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The Ki67 nuclear antigen is expressed in the cell cycle phases G1, S, G2 and M, but is absent in G0. It localizes to the perinucleolar region during G1 and is distributed throughout the nuclear interior at later phases. During mitosis, it is present on all chromosomes.
Ki67 is used as a proliferation marker in tumor specimens and its immunohistochemical expression has prognostic and predictive value in cancer1–5. For example, Ki67 can provide clinicians with immunohistochemical information beyond clinicopathological variables like estrogen receptor, progesterone receptor, and human epidermal growth factor-2 in situ hybridization (HER2-ISH) in node-negative breast cancer2. It is also an independent prognostic factor in epithelioid malignant pleural mesothelioma (MPM)6, and breast cancer experts make use of the Ki67 index to guide clinical decisions on the use of adjuvant chemotherapy7.
Ki67’s ability to predict responses to chemotherapy remains controversial. Data suggests that Ki67 expression is an inappropriate tool for deciding whether to withhold adjuvant chemotherapy in early stage breast cancer with only 1–3 positive axillary nodes8. The American Society of Clinical Oncology (ASCO) Tumor Marker Guidelines Committee also does not recommend routine use of Ki67 as a marker for prognosis in patients with newly diagnosed breast cancer due to a lack of sufficient supporting data9.
Research is in progress to evaluate and improve the clinical utility of Ki67. Using scoring methods based on centrally stained tissue microarray slides can help to overcome reproducibility problems in Ki67 scoring, although this strategy is still being developed10. A clinical trial (POETIC) is also underway to determine whether Ki67 as measured by immunohistochemistry in excised cancer after endocrine therapy and could be a better predictor of time to recurrence than the pre-treatment Ki67 value11. Finally, a new quantum dots-based in situ fluorescent imaging technique that uses both Ki67 and cytokeratin (a type of epithelial-specific marker) has been developed which is a better prognostic marker of breast cancer than Ki67 alone, making interpretation of the results simpler and more accurate12.
Improvements to the reliability of the antibody will have effects on the predictive capacity of Ki67 as a diagnostic and prognostic marker. Knockout (KO)-validated antibodies, for example, can help to remove unnecessary variation between and within laboratories when carrying out standardized testing.
KO valiation ensures that the antibody specificity is confirmed using a true negative control.
The figures below are serial sections of human tonsil. IHC was carried out on paraffin-embedded sections following heat-mediated antigen retrieval using citric acid. Blocking was with 1% bovine serum albumin (BSA). Detection was via a horseradish peroxidase (HRP)-conjugated ABC system (goat anti-rabbit IgG H&L (ab207995) at 1:300 dilution) and 3,3′-diaminobenzidine (DAB) was used as the chromogen.
|Antibody||Leading anti-Ki67 polyclonal||Anti-Ki67 antibody (ab15580)|
|Staining pattern||Low specificity with high background||Specific with low background|
|Antibody||Leading anti-Ki67 monoclonal||Anti-Ki67 antibody [SP6] (ab16667)|
|Staining pattern||Specific with very low background||Specific with very low background|
1. Feeley, L. P., Mulligan, A. M., Pinnaduwage, D., Bull, S. B. & Andrulis, I. L. Distinguishing luminal breast cancer subtypes by Ki67, progesterone receptor or TP53 status provides prognostic information. Mod. Pathol. 27, 554–61 (2014).
2. Pathmanathan, N. et al. The prognostic value of Ki67 in systemically untreated patients with node-negative breast cancer. J. Clin. Pathol. 67, 222–8 (2014).
3. Niikura, N. et al. Prognostic Significance of the Ki67 Scoring Categories in Breast Cancer Subgroups. Clin. Breast Cancer 14, 323–329 (2014).
4. Rossi, L. et al. Prognostic impact of discrepant Ki67 and mitotic index on hormone receptor-positive, HER2-negative breast carcinoma. Br. J. Cancer 113, 996–1002 (2015).
5. Reyal, F. et al. Long-term prognostic performance of Ki67 rate in early stage, pT1-pT2, pN0, invasive breast carcinoma. PLoS One 8, e55901 (2013).
6. Ghanim, B. et al. Ki67 index is an independent prognostic factor in epithelioid but not in non-epithelioid malignant pleural mesothelioma: a multicenter study. Br. J. Cancer 112, 783–92 (2015).
7. Goldhirsch, A. et al. Personalizing the treatment of women with early breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2013. Ann. Oncol. 24, 2206–23 (2013).
8. Andre, F., Arnedos, M., Goubar, A., Ghouadni, A. & Delaloge, S. Ki67—no evidence for its use in node-positive breast cancer. Nat. Rev. Clin. Oncol. 1–6 (2015). doi:10.1038/nrclinonc.2015.46
9. Harris, L. et al. American society of clinical oncology 2007 update of recommendations for the use of tumor markers in breast cancer. Journal of Clinical Oncology 25, 5287–5312 (2007).
10. M.-Y.C., P. et al. An international study to increase concordance in Ki67 scoring. Mod. Pathol. 28, 778–786 (2015).
11. Institute of Cancer Research, U. K. Trial of Perioperative Endocrine Therapy – Individualising Care (POETIC). (2015). at <https://clinicaltrials.gov/ct2/show/NCT02338310?term=NCT02338310&rank=1>
12. Yuan, J. P. et al. Quantum Dots-Based Quantitative and In Situ Multiple Imaging on Ki67 and Cytokeratin to Improve Ki67 Assessment in Breast Cancer. PLoS One 10, e0122734 (2015).