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Supplemental Table 4-6. Table S4: Detail for each sample of the PBRM1 and VHL-mutation status. NA stands for Not Available. Table S5: For each data type, clinical, transcriptome, methylome or SNP array, sensitity and specificity of the two predictors: PD vs (PR+SD) and PR vs (PD+SD) in the training and validation sets. The 'N()' columns indicate the numbers of each responder type. Table S6: List of the 27 genes firstly used by the classifier to predict the subtypes ccrcc2, ccrcc3 and the joint subtype ccrcc14 and list of the 8 genes used by the second classifier to assign the ccrcc14 samples to the two subtypes ccrcc1 and ccrcc4.

Supplemental Figure 7-10. Figure S7: Summary of the results obtained on the TCGA data; Figure S8: Survival analysis of the patients included in the TCGA according to our classification ccrcc 1 to 4; Figure S9: Illustration of the gradient assumption defined by subtype order

Purpose: Selecting patients with metastatic clear-cell renal cell carcinoma (m-ccRCC) who might benefit from treatment with targeted tyrosine kinase inhibitors (TKI) is a challenge. Our aim was to identify molecular markers associated with outcome in patients with m-ccRCC treated with sunitinib.Experimental Design: We performed global transcriptome analyses on 53 primary resected ccRCC tumors from patients who developed metastatic disease and were treated with first-line sunitinib. We also determined chromosome copy-number aberrations, methylation status, and gene mutations in von Hippel–Lindau and PBRM1. Molecular data were analyzed in relation with response rate (RR), progression-free survival (PFS), and overall survival (OS). Validation was performed in 47 additional ccRCC samples treated in first-line metastatic setting with sunitinib.Results: Unsupervised transcriptome analysis identified 4 robust ccRCC subtypes (ccrcc1 to 4) related to previous molecular classifications that were associated with different responses to sunitinib treatment. ccrcc1/ccrcc4 tumors had a lower RR (P = 0.005) and a shorter PFS and OS than ccrcc2/ccrcc3 tumors (P = 0.001 and 0.0003, respectively). These subtypes were the only significant covariate in the multivariate Cox model for PFS and OS (P = 0.017 and 0.006, respectively). ccrcc1/ccrcc4 tumors were characterized by a stem-cell polycomb signature and CpG hypermethylation, whereas ccrcc3 tumors, sensitive to sunitinib, did not exhibit cellular response to hypoxia. Moreover, ccrcc4 tumors exhibited sarcomatoid differentiation with a strong inflammatory, Th1-oriented but suppressive immune microenvironment, with high expression of PDCD1 (PD-1) and its ligands.Conclusions: ccRCC molecular subtypes are predictive of sunitinib response in metastatic patients, and could be used for personalized mRCC treatment with TKIs, demethylating or immunomodulatory drugs. Clin Cancer Res; 21(6); 1329–39. ©2015 AACR.

Supplemental Figure 1-3. Figure S1: Expression of immune modulators among the 4 molecular subgroups and normal Samples; Figure S2: Expression of cell-type specific metagenes among the different subgroups and normal samples; Figure S3: CD8+ cell infiltration according to the molecular ccRCC subtype classification.

Supplementary Figure and Table Legends. Legends of all supplemental Figures and Tables

Supplemental Figure 4-6. Figure S4: Characterisation of the ccRCC molecular subtypes: methylation status and Benporath polycomb signature; Figure S5: Cytogenetic characterization of the ccRCC molecular subtypes; Figure S6: Characterization of the ccRCC molecular subtypes: Myc methylation and (target) amplification

Supplemental Table 7-10. Table S7: Area under the ROC curve or c-index for the predictive and prognostic markers presented in Table 1 and Figures 3A, 3B and 3C. Table S8: P-values of the pathway enrichment analysis for the genes differentially expressed, the genes differentially methylated and the genes differentially methylated and anti-correlated to expression data in the four unsupervised subgroups. Table S9: List of the recurrent chromosomal aberrations characterizing ccrcc4-samples with a sensitivity and a specificity greater than 0.65. Table S10: Correlation of the centroids of our classification in four subtypes with the Brannon classification in three subgroups ccA, ccB and cluster_3 and the subtypes predicted in the TCGA cohort

