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Year : 2020  |  Volume : 57  |  Issue : 3  |  Page : 231--233

Ki-67 in breast cancer: Simulacra and simulation

Tanuja Shet 
 Department of Histopathology, Annexe Building, Tata Memorial Hospital, Dr. E Borges Road, Parel, Mumbai, Maharashtra, India

Correspondence Address:
Tanuja Shet
Department of Histopathology, Annexe Building, Tata Memorial Hospital, Dr. E Borges Road, Parel, Mumbai, Maharashtra

How to cite this article:
Shet T. Ki-67 in breast cancer: Simulacra and simulation.Indian J Cancer 2020;57:231-233

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Shet T. Ki-67 in breast cancer: Simulacra and simulation. Indian J Cancer [serial online] 2020 [cited 2020 Sep 20 ];57:231-233
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The proliferation marker Ki-67 is one of the most controversial biomarkers used for treatment decisions in breast cancer patients.[1] This marker came into limelight for its ability to distinguish between the two molecular subtypes of breast cancer luminal A (low proliferating) and luminal B (high proliferation) tumors.[2],[3] Cheang et al. were the first to demonstrate that a Ki-67 of 13.25% had 72% sensitivity and 77% specificity in distinguishing between luminal A vs luminal B and the fact that an immunopanel of estrogen receptor (ER), progesterone receptor (PR), HER2, and Ki-67 can divide the luminal A and B subtypes similar to the 50-gene expression signature fairly accurately.[4] The Oxford meta-analysis evaluating chemotherapy in early-stage breast cancer concluded that adjuvant chemotherapy reduces cancer-associated death by 36% with a 5% improvement in overall survival as compared to no chemotherapy.[5] Several guidelines soon endorsed the use of the Ki-67 simulacra to predict a luminal B phenotype and aid decisions as to whether or not a patient should receive adjuvant chemotherapy in early breast cancer.[6]

Few large meta-analyses have confirmed that in spite of methodological issues high Ki-67 confers a worse prognosis in both node-positive and node-negative patients.[7],[8],[9] Most studies on the predictive role of Ki-67 are retrospective and there is no compelling evidence that high Ki-67 predicts the efficacy of adjuvant chemotherapy or that a patient with Ki-67 low breast cancer does not derive benefit from adjuvant chemotherapy.[10]

There is a large body of evidence that Ki-67 as a test lacks analytical validity and has wide interobserver variability refuting its role as a routine biomarker.[11] The most important issues marring Ki-67 testing are a) impact of preanalytical factors like fixation on test results, b) variability of testing methods c) interobserver variability in assessment d) cut-off related issues e) variation in actual method of counting.[12]

The published cutoffs for Ki-67 in various studies vary between 5 and 34%.[13],[14] In 2011, St. Gallen recommended a cutoff of 14% for separation of luminal A and B tumors but in 2013 the cutoff was revised to 20%, with the option of using a different cut-off based on the “significant mean value” from an “in house” data set![6],[15] An article in this issue of Indian J Cancer by Meermira et al,[16] is a follow-through of that statement to define an India applicable “Ki-67 cut-off” although after the excitement has abated. The authors described Ki-67 across various molecular subtypes of breast cancer and recommend a mean value of Ki-67 obtained (28.35%) can be used as a cut-off in the laboratory. Interestingly luminal B (defined by Ki-67) had lower mean than triple-negative cancers and in my opinion, a median value would have been more representative than mean. According to the international Ki-67 standardization committee suggestion, every laboratory should analyze all operable breast cancers (nonlocally advanced cancers) with luminal tumors luminal A and luminal B subtypes and take an average by including TNBC (Triple negative breast cancer) and Her2/neu by the above paper perhaps has diluted the impact and beats the philosophy of the use of Ki-67 in breast cancer. It was suggested that each laboratory validates the Ki-67 scores obtained using their own internally standardized protocol and scoring technique against a series of control cases where “outcome” or “molecular profiling” data is known.[15] While this statement addresses the tumor heterogeneity across the continents, it meant that besides testing a whole range of hormone-positive tumors (and not Her2/neu or triple-negative cancers) for Ki-67, we need to have a prognostic/genetic data correlation in the same data set for calculating this mean Ki-67 cut-off, a privilege that many premier centers lack in India and so was the case with the study in focus. One good point to be noted in the study is that there was a significant correlation between the two observers and with the automated scoring, stressing the point that with training and automation better correlations may be obtained.

The fundamental issue of not using the international cut-offs in Indian population is that most of our cancers are high grade and the median is not expected to be low.[17],[18]

Most centers are using the international cut-off 20% but centers such as ours decide on chemotherapy for patients with Ki-67 > 25 to 30% in the context of histology and grade. The fact that the international Ki-67 in breast cancer working group still “was unable to come” with a universal cut-off, subtly attests to the difficulty in having a single/one cut-off point.[14],[15] Also using one cut-off suggests that patients who have tumors with Ki-67 on either side of cut-off are very different whereas, in reality, they are similar or closer.[19] I agree with the thinking that pathologist should probably stop looking for an “optimal” cut-off point for Ki-67 because it simply does not exist.[19] Due to the low analytical validity in this intermediate range and increased heterogeneity of Ki-67 in this range, the clinical utility of intermediate Ki-67 levels is limited, and clinical decisions should not be based on this marker alone.[19]

There has been a long debate on the counting method for Ki-67 whether one should evaluate Ki-67 in the so-called “hot-spots” within the tumor or if the pathologist should report average or global Ki-67 values. Which method should be used depends on how much heterogeneity is seen in Ki-67. Moreover, giving a number range rather than one number more likely gives a snapshot of tumor Ki-67 proliferation. While routinely performed Ki-67 may not be robust, adding Ki-67 to a multiparametric equation like IHC4 or Magee equation seems to improve its prognostic value.[20],[21]

Does this mean Ki-67 should not be done in breast cancer to aid adjuvant chemotherapy decisions in early breast cancer, the answer is “No” because in my opinion a high Ki-67 will assist decision of chemotherapy but the intermediate and low values need the context of traditional histology variables such as lymphovascular emboli, grade, and understanding of testing methodologies is critical.


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