Bladder carcinoma : biomarkers associated with relapse after adjuvant chemotherapy and heterogeneity of potential therapeutic targets.

Introduction: les progrès thérapeutiques pour la prise en charge du carcinome urothélial de la vessie, ou tumeur de vessie infiltrant le muscle (TVIM), sont faibles depuis deux décennies, notamment sur le plan de la chimiothérapie, tant dans les formes localisées que métastatiques. L'identification de nouveaux biomarqueurs pouvant améliorer la prise en charge et le pronostic des patients apparait indispensable, notamment pour prédire la réponse aux traitements systémiques. Notre travail a cherché : (i) à identifier des facteurs biologiques prédictifs de rechute après les chimiothérapies adjuvantes (CA) utilisées actuellement, (ii) à déterminer si les altérations moléculaires, cibles de nouvelles thérapies, identifiées dans la tumeur vésicale sont conservées dans les métastases.Objectifs:(i) Rechercher une association entre la rechute après CA et l'expression de six biomarqueurs, ERCC1, Emmprin, Survivin, MDR1, p53 et topoisomérase IIα, dans la tumeur vésicale et/ou une métastase ganglionnaire(ii) Etudier l'hétérogénéité des mutations de FGFR3 dans les TVIM localement avancéesMatériels et Méthodes: Une cohorte rétrospective de 226 patients traités par cystectomie et CA, et une collection tumorale d'échantillons représentatifs de la tumeur primitive et d'une métastase ganglionnaire ont été constituées. L'expression des six biomarqueurs a été déterminée en immunohistochimie sur ces échantillons. Le statut mutationnel de FGFR3 a été déterminé en SNaPshot sur 84 paires tumeur primitive/métastase ganglionnaire.Résultats: Les survies observées dans la cohorte étaient proches de celles rapportées dans la littérature pour des patients de mêmes stades. La collection tumorale étudiée semble donc représentative des TVIM traitées en France. Aucun des six biomarqueurs n'était retrouvé comme prédictif de rechute après traitement. Une mutation de FGFR3 était retrouvée dans 4 (4,7%) des 84 échantillons appariés sans aucune discordance entre tumeur primitive et métastase ganglionnaire.Conclusions: L'expression de ces six biomarqueurs étudiés en immunohistochimie n'est pas associée à un risque de rechute après CA. Le statut mutationnel de FGFR3 est conservé au cours de la dissémination métastatique, et ses mutations activatrices sont présentes dans près de 5% des TVIM localement avancées. Leur conservation dans le processus métastatique renforce l'intérêt de l'évaluation de nouvelles thérapies ciblant le récepteur FGFR3 muté. Enfin, il est possible de rechercher cette mutation sur la tumeur vésicale ou une métastase avec la même pertinence.Introduction: In muscle invasive urothelial carcinoma of the bladder (MI UCB), few progresses have been made in the last two decades, particularly in chemotherapy, both in localized and metastatic setting. The identification of new biomarkers that can improve the management and prognosis of patients appears essential. Such biomarkers will be clinically relevant if they can predict the response to systemic treatments. In this thesis, we studied biomarkers in two ways: (i) to identify predictive factors of relapse after cisplatin-based adjuvant chemotherapy (AC), (ii) to confirm that the molecular alterations targeted by new therapies and identified in bladder tumor are present in metastases.Objectives:(i) To examine the relationship between relapse after AC and expression of six biomarkers, ERCC1, Emmprin, Survivin, MDR1 p53 and topoisomerase IIα, in bladder tumor and / or lymph node metastases.(ii) To study the heterogeneity of FGFR3 mutations in locally advanced MI UCBMaterials and Methods: A retrospective cohort of 226 patients treated with cystectomy and AC, and tumor collection of representative samples of the primary tumor and lymph node metastases were constituted. The expression of six biomarkers was determined by immunohistochemistry on these samples and determined by morphometry. FGFR3 mutation status was determined by SNaPshot in 84 paired primary tumors and positive lymph nodes.Results: Survivals observed in the cohort were similar to those reported in the literature for patients of same stages, with tumor collection being representative of the MI UCB treated in France. None of the six biomarkers was found as an independent predictive factor of relapse after AC. FGFR3 mutation was found in 4 (4.7%) of the 84 paired samples with complete concordance between primary tumor and lymph node metastases.Conclusions: The expression of the six studied biomarkers by immunohistochemistry is not associated with risk of relapse following AC. FGFR3 mutation status is maintained during metastases process, and FGFR3 activating mutations are present in about 5% of locally advanced MI UCB. FGFR3 mutation remains a promising therapeutic target in a low subset of patients, and the evaluation of new therapies targeting the mutated FGFR3 receptor are needed. Finally, search for these mutations either in bladder tumor or in metastasis is relevant

Association gemcitabine-docétaxel dans la prise en charge des carcinomes de site primitif inconnu (expérience du Centre Val d'Aurelle - Paul Lamarque)

MONTPELLIER-BU Médecine UPM (341722108) / SudocPARIS-BIUM (751062103) / SudocMONTPELLIER-BU Médecine (341722104) / SudocSudocFranceF

Cancers du rein avancés en situations particulières. Comment les traiter ? [Advanced renal carcinomas with special situations. How to treat them?]

