KI67 and MCM2 histology pattern in breast cancer: a comparative analysis for better prognostic assessment
Keywords:
Ki67, MCM2, Breast Cancer, Histology Pattern, Prognostic Biomarkers, Tumor ProliferationAbstract
This review investigates prognostic roles of Ki67 and MCM2 in breast cancer, aiming to evaluate their effectiveness as biomarkers for assessing tumor proliferation and predicting patient outcomes. This paper was created using a literature review approach with Boolean logic operators “OR" and “AND, using keywords including “KI67," “MCM2," “breast cancer," “histology pattern," “prognostic marker,” and “comparative analysis.” We use several databases such as PubMed, ScienceDirect, Springer Nature, and Google Scholar. The results demonstrate that while Ki67 is extensively used and has a substantial correlation with tumor aggressiveness, it is constrained by interpretative diversity and uneven prognostic significance within subtypes. MCM2 has increased sensitivity, especially in heterogeneous cancers, and shows greater correlations with aggressive tumor characteristics and worse survival outcomes in high-risk subtypes. This review also finds deficiencies in standardized MCM2 evaluation methodologies and a lack of thorough investigation into its integration with other biomarkers and therapeutic potential. Standardized techniques, multivariate prognostic models, and more exploration of MCM2 are needed as a therapeutic target. This work deepens the knowledge of breast cancer biology and boosts the possibility for tailored treatment regimens, eventually enhancing prognostic accuracy and patient outcomes.
References
1. Global Cancer Observatory. CANCER TODAY - GLOBOCAN 2022 [Internet]. 2024 Feb [cited 2025 Mar 5]. Available from: https://gco.iarc.who.int/media/globocan/factsheets/cancers/20-breast-fact-sheet.pdf
2. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA Cancer J Clin. 2022 Jan 12;72(1):7–33.
3. Shandiz FH, Shabahang H, Afzaljavan F, Sharifi N, Tavasoli A, Afzalaghaee M, et al. Ki67 Frequency in Breast Cancers without Axillary Lymph Node Involvement and its Relation with Disease-free Survival. Asian Pacific Journal of Cancer Prevention. 2016 Apr 11;17(3):1347–50.
4. Sriwidyani NP, Dewi IGASM, Tanaka T. Association between Ki67 Index and Clinicopathological Parameters in Breast Cancer Patients in Bali. JBN (Jurnal Bedah Nasional). 2023 Oct 16;8(1):16.
5. Mamoor S. Differential expression of minichromosome maintenance complex component 2 in triple negative breast cancer. 2022.
6. Hashmi AA, Hashmi KA, Irfan M, Khan SM, Edhi MM, Ali JP, et al. Ki67 index in intrinsic breast cancer subtypes and its association with prognostic parameters. BMC Res Notes. 2019 Dec 23;12(1):605.
7. Samad A, Haque F, Nain Z, Alam R, Al Noman MA, Rahman Molla MH, et al. Computational assessment of MCM2 transcriptional expression and identification of the prognostic biomarker for human breast cancer. Heliyon. 2020 Oct;6(10):e05087.
8. Joshi S, Watkins J, Gazinska P, Brown JP, Gillett CE, Grigoriadis A, et al. Digital imaging in the immunohistochemical evaluation of the proliferation markers Ki67, MCM2 and Geminin, in early breast cancer, and their putative prognostic value. BMC Cancer. 2015 Dec 25;15(1):546.
9. Huh SJ, Oh H, Peterson MA, Almendro V, Hu R, Bowden M, et al. The Proliferative Activity of Mammary Epithelial Cells in Normal Tissue Predicts Breast Cancer Risk in Premenopausal Women. Cancer Res. 2016 Apr 1;76(7):1926–34.
10. Bustreo S, Osella-Abate S, Cassoni P, Donadio M, Airoldi M, Pedani F, et al. Optimal Ki67 cut-off for luminal breast cancer prognostic evaluation: a large case series study with a long-term follow-up. Breast Cancer Res Treat. 2016 Jun 7;157(2):363–71.
11. Yousef EM, Furrer D, Laperriere DL, Tahir MR, Mader S, Diorio C, et al. MCM2: An alternative to Ki-67 for measuring breast cancer cell proliferation. Modern Pathology. 2017 May;30(5):682–97.
12. Issac MSM, Yousef E, Tahir MR, Gaboury LA. MCM2, MCM4, and MCM6 in Breast Cancer: Clinical Utility in Diagnosis and Prognosis. Neoplasia. 2019 Oct;21(10):1015–35.
