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Objective: To examine the association between surgical waiting times (SWTs) and all-cause mortality (ACM) in non-metastatic patients with RCC, in relation to tumour stage. Patients and methods: This nation-wide population-based cohort study included 9,918 M0 RCC patients registered in the National Swedish Kidney Cancer Register, between 2009 and 2021, followed-up for ACM until 9 December 2021, and having measured SWTs. The associations between primarily SWTs from date of radiological diagnosis to date of surgery (WRS) and secondarily SWTs from date of radiological diagnosis to date of treatment decision (WRT) and date of treatment decision to date of surgery (WTS), in relation to ACM, were analysed using Cox regression analysis, adjusted for clinical and demographic characteristics, stratified and unstratified according to T-stage. Results: During a mean follow-up time of 5 years (49,873 person-years), 23% (n = 2291) of the patients died. The adjusted hazard ratio (AHR) for WRS (months) for all patients was 1.03 (95% confidence interval [CI] = 1.02–1.04; p < 0.001). When subdividing WRS on T-stage, the AHRs were 1.03 (95% CI = 1.01–1.04; p < 0.001) and 1.05 (95% CI = 1.02–1.08; p = 0.003) for stages T1 and T3, respectively, while non-significant for T2 (p = 0.079) and T4 (p = 0.807). Similar results were obtained for WRT and WTS. Conclusions: Prolonged SWTs significantly increased the risk of early overall death among patients with RCC. The increased risk of early death from any cause show the importance of shortening SWTs in clinical work of patients with this malignant disease.

Introduction The effects of single-fraction gamma knife radiosurgery (sf-GKRS) on patients with renal cell carcinoma (RCC) brain metastases (BM) in the era of targeted agents (TA) and immune checkpoint inhibitors (ICI) are insufficiently studied. Methods and materials Clear cell metastatic RCC patients treated with sf-GKRS due to BM in 2005-2014 at three European centres were retrospectively analysed (n= 43). Median follow-up was 56 months. Ninety-five percent had prior nephrectomy, 53% synchronous metastasis and 86% extracranial disease at first sf-GKRS. Karnofsky performance status (KPS) ranged from 60 to 100%. Outcome measures were overall survival (OS), local control (LC) and adverse radiation effects (ARE). Results One hundred and ninety-four targets were irradiated. The median number of targets at first sf-GKRS was two. The median prescription dose was 22.0 Gy. Thirty-seven percent had repeated sf-GKRS. Eighty-eight percent received TA. LC rates at 12 and 18 months were 97% and 90%. Median OS from the first sf-GKRS was 15.7 months. Low serum albumin (HR for death 5.3), corticosteroid use pre-sf-GKRS (HR for death 5.8) and KPS < 80 (HR for death 9.1) were independently associated with worse OS. No further prognostic information was gleaned from MSKCC risk group, synchronous metastasis, age, number of BM or extracranial metastases. Other prognostic scores for BM radiosurgery, including DS-GPA, renal-GPA, LLV-SIR and CITV-SIR, again, did not add further prognostic value. ARE were seldom symptomatic and were associated with tumour volume, 10-Gy volume and pre-treatment perifocal oedema. ARE were less common among patients treated with TA within 1 month of sf-GKRS. Conclusions We identified albumin, corticosteroid use and KPS as independent prognostic factors for sf-GKRS of clear cell RCC BM. Studies focusing on the prognostic significance of albumin in sf-GKRS are rare. Further studies with a larger number of patients are warranted to confirm the above analytical outcome. Also, in keeping with previous studies, our data showed optimal rates of local tumour control and limited toxicity post radiosurgery, rendering GKRS the tool of choice in the management of RCC BM.

Objective: To explore cost-effectiveness of targeted therapies (TTs) in the treatment of metastatic renal cell carcinoma (mRCC) in a real-world context using a nationwide population-based approach. ...

Background:The long-term benefits of local therapy in metastatic renal cell carcinoma (mRCC) have been widely documented. In this context, single fraction gamma knife radiosurgery (SF-GKRS) is routinely used in the management of brain metastases. However, SF-GKRS is not always feasible due to volumetric and regional constraints. We intend to illustrate how a dose-volume adaptive hypofractionated GKRS technique based on two concurrent dose prescriptions termed rapid rescue radiosurgery (RRR) can be utilized in this particular scenario.Case Description:A 56-year-old man presented with left-sided hemiparesis; the imaging showed a 13.1 cc brain metastasis in the right central sulcus (Met 1). Further investigation confirmed the histology to be a metastatic clear cell RCC. Met 1 was treated with upfront RRR. Follow-up magnetic resonance imaging (MRI) at 10 months showed further volume regression of Met 1; however, concurrently, a new 17.3 cc lesion was reported in the boundaries of the left frontotemporal region (Met 2) as well as a small metastasis (Results:Gradual and sustained tumor ablation of Met 1 and Met 2 was demonstrated on a 20 months long follow- up. The patient succumbed to extracranial disease 21 months after the treatment of Met 1 without evidence of neurological impairment post-RRR.Conclusion:Despite poor prognosis and precluding clinical factors (failing systemic treatment, eloquent location, and radioresistant histology), RRR provided optimal tumor ablation and salvage of neurofunction with limited toxicity throughout follow-up.

Background: Recently, the CARMENA and SURTIME studies, suggested that upfront cytoreductive nephrectomy (CN) should be abandoned for patients with intermediate and high-risk metastatic renal cell carcinoma (mRCC). However, CN remains an indication in low-risk and when immediate systemic treatment is not required. The aim was to evaluate the long-term overall survival (OS) in patients with primary mRCC, based on the first line treatment. Methods: There were 1483 patients with primary mRCC in the National Kidney Cancer Registry from 2005 to 2013. Data on primary treatment, TNM stage, RCC type, tumor size, patient age and sex were extracted. Survival time was calculated from time of diagnosis to time of death or until July 2019. Mann-Whitney U and Chi-square tests, the Kaplan-Meyer method and Cox regression analyses were used. Results: Patients primary treated with CN had a significantly longer OS (p

Background The role of B-lymphocytes in solid tumours is unclear. Tumour biology studies have implied both anti- and pro-tumoural effects and prognostic studies have mainly linked B-cells to increased survival. This study aimed to analyse the clinical relevance of B-lymphocytes in renal cell cancer (RCC), where information on the prognostic impact is lacking. Methods Following immunohistochemistry (IHC) stainings with a CD20 antibody, density of CD20+ B-cells was quantified in an RCC discovery- and validation cohort. Associations of B-cell infiltration, determined by CD20 expression or a B-cell gene-signature, and survival was also analysed in 14 publicly available gene expression datasets of cancer, including the kidney clear cell carcinoma (KIRC) dataset. Results IHC analyses of the discovery cohort identified a previously unrecognised subgroup of RCC patients with high infiltration of CD20+ B-cells. The B-cell-high subgroup displayed significantly shorter survival according to uni- and multi-variable analyses. The association between poor prognosis and high density of CD20+ B-cells was confirmed in the validation cohort. Analyses of the KIRC gene expression dataset using the B-cell signature confirmed findings from IHC analyses. Analyses of other gene expression datasets, representing 13 different tumour types, indicated that the poor survival-association of B-cells occurred selectively in RCC. Conclusion This exploratory study identifies a previously unrecognised poor-prognosis subset of RCC with high density of CD20-defined B-cells.

