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 Hendley & 30 others 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

    Research output: Contribution to journalArticle

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    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

    Fingerprint

    Recombinational DNA Repair
    Retinoblastoma Protein
    Ovarian Neoplasms
    Survival
    Survivors
    Homologous Recombination
    Neoplasms
    Disease-Free Survival
    Tumor-Infiltrating Lymphocytes
    Germ-Line Mutation
    Patient Selection
    Research Design
    Genome
    Staining and Labeling
    Drug Therapy
    Mutation
    Therapeutics
    Population
    Genes

    Cite this

    Garsed, Dale W. ; Alsop, Kathryn ; Fereday, Sian ; Emmanuel, Catherine ; Kennedy, Catherine J. ; Etemadmoghadam, Dariush ; Gao, Bo ; Gebski, Val ; Garès, Valérie ; Christie, Elizabeth L. ; Wouters, Maartje C.A. ; Milne, Katy ; George, Joshy ; Patch, Ann-Marie ; Li, Jason ; Arnau, Gisela Mir ; Semple, Timothy ; Gadipally, Sreeja R. ; Chiew, Yoke-Eng ; Hendley, Joy ; Mikeska, Thomas ; Zapparoli, Giada V. ; Amarasinghe, Kaushalya ; Grimmond, Sean M. ; Pearson, John V. ; Waddell, Nicola ; Hung, Jillian ; Stewart, Colin J.R. ; Sharma, Raghwa ; Allan, Prue E. ; Rambau, Peter F. ; Traficante, Nadia ; McNally, Orla ; Mileshkin, Linda ; Hamilton, Anne ; Ananda, Sumitra ; Grossi, Marisa ; Cohen, Paul A. ; Leung, Yee C. ; Rome, Robert M. ; Beale, Philip ; Blomfield, Penny ; Friedlander, Michael ; Brand, Alison ; Dobrovic, Alexander ; Köbel, Martin ; Harnett, Paul ; Nelson, Brad H. ; Bowtell, David D. L. ; deFazio, Anna. / Homologous recombination DNA repair pathway disruption and retinoblastoma protein loss are associated with exceptional survival in high-grade serous ovarian cancer. In: Clinical Cancer Research. 2018 ; Vol. 24, No. 3. pp. 569-580.
    @article{882f327eadbc4c5f8626e8706cd2035a,
    title = "Homologous recombination DNA repair pathway disruption and retinoblastoma protein loss are associated with exceptional survival in high-grade serous ovarian cancer",
    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. {\circledC}2017 AACR.",
    author = "Garsed, {Dale W.} and Kathryn Alsop and Sian Fereday and Catherine Emmanuel and Kennedy, {Catherine J.} and Dariush Etemadmoghadam and Bo Gao and Val Gebski and Val{\'e}rie Gar{\`e}s and Christie, {Elizabeth L.} and Wouters, {Maartje C.A.} and Katy Milne and Joshy George and Ann-Marie Patch and Jason Li and Arnau, {Gisela Mir} and Timothy Semple and Gadipally, {Sreeja R.} and Yoke-Eng Chiew and Joy Hendley and Thomas Mikeska and Zapparoli, {Giada V.} and Kaushalya Amarasinghe and Grimmond, {Sean M.} and Pearson, {John V.} and Nicola Waddell and Jillian Hung and Stewart, {Colin J.R.} and Raghwa Sharma and Allan, {Prue E.} and Rambau, {Peter F.} and Nadia Traficante and Orla McNally and Linda Mileshkin and Anne Hamilton and Sumitra Ananda and Marisa Grossi and Cohen, {Paul A.} and Leung, {Yee C.} and Rome, {Robert M.} and Philip Beale and Penny Blomfield and Michael Friedlander and Alison Brand and Alexander Dobrovic and Martin K{\"o}bel and Paul Harnett and Nelson, {Brad H.} and Bowtell, {David D. L.} and Anna deFazio",
    year = "2018",
    month = "2",
    doi = "10.1158/1078-0432.CCR-17-1621",
    language = "English",
    volume = "24",
    pages = "569--580",
    journal = "Clinical Cancer Reserach",
    issn = "1078-0432",
    publisher = "American Association for Cancer Research Inc.",
    number = "3",

