Gene expression studies have identified five molecularly distinct subtypes of breast cancer that have prognostic value across multiple treatment settings including tow biologically distinct estrogen receptor (ER)-positive subtypes of breast cancer: luminal A and luminal B.The expression of ER-associated genes characterizes the luminal breast cancers, with luminal B tumors having poorer outcomes than luminal tumors. Although some luminal B tumors can be identified by their expression of HER2, the major biological distinction between luminal A and B is the proliferation signature, including genes such as CCNB1, MKI67, and MYBL2, which have higher expression in luminal B tumors than in luminal A tumors.Therefore, a distinction between luminal A and B tumor that is based on proliferation status among ER-positive luminal patients may be important to breast cancer biology and prognosis.
The high cost of gene expression profiling has limited its incorporation into most randomized clinical trials, and thus, DNA microarray-defined proliferation status is not used to provide prognostic information in general practice. Although the Ki67 gene may have prognostic value, evaluations of this marker in the adjuvant setting raise conflicts, and in the absence of a standardized test for Ki67, it is difficult to draw firm conclusions from trials.As a result, Ki67 cannot be used to assign patients to specific treatments or risk groups.
Yet despite great uncertainty, the panel of experts at the St. Gallen Consensus in 2009 proposed to (1) classify tumors as low, intermediate, or high in proliferative potential corresponding to Ki67 labelling index values of less than or equal to 15%, 16-30%, and more than 30%, respectively, and (2) use the Ki67 labeling index as a criterion for selecting to add chemotherapy to endocrine therapy in HR-positive BCs. Since proliferation is uniformly higher in basal-like and HER2 cancers but is variable within ER-positive cancer, the greatest practical prognostic value of proliferative index seems to be within ER-positive disease. Decisions regarding the use of adjuvant therapy in early operable breast cancer depend on an array of factors that predict prognosis and therapeutic efficacy. Multigene signatures related to cell proliferation show consistent accuracy in the clinical characterization of hormone receptor (HR)-positive BC, hence interest in biologic factors that predict the adjuvant response continues to increase.
Based on this consensus, we hypothesized that in a large patient population with a long follow-up, we could determine a cut-off value for the Ki67 labeling index that is sufficiently sensitive and specific to identify the patients with HR-positive luminal BC who will not require the addition of cytotoxic chemotherapy to endocrine treatment. In addition, a comparison of the objective significance level for Ki67 with values for other confirmed biomarkers (e.g., HER2, estrogen receptor, and histologic differentiation) may clarify the value of Ki67 as a biomarker in HR-positive luminal BCs.
