Promoter hypermethylation of HS3ST2, SEPTIN9 and SLIT2 combined with FGFR3 mutations as a sensitive/specific urinary assay for diagnosis and surveillance in patients with low or high-risk non-muscle-invasive bladder cancer

International audienceBackgroundNon-muscle-invasive bladder cancer (NMIBC) is a high incidence form of bladder cancer (BCa), where genetic and epigenetic alterations occur frequently. We assessed the performance of associating a FGFR3 mutation assay and a DNA methylation analysis to improve bladder cancer detection and to predict disease recurrence of NMIBC patients.MethodsWe used allele specific PCR to determine the FGFR3 mutation status for R248C, S249C, G372C, and Y375C. We preselected 18 candidate genes reported in the literature as being hypermethylated in cancer and measured their methylation levels by quantitative multiplex-methylation specific PCR. We selected HS3ST2, SLIT2 and SEPTIN9 as the most discriminative between control and NMIBC patients and we assayed these markers on urine DNA from a diagnostic study consisting of 167 NMIBC and 105 controls and a follow-up study consisting of 158 NMIBC at diagnosis time’s and 425 at follow-up time. ROC analysis was performed to evaluate the diagnostic accuracy of each assay alone and in combination.ResultsFor Diagnosis: Using a logistic regression analysis with a model consisting of the 3 markers’ methylation values, FGFR3 status, age and known smoker status at the diagnosis time we obtained sensitivity/specificity of 97.6 %/84.8 % and an optimism-corrected AUC of 0.96. With an estimated BCa prevalence of 12.1 % in a hematuria cohort, this corresponds to a negative predictive value (NPV) of 99.6 %. For Follow-up: Using a logistic regression with FGFR3 mutation and the CMI at two time points (beginning of the follow-up and current time point), we got sensitivity/specificity/NPV of 90.3 %/65.1 %/97.0 % and a corrected AUC of 0.84. We also tested a thresholding algorithm with FGFR3 mutation and the two time points as described above, obtaining sensitivity/specificity/NPV values of, respectively, 94.5 %/75.9 %/98.5 % and an AUC of 0.82.ConclusionsWe showed that combined analysis of FGFR3 mutation and DNA methylation markers on urine can be a useful strategy in diagnosis, surveillance and for risk stratification of patients with NMIBC. These results provide the basis for a highly accurate noninvasive test for population screening and allowing to decrease the frequency of cystoscopy, an important feature for both patient quality of life improvement and care cost reduction

The IDENTIFY study: the investigation and detection of urological neoplasia in patients referred with suspected urinary tract cancer - a multicentre observational study

Objective To evaluate the contemporary prevalence of urinary tract cancer (bladder cancer, upper tract urothelial cancer [UTUC] and renal cancer) in patients referred to secondary care with haematuria, adjusted for established patient risk markers and geographical variation. Patients and Methods This was an international multicentre prospective observational study. We included patients aged ≥16 years, referred to secondary care with suspected urinary tract cancer. Patients with a known or previous urological malignancy were excluded. We estimated the prevalence of bladder cancer, UTUC, renal cancer and prostate cancer; stratified by age, type of haematuria, sex, and smoking. We used a multivariable mixed-effects logistic regression to adjust cancer prevalence for age, type of haematuria, sex, smoking, hospitals, and countries. Results Of the 11 059 patients assessed for eligibility, 10 896 were included from 110 hospitals across 26 countries. The overall adjusted cancer prevalence (n = 2257) was 28.2% (95% confidence interval [CI] 22.3–34.1), bladder cancer (n = 1951) 24.7% (95% CI 19.1–30.2), UTUC (n = 128) 1.14% (95% CI 0.77–1.52), renal cancer (n = 107) 1.05% (95% CI 0.80–1.29), and prostate cancer (n = 124) 1.75% (95% CI 1.32–2.18). The odds ratios for patient risk markers in the model for all cancers were: age 1.04 (95% CI 1.03–1.05; P < 0.001), visible haematuria 3.47 (95% CI 2.90–4.15; P < 0.001), male sex 1.30 (95% CI 1.14–1.50; P < 0.001), and smoking 2.70 (95% CI 2.30–3.18; P < 0.001). Conclusions A better understanding of cancer prevalence across an international population is required to inform clinical guidelines. We are the first to report urinary tract cancer prevalence across an international population in patients referred to secondary care, adjusted for patient risk markers and geographical variation. Bladder cancer was the most prevalent disease. Visible haematuria was the strongest predictor for urinary tract cancer

