Homologous Recombination DNA Repair Pathway Disruption and Retinoblastoma Protein Loss Are Associated with Exceptional Survival in High-Grade Serous Ovarian Cancer

作者：Dale W. Garsed, Kathryn Alsop, Sián Fereday, Catherine Emmanuel, Catherine J. Kennedy, Dariush Etemadmoghadam, Bo Gao, Val Gebski, Valérie Garès, Elizabeth L. Christie, Maartje C.A. Wouters, Katy Milne, Joshy George, Ann‐Marie Patch, Jason Li, Gisela Mir Arnau, Timothy Semple, Sreeja Gadipally, Yoke-Eng Chiew, Joy Hendley, Thomas Mikeska, Giada V. Zapparoli, Kaushalya Amarasinghe, Sean M. Grimmond, John V. Pearson, Nicola Waddell, Jillian A. Hung, Colin J.R. Stewart, Raghwa Sharma, Prue E. Allan, Peter Rambau, Orla McNally, Linda Mileshkin, Anne Hamilton, Sumitra Ananda, Marisa Grossi, Paul A. Cohen, Yee Leung, Robert Rome, Philip Beale, Penny Blomfield, Michael Friedländer, Alison H. Brand, Alexander Dobrovic, Martin Köbel, Paul R. Harnett, Brad H. Nelson, David D.L. Bowtell, Anna DeFazio, Nadia Traficante, for the Australian Ovarian Cancer Study Group · 发表于：Clinical Cancer Research · 年份：2017 · DOI：10.1158/1078-0432.ccr-17-1621 · 被引用次数：95 · 研究领域：PARP inhibition in cancer therapy、DNA Repair Mechanisms、Ovarian cancer diagnosis and treatment

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, ...