Objective: •To evaluate the impact of baseline serum C-reactive protein (CRP) level on outcome in patients with metastatic renal cell carcinoma (mRCC) treated with sunitinib. Patients and Methods: •We reviewed the charts of patients with mRCC who started sunitinib as a first targeted treatment between 2005 and 2012 in three hospitals in Belgium and France. •Collected data included known prognostic factors for mRCC, anatomical location of metastatic sites, response rate (RR), progression-free survival (PFS) and overall survival (OS). Results: •A total of 200 eligible patients were identified by retrospective chart review. The median PFS and OS were 12 and 20 months, respectively. •We observed a clear impact of baseline CRP levels on outcome: the median PFS was 25 months in the group with baseline CRP ≤5 mg/L and 8 months in the group with baseline CRP >5 mg/L (hazard ratio [HR] 2.48, 95% CI 1.74–3.59). The median OS in each group was 50 vs 12 months, respectively (HR 3.17, 2.20–4.68). In the group with baseline CRP ≤5 mg/L, 61% of patients experienced a partial response compared with 32% of patients in the group with baseline CRP >5 mg/L (difference = 29%, 95% CI 15–42). •When adding baseline CRP (with a log transformation) to the six variables of the International Metastatic RCC Database Consortium (IMDC) model in a multivariable Cox regression model, baseline CRP was independently associated with poor PFS (HR for each doubling in CRP level: 1.14, 95% CI 1.03–1.26; P = 0.01) and OS (HR: 1.29, 95% CI 1.16–1.43; P < 0.001). •Adding baseline CRP to the model increased the c-statistic of PFS at 5 years from 0.63 (0.59–0.68) to 0.69 (0.65–0.73), and the c-statistic of OS at 5 years from 0.65 (0.60–0.69) to 0.70 (0.66–0.74). •Patients with elevated baseline CRP levels had a poor prognosis independent of the IMDC risk group, whereas patients with a low baseline CRP in the IMDC favourable risk group had a very good outcome. Conclusion: •Baseline serum CRP level is a strong independent variable linked with RR, PFS and OS in patients with mRCC treated with sunitinib.

Background: There are no validated markers that predict response in metastatic renal cell cancer (RCC) patients treated with sunitinib. We aim to study the impact of single-nucleotide polymorphisms (SNPs) that have recently been proposed as predictors of outcome to anti-VEGF-targeted therapy in metastatic RCC in an independent cohort of patients. Methods: We genotyped 16 key SNPs in 10 genes involved in sunitinib pharmacokinetics, pharmacodynamics and VEGF-independent angiogenesis in patients with metastatic clear-cell RCC treated with sunitinib as the first-line targeted therapy. Association between SNPs, progression-free survival (PFS) and overall survival (OS) were studied by multivariate Cox regression using relevant clinical factors associated with PFS and OS as covariates. Results: In a series of 88 patients, both PFS and OS were associated significantly with SNP rs1128503 in ABCB1 (P=0.027 and P=0.025), rs4073054 in NR1/3 (P=0.025 and P=0.035) and rs307821 in VEGFR3 (P=0.032 and P=0.011). Progression-free survival alone was associated with rs2981582 in FGFR2 (P=0.031) and rs2276707 in NR1/2 (P=0.047), whereas OS alone was associated with rs2307424 in NR1/3 (P=0.048) and rs307826 in VEGFR3 (P=0.013). Conclusion: Our results confirm former communications regarding the association between SNPs in ABCB1, NR1/2, NR1/3 and VEGFR3 and sunitinib outcome in clear-cell RCC. Prospective validation of these SNPs is now required.

Early-stage epithelial ovarian cancer represents a prognostically heterogenous group. We studied prognostic factors in patients treated with adjuvant paclitaxel/carboplatin chemotherapy.Data was extracted from 147 patients with FIGO stage IA/IB, grade 2/3 or stage IC/IIA (any grade) who underwent primary surgery followed by paclitaxel/carboplatin chemotherapy.Median follow-up was 88 months. Ten-year relapse-free (RFS) and disease-specific survival (DSS) were: 81% (95% confidence interval [CI]: 73-89) and 81% (95% CI: 73-89). On multivariate analysis, non serous histology was associated with reduced risk for RFS (0.294, 95% CI: 0.112-0.577, p=0.001) and DSS (0.194, 95% CI: 0.075-0.504, p=0.001), while high-risk category (stage IC/IIA and grade 2/3) with increased risk for RFS (3.989, 95% CI: 1.189-13.389, p=0.009) and DSS (3.989, 95% CI: 1.064-16.386, p=0.038). The combination of histology and grade identified 3 groups with distinctly different 10-year RFS and DSS rates (p0.001): grade 1 (100% and 100%), non-serous grade 2/3 (83% and 86%) and serous grade 2/3 (60% and 60%).Serous histology is an adverse prognostic factor in early-stage ovarian cancer treated with adjuvant paclitaxel/carboplatin. Risk stratification according to histology and grade is a useful discriminator of prognosis and can be used in the design of future studies.