13. Zhong F, Bi R, Yu B, Yang F, Yang W, Shui R. A Comparison of Visual Assessment and Automated Digital Image Analysis of Ki67 Labeling Index in Breast Cancer. PLoS One. 2016 Feb 29;11(2):e0150505.
14. Cuylen S, Blaukopf C, Politi AZ, Müller-Reichert T, Neumann B, Poser I, et al. Ki-67 acts as a biological surfactant to disperse mitotic chromosomes. Nature. 2016 Jul 14;535(7611):308–12.
15. Sobecki M, Mrouj K, Colinge J, Gerbe F, Jay P, Krasinska L, et al. Cell-Cycle Regulation Accounts for Variability in Ki-67 Expression Levels. Cancer Res. 2017 May 15;77(10):2722–34.
16. Li N, Zhai Y, Zhang Y, Li W, Yang M, Lei J, et al. Structure of the eukaryotic MCM complex at 3.8 Å. Nature. 2015 Aug 29;524(7564):186–91.
17. Powell SK, MacAlpine HK, Prinz JA, Li Y, Belsky JA, MacAlpine DM. Dynamic loading and redistribution of the Mcm2‐7 helicase complex through the cell cycle. EMBO J. 2015 Feb 12;34(4):531–43.
18. Deegan TD, Yeeles JT, Diffley JF. Phosphopeptide binding by Sld3 links Dbf4‐dependent kinase to MCM replicative helicase activation. EMBO J. 2016 May 2;35(9):961–73.
19. Abe S, Yamamoto K, Kurata M, Abe-Suzuki S, Horii R, Akiyama F, et al. Targeting MCM2 function as a novel strategy for the treatment of highly malignant breast tumors. Oncotarget. 2015 Oct 27;6(33):34892–909.
20. Huang H, Strømme CB, Saredi G, Hödl M, Strandsby A, González-Aguilera C, et al. A unique binding mode enables MCM2 to chaperone histones H3–H4 at replication forks. Nat Struct Mol Biol. 2015 Aug 13;22(8):618–26.
21. Richet N, Liu D, Legrand P, Velours C, Corpet A, Gaubert A, et al. Structural insight into how the human helicase subunit MCM2 may act as a histone chaperone together with ASF1 at the replication fork. Nucleic Acids Res. 2015 Feb 18;43(3):1905–17.
22. Shui R, Yu B, Bi R, Yang F, Yang W. An Interobserver Reproducibility Analysis of Ki67 Visual Assessment in Breast Cancer. PLoS One. 2015 May 1;10(5):e0125131.
23. Bustreo S, Osella-Abate S, Cassoni P, Donadio M, Airoldi M, Pedani F, et al. Optimal Ki67 cut-off for luminal breast cancer prognostic evaluation: a large case series study with a long-term follow-up. Breast Cancer Res Treat. 2016 Jun 7;157(2):363–71.
24. Nielsen TO, Leung SCY, Rimm DL, Dodson A, Acs B, Badve S, et al. Assessment of Ki67 in Breast Cancer: Updated Recommendations From the International Ki67 in Breast Cancer Working Group. JNCI: Journal of the National Cancer Institute. 2021 Jul 1;113(7):808–19.
25. Healey MA, Hirko KA, Beck AH, Collins LC, Schnitt SJ, Eliassen AH, et al. Assessment of Ki67 expression for breast cancer subtype classification and prognosis in the Nurses’ Health Study. Breast Cancer Res Treat. 2017 Nov 8;166(2):613–22.
26. Kim JY, Jeong HS, Chung T, Kim M, Lee JH, Jung WH, et al. The value of phosphohistone H3 as a proliferation marker for evaluating invasive breast cancers: A comparative study with Ki67. Oncotarget. 2017 Sep 12;8(39):65064–76.
27. Vanderschelden RK, Jerome JA, Gonzalez D, Seigh L, Carter GJ, Clark BZ, et al. Implementation of Digital Image Analysis in Assessment of Ki67 Index in Breast Cancer. Applied Immunohistochemistry & Molecular Morphology. 2024 Jan;32(1):17–23.
28. Stålhammar G, Robertson S, Wedlund L, Lippert M, Rantalainen M, Bergh J, et al. Digital image analysis of Ki67 in hot spots is superior to both manual Ki67 and mitotic counts in breast cancer. Histopathology. 2018 May 14;72(6):974–89.
29. Behairy MAG, Gabal SM, Metenawy WH El, Kasem LM, Abel-Salam L omar. Comparing Molecular Biomarker Testing With Immunohistochemical Staining In Predicting Response To Neoadjuvant Therapy In Breast Cancer. 2022.
