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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.|
|Other Authors:||Garsed, Dale|
Arnau, Gisela Mir
|Keywords:||Epithelial Ovarian Cancer|
High-Grade Serous Cancer
Long Progression-Free Survival
CD8+ Tumor-Infiltrating Lymphocytes
Cancer Services Clinical Institute, Epworth HealthCare, Victoria, Australia
|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.|
|Journal Title:||Clinical Cancer Research|
|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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