The Relationship Between Ki-67 Expression and Post-Surgical Breast Cancer Recurrence Rates: A Systematic Review
Keywords:
Breast Cancer, Ki-67 Antigen, Post-Surgical Recurrence, Disease-Free Survival, Prognostic Biomarker, Systematic ReviewAbstract
Introduction: Post-surgical recurrence remains the primary driver of mortality in breast cancer. While the proliferation biomarker Ki-67 is recognized as a potent prognostic tool, its clinical implementation is debated due to significant methodological inconsistencies. This systematic review aims to synthesize the extensive body of evidence to confirm the significant, independent association between high Ki-67 expression and post-surgical breast cancer recurrence.
Methods: This review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A systematic search of PubMed, Google Scholar, Semantic Scholar, Springer, Wiley Online Library was performed for studies from January 2007 to October 2024. The PICO (Population, Intervention, Comparator, Outcome) framework was used to select high-quality cohort studies and meta-analyses. Methodological quality was assessed using the Newcastle-Ottawa Scale (NOS) for prognostic studies.
Results: A total of 17 high-impact studies were included, comprising 12 primary cohort studies and 5 major meta-analyses, which collectively represent over 85,000 patients. The synthesis of this data demonstrates a highly significant and robust association between high Ki-67 expression and worse post-surgical outcomes. Major meta-analyses report that high Ki-67 confers a pooled Hazard Ratio (HR) for relapse of 1.93 (95% CI: 1.74–2.14, p < 0.001) and a pooled HR for mortality of 2.05 (95% CI: 1.66–2.53, p < 0.00001). High-impact cohort studies reinforce this, reporting HRs for recurrence risk as high as 7.14, 12.90, and even 30.47 in specific patient groups. This association remains significant across all major breast cancer subtypes, including ER+/HER2- and triple-negative breast cancer.
Discussion: The prognostic signal of Ki-67 is exceptionally robust, remaining statistically significant despite wide heterogeneity in study cutoffs, ranging from 13% to 40%). This confirms its fundamental biological importance. Ki-67 is clinically essential for differentiating low-risk Luminal A from high-risk Luminal B subtypes and is now a critical biomarker for guiding adjuvant therapy decisions, including the use of CDK4/6 inhibitors.
Conclusion: High Ki-67 expression is one of the most significant and clinically relevant independent predictors of post-surgical breast cancer recurrence. The urgent, collective adoption of international standardization guidelines for Ki-67 assessment, as proposed by groups like the International Ki-67 in Breast Cancer Working Group (IKWG), is the final and necessary step to unlock its full clinical utility in routine oncological practice.
References
Abdel-Hadi, R.F., Abdelhameed, D.H. and Abdeltawab, A. (2023) 'Relationship between Ki-67 index and risk of recurrences and survival in patients with ER/PR +ve, HER2 –ve breast cancer', World Cancer Research Journal, 10(4), e2675.
Agha, R.A., Al-Ghazal, S.K., Al-Jilani, M., Al-Kardim, M.I., Al-Naimi, M.S., Al-Saadi, A.Y. and Al-Suwaidi, N.K. (2024) 'Association Between Ki-67 Proliferative Index and Oncotype-Dx Recurrence Score in Hormone Receptor-Positive/HER2-Negative Early Breast Cancers: A Systematic Review of the Literature', Cureus, 16(5), e59591.
Ahn, H., Kim, J.H. and Kim, S. (2023) 'Prognostic Impact of Low Human Epidermal Growth Factor Receptor 2 Expression in Breast Cancer: A Systematic Review and Meta-Analysis', Anticancer Research, 43(10), pp. 4303–4314.
Canadian Ki67 Working Group (2023) 'Ki67 Testing in HR+/HER2- High-Risk Early Breast Cancers: A Canadian Guideline-Informed Call to Action', Current Oncology, 30(3), pp. 3144–3155.
Cleveland Clinic (2022) Breast Cancer Recurrence. Available at: https://my.clevelandclinic.org/health/diseases/8328-breast-cancer-recurrence (Accessed: 10 November 2025).