Renal cell carcinoma (RCC) is the most common type of kidney cancer and has the highest mortality rate among genitourinary cancers. Despite the advances in molecular targeted therapies to treat RCC, the inevitable emergence of resistance has delineated the need to uncover biomarkers to prospectively identify patient response to treatment and more accurately predict patient prognosis. Fringe is a fucose specific β1, 3N-acetylglucosaminyltransferase that modifies the Notch receptors. Given the link between its function and aberrant Notch activation in RCC, Fringe may be implicated in this disease. The Fringe homologs comprise of Lunatic fringe (LFng), Manic fringe (MFng) and Radical fringe (RFng). MFng has been reported to play a role in cancer. MFng is also essential in the development of B cells. However, the expression profile and clinical significance of MFng, and its association with B cells in RCC are unknown. CD20 is a clinically employed biomarker for B cells. This pilot study aimed to determine if MFng protein expression can be utilized as a prospective biomarker for therapeutics and prognosis in RCC, as well as to determine its association with CD20+ B cells. Analysis of publicly available MFng gene expression datasets on The Cancer Genome Atlas Netlwork (TCGA) identified MFng gene expression to be up-regulated in Kidney Clear Cell Renal Carcinoma (KIRC) patients. However there was no significant association between the patient survival probability and the level of MFng expression in this cohort. Immunohistochemistry performed on a tissue microarray containing cores from 64 patients revealed an elevated MFng protein expression in the epithelial and stromal tissues of RCC compared to the normal kidney, suggesting a possible role in tumorigenesis. Our study describes for the first time to our knowledge, the protein expression of MFng in the nuclear compartment of normal kidney and RCC, implicating a prospective involvement in gene transcription. At the cellular level, cytoplasmic MFng was also abundant in the normal kidney and RCC. However, MFng protein expression in the malignant epithelial and stromal tissue of RCC had no positive correlation with the patients' overall survival, progression-free survival and time to metastasis, as well as the gender, age, tumor stage and RCC subtype, indicating that MFng may not be an appropriate prognostic marker. The association between CD20+ B cells and epithelial MFng was found to approach borderline insignificance. Nonetheless, these preliminary findings may provide valuable information on the suitability of MFng as a potential therapeutic molecular marker for RCC, thus warrants further investigation using a larger cohort.

Background: Renal cell carcinoma (RCC) is a highly vascularised tumour, where anti-angiogenic treatment with multi-tyrosine-kinase-inhibitor, is used for first-line treatment of metastatic disease. Variations in vascular characteristics are likely to contribute to variations in intrinsic aggressiveness of the disease. Emerging studies are identifying perivascular status, including perivascular PDGFR-β, as a determinant of prognosis in other tumour types. Methods: This work explored the impact on prognosis of vascular characteristics in RCC through analyses of a population-based collection of tumours from surgery-alone-treated patients. The quantitative data from a panel of vascular metrics were obtained through computerised image analysis of sections double-stained for expression of the endothelial cell marker CD34 together with perivascular markers α-SMA or PDGFR-β. Results: Perivascular expression of PDGFR-β and α-SMA were positively correlated to each other, and negatively correlated to vessel density. High expression of PDGFR-β and α-SMA as well as low vessel density was significantly associated with short survival in uni- and multivariate analyses. Subgroup analyses demonstrated that the prognostic impact of the perivascular markers was particularly prominent in the T4-subgroup. A novel metric, related to PDGFR-β perivascular heterogeneity, was also associated with prognosis in uni-and multi-variate analyses. This novel metric also acted as a prognosis marker in ovarian cancer. Conclusions: The study demonstrates previously unrecognised associations between RCC survival and the absolute levels, and variability, of perivascular PDGFR-β. This marker should be further explored in other RCC cohorts. Findings also suggest mechanistic analyses and studies on the relationship between perivascular status and efficacy of multi-tyrosine-kinase-inhibitors.

Objective To explore cost-effectiveness of targeted therapies (TTs) in the treatment of metastatic renal cell carcinoma (mRCC) in a real-world context using a nationwide population-based approach. Methods Data on patients diagnosed with mRCC between 2002 and 2012 were extracted from Swedish national health data registers. To facilitate comparisons of patients diagnosed before and after TT introduction to the market, three cohorts were derived: pre-TT introduction (preTT), patients diagnosed 2002–2005; early TT introduction (TTi), patients diagnosed 2006–2008; and late TT introduction (TTii), which was limited to patients diagnosed 2009–2010 to ensure availability of total health care resource utilization (HCRU) data. Patients were followed until end of 2012. The value of TTs across cohorts was estimated using mean HCRU costs per life-year (LY) gained. Data on HCRU were obtained through national health registers for dispensed medication and inpatient and outpatient care, and the associated costs were estimated using the Lin method to account for censoring. LYs gained were defined as the difference in mean survival over the study period. Results The preTT, TTi, and TTii cohorts consisted of 1,366, 1,158, and 806 patients, respectively. Mean survival in years from mRCC diagnosis was 1.45 in the preTT cohort, 1.62 in the TTi cohort, and 1.83 in the TTii cohort. The respective mean total HCRU cost per patient over the study period was US$16,894, US$29,922, and US$30,037. The cost per LY gained per cohort was US$78,656 for TTi vs preTT, US$34,132 for TTii vs preTT, and US$523 for TTii vs TTi. Conclusion Given common willingness-to-pay per LY gained thresholds, this study in a real-world population suggests the use of TTs in the Swedish mRCC population is increasingly cost-effective over time.

Background: Metastatic papillary renal cell carcinoma (mPRCC) is understudied. The disease is often aggressive and specific treatment options are lacking. Patients and methods: mPRCC patients (n = 86) referred to three academic centres in Sweden and Germany in the years 2005–2015 were retrospectively identified from medical records. Statistical analyses included Kaplan–Meier curves and calculation of Cox proportional hazards, generating hazard ratios with 95% confidence intervals. The aim of the study was to evaluate overall survival (OS) of mPRCC patients treated outside of clinical trials in the era of targeted agents (TA) and to identify clinically useful prognostic factors. Results: Median OS of all mPRCC patients was 11.2 months. TA were used in 77% of the patients and associated with younger age and better Eastern Cooperative Oncology Group performance status (PS). Brain metastases were common (28%). Patients with synchronous or metachronous metastases had similar OS. Variables independently associated with risk of death included age ≥60 years, worse PS and ≥3 metastatic sites. The MSKCC criteria did not provide additional prognostic information. A subgroup analysis of TA-treated patients revealed an association of lymph node metastasis with risk of death in addition to the other prognostic factors. Conclusion: OS in mPRCC remained short in the era of targeted agents. Age, PS, and number of metastatic sites provided independent prognostic information.

To present the occurrence of metastases and local recurrences in primary non-metastatic patients with renal cell carcinoma (RCC) in a contemporary Swedish population-based cohort. Between 2005 and 2009, a total of 4527 patients were included in the prospective National Swedish Kidney Cancer Register accounting for nearly all RCC patients in Sweden. Among M0 patients, 472 (13 %) had no follow-up data registered within 5-year follow-up time and were excluded from the analysis. In total, 939 (21 %) had distant metastases at presentation with a decrease from 23 to 18 % during the inclusion period. Of 3107 patients with follow-up data and with M0 disease, 623 (20 %) were diagnosed with a tumor recurrence during 5-year follow-up. Mean time to recurrence was 24 months (SD ± 20 months). Among these, 570 patients (92 %) were at primary diagnosis treated with radical nephrectomy, 23 patients (3.7 %) with partial nephrectomy and 12 patients (1.9 %) with minimally invasive treatments. The most frequent sites of metastases were lung (54 %), lymph nodes (22 %) and bone (20 %). The treatment of recurrence was in 50 % systemic treatments, while metastasectomy was performed in 17 % of the patients, out of which 68 % were with a curative intention. In this population-based study, 21 % of the patients had metastatic disease at presentation, with a decreasing trend over the study period. During 5-year follow-up, 20 % of the primary non-metastatic patients had recurrent disease. Of the patients with recurrence, half were given systemic oncological treatment and 17 % underwent metastasectomy.

