2 full doses of DOC was specified for PK analyses. Results: As of 21 Sept. 2012, 22 pts have been enrolled, 3 did not complete both C1 and C2; PK and C1 and C2 safety data are currently available from 15 pts reported here. The median age was 65 (range 46-80 yrs); 11 had ECOG performance status 1 (vs 0). Prior primary therapy included surgery (n=2), radiation (n=4) or both (n=5); median PSA was 44.7ng/mL (1.9-585). ANC<1000mm3 was reported in 14 pts (1 febrile neutropenia), other adverse events in ≥4 pts included fatigue (11), dyspnea (6), alopecia (5), peripheral neuropathy (5), anemia (4) and dysgueusia (4). No seizures were reported. Preliminary PK data (n=15) show similar DOC exposure (within 20%) for DOC in combination with ENZA vs. DOC alone. Conclusions: This is the first evaluation of ENZA given in combination with DOC.In mCRPC pts ENZA does not appear to affect tolerability of DOC or have a clinically meaningful impact on DOC PK. Clinical trial information: NCT01565928.
Chimeric antigen receptor (CAR+) modified T cells targeting prostate-specific membrane antigen (PSMA) in patients (pts) with castrate metastatic prostate cancer (CMPC).
Authors: Slovin Susan F. , Wang Xiuyan , Hullings Melanie , Arauz Gabrielle , Bartido Shirley , Lewis Jason Stuart , Schöder Heiko , Zanzonico Pat , Scher Howard I. , Sadelain Michel , Riviere Isabelle
Published: February 2017

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Background: A phase I dose-escalating study to assess safety, dose and targeting efficiency of genetically modified autologous human T cells targeted to PSMA was initiated. Preclinical models demonstrated anti-tumor activity and accumulation, migration, and persistence of these cells to tumor. The autologous PSMA-targeted T cells utilizes the P28z second generation chimeric antigen receptor following iv cyclophosphamide (Cy). For safety, the herpes simplex virus-1 thymidine kinase (hsvtk) gene is co-expressed with the P28z receptor, rendering T cells sensitive to ganciclovir for immediate T cell elimination. The expression of hsvtk enables PET imaging using radiolabeled FIAU to localize these T cells. Methods: Autologous T cells are activated from a leukapheresis product using anti-CD3/CD28 Dynabeads. Release criteria include mean vector copy number by Q-PCR and vector identity by Southern blot, absence of Replication Competent Retrovirus and residual Dynabeads. Pts were dosed from 107 to 3 x 107 CAR+ T cells/kg. All 7 pts received 300mg/m2 of Cy one day before infusion. Baseline and post treatment imaging included FDG, FDHT and 18F-FIAU PET scans. Results: Three pts in cohort 1 received 1 x 107 CAR+ T cells/kg safely. A fourth pt received the same dose with a modified vector with higher copy number. One pt had stable disease for > 6 months; a second pt has stable scans for > 16 months; the third and fourth patients progressed. Of 3 pts in cohort 2, one received 1.5 x 107 CAR+ T cells/kg and 2 received 3 x 107 CAR+ cell/kg. All 3 had intermittent fever spikes up to 39oC associated with increased levels of IL-4, IL-8, IP-10, sIL-2ra and IL-6 suggesting T cell activation. CAR+ cells persisted in the circulation for up to 2 weeks. Scans with 18F-FIAU labeling suggests that imaging may be cell dose dependent. Conclusions: We have shown that pts can be safetly treated with an ex vivo transduction, expansion and therapeutic protocol for the generation of PSMA targeted T cells. Cytokine production suggests activation of these T cells with their persistence in blood for up to 2 weeks. If imaging with FIAU is suboptimal, a second cohort of pts will be studied with 124I- FIAU. Clinical trial information: NCT01140373.
Importance of Gleason score on 18F-choline PET/CT findings in patients with biochemical relapse of prostate cancer disease (PSA<1.0 ng/ml).
Authors: Hodolic Marina , Cimitan Marino , Fettich Jure
Published: February 2017