Aim Hypertension (HT) complicates treatment with antiangiogenic agents, including the tyrosine kinase inhibitor (TKI) sunitinib. To prospectively evaluate the prevalence and management of HT in patients with advanced renal cell carcinoma (RCC) receiving sunitinib we used 24-h ABPM and we treated HT according to guidelines of the Joint National Committee on Prevention, Detection and Evaluation and the Treatment of High Blood Pressure (JNC7). Patients and methods Normal 24-h ABPM at the baseline and at 2, 4 and 6 weeks of the first cycle was ensured with the successive use of hydrochlorothiazide + irbesartan, nebivolol and amlodipine. Office BP measurements were used in subsequent cycles to monitor HT. Sunitinib dose was modified only if BP was not controlled with four anti-hypertensive agents. Results Forty patients were included in this analysis. Twenty-one patients (53%) had baseline HT, while 12 of 14 (84%) normotensive patients required anti-HT treatment during the 1st cycle of sunitinib. HT was infrequent in subsequent cycles and increase of anti-HT medication was required in only 2 cases. Two patients permanently discontinued sunitinib due to HT. The remaining 34 (94%) required no dose modifications for HT. One cardiac event (2.8%) was observed. There was no correlation of HT with sunitinib efficacy. Conclusion Sunitinib-associated HT is more frequent than previously reported. The use of 24-h ABPM for diagnosis and tailoring of HT according to JNC7 guidelines may achieve uninterrupted, full dose therapy in most patients. The substitution of such protocols for currently used Toxicity Criteria may be warranted.

Sorafenib and sunitinib are inhibitors of receptor protein tyrosine kinases (TKIs) and are approved for the treatment of metastatic renal cell carcinoma (mRCC). Although the mTOR inhibitor everolimus is effective for the treatment of patients who have failed TKI therapy, it is important to consider all available treatment options before switching therapy mode of action. Herein, we report outcomes in patients with mRCC switched to sorafenib following disease progression on sunitinib treatment. The medical records of 35 patients treated between November 2006 and November 2009 at two large referral centers in Greece were retrospectively analyzed for time-to-progression (TTP), overall survival (OS), and tolerability of sorafenib after sunitinib. Median TTP and OS on sorafenib were 4.9 and 11.5 months, respectively. Among 33 patients evaluable for tumor response, three had a partial response and 17 achieved disease stabilization (objective response rate 8.5%; total clinical benefit rate 57%). Sorafenib was well tolerated, with mostly grade 1/2 adverse events and no treatment-related deaths. Sorafenib was effective and well tolerated in this group of patients. The TTP with sorafenib following sunitinib was comparable to outcomes reported previously, providing further support that TKIs should be used in sequence before switching to an mTOR inhibitor.

Objective Second-line treatment options in advanced urothelial cancer are limited. We investigated the efficacy of a methotrexate/vinblastine/doxorubicin/cisplatin (MVAC) combination after failure of gemcitabine/platinum chemotherapy. Patients and methods Twenty-five patients with advanced urothelial cancer, who received second-line MVAC after first-line gemcitabine/cisplatin (n = 9) or gemcitabine/carboplatin (n = 16), were included in this retrospective analysis. Results Twenty-two patients (88%) relapsed within 6 months after first-line treatment. Following MVAC, there were 5 (20%) objective responses. Median follow-up was 20.2 months. Median progression-free survival (PFS) was 3.8 months (95% CI: 2.3–5.2), and median overall survival (OS) was 9 months (95% CI: 6.6–11.4). Eastern Cooperative Oncology Group performance status 0.1 versus 2 was associated with longer PFS (5 months versus 3.3 months, P = 0.049). Response or stabilization of disease during second-line chemotherapy predicted for a significantly longer PFS and OS (7.4 versus 3.5, P = 0.005; 15.5 versus 7, P = 0.046). Conclusions Second-line MVAC chemotherapy may result in prolonged survival in some patients with refractory disease. Further research in this field is necessary.

