Uterine leiomyosarcoma (uLMS) is a rare gynaecological malignancy arising in the muscle wall of the uterus. The 5-year survival rate of uLMS is 35-65.2% for tumours that have not spread beyond the uterus. However, women are often diagnosed at late stage due to a lack of screening options, by which time the tumour has often spread to adjacent and distant organs. Current standard of care for uLMS patients is surgical de-bulking followed by adjuvant chemotherapy, but significant improvement in progression free survival and overall survival is not consistently observed.
The lack of advances for the treatment and screening of uLMS is due in part to the scarcity of appropriate research resources for this rare disease. At the WEHI-Stafford Fox Rare Cancer Program we have recruited 40 uLMS patients, including via our remote consenting program. We collect blood and tumour samples, both fresh and archival formalin fixed paraffin embedded. Fresh tissue is prioritized for whole-genome sequencing, transplanted into immune-compromised mice to facilitate patient-derived xenograft (PDX) generation and viably stored. Archival samples are analysed by whole-exome or targeted panel sequencing, promoter methylation and IHC.
As homologous recombination DNA repair deficiency (HRD) was recently shown to occur in 10% of uLMS patients, we wished to determine whether our cohort had similar rates and whether our patients might benefit from poly ADP ribose polymerase (PARP) inhibitors. To date, we have screened 24 patients for mutations in BRCA1/2 or detection of mutational signature 3, via next generation sequencing. Of the 24 patients screened, we have observed evidence of HRD in four patients (a rate of 17%). We have established PDX from two HRD uLMS cases, enabling an evidence-based approach for testing PARPi combination therapies for these patients. Our work has provided support for screening for HRD in uLMS and a new avenue of therapeutic options for patients with this rare cancer type.