Targeting homologous recombination deficiency in uterine leiomyosarcoma

Background: Uterine leiomyosarcoma (uLMS) is really a rare and aggressive gynaecological malignancy, with folks with advanced uLMS getting a 5-year survival of < 10%. Mutations in the homologous recombination (HR) DNA repair pathway have been observed in ~ 10% of uLMS cases, with reports of some individuals benefiting from poly (ADP-ribose) polymerase (PARP) inhibitor (PARPi) therapy, which targets this DNA repair defect. In this report, we screened individuals with uLMS, accrued nationally, for mutations in the HR repair pathway and explored new approaches to therapeutic targeting. Methods: A cohort of 58 individuals with uLMS were screened for HR Deficiency (HRD) using whole genome sequencing (WGS), whole exome sequencing (WES) or NGS panel testing. Individuals identified to have HRD uLMS were offered PARPi therapy and clinical outcome details collected. Patient-derived xenografts (PDX) were generated for therapeutic targeting. Results: All 13 uLMS samples analysed by WGS had a dominant COSMIC mutational signature 3 11 of these had high genome-wide loss of heterozygosity (LOH) (> .2) only two samples were built with saruparib a CHORD score > 50%, one of these were built with a homozygous pathogenic alteration within an HR gene (deletion in BRCA2). An additional three samples harboured homozygous HRD alterations (all deletions in BRCA2), detected by WES or panel sequencing, with 5/58 (9%) individuals getting HRD uLMS. All five individuals acquired use of PARPi therapy. A couple of three people with mature clinical follow-up achieved an entire response or durable partial response (PR) using the subsequent inclusion of platinum to PARPi upon minor progression during initial PR on PARPi. Corresponding PDX responses were most rapid, complete and sustained using the PARP1-specific PARPi, AZD5305, in contrast to either olaparib alone or olaparib plus cisplatin, even just in a paired sample of the BRCA2-deleted PDX, derived following PARPi therapy within the patient, which in fact had developed PARPi-resistance mutations in PRKDC, encoding DNA-PKcs.

Conclusions: Our work demonstrates the need for identifying HRD for therapeutic targeting by PARPi and platinum in people with the aggressive rare malignancy, uLMS and shows that people with HRD uLMS ought to be incorporated in trials of PARP1-specific PARPi.