Relationship of Extreme Chromosomal Instability with Long-term Survival in a Retrospective Analysis of Primary Breast Cancer

Rebecca Roylance, David Endesfelder, Patricia Gorman, Jil Sander, Ian Tomlinson, Andrew M. Hanby, Valerie Speirs, Andrea L. Richardson, Nicolai Juul Birkbak, Aron Charles Eklund, Julian Downward, Maik Kschischo, Zoltan Imre Szallasi, Charles Swanton

    Research output: Contribution to journalJournal articleResearchpeer-review

    Abstract

    Background: Chromosomal instability (CIN) is thought to be associated with poor prognosis in solid tumors; however, evidence from preclinical and mouse tumor models suggest that CIN may paradoxically enhance or impair cancer cell fitness. Breast cancer prognostic expression signature sets, which reflect tumor CIN status, efficiently delineate outcome in estrogen receptor ER-positive reast cancer in contrast to ERnegative breast cancer, suggesting that the relationship of CIN with prognosis differs in these two breast cancer subtypes. Methods: Direct assessment of CIN requires single-cell analysis methods, such as centromeric FISH, aimed at determining the variation around the modal number of two or more chromosomes within individual tumor nuclei. Here, we document the frequency of tumor CIN by dual centromeric FISH analysis in a retrospective primary breast cancer cohort of 246 patients with survival outcome. Results: There was increased CIN and clonal eterogeneity in ER-negative compared with ER-positive breast cancer. Consistent with a negative impact of CIN on cellular fitness, extreme CIN in ER-negative breast cancer was an independent variable associated with improved long-term survival in multivariate analysis. In contrast, a linear relationship of increasing CIN with poorer prognosis in ER-positive breast cancer was observed, using three independent measures of CIN.
    Conclusions: The paradoxical relationship between extreme CIN and cancer outcome in the ER-negative cohorts may explain why prognostic expression signatures, reflecting tumor CIN status, fail to predict outcome in this subgroup. Impact: Assessment of tumor CIN status may support risk stratification in ER-negative breast cancer and requires prospective validation. Cancer Epidemiol Biomarkers Prev; 20(10); 2183–94. 2011 AACR
    Original languageEnglish
    JournalCancer Epidemiology, Biomarkers & Prevention
    Pages (from-to)2184-2197
    ISSN1055-9965
    DOIs
    Publication statusPublished - 22 Jul 2011

    Cite this

    Roylance, Rebecca ; Endesfelder, David ; Gorman, Patricia ; Sander, Jil ; Tomlinson, Ian ; M. Hanby, Andrew ; Speirs, Valerie ; L. Richardson, Andrea ; Birkbak, Nicolai Juul ; Eklund, Aron Charles ; Downward, Julian ; Kschischo, Maik ; Szallasi, Zoltan Imre ; Swanton, Charles. / Relationship of Extreme Chromosomal Instability with Long-term Survival in a Retrospective Analysis of Primary Breast Cancer. In: Cancer Epidemiology, Biomarkers & Prevention. 2011 ; pp. 2184-2197.
    @article{78f68e26d6414e1990940fec50877d8f,
    title = "Relationship of Extreme Chromosomal Instability with Long-term Survival in a Retrospective Analysis of Primary Breast Cancer",
    abstract = "Background: Chromosomal instability (CIN) is thought to be associated with poor prognosis in solid tumors; however, evidence from preclinical and mouse tumor models suggest that CIN may paradoxically enhance or impair cancer cell fitness. Breast cancer prognostic expression signature sets, which reflect tumor CIN status, efficiently delineate outcome in estrogen receptor ER-positive reast cancer in contrast to ERnegative breast cancer, suggesting that the relationship of CIN with prognosis differs in these two breast cancer subtypes. Methods: Direct assessment of CIN requires single-cell analysis methods, such as centromeric FISH, aimed at determining the variation around the modal number of two or more chromosomes within individual tumor nuclei. Here, we document the frequency of tumor CIN by dual centromeric FISH analysis in a retrospective primary breast cancer cohort of 246 patients with survival outcome. Results: There was increased CIN and clonal eterogeneity in ER-negative compared with ER-positive breast cancer. Consistent with a negative impact of CIN on cellular fitness, extreme CIN in ER-negative breast cancer was an independent variable associated with improved long-term survival in multivariate analysis. In contrast, a linear relationship of increasing CIN with poorer prognosis in ER-positive breast cancer was observed, using three independent measures of CIN.Conclusions: The paradoxical relationship between extreme CIN and cancer outcome in the ER-negative cohorts may explain why prognostic expression signatures, reflecting tumor CIN status, fail to predict outcome in this subgroup. Impact: Assessment of tumor CIN status may support risk stratification in ER-negative breast cancer and requires prospective validation. Cancer Epidemiol Biomarkers Prev; 20(10); 2183–94. 2011 AACR",
    author = "Rebecca Roylance and David Endesfelder and Patricia Gorman and Jil Sander and Ian Tomlinson and {M. Hanby}, Andrew and Valerie Speirs and {L. Richardson}, Andrea and Birkbak, {Nicolai Juul} and Eklund, {Aron Charles} and Julian Downward and Maik Kschischo and Szallasi, {Zoltan Imre} and Charles Swanton",
    year = "2011",
    month = "7",
    day = "22",
    doi = "10.1158/1055-9965.EPI-11-0343",
    language = "English",
    pages = "2184--2197",
    journal = "Cancer Epidemiology, Biomarkers & Prevention",
    issn = "1055-9965",
    publisher = "American Association for Cancer Research (A A C R)",

