Targeting homologous recombination deficiency in uterine leiomyosarcoma
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Published:2023-05-04
Issue:1
Volume:42
Page:
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ISSN:1756-9966
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Container-title:Journal of Experimental & Clinical Cancer Research
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language:en
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Short-container-title:J Exp Clin Cancer Res
Author:
Dall Genevieve, Vandenberg Cassandra J.ORCID, Nesic Ksenija, Ratnayake Gayanie, Zhu Wenying, Vissers Joseph H. A., Bedő Justin, Penington Jocelyn, Wakefield Matthew J., Kee Damien, Carmagnac Amandine, Lim Ratana, Shield-Artin Kristy, Milesi Briony, Lobley Amanda, Kyran Elizabeth L., O’Grady Emily, Tram Joshua, Zhou Warren, Nugawela Devindee, Stewart Kym Pham, Caldwell Reece, Papadopoulos Lia, Ng Ashley P., Dobrovic Alexander, Fox Stephen B., McNally Orla, Power Jeremy D., Meniawy Tarek, Tan Teng Han, Collins Ian M., Klein Oliver, Barnett Stephen, Olesen Inger, Hamilton Anne, Hofmann Oliver, Grimmond Sean, Papenfuss Anthony T., Scott Clare L., Barker Holly E.
Abstract
Abstract
Background
Uterine leiomyosarcoma (uLMS) is a rare and aggressive gynaecological malignancy, with individuals with advanced uLMS having a five-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) (> 0.2) but only two samples had a CHORD score > 50%, one of which had a homozygous pathogenic alteration in an HR gene (deletion in BRCA2). A further three samples harboured homozygous HRD alterations (all deletions in BRCA2), detected by WES or panel sequencing, with 5/58 (9%) individuals having HRD uLMS. All five individuals gained access to PARPi therapy. Two of three individuals with mature clinical follow up achieved a complete response or durable partial response (PR) with the subsequent addition of platinum to PARPi upon minor progression during initial PR on PARPi. Corresponding PDX responses were most rapid, complete and sustained with the PARP1-specific PARPi, AZD5305, compared with either olaparib alone or olaparib plus cisplatin, even in a paired sample of a BRCA2-deleted PDX, derived following PARPi therapy in the patient, which had developed PARPi-resistance mutations in PRKDC, encoding DNA-PKcs.
Conclusions
Our work demonstrates the value of identifying HRD for therapeutic targeting by PARPi and platinum in individuals with the aggressive rare malignancy, uLMS and suggests that individuals with HRD uLMS should be included in trials of PARP1-specific PARPi.
Funder
Australian and New Zealand Gynaecological Oncology Group National Health and Medical Research Council Stafford Fox Medical Research Foundation Cancer Council Victoria Victorian Cancer Agency
Publisher
Springer Science and Business Media LLC
Subject
Cancer Research,Oncology
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