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Altered Cytoplasmic-to-Nuclear Ratio of Survivin Is a Prognostic Indicator in Breast Cancer

Authors' Affiliations: ¹ UCD School of Biomolecular and Biomedical Science and ² UCD School of Medicine and Medical Science, UCD Conway Institute, University College Dublin; ³ Department of Pathology and Laboratory Medicine, St. Vincent's University Hospital, Dublin, Ireland; ⁴ Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts; ⁵ Center for Molecular Pathology, Department of Laboratory Medicine, Lund University, Malmö University Hospital, Malmö, Sweden; ⁶ Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina; and ⁷ Tissue Array Research Program, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland

Requests for reprints: William M. Gallagher, UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland. Phone: 353-1-7166743; Fax: 353-1-2837211; E-mail: william.gallagher{at}ucd.ie.

Purpose: Survivin (BIRC5) is a promising tumor biomarker. Conflicting data exist on its prognostic effect in breast cancer. These data may at least be partly due to the manual interpretation of immunohistochemical staining, especially as survivin can be located in both the nucleus and cytoplasm. Quantitative determination of survivin expression using image analysis offers the opportunity to develop alternative scoring models for survivin immunohistochemistry. Here, we present such a model.

Experimental Design: A breast cancer tissue microarray containing 102 tumors was stained with an anti-survivin antibody. Whole-slide scanning was used to capture high-resolution images. These images were analyzed using automated algorithms to quantify the staining.

Results: Increased nuclear, but not cytoplasmic, survivin was associated with a reduced overall survival (OS; P = 0.038) and disease-specific survival (P = 0.0015). A high cytoplasmic-to-nuclear ratio (CNR) of survivin was associated with improved OS (P = 0.005) and disease-specific survival (P = 0.05). Multivariate analysis revealed that the survivin CNR was an independent predictor of OS (hazard ratio, 0.09; 95% confidence interval, 0.01-0.76; P = 0.027). A survivin CNR of >5 correlated positively with estrogen receptor (P = 0.019) and progesterone receptor (P = 0.033) levels, whereas it was negatively associated with Ki-67 expression (P = 0.04), p53 status (P = 0.005), and c-myc amplification (P = 0.016).

Conclusion: Different prognostic information is supplied by nuclear and cytoplasmic survivin in breast cancer. Nuclear survivin is a poor prognostic marker in breast cancer. Moreover, CNR of survivin, as determined by image analysis, is an independent prognostic factor.