Background and purpose Investigate effects of stereotactic radiotherapy (SRT) or surgical metastasectomy (SM) on overall survival (OS) in metastatic renal cell carcinoma (mRCC) in the era of targeted agents (TA). Material and methods mRCC patients ( n = 117) treated with SRT ( n = 57), SM ( n = 30) or both modalities sequentially ( n = 30) at two oncological centres in Sweden in 2005–2014 were retrospectively included. Median follow-up (mFU) was 63 months. Results A majority had clear cell histology, 1–3 metastases, and ECOG performance status of 0 or 1. Two thirds had intermediate or poor risk and 44% synchronous metastases. 65% received TA. SRT patients were more likely to have adverse risk profiles. Median OS was 51 months without significant differences between SRT and SM. ECOG 1 vs 0 (HR 2.9; CI 1.6–5.2; p p = 0.03) and watchful waiting >18 months prior to treatment (HR 0.3; CI 0.2–0.6; p = 0.001) were independently associated with OS. 15% of curatively treated patients ( n = 60) were relapse-free with mFU of 87 months. Conclusions OS after SRT was comparable to SM and longer than expected considering patients with adverse risk profiles were common. Fit patients with non-brain metastases treated after an initial period of watchful waiting had the best prognosis.

Regulatory T cells (Treg) suppress anti-tumor immune responses and their infiltration in the tumor microenvironment is associated with inferior prognosis in cancer patients. Thus, in order to enhance anti-tumor immune responses, selective depletion of Treg is highly desired. We found that treatment with zoledronic acid (ZA) resulted in a selective decrease in the frequency of Treg that was associated with a significant increase in proliferation of T cells and natural killer (NK) cells in peripheral blood of patients with metastatic cancer. In vitro, genome-wide transcriptomic analysis revealed alterations in calcium signaling pathways in Treg following treatment with ZA. Furthermore, co-localization of the nuclear factor of activated T cells (NFAT) and forkhead box P3 (FOXP3) was significantly reduced in Treg upon ZA-treatment. Consequently, reduced expression levels of CD25, STAT5 and TGFβ were observed. Functionally, ZA-treated Treg had reduced capacity to suppress T and NK cell proliferation and anti-tumor responses compared with untreated Treg in vitro. Treatment with ZA to selectively inhibit essential signaling pathways in Treg resulting in reduced capacity to suppress effector T and NK cell responses represents a novel approach to inhibit Treg activity in patients with cancer.

This retrospective study investigated overall survival (OS) and factors influencing OS in Swedish patients with metastatic renal cell carcinoma (mRCC) during the pre- (2002-2005), early (2006-2008), and late (2009-2012) targeted therapy (TT) era.Three national Swedish registries identified patients with mRCC. Median OS was estimated using the Kaplan-Meier method. Multivariate analysis was performed using Cox proportional hazards regression. Subgroup analysis was conducted for patients with synchronous metastases (M1) and the elderly (aged≥75y).A total of 4,217 patients with mRCC were identified, including 1,533 patients with M1 and 1,275 elderly patients. For patients with mRCC diagnosed in 2002 to 2005, 2006 to 2008, and 2009 to 2012, median OS was 10.0, 13.0, and 18.0 months. Similarly, median OS improved in the M1 and elderly populations. Elderly patients were less likely to be prescribed TT (≥75 vs.75y): 18.3 vs. 63.5% (in 2006-2008) and 28.6% vs. 55.9% (in 2009-2012). Diagnosis of mRCC in 2009 to 2012, nephrectomy and TT prescription were associated with improved OS in the total mRCC, M1, and elderly populations.This real-world study showed continued significant improvement in mRCC OS during the late TT era, including in M1 and elderly populations. TT should be considered for all patients with mRCC based on tolerability, regardless of age.

BACKGROUND: This study aimed to identify biomarkers for estimating the overall and prostate cancer (PCa)-specific survival in PCa patients at diagnosis. METHODS: To explore the importance of embryonic stem cell (ESC) gene signatures, we identified 641 ESC gene predictors (ESCGPs) using published microarray data sets. ESCGPs were selected in a stepwise manner, and were combined with reported genes. Selected genes were analyzed by multiplex quantitative polymerase chain reaction using prostate fine-needle aspiration samples taken at diagnosis from a Swedish cohort of 189 PCa patients diagnosed between 1986 and 2001. Of these patients, there was overall and PCa-specific survival data available for 97.9%, and 77.9% were primarily treated by hormone therapy only. Univariate and multivariate Cox proportional hazard ratios and Kaplan-Meier plots were used for the survival analysis, and a k-nearest neighbor (kNN) algorithm for estimating overall survival. RESULTS: An expression signature of VGLL3, IGFBP3 and F3 was shown sufficient to categorize the patients into high-, intermediate- and low-risk subtypes. The median overall survival times of the subtypes were 3.23, 4.00 and 9.85 years, respectively. The difference corresponded to hazard ratios of 5.86 (95% confidence interval (CI): 2.91-11.78, P

Five patients with non-Hodgkin's lymphoma (NHL) and 4 patients with chronic lymphocytic leukaemia (CLL) were treated with the CDR-grafted (ratXhuman) monoclonal antibody (mAb) Campath-1H (anti-CD52). Tumour regression was noted preferentially in peripheral blood and in the bone marrow but lymph nodes were less affected. Normal blood B and T cells were profoundly reduced in all patients whereas CD16 + NK cells and CD14 + monocytes decreased marginally. In all responding CLL patients CD52-negative T but not B cells appeared during treatment and persisted for several months (4-19+) during unmaintained follow-up. Clonal T cells defined as a predominance of a single T cell receptor (TCR) V gene usage, in one case verified by TCR CDR3 fragment analysis and nucleotide sequencing, emerged within the CD52 - /CD8 + cell population during Campath-1H therapy in 2 CLL patients, both achieving a long-lasting remission. The increase in CD8 + T cell expansions (up to 23-fold) during unmaintained remission and follow-up suggest that the clonal CD8+ cells may represent regulatory T cells controlling the growth of the tumour B cell clone. Clonal T cells might thus be a target for an immune therapeutic intervention in B cell tumours.

Purpose Sunitinib has demonstrated antitumor activity in metastatic renal cell carcinoma (mRCC) when given at 50 mg/d on a 4-weeks-on 2-weeks-off regimen. Herein, we report results of an open-label, multicenter phase II mRCC study of sunitinib administered on a continuous once-daily dosing regimen. Patients and Methods Eligibility criteria included histologically proven mRCC with measurable disease, failure of one prior cytokine regimen, and good performance status. Patients were randomly assigned to a sunitinib starting dose of 37.5 mg/d in the morning (AM) or evening (PM). RECIST-defined objective response rate (ORR) was the primary end point. Secondary end points included progression-free survival (PFS), overall survival (OS), adverse events (AEs), and quality-of-life measures. Results One hundred seven patients were randomly assigned to AM (n = 54) or PM (n = 53) dosing and on study for a median 8.3 months. Eighty-three patients discontinued, 65 due to disease progression and 16 because of AEs; two patients withdrew consent. Dosing was reduced to 25 mg/d in 46 patients (43%) due to grade 3/4 AEs. The most common grade 3 treatment-related AEs were asthenia/fatigue (16%), diarrhea (11%), hypertension (11%), hand-foot syndrome (9%), and anorexia (8%). ORR was 20% with a 7.2-month median response duration. Median PFS and OS were 8.2 and 19.8 months, respectively, at median follow-up of 26.4 months. Efficacy, tolerability, and quality-of-life results were similar between patients dosed in the AM or PM. Conclusion Sunitinib 37.5 mg, administered on a continuous once-daily dosing regimen, has a manageable safety profile as second-line mRCC therapy, providing flexible dosing, which can be explored in combination studies.