    }

    Garsed, DW, Alsop, K, Fereday, S, Emmanuel, C, Kennedy, CJ, Etemadmoghadam, D, Gao, B, Gebski, V, Garès, V, Christie, EL, Wouters, MCA, Milne, K, George, J, Patch, A-M, Li, J, Arnau, GM, Semple, T, Gadipally, SR, Chiew, Y-E, Hendley, J, Mikeska, T, Zapparoli, GV, Amarasinghe, K, Grimmond, SM, Pearson, JV, Waddell, N, Hung, J, Stewart, CJR, Sharma, R, Allan, PE, Rambau, PF, Traficante, N, McNally, O, Mileshkin, L, Hamilton, A, Ananda, S, Grossi, M, Cohen, PA, Leung, YC, Rome, RM, Beale, P, Blomfield, P, Friedlander, M, Brand, A, Dobrovic, A, Köbel, M, Harnett, P, Nelson, BH, Bowtell, DDL & deFazio, A 2018, 'Homologous recombination DNA repair pathway disruption and retinoblastoma protein loss are associated with exceptional survival in high-grade serous ovarian cancer' Clinical Cancer Research, vol. 24, no. 3, pp. 569-580. https://doi.org/10.1158/1078-0432.CCR-17-1621

    Homologous recombination DNA repair pathway disruption and retinoblastoma protein loss are associated with exceptional survival in high-grade serous ovarian cancer. / Garsed, Dale W.; Alsop, Kathryn; Fereday, Sian; Emmanuel, Catherine; Kennedy, Catherine J.; Etemadmoghadam, Dariush; Gao, Bo; Gebski, Val; Garès, Valérie; Christie, Elizabeth L.; Wouters, Maartje C.A.; Milne, Katy; George, Joshy; Patch, Ann-Marie; Li, Jason; Arnau, Gisela Mir; Semple, Timothy; Gadipally, Sreeja R.; Chiew, Yoke-Eng; Hendley, Joy; Mikeska, Thomas; Zapparoli, Giada V.; Amarasinghe, Kaushalya; Grimmond, Sean M.; Pearson, John V.; Waddell, Nicola; Hung, Jillian; Stewart, Colin J.R.; Sharma, Raghwa; Allan, Prue E.; Rambau, Peter F.; Traficante, Nadia; McNally, Orla; Mileshkin, Linda; Hamilton, Anne; Ananda, Sumitra; Grossi, Marisa; Cohen, Paul A.; Leung, Yee C.; Rome, Robert M.; Beale, Philip; Blomfield, Penny; Friedlander, Michael; Brand, Alison; Dobrovic, Alexander; Köbel, Martin; Harnett, Paul; Nelson, Brad H.; Bowtell, David D. L.; deFazio, Anna.

    In: Clinical Cancer Research, Vol. 24, No. 3, 02.2018, p. 569-580.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - Homologous recombination DNA repair pathway disruption and retinoblastoma protein loss are associated with exceptional survival in high-grade serous ovarian cancer

    AU - Garsed, Dale W.

    AU - Alsop, Kathryn

    AU - Fereday, Sian

    AU - Emmanuel, Catherine

    AU - Kennedy, Catherine J.

    AU - Etemadmoghadam, Dariush

    AU - Gao, Bo

    AU - Gebski, Val

    AU - Garès, Valérie

    AU - Christie, Elizabeth L.

    AU - Wouters, Maartje C.A.

    AU - Milne, Katy

    AU - George, Joshy

    AU - Patch, Ann-Marie

    AU - Li, Jason

    AU - Arnau, Gisela Mir

    AU - Semple, Timothy

    AU - Gadipally, Sreeja R.

    AU - Chiew, Yoke-Eng

    AU - Hendley, Joy

    AU - Mikeska, Thomas

    AU - Zapparoli, Giada V.

    AU - Amarasinghe, Kaushalya

    AU - Grimmond, Sean M.

    AU - Pearson, John V.

    AU - Waddell, Nicola

    AU - Hung, Jillian

    AU - Stewart, Colin J.R.

    AU - Sharma, Raghwa

    AU - Allan, Prue E.

    AU - Rambau, Peter F.

    AU - Traficante, Nadia

    AU - McNally, Orla

    AU - Mileshkin, Linda

    AU - Hamilton, Anne

    AU - Ananda, Sumitra

    AU - Grossi, Marisa

    AU - Cohen, Paul A.

    AU - Leung, Yee C.

    AU - Rome, Robert M.

    AU - Beale, Philip

    AU - Blomfield, Penny

    AU - Friedlander, Michael

    AU - Brand, Alison

    AU - Dobrovic, Alexander

    AU - Köbel, Martin

    AU - Harnett, Paul

    AU - Nelson, Brad H.

    AU - Bowtell, David D. L.

    AU - deFazio, Anna

    PY - 2018/2

    Y1 - 2018/2

    N2 - 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.

    AB - 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.

    U2 - 10.1158/1078-0432.CCR-17-1621

    DO - 10.1158/1078-0432.CCR-17-1621

    M3 - Article

    VL - 24

    SP - 569

    EP - 580

    JO - Clinical Cancer Reserach

    JF - Clinical Cancer Reserach

    SN - 1078-0432

    IS - 3

    ER -