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Real-world insights into risk of developing cardiovascular disease following GnRH agonists versus antagonists for prostate cancer: a methodological protocol to a study using five European databases.

ABSTRACT: One of the more recently investigated adverse long-term side effects of gonadotropin-releasing hormone (GnRH) agonists for prostate cancer (PCa) is cardiovascular disease (CVD). Studies suggest lower risk of CVD following GnRH antagonists (degarelix) than GnRH agonists. This protocol describes precise codes used to extract variables from five European databases for a study that compares risk of CVD following GnRH agonists and antagonists for PCa. PCa men on primary GnRH agonists or antagonists were identified from the UK THIN (The Health Improvement Network) database, National Health Service (NHS) Scotland, Belgian Cancer Registry (BCR), Dutch PHARMO Database Network and French National Database (SNIIRAM). Cohort entry was defined as date of treatment initiation. CVD event was defined as any first incident or fatal CVD after cohort entry. Readcodes in THIN and ICD codes in NHS Scotland, BCR, PHARMO and SNIIRAM were used to extract variables. Risk of Bias in Non-randomised studies of Interventions (ROBINS-I) tool was used to assess the potential risk of biases in this study. 51 572 men with a median follow-up time of 2 years started on GnRH agonists and 2 417 men with a median follow-up time of 1 year started on GnRH antagonists between 2010 and 2017 in the UK, Scotland, Belgium, the Netherlands and France. Data from five countries improved the study power and internal validity required to compare risk of CVD between GnRH agonists and antagonists, the latter being a fairly new drug with limited data in individual countries.

SUBMITTER: George G

PROVIDER: S-EPMC6850363 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Real-world insights into risk of developing cardiovascular disease following GnRH agonists versus antagonists for prostate cancer: a methodological protocol to a study using five European databases.

George Gincy G Scailteux Lucie-Marie LM Garmo Hans H Balusson Frédéric F Cardwell Christopher C Coster Greet De G Schutter Harlinde De H Kuiper Josephina G JG McMenamin Úna Ú Verbeeck Julie J Van Hemelrijck Mieke M

Fundamental & clinical pharmacology 20190325 4

One of the more recently investigated adverse long-term side effects of gonadotropin-releasing hormone (GnRH) agonists for prostate cancer (PCa) is cardiovascular disease (CVD). Studies suggest lower risk of CVD following GnRH antagonists (degarelix) than GnRH agonists. This protocol describes precise codes used to extract variables from five European databases for a study that compares risk of CVD following GnRH agonists and antagonists for PCa. PCa men on primary GnRH agonists or antagonists w ...[more]

PMID: 30776136

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Project description:Commercial gonadotropin-releasing hormone (GnRH) antagonists differ by 1-2 amino acids and are used to inhibit gonadotropin production during assisted reproduction technologies (ART). In this study, potencies of three GnRH antagonists, Cetrorelix, Ganirelix and Teverelix, in inhibiting GnRH-mediated intracellular signaling, were compared in vitro. GnRH receptor (GnRHR)-transfected HEK293 and neuroblastoma-derived SH-SY5Y cell lines, as well as mouse pituitary LβT2 cells endogenously expressing the murine GnRHR, were treated with GnRH in the presence or absence of the antagonist. We evaluated intracellular calcium (Ca2+) and cAMP increases, cAMP-responsive element binding-protein (CREB) and extracellular-regulated kinase 1 and 2 (ERK1/2) phosphorylation, β-catenin activation and mouse luteinizing-hormone β-encoding gene (Lhb) transcription by bioluminescence resonance energy transfer (BRET), Western blotting, immunostaining and real-time PCR as appropriate. The kinetics of GnRH-induced Ca2+ rapid increase revealed dose-response accumulation with potency (EC50) of 23 nM in transfected HEK293 cells, transfected SH-SY5Y and LβT2 cells. Cetrorelix inhibited the 3 × EC50 GnRH-activated calcium signaling at concentrations of 1 nM-1 µM, demonstrating higher potency than Ganirelix and Teverelix, whose inhibitory doses fell within the 100 nM-1 µM range in both transfected HEK293 and SH-SY5Y cells in vitro. In transfected SH-SY5Y, Cetrorelix was also significantly more potent than other antagonists in reducing GnRH-mediated cAMP accumulation. All antagonists inhibited pERK1/2 and pCREB activation at similar doses, in LβT2 and transfected HEK293 cells treated with 100 nM GnRH. Although immunostainings suggested that Teverelix could be less effective than Cetrorelix and Ganirelix in inhibiting 1 µM GnRH-induced β-catenin activation, Lhb gene expression increase occurring upon LβT2 cell treatment by 1 µM GnRH was similarly inhibited by all antagonists. To conclude, this study has demonstrated Cetrorelix-, Ganirelix- and Teverelix-specific biased effects at the intracellular level, not affecting the efficacy of antagonists in inhibiting Lhb gene transcription.

Project description:BackgroundEndocrine therapy (ET)-based regimens are the mainstay of treatment for patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer. With the introduction of new treatment classes, it is important to examine patient symptoms and health-related quality of life (HRQoL) at the start of this changing therapeutic landscape. This real-world study describes the patient-reported outcomes (PROs) of women with HR+/HER2- advanced breast cancer receiving ET-based regimens who were naïve to systemic treatment in the advanced setting across five European countries (EU5).MethodsData were collected between March and July 2017 from surveyed oncologists and their patients at a single time point using the multinational Adelphi Advanced Breast Cancer Disease Specific Programme™. Patients completed PRO questionnaires on HRQoL (EORTC QLQ-C30), pain severity and interference, and work and activity impairment. A multiple linear regression model explored factors associated with HRQoL.ResultsAcross EU5, 226 physicians provided data on 781 women with HR+/HER2- advanced breast cancer taking their first ET-based regimen for advanced disease, of whom 252 provided PRO data. This subset had a mean age of 67.1 years, 94% were postmenopausal, 89% were diagnosed with advanced breast cancer at initial presentation, 79% had stage IV disease (66% of these patients had bone metastases and 38% had visceral metastases, including 18% with liver metastases) and 77% were on endocrine-only therapy as their initial treatment for advanced disease. The mean EORTC QLQ-C30 global health score (50.9) was worse than the reference value for patients with advanced breast cancer (60.2). Fatigue, pain, and insomnia were the most severe symptoms, and mean functioning scores were also worse than reference values. "Worst pain" and "pain interference" were moderate/severe for 42 and 80% of patients. Mean activity impairment was 44%, and greater activity impairment was associated with poorer HRQoL.ConclusionsDespite receiving first-line ET-based regimens for advanced disease, these women had a poor HRQoL and high levels of symptoms, pain, pain interference and activity impairment. New treatments that maintain a stable disease state and reduce activity impairment may have a positive effect on the HRQoL of those living with advanced breast cancer.

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Dataset Information

Real-world insights into risk of developing cardiovascular disease following GnRH agonists versus antagonists for prostate cancer: a methodological protocol to a study using five European databases.

Publications

Real-world insights into risk of developing cardiovascular disease following GnRH agonists versus antagonists for prostate cancer: a methodological protocol to a study using five European databases.

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