30. Quan Y, Xia Y, Liu L, Cui J, Li Z, Cao Q, et al. Cell-Cycle-Regulated Interaction between Mcm10 and Double Hexameric Mcm2-7 Is Required for Helicase Splitting and Activation during S Phase. Cell Rep. 2015 Dec;13(11):2576–86.
31. Cheung CHY, Hsu CL, Chen KP, Chong ST, Wu CH, Huang HC, et al. MCM2-regulated functional networks in lung cancer by multi-dimensional proteomic approach. Sci Rep. 2017 Oct 16;7(1):13302.
32. Zhang J, Zhang H, Wang Y, Wang Q. MCM2-7 in Clear Cell Renal Cell Carcinoma: MCM7 Promotes Tumor Cell Proliferation. Front Oncol. 2021 Dec 21;11.
33. Nahed AS, Shaimaa MY. Ki-67 as a prognostic marker according to breast cancer molecular subtype. Cancer Biol Med. 2016;13(4):496.
34. Devi DGAP, Purwanto H, Sandhika W. Changes in Ki67 expression and clinical response to neoadjuvant chemotherapy in locally advanced breast cancer (LABC). Bali Medical Journal. 2021 Nov 12;10(3):925–31.
35. Koopman T, Buikema HJ, Hollema H, de Bock GH, van der Vegt B. Digital image analysis of Ki67 proliferation index in breast cancer using virtual dual staining on whole tissue sections: clinical validation and inter-platform agreement. Breast Cancer Res Treat. 2018 May 18;169(1):33–42.
36. Kim JY, Jeong HS, Chung T, Kim M, Lee JH, Jung WH, et al. The value of phosphohistone H3 as a proliferation marker for evaluating invasive breast cancers: A comparative study with Ki67. Oncotarget. 2017 Sep 12;8(39):65064–76.
37. Denkert C, Budczies J, von Minckwitz G, Wienert S, Loibl S, Klauschen F. Strategies for developing Ki67 as a useful biomarker in breast cancer. The Breast. 2015 Nov;24:S67–72.
38. Duffy MJ, Harbeck N, Nap M, Molina R, Nicolini A, Senkus E, et al. Clinical use of biomarkers in breast cancer: Updated guidelines from the European Group on Tumor Markers (EGTM). Eur J Cancer. 2017 Apr;75:284–98.
39. Song B, Wang L, Zhang Y, Li N, Dai H, Xu H, et al. Combined Detection of HER2, Ki67, and GSTP1 Genes on the Diagnosis and Prognosis of Breast Cancer. Cancer Biother Radiopharm. 2019 Mar;34(2):85–90.
40. Kensler KH, Beca F, Baker GM, Heng YJ, Beck AH, Schnitt SJ, et al. Androgen receptor expression in normal breast tissue and subsequent breast cancer risk. NPJ Breast Cancer. 2018 Sep 21;4(1):33.
41. Jin J, Zheng D, Liu Y. Correlation between the Expression of Topo IIα and Ki67 in Breast Cancer and its clinical Pathological characteristics. Pak J Med Sci. 2017 Aug 4;33(4).
42. Harris LN, Ismaila N, McShane LM, Andre F, Collyar DE, Gonzalez-Angulo AM, et al. Use of Biomarkers to Guide Decisions on Adjuvant Systemic Therapy for Women With Early-Stage Invasive Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline. Journal of Clinical Oncology. 2016 Apr 1;34(10):1134–50.
43. Acs B, Pelekanou V, Bai Y, Martinez-Morilla S, Toki M, Leung SCY, et al. Ki67 reproducibility using digital image analysis: an inter-platform and inter-operator study. Laboratory Investigation. 2019 Jan;99(1):107–17.
44. Coates AS, Winer EP, Goldhirsch A, Gelber RD, Gnant M, Piccart-Gebhart M, et al. Tailoring therapies—improving the management of early breast cancer: St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2015. Annals of Oncology. 2015 Aug;26(8):1533–46.
45. Laurinavicius A, Plancoulaine B, Rasmusson A, Besusparis J, Augulis R, Meskauskas R, et al. Bimodality of intratumor Ki67 expression is an independent prognostic factor of overall survival in patients with invasive breast carcinoma. Virchows Archiv. 2016 Apr 27;468(4):493–502.
46. Swiderska-Chadaj Z, Gallego J, Gonzalez-Lopez L, Bueno G. Detection of Ki67 Hot-Spots of Invasive Breast Cancer Based on Convolutional Neural Networks Applied to Mutual Information of H&E and Ki67 Whole Slide Images. Applied Sciences. 2020 Nov 2;10(21):7761.
