Ki 67 index


Reflects levels of nuclear protein.

Ki-67 positivity is strongly associated with pathologic stage, Gleason score, tumor volume, and nodal status in prostate cancer.

In prostate cancer tumors with more than 5% of cells positive for Ki-67 are significantly more likely to have biochemical failure within 10 years of surgery (Tollefson MK).

Main with prostate cancer and more than 5% of cells positive for Ki-67 are more likely to suffer systemic progression or cancer specific death during a 10 year followup.

The predictive value of Ki-67 was a better predictor of outcome then preoperative PSA, clinical stage or Gleason’s score for prostate cancer(Tollefson MK).

Antigen KI-67 also known as Ki-67, is a protein that in humans is encoded by the MKI67 gene.

Gene location is chromosome 10.

A nuclear protein that is associated with and may be necessary for cellular proliferation.

Associated with ribosomal RNA transcription.

Inactivation of antigen KI-67 leads to inhibition of ribosomal RNA synthesis.

It is used as a marker of proliferating cells.

It is associated with cell proliferation, and during interphase, the Ki-67 antigen can be exclusively detected within the cell nucleus.

In mitosis most of the protein is relocated to the surface of the chromosomes.

Ki-67 protein is present during all active phases of the cell cycle (G1, S, G2, and mitosis).

It is absent in resting cells (G0).

Cellular content of Ki-67 protein increases during cell progression through S phase of the cell cycle.

It identifies a high proliferative subset of patients with ER-positive breast cancer who derive greater benefit from adjuvant chemotherapy.

An excellent marker to determine the growth fraction of a given cell population, and often is correlated with the clinical course of cancer.

The best-studied examples are carcinomas of the breast, prostate, brain and nephroblastoma and neuroendocrine tumors.

MIB-1 is used in clinical applications to determine the Ki-67 labelling index.

In women whose tumors were characterized by high Ki-67 values, predict the risk of breast cancer recurrence at 5 years.



HER2-negative patients randomized to preoperative aromatase inhibitor (POAI) with a low baseline Ki-67 of less than 10% had only a 4.4% risk of recurrence at 5 years compared to those with a high baseline Ki-67 value at 11.8%.



And POAI patients whose tumors had a high baseline Ki-67 but whose Ki-67 levels dropped to less than 10% 2 weeks after receiving AI treatment had a better prognosis at 5 years than patients who continued to have a high Ki-67 two weeks after treatment where the 5-year risk of recurrence was 8.4% versus 21.5%, respectively.



Patients randomized to the POAI group received either letrozole (Femara) at a dose of 2.5 mg per day or anastrozole (Arimidex) at a dose of 1 mg a day, both taken orally, for 14 days before and following surgery.



At a median follow-up of 62.9 months, 10% of POAI patients had a breast cancer recurrence compared with 9% of controls with no significant difference between the 2 groups, at an adjusted Hazard Ratio (HR) of 0.96.



No significant differences between treatment groups were observed for relapse-free survival, time to local recurrence and time to distant recurrences.



Overall survival rates at 5 years were virtually identical between the 2 groups: 88.9% in the POAI group versus 88.9% in controls.



After 2 weeks of POAI, Ki-67 was significantly suppressed compared with little change in the control group.



Women whose Ki-67 remained high after 2 weeks of POAI treatment had over a 2-fold higher risk of recurrence at 5 years than women whose Ki-67 at 2 weeks had dropped below 10%.



In this group of patients, the 5-year recurrence risk was 21.5%: 


At 5 years, recurrence risk in the low risk group, with baseline and low Ki-67 counts 2 weeks after receiving endocrine therapy, was only 4.3%, compared to 8.4% for those with a high baseline Ki-67 but whose Ki-67 value dropped to less than 10% 2 weeks after treatment.



Patients whose Ki-67 was low did well on standard of care, with approximately 85% of those receiving endocrine therapy alone.



In contrast, giving POAI to the group of patients with a high baseline Ki-67 may help differentiate 2 groups of patients according to their 2-week post-treatment Ki-67value: those who convert to a low Ki-67 value after treatment who may not need anything beyond adjuvant endocrine therapy and those whose Ki-67 values remain high and who should be considered for further adjuvant options.


Ki-67 score is at week two after preoperative endocrine therapy categorizes prognosis: at two weeks KI 67 positivity below 10% cut off, at five years had a recurrence rate of less than 10%, while those with a cut off greater than 10% at two weeks, had a five-year risk of recurrence greater than 20%.

In the POETIC study above, those who’s Ki 67 score was less than 10% at baseline and week two had a five-year recurrence rate less than 5%.

Although Ki-67 is a commonly used measure of cellular proliferation in breast cancer tissue.

Ki-67 biomarker may play a more extensive role in breast cancer treatment, by guiding therapeutic decisions.