The driving force behind oncoproteomics is to identify protein signatures that are associated with a particular malignancy. Here, we have used a recombinant scFv antibody microarray in an attempt to classify sera derived from pancreatic adenocarcinoma patients versus healthy subjects. Based on analysis of nonfractionated, directly labeled, whole human serum proteomes we have identified a protein signature based on 19 nonredundant analytes, that discriminates between cancer patients and healthy subjects. Furthermore, a potential protein signature, consisting of 21 protein analytes, could be defined that was shown to be associated with cancer patients having a life expectancy of

The aim of this population-based study was to evaluate the impact of quality indicators on the adherence to guidelines for renal cell carcinoma (RCC).Since 2005, virtually all patients with newly diagnosed RCC in Sweden have been registered in the National Swedish Kidney Cancer Register (NSKCR). The register contains information on histopathology, nuclear grade, clinical stage, preoperative work-up, treatment, recurrence and survival. In addition, a number of quality indicators have been measured in the register aiming to increase the quality of care. The quality indicators are: the coverage of the register, histology reports, preoperative chest computed tomography (CT), partial nephrectomy, laparoscopic surgery, centralization to high-volume hospitals and waiting times.A total of 8556 patients with diagnosed RCC were registered from 2005 to 2013 (99% coverage). In 2013, 99% of the histopathology reports were standardized. The number of patients with preoperatively chest CT increased from 59% in 2005 to 89% in 2013. The proportion of patients with RCC T1aN0M0 who underwent partial nephrectomy increased from 22% in 2005 to 56% in 2013. Similarly, laparoscopic radical nephrectomies increased from 6% in 2005 to 24% in 2013. The median tumour size at detection decreased from 60 mm in 2005 to 55 mm in 2013. The proportion of patients who were incidentally detected increased from 43% in 2005 to 55% in 2013.The data show an improved adherence to the guidelines for RCC as measured by quality indicators and a steady process of earlier detection of patients with RCC.

Methodology. Since the start in 2005 virtually all patients with newly diagnosed renal cell carcinoma (RCC) in Sweden are reported to the National Swedish Kidney Cancer Register (NSKCR). The register contains information on histopathology, nuclear grade, clinical stage, preoperative work-up, treatment, recurrence, and survival.Results. A total of 8556 patients with newly diagnosed RCC were registered in the NSKCR from 2005 to 2013 resulting in a coverage of 99% as compared to the Swedish Cancer Registry. The mean tumor size at detection decreased from 70 mm in 2005 to 64 mm in 2010. The proportion of patients who were incidentally detected increased. The proportion of patients with tumor stage T1a who underwent partial nephrectomy increased from 22% in 2005 to 56% in 2012. Similarly, the proportion of laparoscopically performed radical nephrectomies increased from 6% in 2005 to 17% in 2010. During the five years of follow-up 20% of the patients had a recurrence.Conclusion. Over the last decade there has been a trend of earlier detection and less advanced tumors at detection in patients with RCC. An increasing proportion of the patients undergo laparoscopic and nephron-sparing procedures.

The potential overexpression of HER2 in prostate cancer cells has attended significant interest during the past few years, both as potential target for HER2 pathway focused therapy and as a mechanism involved in the progression to androgen independence. Conflicting results have been reported concerning HER2 status on clinical material, differences which generally have been attributed to methodological differences. Nevertheless, HER2 has been utilized for targeted therapy of prostate cancer in a number of preclinical studies and is still regarded as an exciting target molecule. In this study, the HER2 status of three widely used prostate cancer cell lines and corresponding xenografts has been analysed. By use of validated and FDA approved analytical staining techniques none of these cell lines or xenografts were shown to overexpress/amplify HER2, as demonstrated by immunohistochemistry and fluorescence in situ hybridization. These findings are important for the interpretation and understanding of the therapeutic effects when developing drugs targeting HER2 in prostate cancer cell lines and also emphasize the importance of using broad and validated analytical techniques.

Once bone metastasized and androgen independent, prostate cancer is often associated with skeletal morbidity and disability. New treatment modalities that can palliate symptoms from the skeleton and inhibit further progression are warranted. In this study, the antitumoral effects following treatment with a combination of docetaxel and the new generation bisphosphonate, zoledronic acid, were investigated on two hormone-refractory prostate cancer cell lines: PC3 and DU145. The prostate cancer cells were treated with increasing concentrations of zoledronic acid in the absence or presence of docetaxel. Toxicity was measured using fluorometric microculture cytotoxic assay technique. A concentration of 25 microM, zoledronic acid reduced the viable cell number to 68% and 98% for PC3 and DU145 cells respectively. Docetaxel, on the other hand, at a concentration of 0.1 ng/ml, had no effect on the viability. However, a combination of zoledronic acid and docetaxel reduced the cell number to 60% and 81% respectively. Furthermore, zoledronic acid in the concentration range 12.5 microM-50 microM enhanced the antitumoral effects of docetaxel (0.01-1 ng/ml) in an additive and/or synergistic manner for both cell lines. These data support the hypothesis that zoledronic acid, in addition to having bone resorption inhibiting properties, also exhibits anti-tumoral effects. It also appears that combined treatment with docetaxel causes additive and/or synergistic cytostatic effects on prostate cancer cells.

The idiotypic structures of the myeloma protein might be regarded as tumor-specific antigens. The present study was designed to map T-cell epitopes of the idiotypic myeloma protein to prove the existence of naturally occurring major-histocompatibility-complex-dependent idiotype (peptide)-specific T cells in multiple myeloma. The fine specificity of idiotype-reactive, interferon-γ-producing blood T cells of a patient with multiple myeloma stage I was characterized by identification of idiotype (heavy and light chains)-derived MHC-restricted T-cell epitopes. T cells specifically reacting with peptides corresponding to each of the 3 complementarity-determining regions (CDRs) of the heavy-chain variable part (VH) of the autologous idiotype were found. In contrast, none of the peptides corresponding to the 3 CDRs of the light chain (VL) induced a specific T-cell response. The idiotype amino-acid sequence corresponding to the junction of the VH, diversity (D), and joining (J) gene segments of the VH appeared to be an important target for T cells, since the sequence expressed MHC-class-I- as well as MHC-class-II-restricted epitopes. The study provides further support for the existence of MHC-restricted idiotype-specific T cells, which may target immunogenic CDR peptides in multiple myeloma. Such T cells could be an important part of the specific anti-tumor immune responses induced in idiotype vaccination protocols. Int. J. Cancer 80:671–680, 1999. © 1999 Wiley-Liss, Inc.

Pazopanib and sunitinib provided a progression-free survival benefit, as compared with placebo or interferon, in previous phase 3 studies involving patients with metastatic renal-cell carcinoma. This phase 3, randomized trial compared the efficacy and safety of pazopanib and sunitinib as first-line therapy.We randomly assigned 1110 patients with clear-cell, metastatic renal-cell carcinoma, in a 1:1 ratio, to receive a continuous dose of pazopanib (800 mg once daily; 557 patients) or sunitinib in 6-week cycles (50 mg once daily for 4 weeks, followed by 2 weeks without treatment; 553 patients). The primary end point was progression-free survival as assessed by independent review, and the study was powered to show the noninferiority of pazopanib versus sunitinib. Secondary end points included overall survival, safety, and quality of life.Pazopanib was noninferior to sunitinib with respect to progression-free survival (hazard ratio for progression of disease or death from any cause, 1.05; 95% confidence interval [CI], 0.90 to 1.22), meeting the predefined noninferiority margin (upper bound of the 95% confidence interval,1.25). Overall survival was similar (hazard ratio for death with pazopanib, 0.91; 95% CI, 0.76 to 1.08). Patients treated with sunitinib, as compared with those treated with pazopanib, had a higher incidence of fatigue (63% vs. 55%), the hand-foot syndrome (50% vs. 29%), and thrombocytopenia (78% vs. 41%); patients treated with pazopanib had a higher incidence of increased levels of alanine aminotransferase (60%, vs. 43% with sunitinib). The mean change from baseline in 11 of 14 health-related quality-of-life domains, particularly those related to fatigue or soreness in the mouth, throat, hands, or feet, during the first 6 months of treatment favored pazopanib (P0.05 for all 11 comparisons).Pazopanib and sunitinib have similar efficacy, but the safety and quality-of-life profiles favor pazopanib. (Funded by GlaxoSmithKline Pharmaceuticals; COMPARZ ClinicalTrials.gov number, NCT00720941.).