47. Gao W, Wu J, Chen X, Lin L, Fei X, Shen K, et al. Clinical validation of Ki67 by quantitative reverse transcription-polymerase chain reaction (RT-PCR) in HR+/HER2- early breast cancer. J Cancer. 2019;10(5):1110–6.
48. Keerthana Devi D, Pavithra V, Joseph LD, Challa CB. Correlation of Androgen Receptor Expression With Ki67 Proliferative Index and Other Clinicopathological Characteristics in Invasive Mammary Carcinomas. Cureus. 2024 Oct 4;
49. Hashmi AA, Hashmi KA, Irfan M, Khan SM, Edhi MM, Ali JP, et al. Ki67 index in intrinsic breast cancer subtypes and its association with prognostic parameters. BMC Res Notes. 2019 Dec 23;12(1):605.
50. Lehmann BD, Jovanović B, Chen X, Estrada M V., Johnson KN, Shyr Y, et al. Refinement of Triple-Negative Breast Cancer Molecular Subtypes: Implications for Neoadjuvant Chemotherapy Selection. PLoS One. 2016 Jun 16;11(6):e0157368.
51. Bareche Y, Venet D, Ignatiadis M, Aftimos P, Piccart M, Rothe F, et al. Unravelling triple-negative breast cancer molecular heterogeneity using an integrative multiomic analysis. Annals of Oncology. 2018 Apr;29(4):895–902.
52. Jiang YZ, Ma D, Suo C, Shi J, Xue M, Hu X, et al. Genomic and Transcriptomic Landscape of Triple-Negative Breast Cancers: Subtypes and Treatment Strategies. Cancer Cell. 2019 Mar;35(3):428-440.e5.
53. SUN J, CHEN C, WEI W, ZHENG H, YUAN J, TU Y, et al. Associations and indications of Ki67 expression with clinicopathological parameters and molecular subtypes in invasive breast cancer: A population-based study. Oncol Lett. 2015 Sep;10(3):1741–8.
54. Tao M, Chen S, Zhang X, Zhou Q. Ki-67 labeling index is a predictive marker for a pathological complete response to neoadjuvant chemotherapy in breast cancer. Medicine. 2017 Dec;96(51):e9384.
55. Resende U, Cabello C, Oliveira Botelho Ramalho S, Zeferino LC. Predictors of Pathological Complete Response in Women with Clinical Complete Response to Neoadjuvant Chemotherapy in Breast Carcinoma. Oncology. 2018;95(4):229–38.
56. Fragomeni SM, Sciallis A, Jeruss JS. Molecular Subtypes and Local-Regional Control of Breast Cancer. Surg Oncol Clin N Am. 2018 Jan;27(1):95–120.
57. Keenan TE, Tolaney SM. Role of Immunotherapy in Triple-Negative Breast Cancer. Journal of the National Comprehensive Cancer Network. 2020 Apr;18(4):479–89.
58. Abubakar M, Orr N, Daley F, Coulson P, Ali HR, Blows F, et al. Prognostic value of automated KI67 scoring in breast cancer: a centralised evaluation of 8088 patients from 10 study groups. Breast Cancer Research. 2016 Dec 18;18(1):104.
59. Sun GS, Wang S, Wang Y. Expressions of Topo IIα and Ki67 in breast cancer and its clinicopathologic features and prognosis. Pak J Med Sci. 2019 May 21;35(3).
60. Hosseini S, Shahbaziyan H, Razmjoo S, Jasemizade N. Evaluation the Correlation between Ki67 and 5 Years Disease Free Survival of Breast Cancer Patients. Biosci Biotechnol Res Asia. 2015 Dec 25;12(3):2221–5.
61. Prat A, Pineda E, Adamo B, Galván P, Fernández A, Gaba L, et al. Clinical implications of the intrinsic molecular subtypes of breast cancer. The Breast. 2015 Nov;24:S26–35.
62. Coates AS, Winer EP, Goldhirsch A, Gelber RD, Gnant M, Piccart-Gebhart M, et al. Tailoring therapies—improving the management of early breast cancer: St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2015. Annals of Oncology. 2015 Aug;26(8):1533–46.
63. Sparano JA, Gray RJ, Makower DF, Pritchard KI, Albain KS, Hayes DF, et al. Prospective Validation of a 21-Gene Expression Assay in Breast Cancer. New England Journal of Medicine. 2015 Nov 19;373(21):2005–14.
