TY - JOUR

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

A1 - Roylance,Rebecca

A1 - Endesfelder,David

A1 - Gorman,Patricia

A1 - Sander,Jil

A1 - Tomlinson,Ian

A1 - M. Hanby,Andrew

A1 - Speirs,Valerie

A1 - L. Richardson,Andrea

A1 - Birkbak,Nicolai Juul

A1 - Eklund,Aron Charles

A1 - Downward,Julian

A1 - Kschischo,Maik

A1 - Szallasi,Zoltan Imre

A1 - Swanton,Charles

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

PB - American Association for Cancer Research (A A C R)

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.<br/>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.<br/>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

JO - Cancer Epidemiology, Biomarkers & Prevention

JF - Cancer Epidemiology, Biomarkers & Prevention

SN - 1055-9965

SP - 2184

EP - 2197

ER -