Exploration biologique de la progression du cancer du rein à haut risque : analyse ancillaire de la cohorte française de l’essai S-TRAC

Abstract : Objective: We aimed to explore biological predictive factors of progression after surgery in non-metastatic RCC using the collected tumors in the French cohort of the randomized S-TRAC trial patients. Patients and methods We analyzed the tumors of the French cohort of STRAC that included 44 cases of ccRCC that were collected from 6 centers. The main objective was to explore biological predictive factors of progression (defined as PFS) to sunitinib. Aboard spectrum analysis including immunohistochemistry, FISH, CGH-Array, Transcriptomic analyses were performed on the tumors. Results : Analysis of vascular density showed type 1 vascular stroma corresponding to high vascular density was associated with progression (p<0.034). Loss of PBRM1 (Poly bromo-1) expression showed a distinct profile: a highly histopathological aggressive tumor with a marked angiogenic profile (VEGF over expression and immature vascular stroma type 2), no PD1 or PDL1 expression and WT status of the VHL gene. There were 27 chromosome regions gained in patients with progression (on chromosomes 7 and 16, and to a lesser extent 8, 12, 17, 17, 19, 20 corresponding to 605 associated genes) and 10 regions lost in these same patients on chromosomes 8 and 9, and to a lesser extent 2 and 21 corresponding to 25 associated genes. Conclusion : We found that a angiogenic phenotype defined by a high vascular density with a vascular type 2 stroma was a predictive factor of sunitinib resistance. Regardless of adjuvant treatment, chromosomal gains and losses and genomic alterations including PBRM1 loss were associated with worse outcomes.Résumé : Objectif : L’objectif de cette étude était d’explorer les facteurs biologiques prédictifs de la progression après néphrectomie pour carcinome des cellules rénales (CCR) à haut risque non métastatique en utilisant les tumeurs collectées des patients inclus en France dans l'essai randomisé S-TRAC (NCT00375674). Patients et méthodes : Nous avons analysé les tumeurs de la cohorte française du STRAC qui comprenait 44 cas de CCR qui ont été recueillis dans six centres. l'objectif principal était d'explorer les facteurs biologiques prédictifs de la progression (définis comme SSP) au sunitinib. L'analyse à large spectre, y compris l'immunohistochimie, la fluorescence in situ d'hybridation (FISH), d'hybridation génomique comparative (CGH) et de transcriptomique des analyses ont été effectuées sur les tumeurs. Résultats : L'analyse de la densité vasculaire a montré un stroma vasculaire de type 1 correspondant à une densité vasculaire élevée a été associée à une progression (p < 0,034). La perte de poly bromo-1 a montré un profil distinct : une tumeur agressive hautement avec un profil angiogénique marqué (surexpression du facteur de croissance endothélial vasculaire et stroma vasculaire immature de type 2), pas d'expression PD1 ou PDL1, et statut de type sauvage (WT)du gène VHL. Il y avait 27 régions chromosomiques gagnées chez les patients présentant une progression (sur les chromosomes 7 et 16, et dans une moindre mesure 8, 12, 17, 19, 20 correspondant à 605 gènes associés) et 10 régions perdues chez ces mêmes patients sur les chromosomes 8 et 9, et dans une moindre mesure 2 et 21 correspondant à 25 gènes associés. Conclusion : Nous avons constaté qu'un phénotype angiogénique défini par une forte densité vasculaire avec un stroma vasculaire de type 2 était un facteur prédictif de la résistance au sunitinib. Quel que soit le traitement reçu (sunitinib ou placebo) les gains et de pertes chromosomiques et d'altérations génomiques, y compris la perte de PBRM1 étaient associées à un plus mauvais pronostic