Serum CD105 has been associated with angiogenic activity in cancer, and low CD105 expression has been associated with improved prognosis. The present study evaluated the prognostic significance of serum levels of CD105 and related factors in patients with epithelial ovarian cancer (EOC) after cytoreductive surgery and chemotherapy.Eighty-six patients with stages IIC to IV EOC treated postoperatively with platinum-based chemotherapy were included. The enzyme-linked immunosorbent assay was used to measure prechemotherapy serum levels of CD105, transforming growth factor beta1/2 (TGF-beta1/2), angiopoietin 2, vascular endothelial growth factor, and tumor necrosis factor-alpha.High levels of TGF-beta2 (8908.86 pg/mL) and CD105 (4.25 ng/mL) were independently associated with improved overall survival (not reached vs 39 months, P = 0.009 and 75 vs 39 months, P = 0.029, respectively), whereas a high level of TGF-beta2 and a low level of vascular endothelial growth factor (219.04 pg/mL) were independently associated with improved progression-free survival (49 vs 17 months, P = 0.022 and 57 vs 16 months, P = 0.023, respectively). Among patients with favorable (4.25 ng/mL) CD105 levels, only patients with low TGF-beta1 levels (177.1 ng/mL) had superior survival than patients with low CD105 levels.Our study confirms the prognostic significance of angiogenesis in EOC and supports a biological interaction between CD105 and TGF-beta1. High angiogenic activity may be associated by increased efficacy of postoperative chemotherapy.

Alexandra Karadimou, Meletios A Dimopoulos, Aristotle Bamias Dept of Clinical Therapeutics, University of Athens Medical School, Athens, Greece Abstract: Testicular cancer is a highly curable neoplasm, even in the case of extragonadal disease. Nevertheless, patients with adverse prognostic features or relapsing after first-line cisplatin-based chemotherapy have a worse prognosis with a death rate greater than 50%. Highdose chemotherapy (HDC) has long been used in this group of patients. The introduction of stem cells, instead of bone marrow, as the source of hemopoietic cells and the use of leukocyte growth factors have substantially reduced the mortality and morbidity of this procedure although the role of HDC is not well defined. This review summarizes the available data, focusing on published randomized studies. The problems associated with the design of these studies and the interpretation of data are discussed. Currently this HDC approach is mainly used in patients who relapse after first-line chemotherapy. Nevertheless, selection of patients likely to benefit from this treatment remains an issue of intense clinical research.Keywords: high-dose chemotherapy, testicular cancer, salvage therapy

Purpose: Selecting patients with metastatic clear-cell renal cell carcinoma (m-ccRCC) who might benefit from treatment with targeted tyrosine kinase inhibitors (TKI) is a challenge. Our aim was to identify molecular markers associated with outcome in patients with m-ccRCC treated with sunitinib. Experimental Design: We performed global transcriptome analyses on 53 primary resected ccRCC tumors from patients who developed metastatic disease and were treated with first-line sunitinib. We also determined chromosome copy-number aberrations, methylation status, and gene mutations in von Hippel–Lindau and PBRM1. Molecular data were analyzed in relation with response rate (RR), progression-free survival (PFS), and overall survival (OS). Validation was performed in 47 additional ccRCC samples treated in first-line metastatic setting with sunitinib. Results: Unsupervised transcriptome analysis identified 4 robust ccRCC subtypes (ccrcc1 to 4) related to previous molecular classifications that were associated with different responses to sunitinib treatment. ccrcc1/ccrcc4 tumors had a lower RR (P = 0.005) and a shorter PFS and OS than ccrcc2/ccrcc3 tumors (P = 0.001 and 0.0003, respectively). These subtypes were the only significant covariate in the multivariate Cox model for PFS and OS (P = 0.017 and 0.006, respectively). ccrcc1/ccrcc4 tumors were characterized by a stem-cell polycomb signature and CpG hypermethylation, whereas ccrcc3 tumors, sensitive to sunitinib, did not exhibit cellular response to hypoxia. Moreover, ccrcc4 tumors exhibited sarcomatoid differentiation with a strong inflammatory, Th1-oriented but suppressive immune microenvironment, with high expression of PDCD1 (PD-1) and its ligands. Conclusions: ccRCC molecular subtypes are predictive of sunitinib response in metastatic patients, and could be used for personalized mRCC treatment with TKIs, demethylating or immunomodulatory drugs. Clin Cancer Res; 21(6); 1329–39. ©2015 AACR.

