|Ahead of print
Ki-67 in breast cancer: Simulacra and simulation
Department of Histopathology, Annexe Building, Tata Memorial Hospital, Dr. E Borges Road, Parel, Mumbai, Maharashtra, India
|Date of Submission||22-Jun-2019|
|Date of Decision||18-Oct-2019|
|Date of Acceptance||20-Oct-2019|
|Date of Web Publication||22-Jul-2020|
Department of Histopathology, Annexe Building, Tata Memorial Hospital, Dr. E Borges Road, Parel, Mumbai, Maharashtra
Source of Support: None, Conflict of Interest: None
The proliferation marker Ki-67 is one of the most controversial biomarkers used for treatment decisions in breast cancer patients. 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., 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. 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. 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.
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.,, 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.
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. 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.
The published cutoffs for Ki-67 in various studies vary between 5 and 34%., 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!, An article in this issue of Indian J Cancer by Meermira et al, 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. 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.,
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., 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. 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. 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.
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.,
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.
| » References|| |
Inwald EC, Klinkhammer-Schalke M, Hofstädter F, Zeman F, Koller M, Gerstenhauer M, et al
. Ki-67 is a prognostic parameter in breast cancer patients: Results of a large population-based cohort of a cancer registry. Breast Cancer Res Treat 2013;139:539-52.
Perou CM, Sørlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, et al
. Molecular portraits of human breast tumors. Nature 2000;406:747-52.
Sørlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, et al
. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A 2001;98:10869-74.
Cheang MC, Chia SK, Voduc D, Gao D, Leung S, Snider J, et al
. Ki67 index, HER2 status, and prognosis of patients with luminal B breast cancer. J Natl Cancer Inst 2009;101:736-50.
Peto R, Davies C, Godwin J, Gray R, Pan HC, Clarke M, et al
. Early Breast Cancer Trialists' Collaborative Group (EBCTCG), Comparisons between different polychemotherapy regimens for early breast cancer: Meta-analyses of long-term outcome among 100,000 women in 123 randomised trials. Lancet 2012;379:432-44.
Goldhirsch A, Wood WC, Coates AS, Gelber RD, Thurlimann B, Senn HJ, et al
. Strategies for subtype-dealing with the diversity of breast cancer: Highlights of the St. Gallen international expert consensus on the primary therapy of early breast cancer 2011. Ann Oncol 2011;22:1736e47-52.
Liu Y, Yin W, Yan T, Du Y, Shao Z, Lu J. The clinical significance of Ki-67 as a marker of prognostic value and chemosensitivity prediction in hormone-receptor-positive breast cancer: A meta-analysis of the published literature. Curr Med Res Opin 2013;29;1453-61.
de Azambuja E, Cardoso F, de Castro G Jr, Colozza M, Mano MS, Durbecq V, et al
. Ki67 as prognostic marker in early breast cancer: A meta-analysis of published studies involving 12,155 patients. Br J Cancer 2007;96:1504-13.
Stuart-Harris R, Caldas C, Pinder SE, Pharoah P. Proliferation markers and survival in early breast cancer: A systematic review and meta-analysis of 85 studies in 32,825 patients. Breast 2008;17:323-34.
Andre F, Arnedos M, Goubar A, Ghouadni A, Delaloge S. Ki67--no evidence forits use in node-positive breast cancer. Nat Rev Clin Oncol 2015;12:296-301.
Viale G, Regan MM, Mastropasqua MG, Maffini F, Maiorano E, Colleoni M, et al
. Predictive value of tumor Ki-67 expression in two randomized trials of adjuvant chemoendocrine therapy for node-negative breast cancer. J Natl Cancer Inst 2008;100:207-12.
Polley My, Leung SC, Gao D, Mastropasqua MG, Zabaglo LA, Bartlett JM, et al
. An international study to increase concordance in Ki67 scoring. Mod Pathol 2015;28:778-83.
Urruticoechea A, Smith IE, Dowsett M. Proliferation marker Ki-67 in early breast cancer. J Clin Oncol 2005;23:7212e20.
Denkert C, Budczies J, von Minckwitz G, Wienert S, Loibl S, Klauschen F. Strategies for developing Ki67 as a useful biomarker in breast cancer. Breast 2015;24:S67-72.
Dowsett M, Nielsen TO, A'Hern R, Bartlett J, Coombes RC, Cuzick J, et al
. International Ki-67 in breast Cancer working group. Assessment of Ki67 in breast cancer: Recommendations from the international Ki67 in breast Cancer working group. J Natl Cancer Inst 2011;103:1656-e64.
Meermira D, Swain M, Gowrishankar S. Study of Ki-67 index in the molecular subtypes of breast cancer: Inter-observer variability and automated scoring. Indian J Cancer 2020;57:XX-XX.
Rangarajan B, Shet T, Wadasadawala T, Nair N, Sairam R, Hingmire SS, et al
. Breast cancer: An overview of published Indian data. South Asian J Cancer 2016:5:86-92.
Nair N, Shet T, Parmar V, Havaldar R, Gupta S, Budrukkar A, et al
. Breast cancer in a tertiary cancer center in India- An audit with outcome analysis. Indian J Cancer 2018;55;16-22.
Luporsi E, André F, Spyratos F, Martin PM, Jacquemier J, Penault-Llorca F, et al.
Ki-67: Level of evidence and methodological considerations for its role in the clinical management of breast cancer: Analytical and critical review. Breast Cancer Res Treat 2012:132:895-915.
Yeo B, Zabaglo L, Hills M, Dodson A, Smith I, Dowsett M. Clinical utility of the IHC4+C score in oestrogen receptor-positive early breast cancer: A prospective decision impact study. Br J Cancer 2015;113:390-5.
Hou Y, Zynger DL, Li X, Li Z. Comparison of oncotype DX with modified magee equation recurrence scores in low-grade invasive carcinoma of breast. Am J Clin Pathol 2017;148:167-72.