Exploring biological predictive factors of progression after surgery in high-risk renal cell carcinoma : results from theFrench cohort of the randomized S-TRAC trial patients

Résumé : Objectif : L’objectif de cette étude était d’explorer les facteurs biologiques prédictifs de la progression après néphrectomie pour carcinome des cellules rénales (CCR) à haut risque non métastatique en utilisant les tumeurs collectées des patients inclus en France dans l'essai randomisé S-TRAC (NCT00375674). Patients et méthodes : Nous avons analysé les tumeurs de la cohorte française du STRAC qui comprenait 44 cas de CCR qui ont été recueillis dans six centres. l'objectif principal était d'explorer les facteurs biologiques prédictifs de la progression (définis comme SSP) au sunitinib. L'analyse à large spectre, y compris l'immunohistochimie, la fluorescence in situ d'hybridation (FISH), d'hybridation génomique comparative (CGH) et de transcriptomique des analyses ont été effectuées sur les tumeurs. Résultats : L'analyse de la densité vasculaire a montré un stroma vasculaire de type 1 correspondant à une densité vasculaire élevée a été associée à une progression (p < 0,034). La perte de poly bromo-1 a montré un profil distinct : une tumeur agressive hautement avec un profil angiogénique marqué (surexpression du facteur de croissance endothélial vasculaire et stroma vasculaire immature de type 2), pas d'expression PD1 ou PDL1, et statut de type sauvage (WT)du gène VHL. Il y avait 27 régions chromosomiques gagnées chez les patients présentant une progression (sur les chromosomes 7 et 16, et dans une moindre mesure 8, 12, 17, 19, 20 correspondant à 605 gènes associés) et 10 régions perdues chez ces mêmes patients sur les chromosomes 8 et 9, et dans une moindre mesure 2 et 21 correspondant à 25 gènes associés. Conclusion : Nous avons constaté qu'un phénotype angiogénique défini par une forte densité vasculaire avec un stroma vasculaire de type 2 était un facteur prédictif de la résistance au sunitinib. Quel que soit le traitement reçu (sunitinib ou placebo) les gains et de pertes chromosomiques et d'altérations génomiques, y compris la perte de PBRM1 étaient associées à un plus mauvais pronostic.Abstract : Objective: We aimed to explore biological predictive factors of progression after surgery in non-metastatic RCC using the collected tumors in the French cohort of the randomized S-TRAC trial patients. Patients and methods We analyzed the tumors of the French cohort of STRAC that included 44 cases of ccRCC that were collected from 6 centers. The main objective was to explore biological predictive factors of progression (defined as PFS) to sunitinib. Aboard spectrum analysis including immunohistochemistry, FISH, CGH-Array, Transcriptomic analyses were performed on the tumors. Results : Analysis of vascular density showed type 1 vascular stroma corresponding to high vascular density was associated with progression (p<0.034). Loss of PBRM1 (Poly bromo-1) expression showed a distinct profile: a highly histopathological aggressive tumor with a marked angiogenic profile (VEGF over expression and immature vascular stroma type 2), no PD1 or PDL1 expression and WT status of the VHL gene. There were 27 chromosome regions gained in patients with progression (on chromosomes 7 and 16, and to a lesser extent 8, 12, 17, 17, 19, 20 corresponding to 605 associated genes) and 10 regions lost in these same patients on chromosomes 8 and 9, and to a lesser extent 2 and 21 corresponding to 25 associated genes. Conclusion : We found that a angiogenic phenotype defined by a high vascular density with a vascular type 2 stroma was a predictive factor of sunitinib resistance. Regardless of adjuvant treatment, chromosomal gains and losses and genomic alterations including PBRM1 loss were associated with worse outcomes

