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Abstract Metastatic urothelial carcinoma (mUC) is a lethal cancer, with limited therapeutic options. Large-scale studies in early settings provided critical insights into the genomic and transcriptomic characteristics of non-metastatic UC. The genomic landscape of mUC remains however unclear. Using Whole Exome (WES) and mRNA sequencing (RNA-seq) performed on metastatic biopsies from 111 patients, we show that driver genomic alterations from mUC were comparable to primary UC (TCGA data). APOBEC, platin, and HRD mutational signatures are the most prevalent in mUC, identified in 56%, 14%, and 9% of mUC samples, respectively. Molecular subtyping using consensus transcriptomic classification in mUC shows enrichment in neuroendocrine subtype. Paired samples analysis reveals subtype heterogeneity and temporal evolution. We identify potential therapeutic targets in 73% of mUC patients, of which FGFR3 (26%), ERBB2 (7%), TSC1 (7%), and PIK3CA (13%) are the most common. NECTIN4 and TACSTD2 are highly expressed regardless of molecular subtypes, FGFR3 alterations and sites of metastases.

This ABIGENE pharmacokinetic (PK) study sought mainly to characterize the unchanged drug PK during long-term abiraterone acetate (AA) administration in advanced prostate cancer patients (81 patients). It was observed that individual AA concentrations remained constant over treatment time, with no noticeable changes during repeated long-term drug administration for up to 120 days. There was no correlation between AA concentrations and survival outcomes. However, a significant association between higher AA concentrations and better clinical benefit was observed (p = 0.041). The safety data did not correlate with the AA PK data. A significant positive correlation (r = 0.40, p < 0.001) was observed between mean AA concentration and patient age: the older the patient, the higher the AA concentration. Patient age was found to impact steady-state AA concentration: the older the patient, the higher the mean AA concentration. Altogether, these data may help to guide future research and clinical trials in order to maximize the benefits of AA metastatic castration-resistant prostate cancer patients.

Abstract Background At the start of 2021, oncologists lacked the necessary scientific knowledge to adapt their clinical practices optimally when faced with cancer patients refusing or reluctant to be vaccinated against COVID-19, despite the marked vulnerability of these patients to severe, and even fatal forms of this new viral infectious disease. Oncologists at Foch Hospital were confronted with this phenomenon, which was observed worldwide, in both the general population and the population of cancer patients. Methods Between April and November 2021, the Ethics and Oncology Departments of Foch Hospital decided to investigate this subject, through an empirical and interdisciplinary study in bioethics. Our scientific objective was to try to identify and resolve the principal bio-ethical issues, with a view to improving clinical practices in oncology during future major pandemics of this kind, from a highly specific bio-ethical standpoint (= quality of life/survival). We used a mainly qualitative methodological approach based on questionnaires and interviews. Results In April 2021, 29 cancer patients refused or were reluctant to be vaccinated (5.6%; 29/522). Seventeen of these patients said that making vaccination mandatory would have helped them to accept vaccination. In October 2021, only 10 cancer patients continued to maintain their refusal (1.9%; 10/522). One of the main reasons for the decrease in refusals was probably the introduction of the “pass sanitaire” (health pass) in July 2021, which rendered vaccination indispensable for many activities. However, even this was not sufficient to convince these 10 cancer patients. Conclusion We identified a key bio-ethical issue, which we then tried to resolve: vaccination policy. We characterized a major tension between “the recommendation of anti-COVID-19 vaccination” (a new clinical practice) and “free will” (a moral value), and the duty to “protect each other” (a moral standard). Mandatory vaccination, at least in France, could resolve this tension, with positive effects on quality of life (i.e. happiness), or survival, in cancer patients initially refusing or reluctant to be vaccinated, but only if collective and individual scales are clearly distinguished.

Abstract The lockdown imposed in France during the first wave of the COVID-19 pandemic wreaked havoc with access to healthcare. From March 2020 onwards, the oncologists of Foch Hospital, like many others at hospitals throughout the world, were obliged to adapt to the new conditions, including, in particular, the impossibility of seeing patients in classic consultations for the diagnosis and treatment of cancer. Patients with cancer are particularly susceptible to this new virus, due to their immune status, and this made it difficult to carry out standard hospital visits for these patients. Some patients refused to come to the hospital, whereas the doctors decided, for others, that consultation conditions at the hospital were not sufficiently safe, with sanitary measures that had yet to be precisely defined. Telemedicine was one of the adaptations adopted during this period. This mode of consultation was little used before the pandemic, for various reasons, and reimbursement was not automatic. This new approach proved to have limitations as well as advantages, as demonstrated by our empirical ethics research study, a retrospective qualitative survey of the doctors of the oncology and supportive care departments of Foch Hospital, performed during July 2021. The interview grid was based on the studies on telemedicine, oncology, COVID-19 and empirical ethics available at the time. Based on the experience gained in this domain during the first wave of the epidemic, which hit France between March and June 2020, we identified three eligibility criteria for consultations in telemedicine: the consultation concerned should not be the first consultation, the patient should be a known patient that the doctor trusts not to minimize the description of symptoms, and the results of the patient’s evaluations and examinations must be good. It may be appropriate to continue the use of teleconsultation in the future, provided that these criteria are respected.