Background : Studies in experimental models have implied perivascular cells (PC) as regulators of multiple aspects of tumor biology, including tumor growth, metastasis, immune cell activity and response to treatment. However, the extent of inter- and intra-case variability of perivascular cells in clinical samples, and potential of perivascular cells as biomarkers, remain poorly characterized. Methods: We have developed an integrated analytical pipeline to investigate vascular and PC status in clinical samples. The analytical procedure uses double-staining with one endothelial cell marker (CD34) and one of four PC markers; platelet-derived growth factor receptor-alpha and -beta (PDGFR-α, PDGFR-β;), smooth muscle α actin (ASMA) and desmin. Digital image-analyses are subsequently used to quantitate PC-related metrics including intensity of marker expression in perivascular areas, and fraction of marker-covered vessels. The approach has been applied to multiple cohorts of clinically well-annotated tumor collections from three cancer types; colorectal cancer (CRC), ovarian cancer (OC) and renal cell cancer (RCC). Results: Analyses of PC status uncovered previously un- recognized independent and heterogeneous expression of the analyzed perivascular markers on different levels (perivascular cells, vessels and tumors). Notably, expression of perivascular markers was largely independent of vessel size and density in all three cancer types. Comparative analyses across tumor types identified differences including e.g. higher abundance of PDGFR-β; positive perivascular cells in CRC. A comparison of perivascular status in matched primary tumors and distant metastases uncovered a large degree of dis-concordance of most vascular characteristics except perivascular PDGFR-β; (CRC and OC cohorts). Importantly, this finding implies that vascular status in metastases cannot, in general, be predicted by analyses of primary tumors. Efforts to uncover the basis for inter-case variations in PC status of CRC revealed strong associations between tumor PDGFR-β; PC status and both PC status in adjacent normal tissue and BRAF status, but not RAS mutations. These findings suggest both host features and cancer mutations as determinants of PC characteristics. Concerning relationships between PC features and survival, we observed significant associations between high perivascular PDGFR-β; status and shorter survival in OC and RCC. These associations remain significant in multivariate analyses including standard clinicopathological characteristics. Impact on response to chemotherapy (CT) treatment was analyzed in both early stage and metastatic CRC. Ongoing analyses indicate that low perivascular PDGFR-βdefines a sub-group with shorter survival in the CT-treated group. Explorative analyses of a small set of bevacizumab-treated metastatic CRC also demonstrated significantly shorter progression free survival in the subset with low perivascular PDGFR-β expression. Conclusion: Digital-image-analyses-supported quantifications of PC features in three different tumor types have revealed heterogeneous expression of PC markers in a manner independent of vessel density and vessel size. Host characteristics and oncogenic status have been identified as candidate determinants of perivascular PDGFR-β; status in CRC. Notably, perivascular PDGFR-β; was identified as a novel independent predictor of survival in OC, RCC and CRC. Treatment-stratified analyses in CRC also implied perivascular PDGFR-β; as a determinant of benefit of chemotherapy and VEGF-directed anti-angiogenic drugs. Citation Format: Sara corvigno, artur mezheyeuski, Magnus Frodin, Maja Bradic Lindh, Tormod Kyrre Guren, Per Pfeiffer, H. Elin Kure, Tone Ikdahl, Eva Skovlund, Kjell Magne Tveit, Kristian Pietras, Anna Portyanko, Ina Hrynchyk, David Edler, Anca Dragomir, friedrik Ponten, Jan Mulder, Camilla Qvortrup, Maria Hallström, Katarina Öhrling, G. Bea A. Wisman, Elisabeth Åvall-Lundqvist, Martin Johansson, Ulrika Harmenberg, Hans Nijman, Per Sandström, Hanna Dahlstrand, Halfdan Sorbye, Bengt Gimelius, Ate Van Der Zee, Lars Egevad, Arne Östman. Marker-defined perivascular cells predict prognosis and response to treatment. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr C38.

4509Background: Immunotherapy response patterns differ from traditional therapies, and pts may benefit from treatment after initial RECIST progression (CCR 2009;15:7412–20). We investigated pts tre...

535 Background: Non-clear cell renal cell carcinoma (nccRCC) constitute about 10-15% of all metastatic renal cell carcinoma (mRCC) and typically include papillary, chromophobe and collecting duct histologies. Despite differences in clinical behavior between subtypes they are often grouped as one due to small patient numbers. Hence, there is a lack of knowledge on type-specific prognosis and treatment options. Methods: Patients diagnosed with metastatic nncRRC (56 out of 526 patients; 10.8%) during the years 2005-2013 were retrospectively identified using data from medical records at two large academic centers in Sweden. The characteristics and outcome of those with papillary subtype (n = 44; 79% of nccRCC) was analyzed. Results: Metastatic papillary RCC patients were more often male (82%), had a median age of 69 years and 48% had M1 disease. 9% were type I, 41% type II, 4% mixed and 41% papillary NOS. 89% had a nephrectomy and 56% received at least one line of systemic therapy. The median overall survival (OS) of all papillary patients was 10.1 months. Factors associated with OS included performance status (PS; OS 25.8 months for ECOG PS 0-1 patients vs OS 3.1 months for ECOG PS > 1 patients, p = 0.00002), and systemic therapy (OS 23.4 months vs 3.8 months for patients not treated systemically, p = 0.002). Systemic therapies (ST) included VEGF targeting agents (88%), mTOR inhibitors (50%), or interferon (21%) for all lines. The most common first line ST was VEGF targeting agents (75%). 42% received one line, 33% two lines, and 25% three or more lines of ST. Characteristics of patients treated with ST included lower age at diagnosis, higher proportion of M1 disease and better PS. The reasons for not giving systemic treatment were primarily poor performance status or comorbidities. ECOG PS > 1 (p = 0.04) and poor MSKCC risk group (p = 0.02) were predictive of OS among patients treated with ST. Conclusions: Patients with metastatic papillary RCC and good performance status (ECOG PS 0-1) seem to benefit from systemic therapy using drugs primarily evaluated for clear cell RCC. However, patients not eligible for systemic therapy due to poor performance status or other reasons have a dismal prognosis.

