Uterine sarcoma (US) is a rare mesenchymal malignant cancer type, accounting for 3–7% of uterine malignancies. US prognosis is still poor due to high local and distant recurrence rates. As for molecular features, US may present variable oestrogen receptor (ER) and progesterone receptor (PR) expressions, mostly depending on histotype and grading. Surgery represents the mainstay of treatment for early-stage disease, while the role of adjuvant chemotherapy or local radiotherapy is still debated and defined on the basis of histotype, tumour grading and stage. In metastatic setting, uterine sarcomas’ treatment includes palliative surgery, a metastases resection, chemotherapy, hormonal therapy and targeted therapy. As for the chemotherapy regimen used, drugs that are considered most effective are doxorubicin (combined with ifosfamide or alone), gemcitabine combined with docetaxel and, more recently, trabectedin or pazopanib. Hormonal therapies, including aromatase inhibitors (AIs), progestins and gonadotropin-releasing hormone analogues (GnRH-a) may also represent an effective option, in particular for low-grade endometrial stromal sarcoma (LGESS), due to their favourable toxicity profile and patients’ compliance, while their role is still under investigation in uterine leiomyosarcoma (uLMS), high-grade endometrial stromal sarcoma (HGESS), undifferentiated uterine sarcoma (USS) and other rarer US. The present review aims to analyse the existing evidence and future perspectives on hormonal therapies in US, in order to clarify their potential role in daily clinical practice.
In recent years, BRAF inhibitors (BRAFi) and MEK inhibitors (MEKi), together with immune checkpoint inhibitors (ICIs), have changed the therapeutic strategy of cutaneous melanoma, both in adjuvant and metastatic settings. These inhibitors have significantly improved the clinical outcome for patients with melanoma, including in both BRAF-mutated and BRAF-wild type disease. Some preclinical and clinical studies have revealed that BRAFi and MEKi are able to influence T-and B-cell activation, and to modulate immune system activation within the tumor microenvironment. Dabrafenib and trametinib have been shown to enhance the expression of melanoma antigens on BRAF-mutated cells, and to favor both a cytotoxic and immune response against melanoma cells. Thereby, the present study described a case series of five women treated with BRAFi and MEKi, in both adjuvant and metastatic settings, that experienced potential immune-related adverse events. In particular, these patients exhibited sarcoidosis, mesenteric panniculitis, lymphocytic colitis and neuropathy of phrenic nerve. Considering that T and B cells are responsible for immune-related adverse events, as observed in patients treated with ICIs, the present study suggested a possible role of BRAFi and MEKi as triggers of immune system activation and subsequent immune-related toxicities.
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