Background: Pembrolizumab is approved for patients with metastatic urothelial carcinoma (UC) who progressed under platinum therapy. The aim of this study was to assess the efficacy and safety of pembrolizumab in a cohort of real-life UC patients. Methods: This retrospective, observational study included advanced UC patients treated with pembrolizumab in a single institution in France. The co-primary endpoints were overall survival (OS) and progression-free survival (PFS) at 6 months. Secondary endpoints were objective response rate (ORR), duration of response (DOR), disease control rate (DCR) and safety. Results: 78 patients were included in the study. The median OS was 7.3 months (3.8–12.2). The estimated OS rate at 6 months was 61.5% (50.5–72.6). The median PFS was 3.1 months (1.4–7.2). The estimated PFS rate at 6 months was 42.3% (31.1–53.5). The best ORR was 35.9%. The mean DOR was 95.5 days. The DCR was 30.8%. The most common treatment-related adverse events (AEs) of any grade were fatigue (46.2%), diarrhea (11.5%), pruritus (10.3%) and nausea (9.0%). There were no grade 3 AEs that occurred with an incidence of 5% or more. Conclusion: Our results confirmed those of randomized clinical trials concerning the treatment with pembrolizumab in patients with advanced UC that progressed after platinum-based chemotherapy.

Abiraterone acetate (AA) is the first-in-class of drugs belonging to the second-generation of agents inhibiting androgen neosynthesis in advanced prostate cancer. A cumulative experience attests that germinal gene polymorphisms may play a role in the prediction of anticancer agent pharmacodynamics variability. In the present prospective, multicentric study, gene polymorphisms of CYP17A1 (AA direct target) and the androgen transporter genes SLCO2B1 and SLCO1B3 (potential modulators of AA activity) were confronted with AA pharmacodynamics (treatment response and toxicity) in a group of 137 advanced prostate cancer patients treated in the first line by AA. The median follow-up was 56.3 months (95% CI [52.5–61]). From multivariate analysis, rs2486758 C/C (CYP17A1) and PSA (≥10 ng/mL) were associated with a shorter 3-year biological PFS (HR = 4.05, IC95% [1.46–11.22]; p = 0.007 and HR = 2.08, IC95% [1.31–3.30]; p = 0.002, respectively). From a multivariate analysis, the rs743572 (CYP17A1) and performance status were independently associated with significant toxicity (OR = 3.78 (IC95% [1.42–9.75]; p = 0.006 and OR = 4.54; IC95% [1.46–13.61]; p = 0.007, respectively). Host genome characteristics may help to predict AA treatment efficacy and identify patients at risk for toxicity.

Emmanuel Deshayes,1,2 Mathieu Roumiguie,3 Constance Thibault,4 Philippe Beuzeboc,5 Florent Cachin,6 Christophe Hennequin,7 Damien Huglo,8 François Rozet,9 Diana Kassab-Chahmi,10 Xavier Rebillard,11 Nadine Houédé1,12 1Radiobiology Unit, INSERM U1194, Institut du Cancer de Montpellier (ICM), 2Department of Nuclear Medicine, Institut du Cancer de Montpellier (ICM), Montpellier, 3Urology Department, Andrology and Renal Transplantation, CHU Rangueil, Toulouse, 4Medical Oncology Department, Hôpital Européen Georges Pompidou, 5Oncology Department, Institut Curie, 6Department of Nuclear Medicine, CHU, Clermont-Ferrand, 7Radiotherapy Department, Hôpital Saint Louis, Paris, 8Department of Nuclear Medicine, CHRU, Lille, 9Urology Department, Institut Mutualiste Montsouris, 10Intergroupe coopérateur francophone de recherche en onco-urologie, Paris, 11Urology Department, Clinique BeauSoleil, Montpellier, 12Medical Oncology Department, Institut de Cancérologie du Gard – CHU Caremeau, Nîmes, France Abstract: Prostate cancer is the most common malignant disease in men. Several therapeutic agents have been approved during the last 10 years. Among them, radium-223 dichloride (Xofigo®) is a radioactive isotope that induces irreversible DNA double-strand breaks and consequently tumor cell death. Radium-223 dichloride is a calcium-mimetic agent that specifically targets bone lesions. Radium-223 dichloride has been approved for the treatment of metastatic castration-resistant prostate cancer with symptomatic bone metastases, without known visceral metastases. In this review, first we summarize the interplay between prostate tumor cells and bone microenvironment; then, we discuss radium-223 dichloride mechanism of action and present the results of the available clinical trials and future developments for this new drug. Keywords: bone metastasis, mCRPC, mechanism, drug, agents, development