The aim of this study was to investigate the role of 70 Gy salvage radiotherapy (SRT) combined with short-term neoadjuvant hormonal therapy (NHT) in the treatment of recurrent disease after radical prostatectomy (RP), and to consider quality of life (QoL), survival outcomes and impact of co-morbidities on treatment-related rectal-genitourinary toxicity. Electronic records of 184 SRT patients treated consecutively between October 2001 and February 2007 were analyzed. Median age was 64 years (median follow-up 48 months). NHT was given to 165 patients (median 3 months). Pre-RP and pre-SRT PSA, PSA doubling time, Gleason score (GS), seminal vesicle invasion (SVI) and detectable post-SRT PSA were recorded. Any detectable PSA or PSA0.1 ng/ml + nadir was considered biochemical failure (BcF). The Charlson co-morbidity index was used to correlate co-morbidities and rectal-genitourinary toxicity. Scores from the health-related QoL EORTC QLQ-C30 and PR-25 questionnaires were also evaluated. In 116 (63%) patients, a long-lasting curative effect was indicated by undetectable PSA levels. In univariate analysis, using BcF as an outcome variable, p0.001 was found for GS, pre-SRT PSA, SVI and detectable post-SRT PSA. Multivariate analysis showed p=0.01 for SVI, p=0.09 for GS, and detectable post-SRT PSA (p=0.01); with metastases as an outcome variable, only SVI was significant (p=0.007). Cancer-specific and overall survival were 99 and 95%, respectively. Although microscopy showed SVI or GS 8-10 in the prostatectomy specimens 17/40 (43%) and 13/29 (45%), respectively, of patients still showed undetectable PSA at long-term follow-up (median 55 months) after SRT. Likewise, 11/31 (36%) patients with pre-SRT PSA1.0 ng/ml and 80/134 (60%) patients with PSA doubling time (PSADT)10 still showed undetectable PSA after 50 months. Slightly elevated acute and late rectal-genitourinary grade 3-4 toxicity was observed. No association with co-morbidity/toxicity was found. EORTC QLQ-C30 scores were similar to or slightly better than reference values. SRT with 70 Gy combined with 3-month NHT results in long-term undetectable PSA in50% of patients with recurrence after RP with acceptable rectal-genitourinary toxicity and without negatively affecting long-term QoL. Non-metastatic patients should not be disqualified from receiving SRT although presenting with poor prognostic factors at surgery.

• To assess the economic value of targeted therapies as first-line metastatic renal cell carcinoma (mRCC) treatment in the US and Sweden by indirect comparison of survival data.• A Markov model simulated disease progression, adverse events and survival with sunitinib vs sorafenib in the US and bevacizumab plus interferon-α (IFN-α) in both countries. • Results, in life-years (LYs), progression-free LYs (PFLYs), quality-adjusted LYs (QALYs) gained and treatment costs (2008 USD) were obtained through deterministic and probabilistic analyses over the patient's lifetime.• Sunitinib was more effective and less costly than sorafenib (gains of 0.52 PFLYs, 0.16 LYs and 0.17 QALYs and savings/patient of $13,576 in the US) and bevacizumab plus IFN-α (gains of 0.19 PFLYs, 0.23 LYs and 0.16 QALYs in both countries and savings/patient of $67,798 and $47,264 in the US and Sweden, respectively). • Results were most influenced by hazard ratios for progression-free and overall survival and treatment costs, making results generalizable across other countries if relative costs were to fall within the ranges of those in the US and Sweden.• The present analyses suggest that first-line mRCC treatment with sunitinib is a cost-effective alternative to sorafenib and bevacizumab plus IFN-α.

Study Type – Therapy (economic) Level of Evidence 2b What’s known on the subject? and What does the study add? Cost-effectiveness of new targeted molecular therapies in patients with mRCC have been examined compared to interferon-α. This study compares cost-effectiveness of three new targeted therapies in mRCC head-to-head based on indirect comparison of clinical efficacy. The study shows that sunitinib is a cost-effective therapy in first line treatment for patients with mRCC in the USA and Sweden compared to sorafenib and bevacizumab+interferon-α. OBJECTIVE • To assess the economic value of targeted therapies as first-line metastatic renal cell carcinoma (mRCC) treatment in the US and Sweden by indirect comparison of survival data. METHODS • A Markov model simulated disease progression, adverse events and survival with sunitinib vs sorafenib in the US and bevacizumab plus interferon-α (IFN-α) in both countries. • Results, in life-years (LYs), progression-free LYs (PFLYs), quality-adjusted LYs (QALYs) gained and treatment costs (2008 USD) were obtained through deterministic and probabilistic analyses over the patient’s lifetime. RESULTS • Sunitinib was more effective and less costly than sorafenib (gains of 0.52 PFLYs, 0.16 LYs and 0.17 QALYs and savings/patient of $13 576 in the US) and bevacizumab plus IFN-α (gains of 0.19 PFLYs, 0.23 LYs and 0.16 QALYs in both countries and savings/patient of $67 798 and $47 264 in the US and Sweden, respectively). • Results were most influenced by hazard ratios for progression-free and overall survival and treatment costs, making results generalizable across other countries if relative costs were to fall within the ranges of those in the US and Sweden. CONCLUSION • The present analyses suggest that first-line mRCC treatment with sunitinib is a cost-effective alternative to sorafenib and bevacizumab plus IFN-α.

(1991). Tumour Markers in Gastrointestinal Cancer. Scandinavian Journal of Clinical and Laboratory Investigation: Vol. 51, No. sup206, pp. 21-27.

413 Background: The RENal COMParison (RENCOMP) study showed a significant improvement in OS for Swedish patients diagnosed with renal cell carcinoma (RCC) and metastatic (m)RCC in the first years following the introduction of targeted agents (TAs) in 2006 (Br J Cancer 2013;108:1541). Here we investigated whether a further improvement in OS can be detected in the more recent years of the TA era. Methods: Using data from the Swedish Cancer Register (diagnosis and death records), National Patient Register (in-/out-patient visit records), and Swedish Prescribed Drug Register (prescribed/dispensed drug records), we assessed OS in RCC and mRCC patients diagnosed during two periods after (2009–2012 and 2006–2008) and one period before (2000–2005 [RCC]; 2002–2005 [mRCC]) the introduction of TAs, and factors influencing OS in mRCC. Multivariate analysis was performed using a Cox proportional hazards model, including estimates of adjusted HR. The regression model included the covariates age, gender, geographical region, institution size, nephrectomy status, diagnosis period, and TA prescription. Results: In total, 3,980, 2,956, and 5,225 RCC patients were identified from 2009–2012, 2006–2008, and 2000–2005, respectively. From 2002–2012, 4,217 patients met the criteria for mRCC diagnosis. RCC patients diagnosed 2009–2012 and 2006–2008 had a significant improvement in OS compared with patients diagnosed 2000–2005 (median OS: not reached and 86 vs. 48 months, respectively; both P

23 Background: Bi-weekly docetaxel (T) with prednisone improved progression free survival and overall survival when compared with the standard tri-weekly T as first-line treatment for advanced castration resistant prostate cancer (CRPC) (Lancet Oncol. 2013;14:117-124). We report here the quality of life (QoL) results of this prospective randomized trial. Methods: Three hundred and forty-six patients were randomly allocated centrally to receive intravenous therapy T of either 75 mg/m² d1 q3 wks (the triweekly arm) or 50 mg/m² d1 and d 14, q4 wks (the biweekly arm) (identifier NCT00255606). Prednisone (10 mg/d) was administered orally in both groups. The baseline patients characteristics were well balanced between the groups with respect to the performance status, mean age (69, range 45 to 87 vs. 68, range 46 to 85), and median serum prostate-specific antigen (PSA) content (109 µg/L, range 11 to 1,230 vs. 116 µg/L, range 12 to 1,870). Quality of life (QoL), the frequency and severity of symptoms including pain were assessed using the Functional Assessment of Cancer Therapy-Prostate (FACT-P) version 4.0 questionnaire. Results: The baseline (QoL) of both treatment groups was compared to QoL after six months of the treatment within each treatment group and between groups. Changes in fatigue, symptoms of pain and nausea, and the overall performance status did not differ between the groups. There were statistically significant differences in overall quality of life values (p=0.010) and discomforting pain values (p=0.028) favoring the bi-weekly treatment arm. Conclusions: Bi-weekly T is better tolerated than the tri-weekly standard T. Following the results from the clinical outcome and the QoL outcome in the PROSTY trial we would recommend the use of bi-weekly docetaxel as first line treatment of CRPC Clinical trial information: NCT00255606.