International audienceAdvanced or metastatic renal carcinoma represents a frequent disease in oncologic practice. Few years ago, in immunotherapy era, treatments had quickly reached deadlock. New therapies targeting vascular endothelial growth factors and their receptors (VEGF-R), sorafenib, sunitinib and bevacizumab, and the mammalian target of rapamycin (mTOR), temsirolimus and everolimus, have modified these patients prognosis and their quality of life in a few years. Nevertheless, patients included in randomized trials presented severe inclusion criteria. Then in the daily practice, patients have distinctive characteristics which were not evaluated in large pivotal studies: poor performance status, older patients, renal dysfunction, cerebral metastases or non clear cell renal cancer. In published trials, a few data concerning these situations are reported, and these studies have often included small samples, were retrospective or not randomised. However compared to global population, tolerance have not been very different in geriatric patients, or patients with poor performance status, or with central neurological metastases, or with papillary and chromophobe sub-types. On the contrary progression free or overall survivals increases are more difficult to confirm. Also before starting treatment, ratio between potential benefit and possible toxicities have to be evaluated. In patients with renal insufficiency, VEGF receptor inhibitors seem to be cautiously initiated at reduced doses, and to be increased according to tolerance. Due to these poor proof levels, clinical trials are needed for these specific populations

New therapies in renal cell carcinoma.

International audiencePURPOSE OF REVIEW: We present an update on the dramatic changes that have occurred over the past year in the management of patients with metastatic renal cell carcinoma. RECENT FINDINGS: Although it was demonstrated that benefit from immunotherapy is restricted to a minority of patients, a better understanding of the molecular mechanisms involved in the pathogenesis of clear cell carcinoma has led to development of multiple targeted therapies, with significant clinical benefits. Two compounds that predominantly inhibit the tyrosine kinase activity of vascular endothelial growth factor receptor have been demonstrated to improve the progression-free survival of patients as first-line (sunitinib versus interferon-alpha) or second-line (sorafenib versus placebo) treatment. Temsirolimus, which inhibits the serine-threonine kinase activity of the mammalian target of rapamycin, offers better overall survival than interferon in patients with poor risk characteristics. Finally, bevacizumab combined with interferon is yielding substantial response rates and increased progression-free survival compared with interferon alone. SUMMARY: Four major drugs or regimens with proven efficacy are now available for first-line and second-line therapy in metastatic renal cell carcinoma. Further studies are needed to determine the optimal combinations of these agents in metastatic disease and to assess their impact in the adjuvant setting

Abiraterone Acetate Withdrawal Syndrome: Does It Exist

In 2011 abiraterone acetate (AA) was approved for the treatment of castrate-resistant metastatic prostate cancer patients who have failed docetaxel chemotherapy. We report the case of a patient who experienced a confirmed PSA decrease of ≥50% after stopping AA, mimicking an antiandrogen withdrawal syndrome

Antiangiogenèse et cancer du rein [Renal cell carcinoma and antiangiogenic therapies]

National audienceUntil 2006, immunotherapy (interferon-alpha or interleukin 2) was the standard medical treatment for metastatic renal cell carcinoma (RCC), and its results were disappointing: despite a few cases of complete response with prolonged survival, median survival was one year. Better understanding of the molecular mechanisms of tumor angiogenesis, especially in clear cell carcinoma, has led to the development of multiple targeted therapies to inhibit key effectors: vascular endothelial growth factor (VEGF), VEGF receptor, and mTOR (target of rapamycin). Two inhibitors targeting several protein kinases, including the VEGF receptor, have increased progression-free survival in patients with metastatic RCC and are now commercially available: sunitinib (Sutent) as first-line treatment and sorafenib (Nexavar) as second-line treatment. These targeted therapies will certainly affect overall survival, but it is too early for any firm conclusions. Their side-effects, usually low or moderate, include asthenia, anorexia, diarrhea, hand-and-foot syndrome and hypertension. Optimal management is required to ensure prolonged exposure. Other drugs have been effective: bevacizumab (Avastin), a monoclonal antibody inhibiting VEGF, increases progression-free survival as second-line treatment, and temsirolimus (Torisel), an mTOR protein kinase inhibitor, increases overall survival in the population of patients with poor prognosis. These targeted drugs will serve as the basis for development of future therapeutic strategies

Targeted therapy in renal cell carcinoma.

International audienceOBJECTIVE: To present an update on anti-angiogenic drugs in the treatment of metastatic renal cell carcinoma. RECENT FINDINGS: A better understanding of molecular pathways that are involved in clear cell carcinomas has led to the development of multiple targeted therapies with significant clinical benefits. Two tyrosine kinase inhibitors targeting the vascular endothelial growth factor (VEGF) receptor have been shown to improve the progression-free survival of patients in first-line (Sunitinib vs. interferon-alpha) or second-line treatment (Sorafenib vs. placebo). Temsirolimus, an agent that inhibits the serine-threonine kinase activity of the mammalian target of rapamycin, offers better overall survival than interferon in patients with poor-risk characteristics. Finally, Bevacizumab, which is an antibody directed against VEGF, in association with IFN is providing substantial response rates and increased progression-free survival compared to IFN alone. CONCLUSION: Four major drugs or regimens with proven efficacy are now available in first and second line therapy in metastatic renal cell carcinoma (mRCC). Further studies are needed to determine the optimal combinations of these agents in metastatic disease and to assess their impact in the adjuvant setting

Very Fast Recovery of Acute Disseminated Intravascular Coagulation with Abiraterone Acetate in a Patient with Bone Metastases from Castrate-Resistant Prostate Cancer

Disseminated intravascular coagulation (DIC) is a rare, potentially life-threatening complication of advanced prostate carcinoma. We report the successful treatment with abiraterone acetate of acute DIC related to a progressive bone metastatic disease in a chemotherapy-naïve patient with castrate-resistant prostate cancer