Please use this identifier to cite or link to this item: http://ahro.austin.org.au/austinjspui/handle/1/18397
Title: Homologous Recombination DNA Repair Pathway Disruption and Retinoblastoma Protein Loss Are Associated with Exceptional Survival in High-Grade Serous Ovarian Cancer.
Authors: Garsed, Dale W;Alsop, Kathryn;Fereday, Sian;Emmanuel, Catherine;Kennedy, Catherine J;Etemadmoghadam, Dariush;Gao, Bo;Gebski, Val;Garès, Valérie;Christie, Elizabeth L;Wouters, Maartje C A;Milne, Katy;George, Joshy;Patch, Ann-Marie;Li, Jason;Arnau, Gisela Mir;Semple, Timothy;Gadipally, Sreeja R;Chiew, Yoke-Eng;Hendley, Joy;Mikeska, Thomas;Zapparoli, Giada V;Amarasinghe, Kaushalya;Grimmond, Sean M;Pearson, John V;Waddell, Nicola;Hung, Jillian;Stewart, Colin J R;Sharma, Raghwa;Allan, Prue E;Rambau, Peter F;McNally, Orla;Mileshkin, Linda;Hamilton, Anne;Ananda, Sumitra;Grossi, Marisa;Cohen, Paul A;Leung, Yee C;Rome, Robert M;Beale, Philip;Blomfield, Penny;Friedlander, Michael;Brand, Alison;Dobrovic, Alexander;Köbel, Martin;Harnett, Paul;Nelson, Brad H;Bowtell, David D L;deFazio, Anna
Affiliation: Department of Biochemistry and Molecular Biology, The University of Melbourne, Victoria, Australia
Department of Pathology, The University of Melbourne, Victoria, Australia
Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. david.bowtell@petermac.org
Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia
Centre for Cancer Research, The Westmead Institute for Medical Research, Sydney, New South Wales, Australia
Department of Gynaecological Oncology, Westmead Hospital, Westmead, New South Wales, Australia
Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
Sir Peter MacCallum Department of Oncology, The University of Melbourne, Victoria, Australia
Department of Pathology, University of Melbourne, Victoria, Australia
Crown Princess Mary Cancer Care Centre, Westmead Hospital, Sydney, New South Wales, Australia
NHMRC Clinical Trials Centre, Sydney, New South Wales, Australia
Deeley Research Centre, British Columbia Cancer Agency, Victoria, British Columbia, Canada
The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut
QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
Translational Genomics and Epigenomics Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia
School of Cancer Medicine, La Trobe University, Bundoora, Victoria, Australia
University of Melbourne Centre for Cancer Research, The University of Melbourne, Victoria, Australia
Department of Histopathology, King Edward Memorial Hospital, Perth and the University of Western Australia, Crawley, Western Australia, Australia
Department of Anatomical Pathology, Westmead Hospital, Westmead, New South Wales, Australia
The University of Sydney, Sydney, New South Wales, Australia
Department of Pathology and Laboratory Medicine, Foothill Medical Center, University of Calgary, Calgary, Canada
Department of Obstetrics and Gynaecology, The University of Melbourne, Victoria, Australia
The Royal Women's Hospital, Parkville, Victoria, Australia
Department of Medicine, The University of Melbourne, Victoria, Australia
St John of God Hospital Bendat Family Comprehensive Cancer Centre, Subiaco, Western Australia, Australia
The Institute for Health Research, University of Notre Dame Australia, Fremantle, Western Australia, Australia
School of Women's and Infants' Health, University of Western Australia, Crawley, Western Australia, Australia
Obstetrics and Gynaecology Institute, Epworth Freemasons Hospital, Melbourne, Victoria, Australia
Concord Hospital, Sydney, New South Wales, Australia
Department of Obstetrics and Gynaecology, The Royal Hobart Hospital, Hobart, Tasmania, Australia
Prince of Wales Clinical School, University of New South Wales, Sydney, New South Wales, Australia
Issue Date: 1-Feb-2018
EDate: 2017-10-23
Citation: Clinical cancer research : an official journal of the American Association for Cancer Research 2018; 24(3): 569-580
Abstract: Purpose: Women with epithelial ovarian cancer generally have a poor prognosis; however, a subset of patients has an unexpected dramatic and durable response to treatment. We sought to identify clinical, pathological, and molecular determinants of exceptional survival in women with high-grade serous cancer (HGSC), a disease associated with the majority of ovarian cancer deaths.Experimental Design: We evaluated the histories of 2,283 ovarian cancer patients and, after applying stringent clinical and pathological selection criteria, identified 96 with HGSC that represented significant outliers in terms of treatment response and overall survival. Patient samples were characterized immunohistochemically and by genome sequencing.Results: Different patterns of clinical response were seen: long progression-free survival (Long-PFS), multiple objective responses to chemotherapy (Multiple Responder), and/or greater than 10-year overall survival (Long-Term Survivors). Pathogenic germline and somatic mutations in genes involved in homologous recombination (HR) repair were enriched in all three groups relative to a population-based series. However, 29% of 10-year survivors lacked an identifiable HR pathway alteration, and tumors from these patients had increased Ki-67 staining. CD8+ tumor-infiltrating lymphocytes were more commonly present in Long-Term Survivors. RB1 loss was associated with long progression-free and overall survival. HR deficiency and RB1 loss were correlated, and co-occurrence was significantly associated with prolonged survival.Conclusions: There was diversity in the clinical trajectory of exceptional survivors associated with multiple molecular determinants of exceptional outcome in HGSC patients. Concurrent HR deficiency and RB1 loss were associated with favorable outcomes, suggesting that co-occurrence of specific mutations might mediate durable responses in such patients. Clin Cancer Res; 24(3); 569-80. ©2017 AACRSee related commentary by Peng and Mills, p. 508.
URI: http://ahro.austin.org.au/austinjspui/handle/1/18397
DOI: 10.1158/1078-0432.CCR-17-1621
ORCID: 0000-0003-3414-112X
PubMed URL: 29061645
ISSN: 1078-0432
Type: Journal Article
Appears in Collections:Journal articles

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