Breast
Ki67 breast
Authors: Anas Mohamed, M.D., Joseph Geradts, M.D.
Editorial Board Member: Kristen E. Muller, D.O.
Deputy Editor-in-Chief: Gary Tozbikian, M.D.
Last author update: 9 May 2022
Last staff update: 9 May 2022
Copyright: 2022, PathologyOutlines.com, Inc.
PubMed Search: Ki67
Table of Contents
Definition / general | Essential features | Terminology | Pathophysiology | Clinical features | Interpretation | Uses by pathologists | Prognostic factors | Microscopic (histologic) images | Positive staining - normal | Positive staining - disease | Sample pathology report | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Cite this page: Mohamed A, Geradts J. Ki67 breast. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/breastKi67.html. Accessed April 23rd, 2024.
Definition / general
- Nuclear protein that is expressed during all active phases of the cell cycle (G1, S, G2 and M) but is absent in resting cells (G0) (Pathology 2017;49:166)
- Encoded by MKI67 gene on chromosome 10q25 (Pathology 2017;49:166)
- Ki67 expression level varies throughout the cell cycle (Pathology 2017;49:166)
Essential features
- Cellular proliferation marker that is reported as percentage of tumor cells with nuclear staining
- Low in benign tumors, luminal A carcinomas and low grade carcinomas (Breast Cancer Res 2016;18:104, Mod Pathol 2014;27:554, BMC Res Notes 2019;12:605)
- High in high grade carcinomas, triple negative breast carcinomas, HER2 positive carcinomas and luminal B carcinomas (Breast Cancer Res 2016;18:104, Mod Pathol 2014;27:554, BMC Res Notes 2019;12:605)
- Independent prognostic marker to predict disease free survival, overall survival and complete pathologic response to neoadjuvant chemotherapy (Pathology 2017;49:166, J Natl Cancer Inst 2021;113:808)
- Associated with low interlaboratory reproducibility and high interobserver variability (Breast Cancer Res 2016;18:104, J Natl Cancer Inst 2013;105:1897, Histopathology 2019;75:225)
Terminology
- MIB1 is not equivalent to Ki67; rather, it is a widely used monoclonal antibody against the Ki67 antigen (Breast Cancer 2020;27:1058)
Pathophysiology
- Anti-Ki67 antibody binds Ki67 protein in formalin fixed paraffin embedded tissue block and highlights nuclei of all cells in nonresting cell cycle phases (Pathology 2017;49:166)
- Increased expression in tumor cells is a marker of cell cycle activation and proliferative activity
- Ki67 often is heterogeneously expressed in breast carcinomas, with hot spots and inactive areas (J Natl Cancer Inst 2013;105:1897)
Clinical features
- Can be used to predict and monitor response to neoadjuvant endocrine or chemotherapy (Pathology 2017;49:166, J Natl Cancer Inst 2021;113:808)
- Used in distinguishing luminal A and luminal B breast carcinomas (Breast Cancer Res 2016;18:104, Mod Pathol 2014;27:554, BMC Res Notes 2019;12:605)
- Used by oncologists to guide adjuvant chemotherapy (Pathology 2017;49:166, J Natl Cancer Inst 2021;113:808)
- High Ki67 expression correlated with decreased survival (Pathology 2017;49:166, J Natl Cancer Inst 2021;113:808)
Interpretation
- Nuclear staining (any intensity)
- Number of tumor cells with positive staining divided by total number of tumor cells (hot spots [less reproducible] or average across tumor section [recommended]) (Pathology 2017;49:166)
- No consensus on number of tumor cells to be scored (J Natl Cancer Inst 2013;105:1897)
- Marked variability in published thresholds separating high and low scores (Pathology 2017;49:166)
- Due to significant interlaboratory and interobserver variability, thresholds ideally should be established in each laboratory (J Natl Cancer Inst 2021;113:808)
- In ER+ / HER2- T1-2, N0-1 patients Ki67 is prognostic, with Ki67 ≤ 5% considered low and Ki67 ≥ 30% considered high (J Natl Cancer Inst 2021;113:808)
- Several automated scoring algorithms for Ki67 quantitation have been developed which reduce interobserver variability (Mod Pathol 2019;32:59, Lab Invest 2019;99:107)
Uses by pathologists
