Ki-67 in Breast Cancer
Ki-67 is a protein found inside cells that are actively dividing. Because cancer cells divide more frequently than normal cells, measuring Ki-67 gives pathologists a way to estimate how quickly a breast cancer is growing. The result is expressed as a percentage — the proportion of cancer cells in active division at the time the tissue was examined. A high Ki-67 percentage means the cancer is proliferating rapidly; a low percentage means it is growing more slowly. This information is used alongside tumour grade, estrogen receptor (ER), progesterone receptor (PR), and HER2 status to classify breast cancers into biological subtypes and to help determine whether chemotherapy is likely to add meaningful benefit beyond hormone-blocking therapy alone.
What the test looks for
Ki-67 is a protein that is present in the nucleus of a cell only when the cell is actively going through the process of dividing — that is, during the phases of the cell cycle known as S, G2, and M phases, as well as the preparatory G1 phase. Resting cells do not produce Ki-67. Because of this, Ki-67 acts as a reliable marker of cell proliferation: the more Ki-67 is present, the more cells are actively dividing at any given moment.
In the context of breast cancer, proliferation rate matters because rapidly dividing tumours tend to grow faster, have a higher risk of spread, and often — though not always — respond differently to treatment than slow-growing tumours. A cancer with a high Ki-67 may be more aggressive but can also be more sensitive to chemotherapy, which targets cells in the process of dividing. A cancer with a low Ki-67 tends to grow slowly and is more likely to be managed effectively with endocrine therapy alone, without the addition of chemotherapy.
Why is the test done
- To help determine tumour grade. Ki-67 is one of the components considered in the Nottingham grade of breast cancer, which assesses three features: tubule formation, nuclear pleomorphism, and mitotic figures (cells caught in the act of dividing). Ki-67 closely parallels the mitotic count component and is used alongside grade to characterise the tumour’s biological activity.
- To classify breast cancer into molecular subtypes. The distinction between the Luminal A subtype (low-grade, slow-growing, hormone receptor-positive) and the Luminal B subtype (higher-grade, faster-growing, hormone receptor-positive) depends substantially on Ki-67. This subtype classification influences whether chemotherapy is recommended.
- To guide chemotherapy decisions in hormone receptor-positive, HER2-negative breast cancer. In this subtype, a very low Ki-67 is reassuring evidence that endocrine therapy alone may be sufficient. A high Ki-67 is one factor that may tip the balance toward recommending chemotherapy, particularly when combined with other high-risk features.
- To assess response to neoadjuvant (pre-surgery) chemotherapy. In patients receiving chemotherapy before surgery, Ki-67 measured on the pre-treatment biopsy and again on the surgical specimen can indicate how well the tumour responded to treatment. A substantial drop in Ki-67 after chemotherapy is a favourable sign.
- To complement genomic testing. Genomic assays such as Oncotype DX and Prosigna incorporate proliferation-related genes that broadly reflect Ki-67. In cases where genomic testing is not available or not indicated, Ki-67 provides some of the same biological information.
How the test is performed
Ki-67 is measured using immunohistochemistry (IHC), the same technique used to test ER, PR, and HER2. A thin slice of tumour tissue from the biopsy or surgical specimen is placed on a glass slide and treated with an antibody that binds specifically to the Ki-67 protein inside cell nuclei. Cells that are actively proliferating stain brown; non-proliferating cells remain blue.
A pathologist then counts the stained and unstained nuclei and calculates the percentage of positive cells. This can be done by manual counting under the microscope (examining at least 500–1,000 tumour cells in representative areas) or using image analysis software. Different counting approaches and different antibody clones used by different laboratories can produce somewhat different results — a limitation discussed further below.
How results are reported
Ki-67 is reported as a percentage, representing the proportion of tumour cell nuclei that stain positive. For example, a report might read: “Ki-67: 15% of tumour cell nuclei positive.” Some reports will also note the staining intensity or specify which areas of the tumour were counted.
Thresholds used to interpret Ki-67
Unlike ER and HER2, for which internationally agreed cut-off values define positive and negative results, Ki-67 does not have a single universally accepted threshold. Different guidelines use different cut-offs, and the same numerical result may be interpreted differently depending on the clinical context. The most commonly used thresholds are:
- Below 10%. Generally considered low, the tumour is proliferating slowly. Associated with the Luminal A subtype. Supports the use of endocrine therapy alone in appropriately selected patients.
- 10–20%. Considered an intermediate zone. Interpretation in this range is uncertain and must be integrated with other clinical and pathological features. Genomic testing may be particularly useful when Ki-67 falls in this range.
- Above 20% (some guidelines use above 25–30%). Generally considered high — the tumour is proliferating rapidly. Associated with the Luminal B subtype or with more aggressive breast cancer biology. May support the addition of chemotherapy, particularly in higher-risk situations.
The International Ki-67 in Breast Cancer Working Group has worked to standardise Ki-67 reporting, and thresholds of 5%, 10%, 20%, and 25–30% are used in different guideline contexts. Your oncologist will interpret your Ki-67 result in conjunction with your cancer’s full profile, not in isolation.
Heterogeneity and the hot-spot issue
Breast cancers are not uniform. Some areas of a tumour may be proliferating more actively than others. If a pathologist counts cells from an unusually active region (a “hot spot”), the reported Ki-67 may be higher than the tumour’s average. International guidelines generally recommend counting cells from a representative cross-section of the tumour — including both active and less active areas — rather than selecting the highest-proliferating zone. Some laboratories may note in their reports whether hot-spot or global counting was used.