The ADAPT trial provided evidence that, after a short course of neoadjuvant endocrine therapy (NET), an on-treatment Ki-67 index can identify patients who can be spared intensive chemotherapy in the adjuvant setting.

The monarchE trial was the first to prospectively investigate Ki-67 as a biomarker in a phase 3 trial of cyclin-dependent kinase inhibitors (CDKIs) in the adjuvant setting. 

High Ki-67 levels in conjunction with high-risk features could be used to select patients who would benefit from the addition of abemaciclib (Verzenio) to endocrine therapy (ET) in the adjuvant treatment of ER-positive, HER2- negative stage I or II breast cancer.

A monoclonal antibody is used for IHC staining of the proliferation-associated nuclear protein Ki-67 in tumor cells to determine the percentage of Ki-67–positive cells in formalin-fixed paraffin-embedded sections obtained from a core-cut biopsy sample; Ki-67 index.

Tumors with a high Ki-67 index have a larger number of proliferating cells and are therefore likely to grow more quickly.

The Ki-67 index is useful  in the grading of neuroendocrine tumors of the pancreas and gastrointestinal tract, and other cancer types, including bladder, prostate, and liver cancer; soft tissue sarcomas; and meningiomas, but are much less well defined.

There prognostic value of measuring Ki-67 in breast cancers: for both disease-free survival (DFS) and overall survival (OS).

In patients with a Ki-67 index of 15% or less, 5-year DFS and OS rates were 86.7% and 89.3%, respectively, compared with 75.8% and 82.8% in patients with a high Ki-67 index (> 45%).

The vast majority of breast cancers are ER positive and can be classified into 2 molecular subtypes: luminal A and luminal B. Compared with their luminal B counterparts, luminal A tumors generally are lower grade, have higher expression of estrogen-related genes, have a better prognosis, and are more sensitive to ET.

Ki-67 has emerged as an important surrogate marker because luminal A tumors typically have a lower rate of proliferation than luminal B tumors.

The Ki-67 index was shown to discriminate between the luminal A and luminal B subtypes most effectively when a cutoff of 14% was used.

Ki-67 os a prognostic marker was estimation in anatomically favorable ER-positive and HER2-negative patients, to identify those who do not need adjuvant chemotherapy.

The group’s consensus was that Ki-67 levels of 5% or below or 30% or greater could be used to estimate prognosis and determine the advisability of adjuvant chemotherapy. 

For tumors with a Ki-67 index between these values, multigene expression panels are used.

Hormone receptor–positive, HER2-negative breast cancers are far less likely to exhibit a pCR to preoperative chemotherapy.

Baseline levels of Ki-67 as a biomarker for neoadjuvant endocrine therapy has conflicting results. 

IMPACT, a relatively small study (N= 330) showed that the baseline Ki-67 level did not significantly predict outcome following NET.

The POETIC trial, which was conducted in a much larger patient population (N = 4480) reported that patients with a low baseline Ki-67 index had a lower risk of recurrence and could likely skip  neoadjuvant endocrine therapy.

The Ki-67 index at 2 to 4 weeks after starting neoadjuvant endocrine therapy indicates the level of persistent cell proliferation and resistance or response to ET and is significantly associated with risk of recurrence.

In the POETIC trial, for patients with high Ki-67 levels at baseline and after 2 weeks of NET, the 5-year absolute risk of recurrence was 21.5%. The risk was 8.4% for those with high baseline but low 2-week Ki-67 levels, and 4.3% for those with low levels at both time points.

The Ki-67 index complements the Oncotype DX RS in selecting patients for whom chemotherapy can be omitted.

To help overcome resistance to ET in breast cancer, which occurs almost universally, a number of combinations of several CDKIs for use in combination with endocrine therapy for the treatment of advanced/metastatic ER-positive, HER2-negative disease, and these successes have prompted the evaluation of this therapeutic approach in early-stage breast cancer.

MonarchE trial, 5637 patients with high-risk, node-positive, ER-positive, HER2-negative breast cancer are randomized to receive 5 to 10 years of adjuvant ET, with or without the addition of 2 years of the CDKI abemaciclib.

Subanalysis of cohort 1, the addition of abemaciclib to ET reduced the risk of IDFS by 35.7% compared with ET alone in patients with a high baseline Ki-67 index (≥ 20%). 

Patients with a low Ki-67 index (<20%) also benefited from the addition of abemaciclib, the magnitude of treatment benefit was numerically lower.

With the combination of a CDKI and  neoadjuvant in several recent clinical trials, a change in the Ki-67 index from baseline after therapy served as a primary end point. 

The addition of a CDKI resulted in greater suppression of Ki-67 levels in the MONALEESA-1, neoMONARCH, and PALLET trials.


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