There is growing evidence that sunitinib plasma levels have an impact on treatment outcome in patients with metastatic renal cell carcinoma (mRCC). We studied the impact of single nucleotide polymorphisms (SNPs) in genes involved in sunitinib pharmacokinetics, and additionally, sunitinib pharmacodynamics on dose reductions of the tyrosine kinase inhibitor.We retrospectively analyzed germ-line DNA retrieved from mRCC patients receiving sunitinib as first-line therapy. We genotyped 11 key SNPs, respectively, in ABCB1, NR1/2, NR1/3 and CYP3A5, involved in sunitinib pharmacokinetics as well as VEGFR1 and VEGFR3, which have been suggested as regulators of sunitinib pharmacodynamics. Association between these SNPs and time-to-dose-reduction (TTDR) was studied by Cox regression.We identified 96 patients who were treated with sunitinib and from whom germ-line DNA and data on dose reductions were available. We observed an increased TTDR in patients carrying the TT-genotype in ABCB1 rs1125803 compared to patients with CC- or CT-genotypes (19 vs. 7 cycles; p = 0.031 on univariate analysis and p = 0.012 on multivariate analysis) and an increased TTDR in patients carrying the TT/TA-variant in ABCB1 rs2032582 compared to patients with the GG- or GT/GA-variant (19 vs. 7 cycles; p = 0.046 on univariate analysis and p = 0.024 on multivariate analysis).mRCC patients carrying the rs1128503 TT-variant or the TT/TA-variant in rs2032582 in ABCB1, which encodes for an efflux pump, do require less dose reductions due to adverse events compared to patients with the wild type or heterozygote variants in these genes.

Background Chemokine receptor signaling pathways are implicated in the pathobiology of renal cell carcinoma (RCC). However, the clinical relevance of CXCR2 receptor, mediating the effects of all angiogenic chemokines, remains unclear. SOCS (suppressor of cytokine signaling)-3 is a negative regulator of cytokine-driven responses, contributing to interferon-α resistance commonly used to treat advanced RCC with limited information regarding its expression in RCC. Methods In this study, CXCR2 and SOCS-3 were immunohistochemically investigated in 118 RCC cases in relation to interleukin (IL)-6 and (IL)-8, their downstream transducer phosphorylated (p-)STAT-3, and VEGF expression, being further correlated with microvascular characteristics, clinicopathological features and survival. In 30 cases relationships with hypoxia-inducible factors, i.e. HIF-1a, p53 and NF-κΒ (p65/RelA) were also examined. Validation of immunohistochemistry and further investigation of downstream transducers, p-JAK2 and p-c-Jun were evaluated by Western immunoblotting in 5 cases. Results Both CXCR2 and IL-8 were expressed by the neoplastic cells their levels being interrelated. CXCR2 strongly correlated with the levels of HIF-1a, p53 and p65/RelA in the neoplastic cells. Although SOCS-3 was simultaneously expressed with p-STAT-3, its levels tended to show an inverse relationship with p-JAK-2 and p-c-Jun in Western blots and were positively correlated with HIF-1a, p53 and p65/p65/RelA expression. Neither CXCR2 nor SOCS-3 correlated with the extent of microvascular network. IL-8 and CXCR2 expression was associated with high grade, advanced stage and the presence/number of metastases but only CXCR2 adversely affected survival in univariate analysis. Elevated SOCS-3 expression was associated with progression, the presence/number of metastasis and shortened survival in both univariate and multivariate analysis. Conclusions Our findings implicate SOCS-3 overexpression in RCC metastasis and biologic aggressiveness advocating its therapeutic targeting. IL-8/CXCR2 signaling also contributes to the metastatic phenotype of RCC cells but appears of lesser prognostic utility. Both CXCR2 and SOCS-3 appear to be related to transcription factors induced under hypoxia.

To evaluate the impact of baseline serum C-reactive protein (CRP) level on outcome in patients with metastatic renal cell carcinoma (mRCC) treated with sunitinib.We reviewed the charts of patients with mRCC who started sunitinib as a first targeted treatment between 2005 and 2012 in three hospitals in Belgium and France. Collected data included known prognostic factors for mRCC, anatomical location of metastatic sites, response rate (RR), progression-free survival (PFS) and overall survival (OS).A total of 200 eligible patients were identified by retrospective chart review. The median PFS and OS were 12 and 20 months, respectively. We observed a clear impact of baseline CRP levels on outcome: the median PFS was 25 months in the group with baseline CRP ≤5 mg/L and 8 months in the group with baseline CRP5 mg/L (hazard ratio [HR] 2.48, 95% CI 1.74-3.59). The median OS in each group was 50 vs 12 months, respectively (HR 3.17, 2.20-4.68). In the group with baseline CRP ≤5 mg/L, 61% of patients experienced a partial response compared with 32% of patients in the group with baseline CRP5 mg/L (difference = 29%, 95% CI 15-42). When adding baseline CRP (with a log transformation) to the six variables of the International Metastatic RCC Database Consortium (IMDC) model in a multivariable Cox regression model, baseline CRP was independently associated with poor PFS (HR for each doubling in CRP level: 1.14, 95% CI 1.03-1.26; P = 0.01) and OS (HR: 1.29, 95% CI 1.16-1.43; P0.001). Adding baseline CRP to the model increased the c-statistic of PFS at 5 years from 0.63 (0.59-0.68) to 0.69 (0.65-0.73), and the c-statistic of OS at 5 years from 0.65 (0.60-0.69) to 0.70 (0.66-0.74). Patients with elevated baseline CRP levels had a poor prognosis independent of the IMDC risk group, whereas patients with a low baseline CRP in the IMDC favourable risk group had a very good outcome.Baseline serum CRP level is a strong independent variable linked with RR, PFS and OS in patients with mRCC treated with sunitinib.