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Background: Not all tumors show significant increase of metabolic activity on 18F-FDG PET/CT imaging. This is particularly true for prostate cancer, neuroendocrine tumors and hepatic tumors. As a component of cell membrane phospholipids, choline is an excellent biomarker for the malignant transformation and increased proliferation of cells. 18F-choline (18F-FCH) PET/CT is a nuclear medicine procedure that has greater sensitivity and accuracy than 18F-FDG PET/CT to detect prostate malignancy: sensitivity 73% vs. 31% and accuracy 67% vs. 53%, respectively. The efficiency of FCH to detect prostate cancer disease before and after treatment is related to the PSA levels. Evaluation of recurrent disease with 18F-FCH PET/CT imaging in patients with prostate cancer disease is becoming a routine procedure. Purpose: To investigate the role of Gleason score (GS), as a marker of proliferation, on 18F-FCH PET/CT findings in patients with biochemical relapse of prostate cancer disease defined as increased level of prostate specific antigen (PSA). Methods: 140 patients with biochemical relapse (PSA<1.0 ng/ml) underwent 18F-FCH PET/CT scan after treatment: radical prostatectomy, radiotherapy, hormonal therapy alone or combined treatment. Results: 18F-FCH PET/CT detected prostate cancer recurrence in 97% of patients with GS>7, 82% of patients with GS=7 and 63% of patients with GS<7. All patients had PSA between 0.2 and 1.0 ng/ml. Out of 140 patients 43% had recurrence in prostatic bed and 57% patients had local metastasis. Conclusions: Prostate cancer proliferation defined as Gleason score, influence 18F-FCH PET/CT findings in patients with biochemical relapse of prostate cancer disease at any PSA level.
Impact on overall survival (OS) with chemohormonal therapy versus hormonal therapy for hormone-sensitive newly metastatic prostate cancer (mPrCa): An ECOG-led phase III randomized trial.
Authors: Sweeney Christopher , Chen Yu-Hui , Carducci Michael Anthony , Liu Glenn , Jarrard David Frasier , Eisenberger Mario A. , Wong Yu-Ning , Hahn Noah M. , Kohli Manish , Vogelzang Nicholas J. , Cooney Matthew M. , Dreicer Robert , Picus Joel , Shevrin Daniel H. , Hussain Maha , Garcia Jorge A. , DiPaola Robert S.
Published: February 2017

LBA2

Background: Docetaxel (D) improves OS of men with mPrCa who have progressed on androgen deprivation therapy (ADT). We aimed to assess the benefit of upfront chemohormonal therapy for metastatic PrCa. Methods: 1:1 randomization to ADT alone or ADT + D dosed 75mg/m2 every 3 weeks for 6 cycles within 4 month (mos) of starting ADT. Stratification factors: high volume (HV) vs. low volume (LV) disease (HV: visceral metastases and/or 4 or more bone metastases); anti-androgen use beyond 30 days; Age ≥70 vs. < 70 years; ECOG PS 0-1 vs. 2; Prior adjuvant ADT > 12 vs. ≤ 12 mos; FDA approved drug for delaying skeletal related events. Key eligibility criteria: suitable organ and neurological function for D; adjuvant ADT ≤ 24 mos and no progression within 12 mos of adjuvant ADT. OS was the primary endpoint and the study was powered to assess for a 33.3% improvement in median OS (80% power and 1-sided alpha=2.5%). Projected median OS for ADT alone: HV-33 mos; LV-67 mos. Results: 790 men were accrued from 7/28/06 to 11/21/2012: ADT N=393; ADT + D: N=397; balanced for demographic, stratification and disease factors. Median age: 63 years (range: 36 to 91); 98% ECOG PS 0 or 1; 89% Caucasian; 24% prior radiotherapy, 24% prior prostatectomy; HV 64% on ADT and 67% on ADT + D. Data released after 4th interim analysis in Sept 2013 when O’Brien Fleming upper boundary was crossed with 53.1% information. This report reflects 1/16/2014 data with median follow-up of 29 mos with 137 deaths on ADT alone vs. 104 deaths on ADT+D. ADT+D: Grade (G) 3/4 Neutropenic fever: 4%/2%; G3 neuropathy: 1% sensory, 1% motor; 1 death due to treatment (no deaths due to treatment on ADT). Efficacy data is in the table below. After disease progression, 123 pts on ADT alone and 45 pts on ADT + D received docetaxel. Conclusions: ADT + D improves OS over ADT alone in men with HV mPrCa. Longer follow-up is needed for men with LV mPrCa. Clinical trial information: NCT00309985. [Table: see text]
Efficacy of subcutaneous testosterone on menopausal symptoms in breast cancer survivors.
Authors: Glaser Rebecca L. , York Anne E. , Dimitrakakis Constantine
Published: February 2017