What the result means
- Ki-67 low (below 10%). The cancer is growing slowly. In hormone receptor-positive, HER2-negative breast cancer, a low Ki-67 is a favourable sign and supports the tumour being classified as Luminal A. Endocrine therapy alone is often sufficient for lower-stage Luminal A cancers, and chemotherapy may not be needed. A low Ki-67 is generally associated with a more favourable long-term outlook.
- Ki-67 intermediate (10–20%). This result falls in a grey zone where proliferation is neither clearly low nor clearly high. The clinical significance depends on the rest of the tumour’s profile — including grade, tumour size, lymph node status, and ER/PR levels. Genomic testing is particularly valuable in this range because it can provide more precise information on recurrence risk and chemotherapy benefit than Ki-67 alone can.
- Ki-67 high (above 20–30%, depending on the guideline used). The cancer is proliferating rapidly. In hormone receptor-positive, HER2-negative breast cancer, a high Ki-67 suggests Luminal B biology and may favour the addition of chemotherapy — particularly in patients with other high-risk features such as involved lymph nodes, large tumour size, or high Nottingham grade. High Ki-67 is also typical of HER2-positive and triple-negative breast cancers, where it is expected and does not by itself change the treatment approach (which already includes chemotherapy).
Ki-67 and breast cancer subtypes
Ki-67 plays a central role in distinguishing between the two main hormone receptor-positive subtypes:
- Luminal A (ER+ and/or PR+, HER2−, low grade, low Ki-67). The most common and generally most favourable breast cancer subtype. Grows slowly, responds well to endocrine therapy, and typically does not require chemotherapy. Ki-67 is usually below 10–14%.
- Luminal B (ER+ and/or PR+, HER2− or HER2+, higher grade, high Ki-67). More proliferative than Luminal A. Higher risk of recurrence. Chemotherapy is more likely to be recommended. Ki-67 is typically above 20%, though some Luminal B tumours can have intermediate Ki-67 values when other features (grade, PR negativity, HER2 positivity) indicate higher biological activity.
In HER2-positive and triple-negative breast cancers, Ki-67 is often elevated as part of the inherent biology of these subtypes. It is reported, but rarely changes the treatment plan, which already accounts for the aggressive nature of these cancers.
Limitations of Ki-67 testing
Ki-67 is a valuable but imperfect test, and it is important to understand its limitations:
- No universal cut-off. Different laboratories and different guidelines use different thresholds to define low, intermediate, and high Ki-67. A result of 18%, for example, may be considered intermediate at one institution and high at another. This makes it difficult to apply results from one clinical trial directly to an individual patient’s situation.
- Laboratory variability. The antibody used, the counting method, and the portion of the tumour examined can all influence the result. Studies have shown meaningful variation in Ki-67 scores for the same tumour slide assessed by different laboratories or different pathologists. Standardisation efforts are ongoing.
- Tumour heterogeneity. As noted above, Ki-67 may be higher in some parts of a tumour than others. A single biopsy sample may not fully represent the proliferative activity of the entire tumour.
- Not a stand-alone test. Because of these limitations, oncologists and pathologists consistently emphasise that Ki-67 must be interpreted as one piece of a larger puzzle — alongside grade, stage, receptor status, and often genomic testing — rather than as a decision-making tool on its own.
Ki-67 and genomic testing
Genomic assays such as Oncotype DX (which generates a Recurrence Score) and Prosigna (which generates a Risk of Recurrence score) include proliferation-related genes in their calculations. These genes broadly reflect what Ki-67 measures, but the genomic tests assess multiple biological pathways simultaneously and have been validated in large clinical trials to predict both recurrence risk and chemotherapy benefit more precisely than Ki-67 alone.
For patients with early-stage, hormone receptor-positive, HER2-negative breast cancer — where the main question is whether to add chemotherapy to endocrine therapy — genomic testing is generally preferred over Ki-67 alone when it is available and clinically indicated. Ki-67 remains useful when genomic testing is not available, when tissue is insufficient for genomic testing, or as a complementary data point when the genomic result is intermediate.
What happens next
- Your oncologist will integrate Ki-67 with your full pathology profile. No single number drives the treatment decision. Ki-67 will be considered alongside grade, tumour size, lymph node involvement, ER/PR status, HER2 status, and, in appropriate cases, genomic test results.
- If Ki-67 is low and other features are favourable, your oncologist may discuss endocrine therapy alone without chemotherapy, particularly if you have early-stage Luminal A disease.
- If Ki-67 is intermediate, genomic testing may be recommended to clarify whether chemotherapy is likely to add benefit.
- If Ki-67 is high, this will be weighed alongside other features to determine whether chemotherapy is appropriate. In HER2-positive and triple-negative cancers, high Ki-67 is expected, and the treatment plan is already structured to address rapidly growing tumours.
- If you are receiving chemotherapy before surgery, Ki-67 may be measured again on the surgical specimen to assess treatment response.
Questions to ask your doctor
- What is my Ki-67 percentage, and is it considered low, intermediate, or high at your institution?
- How does my Ki-67 result affect my treatment plan?
- Does my Ki-67 result suggest I need chemotherapy, or is endocrine therapy alone likely to be sufficient?
- Should I have genomic testing (such as Oncotype DX or Prosigna) to get more precise information about my risk of recurrence?
- What is my breast cancer’s molecular subtype — Luminal A, Luminal B, HER2-positive, or triple-negative?
- If my Ki-67 is in the intermediate range, what other factors will you consider when deciding on chemotherapy?
- Will Ki-67 be re-measured after surgery if I have chemotherapy first?