International audience; BACKGROUND: There are no validated markers that predict outcome in metastatic renal cell cancer (mRCC) patients treated with sunitinib. Recently, single nucleotide polymorphism (SNP) rs9582036 in VEGFR1 has been proposed as a predictor of progression-free survival (PFS) and overall survival (OS) to bevacizumab in patients with pancreatic cancer and rs7993418 in VEGFR1 as predictor for PFS in mRCC-patients treated with bevacizumab. Here, we aim to study the impact of these SNPs in mRCC patients treated with sunitinib. METHODS: We included patients with mRCC treated in 15 institutions in France and Belgium. Patients received sunitinib as first-line targeted therapy. We assessed response, time-to-tumor progression (TTP), OS, and clinical and biochemical parameters associated with outcome. We genotyped rs9582036 and rs7993418 as well as three other surrounding SNPs in VEGFR1: rs9554320, rs9554316 and rs9513070. Association between SNPs and treatment outcome were studied by univariate analysis and by multivariate Cox regression using relevant clinical factors associated with TTP and OS as covariates. FINDINGS: Ninety-one patients were included. We found that mRCC patients with the CC-variant in rs9582036 in VEGFR1 have a poorer response rate (RR) (0% vs. 46%, p = 0.028), a poorer PFS (10 vs. 18 months, p = 0.033 on univariate and 0.06 on multivariate analysis) and a poorer OS (14 vs. 31 months, p = 0.019 on univariate and 0.008 on multivariate analysis) compared to patients with the AC- and AA-genotypes. mRCC patients with the AA-variant in rs9554320 in VEGFR1 have a poorer PFS (12 vs. 21 months, p = 0.0066 on univariate and 0.005 on multivariate analysis) and a poorer OS (22 vs. 34 months, p = 0.019 on univariate and 0.067 on multivariate analysis) compared to patients with the AC- and CC-genotypes. Interpretation. mRCC patients with the CC-genotype in VEGFR1 SNP rs9582036 have a poorer response rate, PFS and OS when treated with sunitinib. These findings are in agreement with the association of rs9582036 and outcome observed in bevacizumab treated pancreatic cancer patients. Prospective validation of this SNP is warranted.

The presence of bone metastases in patients with metastatic renal cell carcinoma treated with oral tyrosine kinase inhibitors (TKIs) is associated with poorer outcome as compared with patients without bone involvement. Concomitant bisphosphonates could probably improve outcomes but also induce osteonecrosis of the jaw (ONJ)., Journal Article, Research Support, Non-U.S. Gov't, SCOPUS: ar.j, info:eu-repo/semantics/published

Objectives To determine whether intermittent docetaxel might control disease while limiting the toxicity and improving the quality-of-life parameters in patients with advanced, castrate-resistant prostate cancer. Intermittent docetaxel represents an appealing therapeutic approach. Methods We reviewed the records of 35 patients with chemotherapy-naive castrate-resistant prostate cancer who had received docetaxel 45 mg/m 2 every 2 weeks, with oral prednisone 5 mg twice daily. Treatment was held when the patients had reached a >50% prostate-specific antigen reduction from baseline that was confirmed by a second measurement 4 weeks later, in the absence of disease progression. Docetaxel was resumed at a >25% prostate-specific antigen increase from the nadir level, also confirmed by a second measurement 4 weeks later, or in cases of documented disease progression. Results Of the 35 patients, 18 (51.42%) had entered the first chemotherapy-free interval (CFI) after a median of 6 infusions (range 2-12), 6 patients had entered a second CFI after a median of 4 months (range 2-12), and 1 patient, a third CFI at the last follow-up point. The median interval “off chemotherapy” was 4.5 months (range 1-16) for the first CFI. Two patients discontinued docetaxel because of Grade 4 nonhematologic toxicity. The median interval to treatment failure was 8.1 months (95% confidence interval 5.1-12.2) for the entire cohort and 12.2 months (95% confidence interval 8.3-25+) for the patients who had entered the first CFI. Conclusions The results of our study have shown that intermittent docetaxel is a clinically active and likely more tolerable and less costly therapeutic strategy for patients with castrate-resistant prostate cancer than continuous administration. Additional validation of this approach is warranted.

