journal contribution
posted on 2023-03-31, 19:44 authored by 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 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, 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 Revised Supplementary Data, containing Supplementary Methods, Supplementary Figures, Supplementary Tables Supplementary Figure S1. Outline of cohort selection and analyses. Supplementary Figure S2. Clinical response and therapy course of 96 patients with exceptional responses to chemotherapy. Supplementary Figure S3. Distribution and type of TP53 mutations. Supplementary Figure S4. RB1 protein expression altered by genomic inactivation. Supplementary Figure S5. Characterization of CD8 and Ki-67 in tumors according to homologous recombination mutation status. Supplementary Table S2 Immunohistochemical analysis: primary antibodies and staining conditions Supplementary Table S3 Homologous recombination and DNA repair panel Supplementary Table S6 Comparison of molecular alteration prevalence between clinical subgroups Supplementary Table S7 Patient characteristics of tissue microarray cohort
Funding
Department of Health and Human Services
NHMRC
Cancer Australia
National Breast Cancer Foundation
Canadian Institutes of Health Research
U.S. Army Medical Research and Materiel Command
Cancer Institute New South Wales
History
ARTICLE 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; 24(3); 569–80. ©2017 AACR.See related commentary by Peng and Mills, p. 508
