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, The Jackson Laboratory
Ann-Marie Patch
Jason Li
Gisela Mir Arnau
Timothy Semple
Sreeja R Gadipally
Yoke-Eng Chiew
Joy Hendley
Thomas 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


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.