- As an independent prognostic marker to predict disease free survival, overall survival and complete pathologic response to neoadjuvant chemotherapy
- Subtyping ER positive breast carcinomas into 2 prognostically distinct subtypes:
- Luminal A (low Ki67 index; better prognosis)
- Luminal B (high Ki67 index; worse prognosis) (Mod Pathol 2014;27:554)
- Ki67 IHC MIB1 pharmDx has been approved by the FDA as a companion diagnostic for detecting Ki67 expression in patients with high risk breast cancer who may be eligible for treatment with abemaciclib combined with endocrine therapy
- FDA approval of abemaciclib was restricted to patients at high risk of recurrence and with a Ki67 score ≥ 20%, as determined by an FDA approved test; however, restricting the approval to patients with a high Ki67 and the 20% cutoff is debated (Ann Oncol 2022;33:234)
Prognostic factors
- Prognostic factor in early stage, ER positive breast cancer (Breast Cancer Res 2016;18:104, Pathology 2017;49:166)
- High Ki67 expression in a breast carcinoma is associated with higher pathologic stage, higher grade, estrogen and progesterone receptor negativity, HER2 overexpression, extracapsular extension and lymphovascular invasion (Eur J Breast Health 2019;15:256)
- High Ki67 index is associated with shortened disease free survival and overall survival (Breast Cancer Res Treat 2013;139:539)
- High Ki67 proliferative index is a predictive marker for pathological complete response to neoadjuvant chemotherapy (Medicine (Baltimore) 2017;96:e9384)
Microscopic (histologic) images
Contributed by Anas Mohamed, M.D. and Joseph Geradts, M.D.
Lobular carcinoma, low proliferation
Lobular carcinoma, low Ki67
Ductal carcinoma, low proliferation
Ductal carcinoma, low Ki67
Ductal carcinoma, intermediate proliferation
Ductal carcinoma, intermediate Ki67
Ductal carcinoma, high proliferation
Ductal carcinoma, high Ki67
Positive staining - normal
- Normal breast tissue demonstrates very low levels of Ki67 index (< 3%) (Front Endocrinol (Lausanne) 2021;12:687244)
Positive staining - disease
- Low Ki67 index is observed in benign breast tumors, luminal A carcinomas, low grade ductal carcinomas, lobular carcinomas and tubular carcinomas
- High Ki67 index is observed in triple negative breast carcinomas, including metaplastic and medullary carcinomas, HER2 positive carcinomas, luminal B carcinomas, high grade carcinomas and pleomorphic lobular carcinomas (BMC Res Notes 2019;12:605)
Sample pathology report
- Right breast, core needle biopsy:
- Invasive ductal carcinoma, grade 2
- Ki67 index: 5% (low)
- Left breast, total mastectomy:
- Invasive mammary carcinoma with medullary pattern
- Ki67 index: 40% (high)
Additional references
Board review style question #1
Which of the following breast neoplasms is most likely to be associated with an elevated Ki67 labeling index?
- Invasive ductal carcinoma, grade 1
- Invasive lobular carcinoma, classic type
- Metaplastic carcinoma
- Tubular carcinoma
Board review style answer #1
C. Metaplastic carcinoma. High Ki67 index is observed in triple negative breast carcinomas, including metaplastic and medullary carcinomas, as well as HER2 positive carcinomas, luminal B carcinomas, high grade carcinomas and pleomorphic lobular carcinomas (BMC Res Notes 2019;12:605).
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Reference: Ki67 breast
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Board review style question #2
Which of the following breast tumors is likely to demonstrate a Ki67 labeling index similar to the one shown in the picture?
- Invasive cribriform carcinoma
- Invasive ductal carcinoma, grade 3
- Medullary carcinoma
- Pleomorphic lobular carcinoma
Board review style answer #2
A. Invasive cribriform carcinoma. Low Ki67 index is observed in benign breast tumors, luminal A carcinomas, low grade ductal carcinomas, lobular carcinomas and tubular carcinomas and lower grade breast cancer subtypes, such as invasive cribriform carcinoma (BMC Res Notes 2019;12:605).
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Reference: Ki67 breast
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