Usefulness of Ki67 Index in Hormone Receptor-positive Breast Cancer
Condition: Breast Cancer
MeSH terms: Breast Neoplasms
Study type: Observational

Summary: 
      Gene expression studies have identified at least four molecularly distinct subtypes of breast
      cancer including two biologically distinct ER-positive subtypes of breast cancer: luminal A
      and luminal B (with luminal B tumors having poorer outcomes than luminal A 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 signatures, including genes such as
      CCNB1, MKI67, and MYBL2, which have higher expression in luminal B tumors than in luminal A
      tumors. The high cost of gene expression profiling has limited its incorporation into general
      clinical practice. To date, there is no available IHC-based surrogate assay that can
      distinguish between luminal A and luminal B tumors. We hypothesized that the IHC
      determination of the Ki67 index as well as ER, PgR, and HER2 status is able to distinguish
      the luminal B subtype of breast cancers from the luminal A subgroup.
    

Detailed description: 
      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.
    

Observational model: Cohort
Time perspective: Retrospective
Sampling method: Probability Sample
Study population: 
        postoperative hormone receptor-positive breast cancer patients from 2004 to 2007 at Samsung
        Medical Center
      
Keywords: hormone receptor-positive breast cancer; nomogram; Ki67; Effects of Chemotherapy