Homologous recombination DNA repair pathway disruption and retinoblastoma protein loss are associated with exceptional survival in high-grade serous ovarian cancer

Dale W. Garsed, Kathryn Alsop, Sian 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 R. Gadipally, Yoke-Eng Chiew, Joy HendleyThomas Mikeska, Giada V. Zapparoli, Kaushalya Amarasinghe, Sean M. Grimmond, John V. Pearson, Nicola Waddell, Jillian Hung, Colin J.R. Stewart, Raghwa Sharma, Prue E. Allan, Peter F. Rambau, Nadia Traficante, Orla McNally, Linda Mileshkin, Anne Hamilton, Sumitra Ananda, Marisa Grossi, Paul A. Cohen, Yee C. Leung, Robert M. Rome, Philip Beale, Penny Blomfield, Michael Friedlander, Alison Brand, Alexander Dobrovic, Martin Köbel, Paul Harnett, Brad H. Nelson, David D. L. Bowtell, Anna deFazio

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    28 Citations (Scopus)

    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; 1–12. ©2017 AACR.
    Original languageEnglish
    Pages (from-to)569-580
    Number of pages12
    JournalClinical Cancer Research
    Volume24
    Issue number3
    Early online date2017
    DOIs
    Publication statusPublished - Feb 2018

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