Interrogating the Genomic Landscape of Uterine Leiomyosarcoma: A Potential for Patient Benefit

SIMPLE SUMMARY: Uterine leiomyosarcoma is an aggressive and rare cancer that is difficult to treat. There are a number of mutations that are common to uterine leiomyosarcoma that are currently not routinely targeted therapeutically in this cancer type. In this review, we summarise the studies being undertaken to investigate the effectiveness of targeting these mutations either pre-clinically in models of uterine leiomyosarcoma or in other cancers in the clinic. We hope this review will encourage the inclusion of uterine leiomyosarcoma in clinical trial design, which in turn will lead to improved survival outcomes for patients. ABSTRACT: Uterine leiomyosarcoma (uLMS) is a rare and aggressive gynaecological malignancy. Surgical removal and chemotherapy are commonly used to treat uLMS, but recurrence rates are high. Over the last few decades, clarification of the genomic landscape of uLMS has revealed a number of recurring mutations, including TP53, RB1, ATRX, PTEN, and MED12. Such genomic aberrations are difficult to target therapeutically or are actively targeted in other malignancies, and their potential as targets for the treatment of uLMS remains largely unexplored. Recent identification of deficiencies in homologous recombination in a minority of these tumours, however, has provided a rationale for investigation of PARP inhibitors in this sub-set. Here, we review these mutations and the evidence for therapeutic avenues that may be applied in uLMS. We also provide a comprehensive background on diagnosis and current therapeutic strategies as well as reviewing preclinical models of uLMS, which may be employed not only in testing emerging therapies but also in understanding this challenging and deadly disease.