Gynecological carcinosarcomas: Overview and future perspectives.

Gynecologic carcinosarcoma (CS) are rare and aggressive tumors composed of high-grade carcinoma and sarcoma. Carcinosarcoma account for less than 5% of uterine and ovarian carcinoma and patients have poor outcome with a 5-year overall survival of less than 30%. In early-stage setting, the treatment mainstay is surgery and adjuvant chemoradiotherapy or adjuvant chemotherapy in uterine (UCS) and ovarian CS (OCS), respectively. In metastatic or advanced stage disease, chemotherapy is the rule with a lower response rate and poorer prognosis compared to other high-grade carcinomas. Although very few treatment options are available, CS are often excluded from the clinical trials precluding therapeutic improvement. However, recent molecular advances are paving the way for new therapeutic strategies. In the current proposal, we extensively review the uterine and ovarian carcinosarcomas including epidemiology, pathology, genomic landscape, as well as current therapies and future perspectives.

[Treatments for rare ovarian tumors: What's new?] / Avancées thérapeutiques dans la prise en charge des tumeurs rares malignes ovariennes.

Even if each rare ovarian tumor (ROT) has a low incidence, the sum of all these entities represents almost the half of all ovarian neoplasms. Thus, development of dedicated clinical trial emerged as a prerequisite to improve their managements. Owing to the spreading of dedicated institutional networks and (supra)national collaborations, the number of clinical trials has increased the past few years, with different types of trials; while some focused on specific molecular features, others assessed innovative molecules. Furthermore, relevant randomized clinical trials were designed as a mean to position new treatment options. Currently, innovative molecular-driven trials, based on master protocol trials are emerging and may shed light towards the improvement of personalized medicine regarding ROT.

Cardiovascular Diseases Following Breast Cancer: Towards a Case-by-Case Assessment Through a Prediction Risk Score Model in 943 Patients.

OBJECTIVES: To identify patients at high risk of developing cardiovascular disease through the identification of risk factors among a large population of breast cancer women and to assess the performance of Abdel-Qadir risk prediction model score. MATERIALS AND METHODS: The medical records and baseline characteristics of all patients/tumors diagnosed with breast cancer from 2010 to 2011 in a French comprehensive cancer center were collected. Cardiovascular events were defined as arterial and cardiac events, atrial fibrillation and venous thromboembolism occurring during the 5-year follow-up. Abdel-Qadir multivariable prediction model for major adverse cardiovascular events were used with the concordance index (c-index) score to assess calibration by comparing predicted risks to observed probabilities. RESULTS: Among the 943 breast cancer patients included, 83 patients (8.8%) presented with at least one cardiovascular event, leading to a cumulative incidence of 0.07 at 5 years (95% confidence interval [CI], 0.055-0.088). The cumulative incidence of atrial fibrillation at 5 years was 0.01 (95% CI, 0.005-0.018). Factors associated with the occurrence of cardiovascular events were pre-existing cardiovascular diseases including high blood pressure (hazard ratio [HR]=1.78, 95% CI=1.07-2.97, P=0.028), acute coronary syndrome (HR=5.28, 95% CI: 2.16-12.88, P<0.05) and grade 3 Scarff-Blool-Richardson (HR=1.95, 95% CI: 1.21-3.15, P=0.006). With a c-index inferior to 0.7, the Abdel-Qadir score was not fully validated in our population. CONCLUSION: These findings call for the assessment of the performance of risk prediction models such as Abdel-Qadir score coupled with other factors such as Scarff Bloom and Richardson grading in order to identify patients at high risk of experiencing cardiotoxicity.

Breast cancer treatment-related cardiovascular disturbances: advocacy for a watchful attitude in this never-ending story.

INTRODUCTION: Thanks to the emergence of new therapeutics, prognosis and outcome of breast cancer patients (any subtype) have improved significantly. This raises the issue of the interactions and side effects related to the use of multiple drugs. Thus, to decide on a treatment, the optimal benefit risk-ratio should be carefully watched as toxicities such as cardiac ones effect on long-term survival. Indeed, nowadays in France, cardiovascular diseases rank first as causes of death in women. AREAS COVERED: This non-exhaustive review aims to report the currently available data on cardiac side effects caused by the use of emerging drugs in breast cancer, in localized or metastatic diseases alike. We will focus on HER2-inhibitors, cyclin-dependent-kinase 4/6 and PARP inhibitors, chemotherapy and immunotherapy, before discussing the means of prevention. EXPERT OPINION: Although this issue has largely been studied, the recent emergence of new drugs emphasizes the necessity for oncologists to adapt their practice to a multidisciplinary model that includes cardio-oncology.

