Validation of cytoplasmic-to-nuclear ratio of survivin as an indicator of improved prognosis in breast cancer

Hdl Handle:
http://hdl.handle.net/10147/117428
Title:
Validation of cytoplasmic-to-nuclear ratio of survivin as an indicator of improved prognosis in breast cancer
Authors:
Rexhepaj, Elton; Jirstrom, Karin; O'Connor, Darran P; O'Brien, Sallyann L; Landberg, Goran; Duffy, Michael J; Brennan, Donal J; Gallagher, William M
Citation:
BMC Cancer. 2010 Nov 23;10(1):639
Issue Date:
23-Nov-2010
URI:
http://hdl.handle.net/10147/117428
Abstract:
Abstract Background Conflicting data exist regarding the prognostic and predictive impact of survivin (BIRC5) in breast cancer. We previously reported survivin cytoplasmic-to-nuclear ratio (CNR) as an independent prognostic indicator in breast cancer. Here, we validate survivin CNR in a separate and extended cohort. Furthermore, we present new data suggesting that a low CNR may predict outcome in tamoxifen-treated patients. Methods Survin expression was assessed using immunhistochemistry on a breast cancer tissue microarray (TMA) containing 512 tumours. Whole slide digital images were captured using an Aperio XT scanner. Automated image analysis was used to identify tumour from stroma and then to quantify tumour-specific nuclear and cytoplasmic survivin. A decision tree model selected using a 10-fold cross-validation approach was used to identify prognostic subgroups based on nuclear and cytoplasmic survivin expression. Results Following optimisation of the staining procedure, it was possible to evaluate survivin protein expression in 70.1% (n = 359) of the 512 tumours represented on the TMA. Decision tree analysis predicted that nuclear, as opposed to cytoplasmic, survivin was the most important determinant of overall survival (OS) and breast cancer-specific survival (BCSS). The decision tree model confirmed CNR of 5 as the optimum threshold for survival analysis. Univariate analysis demonstrated an association between a high CNR (>5) and a prolonged BCSS (HR 0.49, 95% CI 0.29-0.81, p = 0.006). Multivariate analysis revealed a high CNR (>5) was an independent predictor of BCSS (HR 0.47, 95% CI 0.27-0.82, p = 0.008). An increased CNR was associated with ER positive (p = 0.045), low grade (p = 0.007), Ki-67 (p = 0.001) and Her2 (p = 0.026) negative tumours. Finally, a high CNR was an independent predictor of OS in tamoxifen-treated ER-positive patients (HR 0.44, 95% CI 0.23-0.87, p = 0.018). Conclusion Using the same threshold as our previous study, we have validated survivin CNR as a marker of good prognosis in breast cancer in a large independent cohort. These findings provide robust evidence of the importance of survivin CNR as a breast cancer biomarker, and its potential to predict outcome in tamoxifen-treated patients.
Item Type:
Journal Article

Full metadata record

DC FieldValue Language
dc.contributor.authorRexhepaj, Elton-
dc.contributor.authorJirstrom, Karin-
dc.contributor.authorO'Connor, Darran P-
dc.contributor.authorO'Brien, Sallyann L-
dc.contributor.authorLandberg, Goran-
dc.contributor.authorDuffy, Michael J-
dc.contributor.authorBrennan, Donal J-
dc.contributor.authorGallagher, William M-
dc.date.accessioned2010-12-08T14:39:04Z-
dc.date.available2010-12-08T14:39:04Z-
dc.date.issued2010-11-23-
dc.identifierhttp://dx.doi.org/10.1186/1471-2407-10-639-
dc.identifier.citationBMC Cancer. 2010 Nov 23;10(1):639-
dc.identifier.urihttp://hdl.handle.net/10147/117428-
dc.description.abstractAbstract Background Conflicting data exist regarding the prognostic and predictive impact of survivin (BIRC5) in breast cancer. We previously reported survivin cytoplasmic-to-nuclear ratio (CNR) as an independent prognostic indicator in breast cancer. Here, we validate survivin CNR in a separate and extended cohort. Furthermore, we present new data suggesting that a low CNR may predict outcome in tamoxifen-treated patients. Methods Survin expression was assessed using immunhistochemistry on a breast cancer tissue microarray (TMA) containing 512 tumours. Whole slide digital images were captured using an Aperio XT scanner. Automated image analysis was used to identify tumour from stroma and then to quantify tumour-specific nuclear and cytoplasmic survivin. A decision tree model selected using a 10-fold cross-validation approach was used to identify prognostic subgroups based on nuclear and cytoplasmic survivin expression. Results Following optimisation of the staining procedure, it was possible to evaluate survivin protein expression in 70.1% (n = 359) of the 512 tumours represented on the TMA. Decision tree analysis predicted that nuclear, as opposed to cytoplasmic, survivin was the most important determinant of overall survival (OS) and breast cancer-specific survival (BCSS). The decision tree model confirmed CNR of 5 as the optimum threshold for survival analysis. Univariate analysis demonstrated an association between a high CNR (>5) and a prolonged BCSS (HR 0.49, 95% CI 0.29-0.81, p = 0.006). Multivariate analysis revealed a high CNR (>5) was an independent predictor of BCSS (HR 0.47, 95% CI 0.27-0.82, p = 0.008). An increased CNR was associated with ER positive (p = 0.045), low grade (p = 0.007), Ki-67 (p = 0.001) and Her2 (p = 0.026) negative tumours. Finally, a high CNR was an independent predictor of OS in tamoxifen-treated ER-positive patients (HR 0.44, 95% CI 0.23-0.87, p = 0.018). Conclusion Using the same threshold as our previous study, we have validated survivin CNR as a marker of good prognosis in breast cancer in a large independent cohort. These findings provide robust evidence of the importance of survivin CNR as a breast cancer biomarker, and its potential to predict outcome in tamoxifen-treated patients.-
dc.titleValidation of cytoplasmic-to-nuclear ratio of survivin as an indicator of improved prognosis in breast cancer-
dc.typeJournal Article-
dc.language.rfc3066en-
dc.rights.holderRexhepaj et al.; licensee BioMed Central Ltd.-
dc.description.statusPeer Reviewed-
dc.date.updated2010-12-08T13:01:46Z-
All Items in Lenus, The Irish Health Repository are protected by copyright, with all rights reserved, unless otherwise indicated.