The tumour-associated antigen (TAA) GA733-2 is overexpressed by90% of human colorectal carcinomas (CRC). The antigen has previously been shown to be recognised by B and T cells. The aim of the present study was to define B cell epitopes of GA733-2. Fifteen percent of CRC patients with no previous immunotherapy have recently been shown to elicit an anti-GA733-2 IgG antibody response. Sera of these patients ( n=136) were analysed by enzyme-linked immunosorbent assay (ELISA) for immunoglobulin G (IgG) antibodies against 23 partly overlapping synthetic peptides (18 amino acids: aa) derived from the extracellular domain of GA733-2. An 18-aa long sequence at the N-terminal region of the antigen (peptide 2) was found to be an immunodominant B cell epitope. Fifty percent of the patients had antibodies against peptide 2, while 8% to 9% had antibodies against peptides 1, 4, 7, 8 or 20. In healthy donors ( n=30) antibodies against peptides 2 and 8 were also detected in 13% and 3% of cases respectively, while no antibodies were found against the other peptides and the complete protein. Thirteen percent of CRC patients ( n=30) with no IgG antibodies against the GA733-2 antigen elicited antibodies against peptide 2. The specificity of peptide-reactive sera was verified by inhibition ELISA. The binding of sera to GA733-2 was significantly inhibited by peptides to which CRC sera bound, but not by control peptides. Binding to peptide 2 of sera showing both peptide 2 and GA733-2 reactivity was specifically inhibited by the complete GA733-2 antigen, while binding of peptide 2-reactive sera showing no GA733-2 reactivity was not inhibited. CRC sera interfered with the binding of monoclonal antibody (mAb) 17-1A and mAb C215 that recognise distinct epitopes of GA733-2. No significant correlation was found between the presence of anti-peptide antibodies in CRC patients and clinical stage or overall survival. The results provide additional evidence for immune recognition of CRC by the host.

The tumour-associated antigen (TAA) GA733-2 is expressed as a non-secreted surface molecule on the majority of human colorectal carcinoma cells. The antigen has been used as a target for passive and active immunotherapy during the last decade. To determine the incidence of autoantibodies against this antigen, sera from 1068 patients with colorectal carcinoma were analysed for naturally occurring IgG antibodies against the baculovirus-produced GA733-2E protein. A total of 14.5% of the patients had IgG antibodies against the antigen. In 519 patients, sera were collected at the time of diagnosis and 15% of those patients had anti-GA733-2E IgG antibodies. There was a tendency to a higher frequency of patients with antibodies among those in the advanced Dukes stages: 11% in stage A and 32% in stage D respectively (P = 0.06). Antibodies could be detected for up to 10 years after the diagnosis. Patients with Crohn's disease or colitis ulcerosa (n = 20) did not elicit anti-GA733-2E antibodies. No healthy control donor (n = 45) had detectable antibodies against the antigen. The specificity of GA733-2E-reactive serum IgG was indicated by significant inhibition of mAb17-1A (originally used to define GA733-2) binding to the GA733-2E antigen. Sera of positive patients bound to the GA733-2-expressing human colorectal carcinoma cell line, SW948. No significant correlation was found between the presence of antibodies and survival in the present patient population. However, the high incidence of autoantibodies against this tumour antigen in colorectal carcinoma patients confirms its antigenicity in humans and supports the use of the GA733-2 antigen as a target for immunotherapy.

51 Background: For prostate cancer patients, prostate cancer specific and non-prostate cancer specific survival have the same importance. This study aimed at identifying expression biomarkers that can predict prostate cancer specific, non-prostate cancer specific and overall survival at diagnosis. Methods: Selected ESCGPs (embryonic stem cell gene predictors) and control genes were analyzed by multiplex quantitative PCR using prostate fine-needle aspiration samples taken at diagnosis from a Swedish cohort of 189 prostate cancer patients diagnosed between 1986 and 2000. Of all patients, 97.9% had overall and cancer-specific survival data and 77.9% were primarily treated only by hormone therapy. The cohort was divided into one discovery and two validation subsets. Univariate and multivariate Cox proportional hazard ratios and Kaplan-Meier plots were used for the survival analysis. A published dataset was used for external validation. Results: An expression signature of F3, VGLL3 and IGFBP3, was sufficient to categorize the patients into high-risk, intermediate-risk and low-risk subtypes. The median overall survival of the subtypes was 3.23, 4.00 and 9.85 years respectively. The difference corresponded to HRs of 5.86 (95% CI 2.91-11.78, P

Survival and costs in metastatic renal cell carcinoma : A comparison of mrcc treatment pre- and post tyrosine kinase inhibitor (tki) introduction using retrospective registry data

Overall survival (OS) in metastatic renal cell carcinoma (MRCC) : a comparison between sorafenib (SO) and best supportive care (BSC)after first line treatment with sunitinib (SU) inSweden

Background Pazopanib and sunitinib are oral multi-kinase angiogenesis inhibitors that have shown progression-free survival (PFS) benefit for mRCC patients in clinical trials (NEJM 2007;356:115; JCO 2009;29:475). The COMPARZ study (NCT00720941) was designed to provide a direct comparison of efficacy, safety, and tolerability of pazopanib and sunitinib. Pazopanib N = 557 Sunitinib N = 553 Hazard Ratio 95% CI PFS (IRC, primary) Median (mo) 8.4 9.5 1.0466 0.8982, 1.2195 PFS (investigator) Median (mo) 10.5 10.2 0.998 0.863, 1.154 OS Median (mo) 28.4 29.3 0.91 0.76, 1.08 ORR (IRC) P = 0.03 31% 25% – – Most common AEs (≥40%) Any Grade, % N = 554 N = 548 Risk Ratio 95% CI Diarrhea 63 57 1.09 0.99, 1.20 Fatigue 55 63 0.87 0.79, 0.96 Hypertension 46 41 1.14 1.00, 1.31 Nausea 45 46 0.98 0.86, 1.11 Hand-foot syndrome 29 50 0.59 0.50, 0.68 Other selected class effect AEs Dysgeusia 26 36 0.71 0.60, 0.86 Dyspepsia 14 24 0.58 0.45, 0.75 Hypothyroidism 12 24 0.50 0.38, 0.65 Mucositis 11 26 0.43 0.33, 0.56 ALT increase 31 18 1.74 1.40, 2.17 AST increase 27 18 1.49 1.19, 1.87 Neutropenia 11 27 0.41 0.31, 0.54 Thrombocytopenia 10 34 0.30 0.23, 0.40 Anemia 7 19 0.36 0.26, 0.52 Methods A total of 1110 treatment-naive patients with clear cell mRCC and measurable disease were randomized 1:1 to pazopanib 800 mg QD continuous dosing or sunitinib 50 mg QD in 6-week cycles (4 weeks on followed by 2 weeks off). Primary endpoint was PFS. Based on a planned 631 PFS events by independent review committee (IRC) the study had 80% power to detect non-inferiority of pazopanib to sunitinib where the non-inferiority margin was chosen to exclude a difference of >25% in the hazards. Key secondary endpoints included overall survival (OS), overall response rate (ORR), adverse events (AEs), and quality of life (QoL). Results Patient characteristics were balanced. The upper bound of the 95% CI for PFS by IRC was Conclusions Pazopanib has similar efficacy to sunitinib with a differentiated safety and QoL profile. Disclosure R.J. Motzer: Research Funding : GlaxoSmithKline >10,000 US dollars Research Funding: Pfizer \\\" Paid Consultancy: Pfizer T.E. Hutson: Stock ownership: None Membership on an advisory board or board of directors: Pfizer, Bayer, Aveo, Novartis Corporate-sponsored research: Glaxo SK, Pfizer, Aveo, Novartis Other substantive relationships: None M. Staehler: Stock ownership: None Membership on an advisory board or board of directors: advisory board GSK, Pfizer Corporate-sponsored research: GSK, Pfizer Other substantive relationships: None U. Harmenberg: Stock ownership: No Membership on an advisory board or board of directors: /advisory fees from GlaxoSmithKline, Pfizer, Bayer and Novartis. Corporate-sponsored research: No Other substantive relationships: No K. Fife: Stock ownership: none Membership on an advisory board or board of directors: GSK Corporate-sponsored research: GSK, Roche Other substantive relationships: I received financial assistance to attend 2 conferences in 2011 from Bayer and GSK. R. Hawkins: Stock ownership: Wife owns stock in GSK R. Jones: Membership on an advisory board: Past membership with GSK and Pfizer Corporate-sponsored research: GSK and Pfizer. Received funding to participate in commercially sponsored research by both companies, including, but not-limited to, the COMPARZ trial. P. Nathan: Membership on an advisory board or board of directors: GSK Advisory Board J. Merchan: Corporate-sponsored research: GSK, Pfizer, BMS (research –clinical trial- support) P. De Souza: Membership on an advisory board or board of directors: GSK Australia D. Cella: Stock ownership: No, Membership on an advisory board or board of directors: No, Corporate-sponsored research: Yes: Pfizer, Aveo, DSI, GSK, Novartis, Abbott, Other substantive relationships: Consultant: GSK L. McCann: Stock ownership: Yes Membership on an advisory board or board of directors: None Corporate-sponsored research: None Other substantive relationships: GSK employee K. Deen: Stock ownership: Yes Membership on an advisory board or board of directors: None Corporate-sponsored research: None Other substantive relationships: GSK employee T. Choueri: Stock ownership: None Membership on an advisory board or board of directors: Advisory board: Pfizer, GSK, Novartis, Genentech, Aveo, Bayer/Onyx Corporate-sponsored research: Pfizer Other substantive relationships: none–no speaker's bureau. All other authors have declared no conflicts of interest.

