Target Therapies for Uterine Carcinosarcomas: Current Evidence and Future Perspectives.

Salvatore Vitale,Gaetano Valenti,Roberto Angioli,Salvatore Butticè,Salvatore Lopez,Diego Rossetti,Antonio Laganà,Giuseppe Sarpietro,Stella Capriglione,Valentina La Rosa,Daniele Fanale,Fabrizio Sapia,Alessandro Tropea,Carmelo Tuscano

doi:10.3390/ijms18051100

Abstract

Carcinosarcomas (CS) in gynecology are very infrequent and represent only 2–5% of uterine cancers. Despite surgical cytoreduction and subsequent chemotherapy being the primary treatment for uterine CS, the overall five-year survival rate is 30 ± 9% and recurrence is extremely common (50–80%). Due to the poor prognosis of CS, new strategies have been developed in the last few decades, targeting known dysfunctional molecular pathways for immunotherapy. In this paper, we aimed to gather the available evidence on the latest therapies for the treatment of CS. We performed a systematic review using the terms “uterine carcinosarcoma”, “uterine Malignant Mixed Müllerian Tumors”, “target therapies”, “angiogenesis therapy”, “cancer stem cell therapy”, “prognostic biomarker”, and “novel antibody-drug”. Based on our results, the differential expression and accessibility of epithelial cell adhesion molecule-1 on metastatic/chemotherapy-resistant CS cells in comparison to normal tissues and Human Epidermal Growth Factor Receptor 2 (HER2) open up new possibilities in the field of target therapy. Nevertheless, future investigations are needed to clarify the impact of these new therapies on survival rate and medium-/long-term outcomes.

Highlights

Carsinosarcoma (CS), defined as Malignant Mixed Müllerian Tumor (MMMT), is one of the less common and most challenging tumors to treat
Further to mutations in cancer genes already observed in uterine and ovarian CS such as TP53, PIK3CA, PPP2R1A, KRAS, PTEN, CHD4, and BCOR, this study identified an excess of mutations in genes encoding histone H2A and H2B, demonstrating a stable transgenic expression of H2A and H2B in a uterine serous carcinoma cell line
Another study reported that surface expression of Epithelial Cell Adhesion Molecule-1 (EpCAM) was observed in 80.0% of the CS cell lines tested by flow cytometry [37]

Summary

Introduction

Carsinosarcoma (CS), defined as Malignant Mixed Müllerian Tumor (MMMT), is one of the less common and most challenging tumors to treat It consists of a mixture of carcinomatous (malignant epithelial) and sarcomatous (mesenchymal) components. The most frequent primary site is the endometrium, with late differentiation into the sarcomatous components Both components express very similar immunohistochemical markers, share common somatic mutations, and often show identical X chromosome inactivation patterns [3]. It is established that the sarcomatous component can express cytokeratins and the epithelial element is often immunoreactive for vimentin. These results reflect the common mesodermal origin of these two tumors. According to the International Federation of Gynecology and Obstetrics (FIGO) guidelines, it is mandatory to perform an accurate surgical staging, including total hysterectomy, bilateral salpingo-oophorectomy, pelvic and para-aortic lymph node dissection, peritoneal cytology, omentectomy, and peritoneal biopsies

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