Cardio-Oncology Preclinical Models: A Comprehensive Review.

Cardiotoxicity is a common side effect induced by cancer therapies, which increases the risk of long-term morbidity and mortality in cancer survivors. To date, the mechanism leading to this toxicity is still unclear, thus complicating cardiac safety assessment and predictive factor identification. The advances in technology, particularly regarding radiation therapy and constant development of novel antineoplastic agents, require urgent development of efficient preclinical models to detect drug cardiotoxicity. A myriad of empirical preclinical models have been used to investigate cardiotoxicity, though with limited success. Recently, multicellular spheroid models have gained attention by mimicking the in vivo microenvironment. The aim of this review is to focus on the most relevant preclinical models used to assess antineoplastic drug- and radiotherapy-related cardiotoxicities, with an overview on their current use. It also aims to discuss the possible directions of translational research in the cardio-oncology field.

A Review of the Role of Hypoxia in Radioresistance in Cancer Therapy.

Hypoxia involves neoplastic cells. Unlike normal tissue, solid tumors are composed of aberrant vasculature, leading to a hypoxic microenvironment. Hypoxia is also known to be involved in both metastasis initiation and therapy resistance. Radiotherapy is the appropriate treatment in about half of all cancers, but loco-regional control failure and a disease recurrence often occur due to clinical radioresistance. Hypoxia induces radioresistance through a number of molecular pathways, and numerous strategies have been developed to overcome this. Nevertheless, these strategies have resulted in disappointing results, including adverse effects and limited efficacy. Additional clinical studies are needed to achieve a better understanding of the complex hypoxia pathways. This review presents an update on the mechanisms of hypoxia in radioresistance in solid tumors and the potential therapeutic solutions.

Radioresistance and genomic alterations in head and neck squamous cell cancer: Sub-analysis of the ProfiLER protocol.

BACKGROUND: Genome analysis could provide tools to assess predictive molecular biomarkers of radioresistance. METHODS: Head and neck squamous cell carcinoma patients included in ProfiLER study and who underwent a curative radiotherapy were screened. Univariate and Cox multivariate analyses were performed to explore the relationships between molecular abnormalities, infield relapse and complete tumor response after radiation. RESULTS: One hundred and forty-three patients were analyzed. PIK3CA mutation and genomic instability of MAP kinases pathway were found to be prognostic factors of loco-regional relapse in multivariate analysis with respectively HR 0.33, 95% CI 0.13-0.83, p = 0.005 and HR 0.61, 95% CI 0.38-0.96, p = 0.025. Instability of apoptosis pathway was found to be a prognostic factor of complete response after radiotherapy with HR 0.24, 95% CI 0.07-0.88, p = 0.04. CONCLUSION: This sub analysis suggests that PIK3CA mutation, variation of copy number of MAP kinases and apoptosis pathways play a significant role in the radioresistance phenomenon.

Genetic Analysis in Anal and Cervical Cancer: Exploratory Findings About Radioresistance in the ProfiLER Database.

BACKGROUND/AIM: This study aimed to describe genomic alterations on squamous cell cervical and anal carcinomas. MATERIALS AND METHODS: From 2013 to 2019, 3,269 patients were included in the molecular screening ProfiLER trial. Only patients with non-metastatic cervical or anal cancer, and those initially treated with radiotherapy in a curative intent were selected. Genetic analyses were performed by next generation sequencing (NGS). RESULTS: Genomic alterations were observed in most patients: 5 patients out of 15 (33.3%) had at least one mutation on NGS and 4 out of 15 (26.7%) had at least one aberration of the number of copies of genes in the comparative genomic hybridation (CGH) analysis. The most common mutated gene was PIK3CA. CONCLUSION: All omic approaches must be integrated in the locally advanced cancer setting by new clinical trial design to develop two routes in the treatment strategy: intensification or de-escalation treatment strategy according to omic markers.

Cardiovascular disease events within 5 years after a diagnosis of breast cancer.

