Ovarian Suppression: Early Menopause and Late Effects.

OPINION STATEMENT: Around 90% of breast tumours are diagnosed in the early stage, with approximately 70% being hormone receptor-positive. The cornerstone of adjuvant therapy for early-stage hormone receptor-positive breast cancer is endocrine therapy, tailored according to disease stage, biological characteristics of the tumour, patient's comorbidities, preferences and age. In premenopausal patients with hormone receptor-positive breast cancer, ovarian function suppression is a key component of the adjuvant endocrine treatment in combination with an aromatase inhibitor or tamoxifen. Moreover, it can be used during chemotherapy as a standard strategy for ovarian function preservation in all breast cancer subtypes. In the metastatic setting, ovarian function suppression should be used in all premenopausal patients with hormone receptor-positive breast cancer to achieve a post-menopausal status. Despite its efficacy, ovarian function suppression may lead to several side effects that can have a major negative impact on patients' quality of life if not properly managed (e.g. hot flashes, depression, cognitive impairment, osteoporosis, sexual dysfunction, weight gain). A deep knowledge of the side effects of ovarian function suppression is necessary for clinicians. A correct counselling in this regard and proactive management should be considered a fundamental part of survivorship care to improve treatment adherence and patients' quality of life.

The Role of Cyclin-Dependent Kinases (CDK) 4/6 in the Ovarian Tissue and the Possible Effects of Their Exogenous Inhibition.

The combination of cyclin-dependent kinase (CDK) 4/6 inhibitors with endocrine therapy is the standard treatment for patients with HR+/HER2- advanced breast cancer. Recently, this combination has also entered the early setting as an adjuvant treatment in patients with HR+/HER2- disease at a high risk of disease recurrence following (neo)adjuvant chemotherapy. Despite their current use in clinical practice, limited data on the potential gonadotoxicity of CDK4/6 inhibitors are available. Hence, fully informed treatment decision making by premenopausal patients concerned about the potential development of premature ovarian insufficiency and infertility with the proposed therapy remains difficult. The cell cycle progression of granulosa and cumulus cells is a critical process for ovarian function, especially for ensuring proper follicular growth and acquiring competence. Due to the pharmacological properties of CDK4/6 inhibitors, there could be a potentially negative impact on ovarian function and fertility in women of reproductive age. This review aims to summarize the role of the cyclin D-CDK4 and CDK6 complexes in the ovary and the potential impact of CDK4/6 inhibition on its physiological processes.

Choosing the appropriate pharmacotherapy for breast cancer during pregnancy: what needs to be considered?

INTRODUCTION: Breast cancer is the most commonly diagnosed malignancy during pregnancy. Breast cancer during pregnancy is a challenging clinical condition requiring proper and timely multidisciplinary management. AREAS COVERED: This review focuses on the management of breast cancer during pregnancy with a focus about the current state-of-the-art on the feasibility and safety of pharmacotherapy approaches in this setting. EXPERT OPINION: Multidisciplinary care is key for a proper diagnostic-therapeutic management of breast cancer during pregnancy. Engaging patients and their caregivers in the decision-making process is essential and psychological support should be provided. The treatment of patients with breast cancer during pregnancy should follow the same recommendations as those for breast cancer in young women outside pregnancy but taking into account the gestational age at the time of treatment.Anthracycline-, cyclophosphamide-, and taxane-based regimens can be safely administered during the second and third trimesters with standard protocols, preferring weekly regimens whenever possible. Endocrine therapy, immune checkpoint inhibitors, and targeted agents are contraindicated throughout pregnancy, also due to the very limited data available to guide their administration in this setting. During treatment, careful fetal growth monitoring is mandatory, and even after delivery proper health monitoring for the children exposed in utero to chemotherapy should be continued.

Healthcare Worker Study Cohort to Determine the Level and Durability of Cellular and Humoral Immune Responses after Two Doses of SARS-CoV-2 Vaccination.

We prospectively studied immunological response against SARS-CoV-2 after vaccination among healthcare workers without (group A) and with previous infection (group B). The analyses were collected at T0 (before the BNT162b2), T1 (before the second dose), T2 and T6 (1 and 6 months after the second dose). For cellular immune response, the activation-induced cell marker assay was performed with CD4 and CD8 Spike peptide megapools expressed as Stimulation Index. For humoral immune response, we determined antibodies to Spike-1 and nucleocapsid protein. The linear mixed model compared specific times to T0. The CD4+ Spike response overall rate of change was significant at T1 (p = 0.038) and at T2 (p < 0.001), while decreasing at T6. For CD8+ Spike reactivity, the interaction between the time and group was significant (p = 0.0265), and the p value for group comparison was significant at the baseline (p = 0.0030) with higher SI in previously infected subjects. Overall, the anti-S Abs significantly increased from T1 to T6 compared to T0. The group B at T6 retained high anti-S titer (p < 0.001). At T6, in both groups we found a persistent humoral response and a high CD4+ T cell response able to cross recognize SARS-COV-2 variants including epsilon, even if not a circulating virus at that time.

Case report: Sotrovimab, remdesivir and nirmatrelvir/ritonavir combination as salvage treatment option in two immunocompromised patients hospitalized for COVID-19.

COVID-19 in immunocompromised patients is difficult to treat. SARS-CoV-2 interaction with the host immune system and the role of therapy still remains only partly understood. There are no data regarding the use of monoclonal antibodies and the combination of two antivirals in fighting viral replication and disease progression. We report the cases of two patients, both treated with rituximab for non-Hodgkin lymphoma and granulomatosis with polyangiitis, respectively, and both hospitalized for COVID-19 with positive SARS-CoV-2 RNAemia, who were successfully treated with a salvage combination therapy with sotrovimab, remdesivir and nirmatrelvir/ritonavir.