Ovarian cancer is one of the leading causes of cancer-related death among women. Resistance to the disease occurs in more than 70% of the cases even after treated with chemotherapy agents such as paclitaxel- and platinum-based agents. The immune system is increasingly becoming a target for intense research in order to study the host's immune response against ovarian cancer. T cell populations, including NK T cells and Tregs, and cytokines have been associated with disease outcome, indicating their increasing clinical significance, having been associated with prognosis and as markers of disease progress, respectively. Harnessing the immune system capacity in order to induce antitumor response remains a major challenge. This paper examines the recent developments in our understanding of the mechanisms of development of the immune response in ovarian cancer as well as its prognostic significance and the existing experience in clinical studies.

425 Background: The aim of our study was to determine whether baseline serum C-reactive protein (CRP) level could predict outcome of patients with metastatic renal cell carcinoma (mRCC) receiving sunitinib in first-line setting. Methods: We reviewed the charts of 187 consecutive patients in three hospitals in Belgium and France who started sunitinib as first targeted treatment between 2005 and 2012. Data were collected from each individual patient file on known prognostic factors for mRCC and anatomical location of metastatic sites, response rate, progression free survival (PFS), and overall survival (OS). Results: 187 eligible patients were identified by retrospective chart review. Median PFS was 26 months in the group with baseline CRP within normal limits (≤5 mg/l) versus 8 months in the group with elevated baseline CRP (>5 mg/l) (p < 0.0001). Median OS was 50 versus 12 months respectively (p < 0.0001). In the group with normal baseline CRP, 69% of patients experienced a partial response (PR) compared to 31% of patients in the group with elevated baseline CRP (p < 0.0001). On multivariate analysis, taking into account baseline neutrophil count, platelet count, ECOG PS, serum lactate dehydrogenase (LDH) activity, hemoglobin levels, corrected serum calcium levels, interval between initial diagnosis of RCC and start of systemic therapy

359 Background: There are no established biomarkers predicting outcome of SUN treatment in mRCC. Methods: We assessed 30 single nucleotide polymorphisms (SNPs) in 10 genes on fresh frozen clear cell RCC nephrectomy specimens originating from pts who developed metastatic disease. Results: We processed 79 samples. In 49 pts, normal kidney tissue adjacent to the tumor was used, in 30 pts only tumoral tissue was available. After nephrectomy and in presence of synchronous or metachronous metastasis, all pts received SUN as 1st line treatment. We observed associations between several SNPs and mTTP: In the promotor region of the gene encoding for IL-8 (proangiogenic growth factor): rs4073: TT or TA versus (vs) AA variant: mTTP 12 mo vs not reached (NR) (p=0.02). In ABCB1 (involved in drug transport): rs2032582: TA or TT vs GT/GA or GG: 9 vs 16 mo (p=0.03). rs1128503: TT vs CT or CC: 9 vs 16 mo (p=0.02). In VEGFR3 (a target of SUN): rs307826 : GA vs AA: 9.3 vs 18 mo (p=0.01). rs307821 : GT vs GG: 10 vs 16 mo (p=0.08). rs448012 : CC/CG vs GG: 12 mo vs NR (p=0.02). In NR1/2 (promotor leading to increased CYP3A4 expression): rs3814055: TT vs CC/CT: 13 vs 18 mo (p=0.02). rs1054190: CC vs CT: 14 vs 20 mo (p=0.14). In PDGFR-alpha (another SUN target): rs1800812: TT vs GG/GT: 3.5 vs 16 mo (p Conclusions: SNPs in genes linked to the pharmacokinetics and -dynamics of SUN can probably predict outcome of SUN treatment in mRCC. Our results confirm in part previous observations made by other groups in pazopanib or SUN (in IL-8, VEGFR3 and NR1/2) and highlight the potential role of other SNPs (in ABCB1, NR1/2 and PDGFR). Extension of the series and univariate/multivariate validation are ongoing. [Table: see text]

e15552 Background: The role of vascular endothelial growth factor (VEGF) in tumor angiogenesis is well characterized; nevertheless, it is also a key element in promoting tumor evasion of the immune...

