Abstract
BackgroundConflicting 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.MethodsSurvin 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.ResultsFollowing 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).ConclusionUsing 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.
Highlights
Conflicting data exist regarding the prognostic and predictive impact of survivin (BIRC5) in breast cancer
As opposed to cytoplasmic, survivin correlates with outcome in breast cancer We previously described a relationship between the cytoplasmic-to-nuclear ratio (CNR) of survivin and patient outcome [15]; the relationship between nuclear and cytoplasmic survivin expression within individual tumours was not investigated
Survivin nuclear autoscore is an independent predictor of outcome In our initial study, we reported no link between survivin nuclear or cytoplasmic intensity and survival; an increased survivin nuclear autoscore (SNAS) was associated with a reduced breast cancerspecific survival (BCSS) [15]
Summary
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. Effective implementation of personalised cancer therapeutic regimes, depends upon the Survivin (encoded by the gene, BIRC5), a member of the inhibitor of apoptosis protein family, is a multifunctional protein implicated in a number of cellular processes including apoptosis, mitosis and angiogenesis [2]. Using IHC or subcellular fractionation, two pools of survivin have been located (nuclear and cytoplasmic). These different pools are immunochemically and functionally different and are independently modulated during cell cycle progression [4]
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