![]() ![]() Ki-67 is recommended as a valuable factor to distinguish between Luminal A- and B-like tumors, a fundamental distinction in clinical decision-making today.ĭespite its widespread use, driven by the premise of solving delicate therapeutic dilemmas combined with several advantages such as universal accessibility, easy application and low cost, the assessment of Ki-67, ER and PR is affected by technical and observer-based variabilities of the IHC method. ![]() The recently proposed St Gallen recommendations for the identification of the intrinsic subtypes using surrogate pathologic-based definitions have underlined the value of Ki-67 as a clinical tool in routine clinical practice. Ki-67 is present in the cell nucleus throughout all stages of the cell-cycle excluding the resting phase G0. Nuclear staining of the nuclear antigen Ki-67 is most widely used as a surrogate for proliferative activity. The most widely used method to assess proliferation as well as hormone receptor expression is immunohistochemistry (IHC). The proliferative activity of individual cells is a hallmark of tumor biological aggressiveness and a key determinant of sensitivity to (neo)adjuvant chemotherapy, thus being among the principal factors guiding clinical management in primary breast cancer. However, RT-qPCR was significantly more specific. Both methods yield improvements to error-prone manual scoring of Ki-67. Moreover, correlation between Ki-67 qIHC and RT-qPCR is only moderate and RT-qPCR with MammaTyper® outperforms qIHC in predicting pCR. However, RT-qPCR displays a broader dynamic range and higher sensitivity than IHC. IHC for ER and PR reveals high concordance with RT-qPCR. Conclusionĭigital image analysis can successfully be implemented for assessing ER, PR and Ki-67. Moreover, the proliferation levels in patients achieving a pCR versus not differed significantly using MKI67 RNA expression (Mann-Whitney p = 0.002), but not with qIHC of Ki-67 (Mann-Whitney p = 0.097) or vIHC of Ki-67 ( p = 0.131). Setting the desired sensitivity at 100%, specificity for the prediction of pCR (ypT0ypN0) was significantly higher for mRNA than for protein (68.9% vs. Up to now no predictive cut-off for Ki-67 assessment by IHC has been established to predict response to neoadjuvant chemotherapy. In contrast, only a moderate correlation was observed between qIHC and RT-qPCR continuous data for Ki-67/MKI67 (Spearman’s r = 0.50, p = 0.0001). When comparing qIHC of ER and PgR with RT-qPCR of ESR1 and PGR the overall agreement was 96.6 and 91.4%, respectively, while overall agreement of visual IHC with RT-qPCR was slightly lower for ER/ESR1 and PR/PGR (91.2 and 92.9%, respectively). ResultsĬorrelation between methods (qIHC versus RT-qPCR) was high for ER and PgR (spearman´s r = 0.82, p < 0.0001 and r = 0.86, p < 0.0001, respectively) resulting in high levels of concordance using predefined cut-offs. The potential of Ki-67 IHC and RT-qPCR to predict pathological complete response (pCR) was evaluated using ROC analysis and non-parametric Mann-Whitney Test. Concordance between the three methods (vIHC, qIHC and RT-qPCR) was assessed for all 3 markers. Expression of ESR1, PGR and MKI67 by RT-qPCR was performed on RNA extracted from the same formalin-fixed paraffin-embedded tissue. Ki-67 IHC visual assessment was compared to the IHC nuclear tool (AperioTM) on core biopsies from a randomized neoadjuvant clinical trial. Automatic scoring of Ki-67 with digital image analysis (qIHC) or assessment of MKI67 gene expression with RT-qPCR may improve diagnostic accuracy. This method carries significant intra- and inter-observer variability. Proliferation may predict response to neoadjuvant therapy of breast cancer and is commonly assessed by manual scoring of slides stained by immunohistochemistry (IHC) for Ki-67 similar to ER and PgR. ![]()
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