4510 Background: The combinations of methotrexate, vinblastine, doxorubicin hydrochloride (Adriamycin), cisplatin (MVAC) and gemcitabine, cisplatin (GC) are standard regimens for advanced urothelia...

388 Background: With a median progression-free survival(PFS) of 8.2 months (mo) (vs. 19.1 mo; p Methods: We collected data on classical prognostic factors for m-RCC, Fuhrman grade, number of BM, and bone-oriented therapy in the charts of 80 m-RCC pts with BM who started first-line SUN between 01/2005 and 12/2009 in 4 academic centers in Belgium and France. Univariate analysis was conducted using Maentel Hetzel test. Validation of these findings on a second series of m-RCC patients is ongoing. Multivariate analysis will be performed on the total series. Results: In the total population, median PFS and OS were 9.8 and 20.6 mo. Pts with Fuhrman grade 4 tumors (MSKCC prognosis: intermediate 50%; poor 50%) had a PFS of 4.5 mo vs. 12.3 mo for Fuhrman grade 1-2-3 tumors (MSKCC prognosis: good 20%; intermediate 60%; poor 20%) (p=0.005). OS was 13.5 mo vs. 26.5 mo respectively (p=0.003). There was no difference in PFS and OS between pts with Fuhrman grade 1-2 and Fuhrman grade 3 tumors. The number of BM had no significant influence on PFS and OS. Whether or not radiation therapy and/or surgery had been applied to all BM before starting SUN was a factor without influence on PFS or OS. Concomitant bisphosphonates (BF) and SUN administration was analyzed on all the evaluable pts (24) treated at the University Hospitals Leuven. 14 pts (MSKCC prognosis: poor: 8; intermediate: 6) received concomitant BF. 10 pts (MSKCC prognosis: poor: 5; intermediate: 5) did not. Median PFS was 16.3 and 3.4 mo (p=0.03) and OS 18.1 and 13.9 mo respectively (not significant). Results of the validation series and multivariate analysis will be presented. Conclusions: m-RCC pts combining BM and Fuhrman grade 4 tumors have a very poor outcome on SUN. Concomitant use of BF may be a strategy to improve PFS in pts with bone metastatic RCC. No significant financial relationships to disclose.

e15085 Background: Treatment with cytokines has suggested an anticancer role of the immune system in mRCC patients. Given the antitumor activity of select tyrosine kinase inhibitors in mRCC, it is ...

e15066 Background: Platinum-based combination chemotherapy represents the standard treatment for advanced urothelial cancer. Determination of prognosis is based on clinical characteristics: ECOG PS...

Background The treatment paradigm in advanced renal cell carcinoma (RCC) has changed in the recent years. Sunitinib has been established as a new standard for first-line therapy. We studied the prognostic significance of baseline characteristics and we compared the risk stratification with the established Memorial Sloan Kettering Cancer Center (MSKCC) model. Methods This is a retrospective analysis of patients treated in six Greek Oncology Units of HECOG. Inclusion criteria were: advanced renal cell carcinoma not amenable to surgery and treatment with Sunitinib. Previous cytokine therapy but no targeted agents were allowed. Overall survival (OS) was the major end point. Significance of prognostic factors was evaluated with multivariate cox regression analysis. A model was developed to stratify patients according to risk. Results One hundred and nine patients were included. Median follow up has been 15.8 months and median OS 17.1 months (95% CI: 13.7-20.6). Time from diagnosis to the start of Sunitinib (12 months, p = 0.001), number of metastatic sites (1 vs. >1, p = 0.003) and performance status (PS) (1, p = 0.001) were independently associated with OS. Stratification in two risk groups ("low" risk: 0 or 1 risk factors; "high" risk: 2 or 3 risk factors) resulted in distinctly different OS (median not reached [NR] vs. 10.8 [95% confidence interval (CI): 8.3-13.3], p < 0.001). The application of the MSKCC risk criteria resulted in stratification into 3 groups (low and intermediate and poor risk) with distinctly different prognosis underlying its validity. Nevertheless, MSKCC model did not show an improved prognostic performance over the model developed by this analysis. Conclusions Studies on risk stratification of patients with advanced RCC treated with targeted therapies are warranted. Our results suggest that a simpler than the MSKCC model can be developed. Such models should be further validated.