BACKGROUND: Concern for cardiovascular disease (particularly atrial fibrillation-AF) among women with breast cancer is becoming a major issue. We aimed at determining the incidence of cardiovascular disease events (AF, arterial and cardiac events, venous-thromboembolism-VTE) in patients diagnosed with breast cancer, and assessing potential risk factors. METHODS: We reviewed medical records of all patients diagnosed with breast cancer from 2010 to 2011 in our cancer center. Baseline characteristics of patients and tumors were collected. The main outcome was the occurrence of cardiovascular disease events (AF, VTE, arterial and cardiac events) during the 5-years follow-up. RESULTS: Among the 682 breast cancer patients, 22 (3.2%) patients had a history of atrial fibrillation. Thirty-four patients (5%) presented at least one cardiovascular disease event, leading to a cumulative incidence of 5.8% events at 5-years ([3.8-7.7] CI 95%), with most of them occurring in the first 2 years. AF cumulative incidence was 1.1% ([0.1-2.1] CI 95%). Factors associated with the occurrence of cardiovascular disease events (including AF) were an overexpression of HER-2 (HR 2.6 [1.21-5.56] p < 0.011), UICC-stage III tumors or more (HR 5.47 [2.78-10.76] p < 0.001) and pre-existing cardiovascular risk factors (HR 2.91 [1.36-6.23] p < 0.004). CONCLUSION: The incidence of cardiovascular disease events was 5.8% ([3.8-7.7] CI 95%), with HER-2 over-expression, UICC-stage III tumors or more and pre-existing cardiovascular diseases being associated with them. These findings call for the development of preventive strategies in patients diagnosed with breast cancer.

[From bench to bedside for new treatment paradigms in chordomas: An update]. / Depuis la recherche translationnelle jusqu'aux nouveaux paradigmes thérapeutiques : mise à jour des données dans les chordomes.

Chordomas are rare malignant tumours, which typically occur in the axial skeleton and skull base. They arise from embryonic remnants of the notochord. They constitute less than 5 % of primary bone tumours. They are characterised by their locally aggressive potential with high frequency of recurrences and a median overall survival of 6 years. The initial therapeutic strategy must be discussed in an expert centre and may involve surgery, preoperative radiotherapy, exclusive radiotherapy or therapeutic abstention. Despite this, more than 50 % of patients will be facing recurrences with few therapeutic options available at this advanced stage. This review aims to outline current treatment options available in chordomas, as well as discussing potentiality of new therapeutic approaches through their molecular characterization and the comprehension of their immunological environment.

Current management of stage I testicular germ cell tumors in a French cancer institute. A practice analysis over the 10 past years.

BACKGROUND: Testicular Germ Cell Tumors (TGCTs) represent the most frequent malignant tumour among young male adults. Orchiectomy alone cure 80% of stage I. Standard options after orchiectomy include radiotherapy (RT), chemotherapy (CT) by 1 cycle of carboplatin AUC 7 or active surveillance (SV) for seminomatous GCTs (SGCT) and retroperitoneal lymphadenectomy (RPLND), CT by 1 or 2 cycles of Bleomycine Etoposide Cisplatine (BEP) or active surveillance for nonseminomatous GCTs (NSGCT). Adjuvant treatments decrease the relapse rate after orchiectomy with substantial toxicities without any benefit on overall survival. Recent guidelines accorded utmost importance on SV rather than adjuvants strategies. The main objective of this study was to describe our current practice over the 10 past years in regard of these recommendations. METHODS: Data of 50 patients with stage I GCT treated in our institute were collected between 2006 and 2016. Demographic and anatomopathologic data were reported. Clinical practice in our center was analyzed during two periods [2006-2011] and [2012-2016] according to the European Association of Urology Guidelines in 2011. RESULTS: Patient's median age was 35.3 years. The analysis of clinical practice during the last 10 years showed that in SGCT, main treatment was RT than SV and CT. This option declined over the years (89% between 2006-2010 versus 53% between 2011-2016) whereas SV was more often employed (27% between 2011-2016 versus none between 2006-2010). Surveillance was used for 64% of NSGCT. CONCLUSIONS: In our center, RT was less used over the years for the benefit of SV which is recommended by guidelines.

Maintenance Therapy in Metastatic Solid Tumors: Innovative Strategy or Simple Second-line Treatment?

Managing metastatic diseases involves defining the best strategy that is supposed to take into account both efficacy and quality of life. To this end, clinicians use stop and go or maintenance strategies. As a matter of fact, 2 maintenance strategies can be distinguished: continuation maintenance using a drug already present in induction treatment and switch maintenance with a newly introduced drug. Several drugs have been approved as maintenance therapy with several current indications in solid tumors. Questions remain concerning such strategies, notably duration, cost, tolerability, and shortcut between switch maintenance and early second line. If the concept of maintenance strategy remains trendy with numerous trials ongoing, several issues are still pending. The aims of this review were to accurately define and describe the various facets of maintenance therapy through its several indications in real life and then to discuss the future challenges of maintenance therapy in oncology.

