Clinical trial NCT01273415: Usefulness of Ki67 Index in Hormone Receptor-positive Breast Cancer
Official title: Usefulness of Ki67 Proliferative Index to Predict Recurrence and Benefit From Adjuvant Chemotherapy in Hormone Receptor (HR)-Positive Breast Cancer
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Breast Cancer
Keywords: hormone receptor-positive breast cancer
nomogram
Ki67
Effects of Chemotherapy
Lead sponsor: Samsung Medical Center
Sponsor class: OTHER
First posted: 2011-01-10
Enrollment: 1070
Sex: FEMALE
Minimum age (years): 20
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
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

Brief 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.

Eligibility criteria: Inclusion Criteria:

* hormone receptor-positive breast cancer patient who received curative surgery from 2004 to 2007 at Samsung Medical Center

Exclusion Criteria:

* the patients who received neoadjuvant chemotherapy the patients whose biopsy showed DCIS the patients who were not available immunohistochemical findings the patients who were not available medical record

Primary outcomes:
measure: to validate Ki67 index to predict recurrence
timeFrame: from the date of diagnosis to the date of relapse
Secondary outcomes:
measure: to investigate cut-off value of Ki67 index
timeFrame: from the date of diagnosis to the date of relapse
Other outcomes:
Locations:
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
Study officials:
affiliation: Samsung Medical Center
name: Young-Hyuck Im, M.D., Ph.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Park YH, Im SA, Cho EY, Ahn JH, Woo SY, Kim S, Keam B, Lee JE, Han W, Nam SJ, Park IA, Noh DY, Yang JH, Ahn JS, Im YH. Validation and comparison of CS-IHC4 scores with a nomogram to predict recurrence in hormone receptor-positive breast cancers. Oncology. 2014;86(5-6):279-88. doi: 10.1159/000362281. Epub 2014 Jun 4.