Results of the First Trial Assessing Adjuvant Tyrosine Kinase Inhibitors in Renal Cell Carcinoma Do Not reASSURE

International audienceReferred to by Matteo Santoni, Marina Scarpelli, Antonio Lopez-Beltran, Liang Cheng, Alberto Briganti, Francesco Montorsi, Rodolfo Montironi, Daniele Santini Re: Idir Ouzaid and Karim Bensalah. Results of the First Trial Assessing Adjuvant Tyrosine Kinase Inhibitors in Renal Cell Carcinoma Do Not reASSURE. Eur Urol 2015;68:542–3 European Urology, Available online 1 October 201

Intérêt de l IRM multiparamétrique dans le cancer de la prostate localisé

Evaluer l intérêt de l imagerie par résonnance magnétique de diffusion (DW-MRI) dans la stadification locale, de la cartographie, et la prédiction de la sévérité du cancer de la prostate (CaP).Entre janvier 2009 et octobre 2011, 133 patients avec un CaP ont eu une prostatectomie totale (PT). Les patients ont une IRM multiparamétrique préopératoire. Les données anatomopathologiques (pTNM) et radiologiques (iTNM) ont été corrélées pour évaluer le pouvoir de l IRM de diffusion dans la cartographie, l extension locale et la prédiction de la sévérité (Score de Gleason) de la maladie. La comparaison anatomo-IRM a permis de calculer la sensibilité (Se), la spécificité (Sp), les valeurs prédictives positive (VPP) et négative (VPN). Les résultats sur la cartographie et de la prédiction du Gleason ont été obtenus par une étude anatomopathologiques en grandes coupes des pièces de PT de 16 patients avec une corrélation Anatomo-IRM stricte foyer par foyer.L âge et PSA préopératoire moyens des patients étaient respectivement de 63 (52-74) ans et 8,08 (3,3-25,6) ng/ml. Les sensibilités pour détecter les lésions intra prostatiques et de l envahissement de la capsule étaient respectivement de 80% et 78%. La spécificité de l atteinte des VS était de 97%. Sur l analyse en grandes coupes, 48 foyers ont été identifiés. Les Se, Sp, VVP, VPN de l IRM dans la cartographie des lésions était respectivement de 60,41%, 95,41%, 72,5%, et 92,33%. Les résultats étaient meilleurs lorsque la zone périphériques et les tumeurs de plus de 2 mm étaient considérées. Les foyers avec un grade de Gleason >= 4 majoritaire avaient un coefficient apparent de diffusion moins élevé que les foyers avec un grade 3 majoritaire (p=0,016).Cette étude a mis en évidence l intérêt de cette technique d imagerie dans l évaluation du CaP localisé. Cet outil peut se révéler incontournable dans les nouvelles stratégies de prise en charge du CaP localisé : préservation nerveuse en cas de PT, thérapie focale voire la surveillance active.PARIS6-Bibl.Pitié-Salpêtrie (751132101) / SudocSudocFranceF

Lymphadenectomy for Upper Tract Urothelial Carcinoma: A Systematic Review

Background: The role of lymphonodal dissection during surgery for a tumor of the urinary tract remains controversial. Objective: To analyze anatomical bases of lymphonodal dissection in tumors of the upper urinary tract and analyze its impact on survival, recurrence, and staging. Acquisition of data: A web-based search for scientific articles using Medline/Pubmed was carried out to identify and analyze articles on the practice and the role of lymphonodal dissection in this indication. Data Synthesis: The lymphatic drainage of the upper urinary tract has rarely been studied and is poorly understood. The lymphonodal metastatic extension is the most common extension in upper urinary tract urothelial carcinoma. Lymphnode invasion is a clear independent poor prognostic factor. Therefore, it seems legitimate to offer an extended lymphonodal dissection to patients undergoing surgery to cure these tumors. When lymphnodes dissection respects clear anatomical principles based on the location of the primary tumor and its extension, it improves both survival and recurrence rates. This result could be secondary to the treatment of subclinical metastatic disease. Conclusion: An extended lymphadenectomy during surgery for upper urinary tract urothelial carcinoma following strict anatomical pattern improves staging with a highly probable therapeutic benefit