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Background: Menopausal symptoms can be severe in breast cancer survivors in whom estrogen therapy is contraindicated. Our previous pilot trial demonstrated that testosterone (T) combined with anastrozole (A) in subcutaneous implants provided therapeutic T levels without elevating estradiol. Our current goal was to document the clinical effect of T+A combination implants (no estrogen) on menopausal symptoms. Methods: This IRB approved study was designed to prospectively follow breast cancer survivors (stage 0-4) treated with subcutaneous T+A, for breast cancer recurrence. The therapeutic effectiveness of T on the relief of psychological, somatic and urogenital symptoms was documented using the validated, self administered, 11 item Menopause Rating Scale. Patients completed the survey prior to and following therapy. Results: Over 950 T/T+A pellet insertions have been performed in breast cancer survivors since 2006. Since 4/2013, 72 patients have been enrolled in the study. T dosing is weight based. Implants are inserted at 3-month intervals on average. Therapeutic T levels were confirmed without elevation of estradiol in any postmenopausal survivor. There have been no cancer recurrences in up to 8 years of therapy. A single patient with active metastatic disease at enrollment developed ascites. There was statistically significant improvement (P < 0.0001) in psychological symptoms (depression, irritability/aggression, anxiety), somatic symptoms (hot flashes/sweating, heart discomfort, sleep problems/insomnia, physical exhaustion, impaired memory, joint/muscular pain) and urogenital symptoms (vaginal dryness, bladder problems/incontinence, sexual problems). Conclusions: Testosterone in combination with an aromatase inhibitor, delivered by subcutaneous implant, was extremely effective for the relief of hormone deficiency symptoms in breast cancer survivors. Furthermore, this supports testosterone’s therapeutic effect via the androgen receptor. [Table: see text]
Mortality among women diagnosed with stage II or III breast cancer based on SEER-Medicare data.
Authors: Hernandez Rohini Khorana , Liede Alexander , Li Shuling , Liu Jiannong , Hu Yan , Stryker Scott , Blaes Anne Hudson , Collins Allan J
Published: February 2017

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Background: Increasing emphasis on assessing the quality of treatment (tx) for cancer patients highlights the need for real-world data sets that can address critical policy questions about cancer care in the US. This study examined treatment and mortality in women with incident early-stage breast cancer (BC) 2007-2009 using the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked data. Methods: We identified women age ≥66 years at the diagnosis of AJCC stage II/III BC between 2007-2009, who received surgery and were enrolled with Medicare Parts A and B. Women were followed from definitive surgery until the end of 2010, death, or change in enrollment status. Risk (cumulative incidence proportion [CIP]) of all-cause death was calculated with 95% confidence intervals (CI) using the Kaplan-Meier method stratified by tumor characteristics and tx type. Results: The cohort included 10,048 women with stage II (78%) or III (22%); 58% were ≥75 years and 78% had hormone-receptor (HR) positive tumors (77% ER positive, 64% PR positive). After the definitive surgery, 1,271 deaths reflected a CIP of 5.7% (95% CI 5.3-6.2) at 1 year, 10.9% (10.2-11.5) at 2 years, and 16.9% (15.9-17.9) at 3 years. Unadjusted mortality (Table) was higher among those without chemotherapy (chemo), women with neo-adjuvant tx, and those identified as “triple negative” phenotype (HR negative, no trastuzumab). Conclusions: Linking SEER and Medicare allowed us to assess mortality according to tumor characteristics and cancer treatments, respectively, which are both related to prognosis. The use of administrative data from Medicare should be further enhanced with inclusion of test results from standard gene expression panels to ensure a better match of therapy for the patient and adequate assessment of resource utilization. [Table: see text]