Uterine sarcomas make up 1-4% of uterine malignancies. Of these 60% are classified as leiomyosarcoma (uLMS). 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 a late stage due to a lack of screening options by which time the tumour has often spread to adjacent and distant tissues. 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.
Deficiency in homologous recombination (HR) repair of DNA damage is observed in 10% of uLMS patients indicating a subset of uLMS patients may derive benefit from PARP inhibition therapy. One such example of this was recently observed in the Walter and Eliza Hall Institute of Medical Research Stafford Fox Rare Cancer Program (WEHI-SFRCP): a patient with uLMS was recruited to WEHI-SFRCP with progressive disease after three lines of chemotherapy. A tumour biopsy was sent for urgent whole-genome sequencing and deletion of the entire BRCA2 gene was detected. Subsequently the patient was provided with Olaparib treatment and has achieved a partial response. Intriguingly, the patient-derived xenograft (PDX) model generated from the same tumour is not responding to an equivalent dosing schedule. Several hypotheses have been put forward to explain this finding, including but not limited to, an involvement of the immune system. PDX models within the WEHI-SFRCP are typically grown in NOD scid gamma (NSG) mice which lack T cells, B cells and Natural Killer cells. To explore the possibility of the requirement of an immune response to facilitate the efficacy of Olaparib in this particular PDX line, we have successfully transplanted the tumour into humanised NSG mice which are currently undergoing treatment. Sequencing of the PDX line is also planned to further characterise the tumour, which may provide additional benefit to the patient particularly in predicting therapy resistance.