New immunotherapy treatments in non-muscle invasive bladder cancer

: Non-muscle invasive bladder cancer (NMIBC) is a highly heterogeneous disease that hides classes of patients who behave significantly differently under a favorable overall prognosis facade. Individual risk stratification and good decision making improve the patient outcomes. To date, radical cystectomy remains the treatment of choice in particularly aggressive subsets of disease, also due to the lack of proven alternative bladder-sparing strategies.Cancer immunotherapy, by inhibiting the PD-1/PD-L1axis, has shown durable efficacy in the treatment of advanced and metastatic unresectable urothelial carcinoma, and is studied with great interest in early disease settings. The updated data of the KEYNOTE-057 study have recently promoted the United States (US) Food and Drug Administration (FDA) approval of pembrolizumabin patients with CIS-containing BCG-unresponsive NMIBC. This significant step forward paves the way to a new window of therapeutic opportunities, while underlining new needs and questions to be addressed

Can Molecular Classifications Help Tailor First-line Treatment of Metastatic Renal Cell Carcinoma? A Systematic Review of Available Models

International audienceCONTEXT: The advent of immune check inhibitors (ICIs) has tremendously changed the prognosis of metastatic renal cell carcinoma (mRCC), adding an unseen substantial overall survival benefit. These agents could be administered alone or in combination with anti-vascular endothelial growth factor (anti-VEGF) therapies. So far, treatment allocation is based only on clinical stratification risk models. OBJECTIVE: Herein, we aimed to report the different molecular classifications reported in the first-line treatment of mRCC and discuss the awaited clinical implications in terms of treatment selection. EVIDENCE ACQUISITION: Medline database as well as European Society for Medical Oncology (ESMO)/American Society of Clinical Oncology (ASCO) conference proceedings were searched to identify biomarker studies. Inclusion criteria comprised randomized and nonrandomized clinical trials that included patients treated in the first line of mRCC setting, patients treated with anti-VEGF therapies or ICIs, biological modeling, and available survival outcomes. EVIDENCE SYNTHESIS: Four classification models were identified with subsequent clinical implications: Beuselinck model (34 gene signatures), IMmotion150, Hakimi, and JAVELIN 101 model. Tumor profiling shows distinct outcomes when treated with one or other combination. Patients are clustered into two gene signatures: angiogenic and proinflammatory (as per JAVELIN). The first is more likely to respond to therapy that includes anti-VEGF agents, while the best outcomes are obtained with an ICI combination with the second. CONCLUSIONS: The findings presented here were mostly derived from ancillary registered studies of new drugs in the setting of mRCC. Further validation is needed, which sets new paradigms for investigation in clinical research based on tumor biology for treatment allocation and not only on clinical stratification tools. PATIENT SUMMARY: First-line treatment of metastatic kidney includes immunotherapy alone or in combination with antiangiogenic therapy. However, clinical practice demonstrated that the &quot;one treatment fits all&quot; strategy might not be the best approach. In fact, recent studies showed that the addition of immunotherapy agents will not benefit all patients equally, and some still respond either equally to or better than anti-vascular endothelial growth factor alone. This review revealed biomarker modeling that impacts treatment selection. Recent tumor profiling into &quot;angiogenic signature&quot; more sensitive to angiogenic agents versus &quot;immune signature&quot; more likely to achieve the best response with immunotherapy should be validated. Tumor biology features might be more powerful than clinical classification for a tailored treatment approach