Renal Cell Carcinoma: Focus on Safety and Efficacy of Temsirolimus

Metastatic renal cell carcinoma has harboured a poor prognosis for decades with immunotherapy being the only available therapy with high toxicity and modest effect. Dependance of renal cell carcinoma oncogenesis on the mTOR pathway has led to clinical development of temsirolimus in this setting. This sirolimus derivative has shown clinical efficacy in monotherapy for poor-risk renal cell carcinoma leading to an overall survival of 10.8 months in the pivotal phase III trial of this agent. Its specific adverse events consist of metabolic dysregulation (hyperlipemia, hyperglycemia), mucositis, rash and pneumonitis which can be severe and need careful monitoring and management. In this review, we will discuss of the clinical development of this molecule, its efficacy, its safety profile and future perspectives

Consensus on drivers of maintenance treatment choice and patterns of care in advanced ovarian cancer

Objectives Maintenance therapies, including poly (ADP-ribose) polymerase (PARP) inhibitors and/or bevacizumab, have substantially improved the prognosis of patients with advanced ovarian cancer. Owing to the variability in treatment strategies across Europe, a Delphi study was conducted among European experts to understand the heterogeneity of clinical practice and identify key factors driving maintenance treatment decisions for advanced ovarian cancer.Methods A pragmatic literature review was conducted to identify key questions regarding maintenance treatment strategies in patients with advanced ovarian cancer. Utilizing a Delphi methodology, consensus was assessed among a panel of 16 experts using a questionnaire based on results of the pragmatic literature review.Results Panelists agreed that BRCA mutation and homologous recombination status should be assessed in parallel at diagnosis, and that first-line platinum chemotherapy may be initiated concurrently. There was a consensus that alternative homologous recombination deficiency tests are acceptable provided they are clinically validated. Panelists agreed that Response Evaluation Criteria in Solid Tumors (RECIST) and CA-125 elimination rate constant K (KELIM) scores can help assess tumor chemosensitivity and guide treatment-related decisions. Panelists defined high-risk disease as International Federation of Gynecology and Obstetrics (FIGO) stage IV disease or stage III with residual disease after initial/interval cytoreduction. Risk of disease progression was a key determinant of choice between PARP inhibitor, bevacizumab, or both in combination, as maintenance therapy in advanced ovarian cancer.Conclusions Key drivers for selecting advanced ovarian cancer maintenance treatments include tumor mutational status as a key biomarker and clinician perception of the risk for early disease progression

Clinical practice guidelines for BRCA1 and BRCA2 genetic testing

BRCA1 and BRCA2 gene pathogenic variants account for most hereditary breast cancer and are increasingly used to determine eligibility for PARP inhibitor (PARPi) therapy of BRCA-related cancer. Because issues of BRCA testing in clinical practice now overlap with both preventive and therapeutic management, updated and comprehensive practice guidelines for BRCA genotyping are needed. The integrative recommendations for BRCA testing presented here aim to (1) identify individuals who may benefit from genetic counselling and risk-reducing strategies; (2) update germline and tumour-testing indications for PARPi-approved therapies; (3) provide testing recommendations for personalised management of early and metastatic breast cancer; and (4) address the issues of rapid process and tumour analysis. An international group of experts, including geneticists, medical and surgical oncologists, pathologists, ethicists and patient representatives, was commissioned by the French Society of Predictive and Personalised Medicine (SFMPP). The group followed a methodology based on specific formal guidelines development, including (1) evaluating the likelihood of BRCAm from a combined systematic review of the literature, risk assessment models and expert quotations, and (2) therapeutic values of BRCAm status for PARPi therapy in BRCA-related cancer and for management of early and advanced breast cancer. These international guidelines may help clinicians comprehensively update and standardise BRCA testing practices

Prognostic impact of vitamin B6 metabolism in lung cancer

Patients with non-small cell lung cancer (NSCLC) are routinely treated with cytotoxic agents such as cisplatin. Through a genome-wide siRNA-based screen, we identified vitamin B6 metabolism as a central regulator of cisplatin responses in vitro and in vivo. By aggravating a bioenergetic catastrophe that involves the depletion of intracellular glutathione, vitamin B6 exacerbates cisplatin-mediated DNA damage, thus sensitizing a large panel of cancer cell lines to apoptosis. Moreover, vitamin B6 sensitizes cancer cells to apoptosis induction by distinct types of physical and chemical stress, including multiple chemotherapeutics. This effect requires pyridoxal kinase (PDXK), the enzyme that generates the bioactive form of vitamin B6. In line with a general role of vitamin B6 in stress responses, low PDXK expression levels were found to be associated with poor disease outcome in two independent cohorts of patients with NSCLC. These results indicate that PDXK expression levels constitute a biomarker for risk stratification among patients with NSCLC.publishedVersio