64. Chen R, Ye Y, Yang C, Peng Y, Zong B, Qu F, et al. Assessment of the predictive role of pretreatment Ki-67 and Ki-67 changes in breast cancer patients receiving neoadjuvant chemotherapy according to the molecular classification: a retrospective study of 1010 patients. Breast Cancer Res Treat. 2018 Jul 26;170(1):35–43.
65. Chen C, Zhang Y, Huang Z, Wu J, Huang W, Zhang G. Decrease in the Ki67 index during neoadjuvant chemotherapy predicts favorable relapse-free survival in patients with locally advanced breast cancer. Cancer Biol Med. 2019 Aug 1;16(3):575–86.
66. Sullu Y, Demirag G, Kuru B, Ozen N, Karagoz F. Assessment of the relationships between Ki67 expression and neoadjuvant treatment response and prognosis in breast cancer using two types of response evaluation systems. 2022.
67. Sheikhpour R, Poorhosseini F. Correlation between Expression of Ki67 with Her-2 and p53 Tumour Markers in Breast Cancer Patients. West Indian Medical Journal. 2015 May 21;
68. Shin HJ, Kim SH, Lee HJ, Gong G, Baek S, Chae EY, et al. Tumor apparent diffusion coefficient as an imaging biomarker to predict tumor aggressiveness in patients with estrogen-receptor-positive breast cancer. NMR Biomed. 2016 Aug;29(8):1070–8.
69. Liu X, Liu Y, Wang Q, Song S, Feng L, Shi C. The Alterations and Potential Roles of MCMs in Breast Cancer. J Oncol. 2021 Aug 24;2021:1–17.
70. ZHANG X, TENG Y, YANG F, WANG M, HONG X, YE LG, et al. MCM2 is a therapeutic target of lovastatin in human non-small cell lung carcinomas. Oncol Rep. 2015 May;33(5):2599–605.
71. Deng M, Sun J, Xie S, Zhen H, Wang Y, Zhong A, et al. Inhibition of MCM2 enhances the sensitivity of ovarian cancer cell to carboplatin. Mol Med Rep. 2019 Jul 9;
72. Surendra A, Rostinawati T, Amalia R. Development of Imaging and Liquid Biomarker Analysis for Breast Cancer Screening: A Review. Pharmaceutical Sciences. 2021 Jul 8;
73. Miller I, Min M, Yang C, Tian C, Gookin S, Carter D, et al. Ki67 is a Graded Rather than a Binary Marker of Proliferation versus Quiescence. Cell Rep. 2018 Jul;24(5):1105-1112.e5.
74. Jang MH, Kim HJ, Chung YR, Lee Y, Park SY. A comparison of Ki-67 counting methods in luminal Breast Cancer: The Average Method vs. the Hot Spot Method. PLoS One. 2017 Feb 10;12(2):e0172031.
75. Tan S, Fu X, Xu S, Qiu P, Lv Z, Xu Y, et al. Quantification of Ki67 Change as a Valid Prognostic Indicator of Luminal B Type Breast Cancer After Neoadjuvant Therapy. Pathology and Oncology Research. 2021 Dec 20;27.
76. Finkelman BS, Zhang H, Hicks DG, Turner BM. The Evolution of Ki-67 and Breast Carcinoma: Past Observations, Present Directions, and Future Considerations. Cancers (Basel). 2023 Jan 28;15(3):808.
77. Løkkegaard S, Elias D, Alves CL, Bennetzen M V., Lænkholm AV, Bak M, et al. MCM3 upregulation confers endocrine resistance in breast cancer and is a predictive marker of diminished tamoxifen benefit. NPJ Breast Cancer. 2021 Jan 4;7(1):2.
78. Wu W, Wang X, Shan C, Li Y, Li F. Minichromosome maintenance protein 2 correlates with the malignant status and regulates proliferation and cell cycle in lung squamous cell carcinoma. Onco Targets Ther. 2018 Aug;Volume 11:5025–34.
79. Şahin S, Işık Gönül İ, Çakır A, Seçkin S, Uluoğlu Ö. Clinicopathological Significance of the Proliferation Markers Ki67, RacGAP1, and Topoisomerase 2 Alpha in Breast Cancer. Int J Surg Pathol. 2016 Oct 28;24(7):607–13.
80. Jang MH, Kim HJ, Chung YR, Lee Y, Park SY. A comparison of Ki-67 counting methods in luminal Breast Cancer: The Average Method vs. the Hot Spot Method. PLoS One. 2017 Feb 10;12(2):e0172031.