    }

    Roylance, R, Endesfelder, D, Gorman, P, Sander, J, Tomlinson, I, M. Hanby, A, Speirs, V, L. Richardson, A, Birkbak, NJ, Eklund, AC, Downward, J, Kschischo, M, Szallasi, ZI & Swanton, C 2011, 'Relationship of Extreme Chromosomal Instability with Long-term Survival in a Retrospective Analysis of Primary Breast Cancer', Cancer Epidemiology, Biomarkers & Prevention, pp. 2184-2197. https://doi.org/10.1158/1055-9965.EPI-11-0343

    Relationship of Extreme Chromosomal Instability with Long-term Survival in a Retrospective Analysis of Primary Breast Cancer. / Roylance, Rebecca; Endesfelder, David; Gorman, Patricia; Sander, Jil; Tomlinson, Ian; M. Hanby, Andrew; Speirs, Valerie; L. Richardson, Andrea; Birkbak, Nicolai Juul; Eklund, Aron Charles; Downward, Julian; Kschischo, Maik; Szallasi, Zoltan Imre; Swanton, Charles.

    In: Cancer Epidemiology, Biomarkers & Prevention, 22.07.2011, p. 2184-2197.

    Research output: Contribution to journalJournal articleResearchpeer-review

    TY - JOUR

    T1 - Relationship of Extreme Chromosomal Instability with Long-term Survival in a Retrospective Analysis of Primary Breast Cancer

    AU - Roylance, Rebecca

    AU - Endesfelder, David

    AU - Gorman, Patricia

    AU - Sander, Jil

    AU - Tomlinson, Ian

    AU - M. Hanby, Andrew

    AU - Speirs, Valerie

    AU - L. Richardson, Andrea

    AU - Birkbak, Nicolai Juul

    AU - Eklund, Aron Charles

    AU - Downward, Julian

    AU - Kschischo, Maik

    AU - Szallasi, Zoltan Imre

    AU - Swanton, Charles

    PY - 2011/7/22

    Y1 - 2011/7/22

    N2 - Background: Chromosomal instability (CIN) is thought to be associated with poor prognosis in solid tumors; however, evidence from preclinical and mouse tumor models suggest that CIN may paradoxically enhance or impair cancer cell fitness. Breast cancer prognostic expression signature sets, which reflect tumor CIN status, efficiently delineate outcome in estrogen receptor ER-positive reast cancer in contrast to ERnegative breast cancer, suggesting that the relationship of CIN with prognosis differs in these two breast cancer subtypes. Methods: Direct assessment of CIN requires single-cell analysis methods, such as centromeric FISH, aimed at determining the variation around the modal number of two or more chromosomes within individual tumor nuclei. Here, we document the frequency of tumor CIN by dual centromeric FISH analysis in a retrospective primary breast cancer cohort of 246 patients with survival outcome. Results: There was increased CIN and clonal eterogeneity in ER-negative compared with ER-positive breast cancer. Consistent with a negative impact of CIN on cellular fitness, extreme CIN in ER-negative breast cancer was an independent variable associated with improved long-term survival in multivariate analysis. In contrast, a linear relationship of increasing CIN with poorer prognosis in ER-positive breast cancer was observed, using three independent measures of CIN.Conclusions: The paradoxical relationship between extreme CIN and cancer outcome in the ER-negative cohorts may explain why prognostic expression signatures, reflecting tumor CIN status, fail to predict outcome in this subgroup. Impact: Assessment of tumor CIN status may support risk stratification in ER-negative breast cancer and requires prospective validation. Cancer Epidemiol Biomarkers Prev; 20(10); 2183–94. 2011 AACR

    AB - Background: Chromosomal instability (CIN) is thought to be associated with poor prognosis in solid tumors; however, evidence from preclinical and mouse tumor models suggest that CIN may paradoxically enhance or impair cancer cell fitness. Breast cancer prognostic expression signature sets, which reflect tumor CIN status, efficiently delineate outcome in estrogen receptor ER-positive reast cancer in contrast to ERnegative breast cancer, suggesting that the relationship of CIN with prognosis differs in these two breast cancer subtypes. Methods: Direct assessment of CIN requires single-cell analysis methods, such as centromeric FISH, aimed at determining the variation around the modal number of two or more chromosomes within individual tumor nuclei. Here, we document the frequency of tumor CIN by dual centromeric FISH analysis in a retrospective primary breast cancer cohort of 246 patients with survival outcome. Results: There was increased CIN and clonal eterogeneity in ER-negative compared with ER-positive breast cancer. Consistent with a negative impact of CIN on cellular fitness, extreme CIN in ER-negative breast cancer was an independent variable associated with improved long-term survival in multivariate analysis. In contrast, a linear relationship of increasing CIN with poorer prognosis in ER-positive breast cancer was observed, using three independent measures of CIN.Conclusions: The paradoxical relationship between extreme CIN and cancer outcome in the ER-negative cohorts may explain why prognostic expression signatures, reflecting tumor CIN status, fail to predict outcome in this subgroup. Impact: Assessment of tumor CIN status may support risk stratification in ER-negative breast cancer and requires prospective validation. Cancer Epidemiol Biomarkers Prev; 20(10); 2183–94. 2011 AACR

    U2 - 10.1158/1055-9965.EPI-11-0343

    DO - 10.1158/1055-9965.EPI-11-0343

    M3 - Journal article

    SP - 2184

    EP - 2197

    JO - Cancer Epidemiology, Biomarkers & Prevention

    JF - Cancer Epidemiology, Biomarkers & Prevention

    SN - 1055-9965

    ER -