Trial Information

Usefulness of Ki67 Proliferative Index to Predict Recurrence and Benefit From Adjuvant Chemotherapy in Hormone Receptor (HR)-Positive Breast Cancer

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.