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Title: Homologous recombination DNA repair pathway disruption and retinoblastoma protein loss are associated with exceptional survival in high-grade serous ovarian cancer.
Authors: Rome, Robert
Other Authors: Garsed, Dale
Alsop, Kathryn
Fereday, Sian
Emmanuel, Catherine
Kennedy, Catherine
Etemadmoghadam, Dariush
Gao, Bo
Gebski, Val
Garès, Valérie
Christie, Elizabeth
Wouters, Maartje
Milne, Katy
George, Joshy
Patch, Ann-Marie
Li, Jason
Arnau, Gisela Mir
Semple, Timothy
Gadipally, Sreeja
Chiew, Yoke-Eng
Hendley, Joy
Mikeska, Thomas
Zapparoli, Giada
Amarasinghe, Kaushalya
Grimmond, Sean
Pearson, John
Waddell, Nicola
Hung, Jillian
Stewart, Colin
Sharma, Raghwa
Allan, Prue
Rambau, Peter
Traficante, Nadia
McNally, Orla
Mileshkin, Linda
Hamilton, Anne
Ananda, Sumitra
Grossi, Marisa
Cohen, Paul
Leung, Yee
Beale, Philip
Blomfield, Penny
Friedlander, Michael
Brand, Alison
Dobrovic, Alexander
Köbel, Martin
Harnett, Paul
Nelson, Brad
Bowtell, David
deFazio, Anna
Keywords: Epithelial Ovarian Cancer
High-Grade Serous Cancer
Ovarian Cancer
Genome Sequencing
Long Progression-Free Survival
Pathogenic Germline
Somatic Mutations
Ki-67 Staining
CD8+ Tumor-Infiltrating Lymphocytes
Long-Term Survivors
Clinical Determinants
Pathological Determinants
Molecular Determinants
Treatment Response
Multiple Responder
Long-Term Survivors
Homologous Recombination
RB1 Loss
Cancer Services Clinical Institute, Epworth HealthCare, Victoria, Australia
Issue Date: Oct-2017
Publisher: American Association for Cancer Research
Citation: Clin Cancer Res. 2017 Oct 23. pii: clincanres.1621.2017
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.
DOI: 10.1158/1078-0432.CCR-17-1621
PubMed URL:
ISSN: 1078-0432
Journal Title: Clinical Cancer Research
Type: Journal Article
Affiliated Organisations: Cancer Research, Peter MacCallum Cancer Centre.
Research, Peter MacCallum Cancer Centre.
Cancer Genetics and Genomics Laboratory and Australian Ovarian Cancer Study, Peter MacCallum Cancer Centre.
Department of Gynaecological Oncology, Centre for Cancer Research, The Westmead Institute for Medical Research, University of Sydney.
Gynaecological Oncology and Westmead Institute for Cancer Research, University of Sydney at the Westmead Millennium Institute.
NHMRC Clinical Trials Centre, University of Sydney.
NHMRC Clinical Trials Centre.
Cancer Genomics and Genetics Program, Peter MacCallum Cancer Centre.
Deeley Research Centre, BC Cancer Agency.
Deeley Research Centre, British Columbia Cancer Agency.
Computational Sciences and Statistical Analysis, Jackson Laboratory for Genomic Medicine.
Department of Medical Genomics, QIMR Berghofer Medical Research Institute
Peter MacCallum Cancer Centre.
Westmead Institute for Cancer Research, University of Sydney at Westmead Millennium Institute.
Translational Genomics and Epigenomics Laboratory, Olivia Newton-John Cancer Research Institute.
University of Melbourne Centre for Cancer Research,, University of Melbourne.
Research, QIMR Berghofer Medical Research Institute.
Gynaecological Oncology, Westmead Hospital.
Dept of Histopathology, King Edward Memorial Hospital.
Department of Tissue Pathology, ICPMR, Sydney West Area Health Service.
Pathology, Peter MacCallum Cancer Centre.
University of Calgary.
Department of Obstetrics and Gynaecology, Royal Women's Hospital.
Division of Haematology and Medical Oncology, Peter MacCallum Cancer Centre.
Medical Oncology, Peter MacCallum Cancer Centre
Gynecologic Oncology, St John of God Hospital Bendat Family Cancer Centre Subiaco.
Division of Obstetrics and Gynaecology, University of Western Australia.
Sydney Cancer Centre, Concord Repatriation General Hospital.
The Royal Hobart Hospital.
MEDICAL ONCOLOGY, University of New South Wales.
Department of Gynaecological Oncology, Crown Princess Mary Cancer Centre.
Pathology, University of Calgary.
Crown Princess Mary Cancer Centre, Westmead Hospital.
Centre for Cancer Research, University of Sydney, Westmead Institute for Medical Research.
Type of Clinical Study or Trial: Case Series and Case Reports
Appears in Collections:Cancer Services

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