Role of CD95/CD95L in triple negative breast cancer and ovarian cancers

Les cancers du sein triple négatifs et les cancers de l’ovaire séreux de haut grade partagent des caractéristiques biologiques communes, et le système immunitaire joue un rôle important dans le contrôle de l’évolution tumorale dans ces 2 maladies. Initialement caractérisée par son rôle dans l’apopotose des cellules immunitaires, la signalisation activée par l’interaction CD95/CD95L et son ligand soluble sCD95L est impliquée dans de nombreux rôles biologiques au-delà de l’apoptose, notamment dans les processus d’oncogénèse. Notre équipe avait montré le rôle pronostic négatif du sCD95L, favorisant l’invasion tumorale et les métastases chez les patientes atteintes de cancer du sein triple négatif. Dans les cancers de l’ovaire, le niveau de sCD95L est un facteur pronostic positif corrélé à l’infiltrat immunitaire, soulevant l’hypothèse d’une régulation de cet infiltrat par la signalisation CD95/CD95L. Dans les cancers du sein triple négatifs, la signalisation CD95 impacte la réponse immune anti-tumorale. Ces travaux montrent qu’une meilleure compréhension des mécanismes biologiques activés par la voie CD95/CD95L dans les cancers de l’ovaire séreux de haut grade et dans les cancers du sein triple négatif pourrait permettre de mieux sélectionner les patientes pour des traitements modulant la réponse immune. Le ciblage de cette voie pourrait permettre d’améliorer la prise en charge thérapeutiques.Triple-negative breast cancer and high-grade serous ovarian cancer share common biological features, and the immune system plays an important role in controlling tumor progression in both diseases. Initially characterized by its role in immune cell apoptosis, the signaling activated by the CD95/CD95L interaction and its soluble ligand sCD95L is involved in many biological roles beyond apoptosis, notably in oncogenesis processes. Our team had shown the negative prognostic role of sCD95L, promoting tumor invasion and metastasis in patients with triple negative breast cancer. In ovarian cancer, the level of sCD95L is a positive prognostic factor correlated with the immune infiltrate, raising the hypothesis that this infiltrate is regulated by CD95/CD95L signaling. In triple-negative breast cancer, CD95 signaling impacts the anti-tumor immune response. This work shows that a better understanding of the biological mechanisms activated by the CD95/CD95L pathway in high-grade serous ovarian cancer and in triple-negative breast cancer could allow better selection of patients for treatments modulating the immune response. Targeting this pathway could lead to improved therapeutic management

Rôle de CD95/CD95L dans les cancers du sein triple négatifs et de l’ovaire

Triple-negative breast cancer and high-grade serous ovarian cancer share common biological features, and the immune system plays an important role in controlling tumor progression in both diseases. Initially characterized by its role in immune cell apoptosis, the signaling activated by the CD95/CD95L interaction and its soluble ligand sCD95L is involved in many biological roles beyond apoptosis, notably in oncogenesis processes. Our team had shown the negative prognostic role of sCD95L, promoting tumor invasion and metastasis in patients with triple negative breast cancer. In ovarian cancer, the level of sCD95L is a positive prognostic factor correlated with the immune infiltrate, raising the hypothesis that this infiltrate is regulated by CD95/CD95L signaling. In triple-negative breast cancer, CD95 signaling impacts the anti-tumor immune response. This work shows that a better understanding of the biological mechanisms activated by the CD95/CD95L pathway in high-grade serous ovarian cancer and in triple-negative breast cancer could allow better selection of patients for treatments modulating the immune response. Targeting this pathway could lead to improved therapeutic management.Les cancers du sein triple négatifs et les cancers de l’ovaire séreux de haut grade partagent des caractéristiques biologiques communes, et le système immunitaire joue un rôle important dans le contrôle de l’évolution tumorale dans ces 2 maladies. Initialement caractérisée par son rôle dans l’apopotose des cellules immunitaires, la signalisation activée par l’interaction CD95/CD95L et son ligand soluble sCD95L est impliquée dans de nombreux rôles biologiques au-delà de l’apoptose, notamment dans les processus d’oncogénèse. Notre équipe avait montré le rôle pronostic négatif du sCD95L, favorisant l’invasion tumorale et les métastases chez les patientes atteintes de cancer du sein triple négatif. Dans les cancers de l’ovaire, le niveau de sCD95L est un facteur pronostic positif corrélé à l’infiltrat immunitaire, soulevant l’hypothèse d’une régulation de cet infiltrat par la signalisation CD95/CD95L. Dans les cancers du sein triple négatifs, la signalisation CD95 impacte la réponse immune anti-tumorale. Ces travaux montrent qu’une meilleure compréhension des mécanismes biologiques activés par la voie CD95/CD95L dans les cancers de l’ovaire séreux de haut grade et dans les cancers du sein triple négatif pourrait permettre de mieux sélectionner les patientes pour des traitements modulant la réponse immune. Le ciblage de cette voie pourrait permettre d’améliorer la prise en charge thérapeutiques