Background At the ASCO annual meeting 2012, we have presented the identification of an embryonic stem cell gene predictor (ESCGP) signature in a cohort of 189 patients with 7-21 years complete survival follow up. The expression signature is composed of F3, IGFBP3 and VGLL3 and can significantly improve the accuracy of survival prediction at the time of diagnosis. We further hypothesize that measuring stem cell gene expression signature in prostate cancer biopsy samples taken at the time of diagnosis can predict the survival benefit of hormone therapy. Methods In the previous cohort, 139 of the 189 patients were primarily treated by hormone therapy. Of these 139 patients 65 had data of the ESCGP signature. Kaplan-Meier plots were used in the survival analysis of this subset of patients. Results Of the 65 patients, 22 were classified as having high risk, 25 as having intermediate risk and 18 as having low risk subtype cancers. The obvious overall and cancer specific survival difference between the three subtypes was still maintained (Kaplan-Meier survival curve, p Conclusions The expression signature of F3, IGFBP3 and VGLL3 can be accurately measured in prostate fine needle aspiration samples. If the finding is further validated in a large and independent cohort, the ESCGP expression signature can be used to predict the survival benefit of primary hormone treatment for patients with newly diagnosed prostate cancer. Disclosure C. Li: Chunde Li is the major stock holder of Chundesell Medcals AB. All other authors have declared no conflicts of interest.

Background Tumor EGFR and KRas mutations are both predictive and prognostic biomarkers in patients with advanced NSCLC. We analyzed the correlation between these biomarkers and treatment outcomes in a phase III trial of 3rd/4th line sorafenib in patients with NSCLC. Methods The global, randomized, placebo-controlled MISSION trial enrolled 703 patients with advanced relapsed/refractory NSCLC of predominantly non-squamous histology. The primary study endpoint was overall survival (OS). EGFR and KRas mutations were analyzed in archival tumor samples and in circulating tumor DNA isolated from plasma. Results Tumor and/or plasma mutation data were available from 347 patients (49%). EGFR and KRas mutations were detected in 89 (26%) and 68 (20%) patients, respectively, and were well balanced between treatment arms. Analysis of the interaction between EGFR mutation status and treatment effect on survival suggested that patients with EGFR mutations (mEGFR) benefitted from sorafenib, while those with wild-type EGFR (wtEGFR) did not (p = 0.023). Median OS was two-fold longer in mEGFR patients receiving sorafenib versus placebo (423 vs 197 days, HR 0.48, p = 0.002). There was no significant difference in OS between patients with wtEGFR receiving sorafenib or placebo (253 vs 256 days, HR 0.92, p = 0.559). An interaction was also seen between EGFR mutation status and the sorafenib effect on PFS (p = 0.015). Patients with mEGFR treated with sorafenib had better outcomes compared to placebo based on Cox regression analysis (HR 0.27, p Conclusion Post-hoc analyses of efficacy outcomes in MISSION suggest that advanced NSCLC patients with EGFR mutations may derive a survival benefit from receiving 3rd/4th line sorafenib. These results must be interpreted with caution due to the small, non-representative nature of the genetic biomarker subpopulation analyzed in this trial. Further prospective investigation may be warranted. Disclosure T.S.K. Mok: Honoraria: AstraZeneca, Roche, Eli Lilly, Merck Serono, Eisai, BMS, BeiGene, AVEO, Pfizer, Taiho, Boehringer Ingelheim, and GSK Biologicals Speaker: Astrazeneca, Roche, Eli Lilly, Boehringer Ingelheim, and Merck Serono Research funding: Astrazeneca. L. Paz-Ares: Dr. Paz-Ares has received honoraria from Bayer HealthCare Pharmaceuticals, Lilly, Roche and Pfizer. Y. Wu: Dr. Wu has received lecture fees from Roche, AstraZeneca, Eli Lilly, and Pfizer. V. Hirsh: Member of the steering committee for the MISSION trial. C. Lathia: Dr. Lathia is an employee of Bayer HealthCare. T.J. Ong: Dr. Ong is an employee of, and owns shares in, Bayer HealthCare. C. Pena: Dr. Pena is an employee of Bayer HealthCare. All other authors have declared no conflicts of interest.

4561 Background: Current clinical parameters are not accurate in the prediction of overall survival of prostate cancer patients. Methods: Driven by cancer stem cell hypothesis and by using a simple bioinformatics analysis, we identified 641 genes with either consistently high or low level of expression in human embryonic stem cells. We showed that these 641 genes had strong power to classify cancers into different biological subtypes and named them as embryonic stem cell gene predictors (ESCGPs). Nineteen selected ESCGPs and five control genes were analyzed by multiplex quantitative PCR in prostate fine needle aspiration (FNA) samples taken at diagnosis. The cohort included 189 patients diagnosed during 1986-2001. Of these patients, 97.9% had overall and cancer specific survival data and 77.9% were treated by medical or surgical castration as the primary treatment. The cohort was divided into a discovery and two validation subsets. The univariate and multivariate Cox proportional hazards and Kaplan-Meier plots were used in the survival analysis. A published dataset was used for an external validation. Results: Ten gene markers F3, WNT5B, VGLL3, CTGF, IGFBP3, c-MAF-a, c-MAF-b, AMACR, MUC1 and EZH2, showed a significant correlation to overall or cancer specific survival. Four of these genes, F3, IGFBP3, CTGF and AMACR, were independent of all clinical parameters. An expression signature of F3, VGLL3 and IGFBP3 characterized patients into three subtypes. The median overall survival was 2.60 years in the high risk, 3.85 years in the intermediate risk and 7.98 years in the low risk subtype, corresponding to a HR of 5.86 (95% CI 2.91-11.78, p