High-throughput sequencing in clinical oncology: from past to present.

The war on cancer remains a major challenge as one of the hurdles for additional progress is the complexity of the mechanisms underlying the disease. Cutting-edge technologies and computing tools have led to whole genome sequencing as well as an integrated and inclusive omic approach of cancers with accurate molecular tumors' signatures through impressive progress in the field of Next Generation Sequencing (NGS). Genomic data may foster strategies for new drug development in addition to a better understanding of cancer genesis, opening a new era in oncology clinical practice. This review discusses the development of genomics approaches in cancer research and its perspectives for precision medicine, as well as clinical implications and remaining challenges.

Advocacy for a New Oncology Research Paradigm: The Model of Bevacizumab in Triple-Negative Breast Cancer in a French Cohort Study.

BACKGROUND: Triple-negative breast cancer remains a disease with poor prognosis and few treatment options, due to the lack of therapeutic targets. Bevacizumab, the first anti-VEGF agent approved in the treatment of cancer, has demonstrated efficacy in breast cancer in combination with paclitaxel for the first-line treatment of HER2-negative metastatic breast cancer. Despite the fact that the benefit was particularly significant for triple-negative breast cancer with its approval in 2008 by the FDA, this decision was later reversed as there was no improvement in overall survival in addition to significant costs. OBJECTIVES: The scope of the present study is to focus on the role of bevacizumab in triple-negative breast cancer through the analysis of overall survival, progression-free survival, and cost benefit among 45 patients in a French monocentric study and to discuss new paradigms of endpoints. METHODS: All patients diagnosed with metastatic triple-negative breast cancer, for whom first-line treatment was bevacizumab in combination with paclitaxel between January 2011 and April 2018 were included in this single-center retrospective study, and a chart review of all recruited subjects was performed from medical records. RESULTS: In this real-life study among 45 patients with metastatic triple-negative breast cancer, bevacizumab provided a significant benefit for a category of patients, with longer median progression-free survival and the ability of maintenance therapy associated to limited side effects. CONCLUSIONS: Beyond being the phoenix of breast oncology and a magnet of controversy, the case of bevacizumab in metastatic breast cancer highlights one of the greatest challenges in oncology, namely to balance modest clinical benefits with exponential costs. A balance needs to be found between health care affordability, high price of progress, and the best medical decision for the patients, in order to avoid the "unbreathable tipping point" we are actually dealing with.

Cancer du rein métastatique : recommandations et perspectives en 1re ligne.

METASTATIC RENAL CELL CARCINOMA: WHICH TREATMENTS IN FIRST-LINE SETTING?: The treatment of metastatic kidney cancer has radically changed during the past decade, notably with the development of tyrosin kinase inhibitors (TKI) and the rise of immunotherapy. Kidney cancer, especially clear cell renal cell carcinoma (CCRC) which regroups 80% of cases, is associated with increased angiogenesis and VEGF (vascular endothelial growth factor) dependent signaling pathways. Targeted therapies have therefore modified therapeutical strategies through direct inhibition of VEGF on its receptor or inhibition of the PI3K/AKT/mTOR pathway. Consequently, new anti-angiogenic molecules are now available as first line treatment and are to be prioritized depending on tumoral histology and prognostic groups. These new molecules have allowed increased patient survival. Immunotherapy is again currently transforming our first line therapeutical approach of metastatic kidney cancer with numerous ongoing therapeutical trials including combination of targeted therapies with immune checkpoint inhibitors or association of various immunotherapies. Beyond these major first line changes, difficulties still remain in the therapeutical sequence which is crucial in the care of these patients. This report aims to underline first line therapeutical recommendations in metastatic kidney cancer and expose results of recent assays.

Cancer du rein et radiothérapie : radiorésistance et au-delà.

KIDNEY CANCER AND RADIOTHERAPY: RADIORESISTANCE AND BEYOND: Metastatic renal cancer has a poor prognosis because of the limited impact of usual treatment modalities, and notably radiotherapy. Renal cell carcinoma is traditionally considered to be radioresistant, and conventional radiotherapy fraction sizes of 1.8 to 2 Gy are thought to have little role in its management. Technological advances in radiation oncology have led to stereotactic approaches that overcome radio resistance mechanisms of renal cancer cells and could be successful. The technical ability of applying high dose per fraction, leads to a distinct biological response which is different from the one observed with conventional irradiation through high responses rates. The increased radiobiological effect is attributed to endothelial apoptosis triggered by high fractional dose. The combination of such radiotherapy regimens with targeted drugs paves the way for new therapeutic opportunities.