Rôle de CD95/CD95L dans les cancers du sein triple négatifs et de l’ovaire

Triple-negative breast cancer and high-grade serous ovarian cancer share common biological features, and the immune system plays an important role in controlling tumor progression in both diseases. Initially characterized by its role in immune cell apoptosis, the signaling activated by the CD95/CD95L interaction and its soluble ligand sCD95L is involved in many biological roles beyond apoptosis, notably in oncogenesis processes. Our team had shown the negative prognostic role of sCD95L, promoting tumor invasion and metastasis in patients with triple negative breast cancer. In ovarian cancer, the level of sCD95L is a positive prognostic factor correlated with the immune infiltrate, raising the hypothesis that this infiltrate is regulated by CD95/CD95L signaling. In triple-negative breast cancer, CD95 signaling impacts the anti-tumor immune response. This work shows that a better understanding of the biological mechanisms activated by the CD95/CD95L pathway in high-grade serous ovarian cancer and in triple-negative breast cancer could allow better selection of patients for treatments modulating the immune response. Targeting this pathway could lead to improved therapeutic management.Les cancers du sein triple négatifs et les cancers de l’ovaire séreux de haut grade partagent des caractéristiques biologiques communes, et le système immunitaire joue un rôle important dans le contrôle de l’évolution tumorale dans ces 2 maladies. Initialement caractérisée par son rôle dans l’apopotose des cellules immunitaires, la signalisation activée par l’interaction CD95/CD95L et son ligand soluble sCD95L est impliquée dans de nombreux rôles biologiques au-delà de l’apoptose, notamment dans les processus d’oncogénèse. Notre équipe avait montré le rôle pronostic négatif du sCD95L, favorisant l’invasion tumorale et les métastases chez les patientes atteintes de cancer du sein triple négatif. Dans les cancers de l’ovaire, le niveau de sCD95L est un facteur pronostic positif corrélé à l’infiltrat immunitaire, soulevant l’hypothèse d’une régulation de cet infiltrat par la signalisation CD95/CD95L. Dans les cancers du sein triple négatifs, la signalisation CD95 impacte la réponse immune anti-tumorale. Ces travaux montrent qu’une meilleure compréhension des mécanismes biologiques activés par la voie CD95/CD95L dans les cancers de l’ovaire séreux de haut grade et dans les cancers du sein triple négatif pourrait permettre de mieux sélectionner les patientes pour des traitements modulant la réponse immune. Le ciblage de cette voie pourrait permettre d’améliorer la prise en charge thérapeutiques

Evolution des modalités thérapeutiques des tumeurs du sac vitellin de l'ovaire (étude de l'efficacité, de la fertilité après traitement et des facteurs pronostiques)

Les tumeurs du sac vitellin de l ovaire (TSVO) sont la 2ème cause de tumeur germinale maligne de l ovaire. Cette étude décrit une population de patientes atteintes d une TSVO, le traitement réalisé, les facteurs pronostiques, les possibilités de grossesse après traitement et les toxicités tardives. De janvier 1976 à décembre 2006, un traitement ou un avis a été dispensé à l Institut Gustave Roussy à 80 patientes ayant une TSVO. Les caractéristiques des patientes, les traitements réalisés et la survenue de grossesse ont été recueillies de manière rétrospective. La survie globale à 10 ans était de 83%. Les facteurs pronostiques sont l âge, le stade, le type de chimiothérapie, une ascite au diagnostic, le taux d a-foeto-protéine avant chimiothérapie et son temps de normalisation. Une grossesse a été obtenue chez 13 patientes sur 19 désirant concevoir. Un traitement efficace préservant la fertilité (chirurgie + chimiothérapie par BEP) est réalisable chez les patientes atteintes d une TSVO.ST QUENTIN EN YVELINES-BU (782972101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

From Targeting Somatic Mutations to Finding Inherited Cancer Predispositions: The Other Side of the Coin

International audienceThe expanding use of tumor genome analysis by next generation sequencing to drive target therapies has led to increased germline findings in genes predisposing to hereditary cancer. These putative germline findings obtained from theranostic analyses, such as BRCA1/2 gene testing, large panels, whole-exome, or whole-genome sequencing, need to be managed carefully and in an anticipated way with the patient. Before the genetic analysis of a tumor, specific information should be given to patients, who should be aware that the results may have extra-therapeutic medical issues for themselves and relatives. We previously published a list of 36 actionable genes predisposing to cancer for which informing the patient is recommended prior to pangenomic germline analysis because of available screening or preventive strategies. Here, we report clinical practice considerations and schemes for managing germline findings in tumor analyses, including written informed consent and a multidisciplinary approach involving an oncologist, molecular biologist/pathologist, and geneticist in case of germline findings. A somatic result showing a deleterious mutation in a known predisposing gene in a patient who has consented to this purpose should result in referral to a geneticist who is part of the multidisciplinary team. At any time of the somatic analysis process, the patient may have access to a geneticist consultation if additional information is required. This framework will optimally manage both personalized theranostic issues and specific preventive strategies for individuals and relatives; it will also simplify and accelerate the process of genetic testing