Targeting homologous recombination deficiency in uterine leiomyosarcoma.

Autor: Dall G; Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia.; Department of Medical Biology, University of Melbourne, Parkville, VIC, 3052, Australia., Vandenberg CJ; Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia. vandenberg@wehi.edu.au.; Department of Medical Biology, University of Melbourne, Parkville, VIC, 3052, Australia. vandenberg@wehi.edu.au., Nesic K; Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia.; Department of Medical Biology, University of Melbourne, Parkville, VIC, 3052, Australia., Ratnayake G; Royal Women's Hospital, Parkville, VIC, 3052, Australia., Zhu W; Centre for Cancer Research and Department of Clinical Pathology, University of Melbourne, Parkville, VIC, 3010, Australia., Vissers JHA; Centre for Cancer Research and Department of Clinical Pathology, University of Melbourne, Parkville, VIC, 3010, Australia., Bedő J; Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia.; School of Computing and Information Systems, the University of Melbourne, Parkville, VIC, 3010, Australia., Penington J; Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia., Wakefield MJ; Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia.; Department of Medical Biology, University of Melbourne, Parkville, VIC, 3052, Australia., Kee D; Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia.; Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, 3084, Australia.; Austin Health, Heidelberg, VIC, 3084, Australia.; Australian Rare Cancer Portal, BioGrid Australia, Melbourne Health, Parkville, VIC, 3052, Australia.; Peter MacCallum Cancer Centre and Sir Peter MacCallum Department of Oncology, The University of Melbourne, Victoria, 3010, Australia., Carmagnac A; Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia., Lim R; Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia., Shield-Artin K; Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia.; Department of Medical Biology, University of Melbourne, Parkville, VIC, 3052, Australia., Milesi B; Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia.; Royal Women's Hospital, Parkville, VIC, 3052, Australia., Lobley A; Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia.; Royal Women's Hospital, Parkville, VIC, 3052, Australia., Kyran EL; Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia., O'Grady E; Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia., Tram J; Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia., Zhou W; Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia., Nugawela D; Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia., Stewart KP; Centre for Cancer Research and Department of Clinical Pathology, University of Melbourne, Parkville, VIC, 3010, Australia., Caldwell R; Australian Rare Cancer Portal, BioGrid Australia, Melbourne Health, Parkville, VIC, 3052, Australia., Papadopoulos L; Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia.; Australian Rare Cancer Portal, BioGrid Australia, Melbourne Health, Parkville, VIC, 3052, Australia., Ng AP; Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia.; Department of Medical Biology, University of Melbourne, Parkville, VIC, 3052, Australia.; Peter MacCallum Cancer Centre and Sir Peter MacCallum Department of Oncology, The University of Melbourne, Victoria, 3010, Australia.; Royal Melbourne Hospital, Parkville, VIC, 3052, Australia., Dobrovic A; Austin Health, Heidelberg, VIC, 3084, Australia., Fox SB; Peter MacCallum Cancer Centre and Sir Peter MacCallum Department of Oncology, The University of Melbourne, Victoria, 3010, Australia., McNally O; Royal Women's Hospital, Parkville, VIC, 3052, Australia.; Peter MacCallum Cancer Centre and Sir Peter MacCallum Department of Oncology, The University of Melbourne, Victoria, 3010, Australia.; Department of Obstetrics and Gynaecology, University of Melbourne, Parkville, VIC, 3010, Australia., Power JD; Launceston General Hospital, Launceston, TAS, 7250, Australia., Meniawy T; University of Western Australia, Perth, WA, 6009, Australia., Tan TH; Peter MacCallum Cancer Centre and Sir Peter MacCallum Department of Oncology, The University of Melbourne, Victoria, 3010, Australia., Collins IM; SouthWest Healthcare, Warrnambool, VIC, 3280, Australia.; Faculty of Health, School of Medicine, Deakin University, Warrnambool, VIC, 3280, Australia., Klein O; Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, 3084, Australia.; Austin Health, Heidelberg, VIC, 3084, Australia., Barnett S; Royal Melbourne Hospital, Parkville, VIC, 3052, Australia.; Western Hospital, Footscray, VIC, 3011, Australia., Olesen I; Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia.; University Hospital Geelong, Geelong, VIC, 3220, Australia., Hamilton A; Royal Women's Hospital, Parkville, VIC, 3052, Australia.; Peter MacCallum Cancer Centre and Sir Peter MacCallum Department of Oncology, The University of Melbourne, Victoria, 3010, Australia., Hofmann O; Centre for Cancer Research and Department of Clinical Pathology, University of Melbourne, Parkville, VIC, 3010, Australia., Grimmond S; Centre for Cancer Research and Department of Clinical Pathology, University of Melbourne, Parkville, VIC, 3010, Australia., Papenfuss AT; Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia.; Department of Medical Biology, University of Melbourne, Parkville, VIC, 3052, Australia.; Peter MacCallum Cancer Centre and Sir Peter MacCallum Department of Oncology, The University of Melbourne, Victoria, 3010, Australia., Scott CL; Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia.; Department of Medical Biology, University of Melbourne, Parkville, VIC, 3052, Australia.; Royal Women's Hospital, Parkville, VIC, 3052, Australia.; Australian Rare Cancer Portal, BioGrid Australia, Melbourne Health, Parkville, VIC, 3052, Australia.; Peter MacCallum Cancer Centre and Sir Peter MacCallum Department of Oncology, The University of Melbourne, Victoria, 3010, Australia.; Royal Melbourne Hospital, Parkville, VIC, 3052, Australia.; Department of Obstetrics and Gynaecology, University of Melbourne, Parkville, VIC, 3010, Australia., Barker HE; Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia.; Department of Medical Biology, University of Melbourne, Parkville, VIC, 3052, Australia.
Jazyk: angličtina
Zdroj: Journal of experimental & clinical cancer research : CR [J Exp Clin Cancer Res] 2023 May 04; Vol. 42 (1), pp. 112. Date of Electronic Publication: 2023 May 04.
DOI: 10.1186/s13046-023-02687-0
Abstrakt: 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.
(© 2023. The Author(s).)
Databáze: MEDLINE
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