Connolly, E.L., Minter, A. and Tandon, A. (2022) 'The Evolving Role of Ki-67 in Breast Cancer', Cancers, 15(3), p. 808.
de Azambuja, E., Cardoso, F., de Castro, G., Jr., Colozza, M., Mano, M.S., Durbecq, V., Sotiriou, C., Larsimont, D., Piccart-Gebhart, M.J. and Paesmans, M. (2007) 'Ki-67 as prognostic marker in early breast cancer: a meta-analysis of published studies involving 12,155 patients', British Journal of Cancer, 96(10), pp. 1504–1513.
Dowsett, M., Nielsen, T.O., A'Hern, R., Bartlett, J., Coombes, R.C., Cuzick, J., Ellis, M., Henry, N.L., Hugh, J.C., Lively, T., McShane, L., Paik, S., Penault-Llorca, F., Pogue-Geile, K., Regan, M.M., Salter, J., Sotiriou,C., Smith, I.E., Viale, G., Zujewski, J.A., Hayes, D.F. and International Ki-67 in Breast Cancer Working Group (2011) 'Assessment of Ki67 in Breast Cancer: Recommendations from the International Ki67 in Breast Cancer Working Group', Journal of the National Cancer Institute, 113(7), pp. 808-819.
Dowsett, M., Sestak, I., Lopez-Knowles, E., Dodson, A., Morden, J., Møller-Sørensen, H.,... & International Ki-67 in Breast Cancer Working Group (2021) 'Analytical validation of Ki67 immunohistochemistry in breast cancer: results of the international Ki67 in breast cancer working group', Journal of the National Cancer Institute, 113(7), pp. 808-819.
Enrico, M.P., et al. (2018) 'Ki-67 Proliferation Index as a Prognostic Marker in Patients With Stage I-III Breast Cancer', Annals of Surgical Oncology, 25(8), pp. 2467-2474.
Fan, J., Chen, D., Shen, C., et al. (2017) 'The prognostic value of clinicopathological and molecular markers on patients with lung metastases from breast cancer after pulmonary metastasectomy', Journal of Thoracic Disease, 9(7), pp. 1953–1964.
Fasching, P.A., Heusinger, K., Haeberle, L., Niklos, M., Hein, A., Bayer, C.M., Rauh, C., Schulz-Wendtland, R., Bani, M.R., Schrauder, M., Kahmann, L., Lux, M.P., Strehl, J.D., Hartmann, A., Dimmler, A., Beckmann, M.W. and Wachter, D.L. (2011) 'Ki67, chemotherapy response, and prognosis in breast cancer patients receiving neoadjuvant treatment', BMC Cancer, 11, p. 486.
Gerdes, J., Schwab, U., Lemke, H. and Stein, H. (1983) 'Production of a mouse monoclonal antibody reactive with a human nuclear antigen associated with cell proliferation', International Journal of Cancer, 31(1), pp. 13-20.
Giaquinto, A.N., Miller, K.D. and Sledge, G.W. (2022) 'Ki-67 as a Prognostic Biomarker in Invasive Breast Cancer: A Review', JAMA Oncology, 8(3), pp. 447-454.
Goldhirsch, A., Wood, W.C., Coates, A.S., Gelber, R.D., Thürlimann, B. and Senn, H.J. (2011) 'Strategies for subtypes--dealing with the diversity of breast cancer: highlights of the St. Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2011', Annals of Oncology, 22(8), pp. 1736-1747.
International Ki-67 in Breast Cancer Working Group (IKWG) (2024) Our Mission. Available at: https://www.ki67inbreastcancerwg.org/ (Accessed: 10 November 2025).
Johnston, S.R.D., Harbeck, N., H egg, R., Toi, M., et al. (2021) 'Abemaciclib combined with endocrine therapy for the adjuvant treatment of HR+, HER2−, node-positive, high-risk, early breast cancer (monarchE)', Journal of Clinical Oncology, 39(34), pp. 3829-3840.
Jung, S.M., et al. (2025) 'High Ki-67 expression is associated with increased risk of distant recurrence in Oncotype Dx low risk breast cancer', Clinical Breast Cancer, 25(6), pp. e690-e696.
Kilickap, S., Kaya, Y., Yucel, B., Tuncer, E., Babacan, N.A. and Elagoz, S. (2014) 'Higher Ki67 expression is associates with unfavorable prognostic factors and shorter survival in breast cancer', Asian Pacific Journal of Cancer Prevention, 15(3), pp. 1381-1385.
Kim, J.Y., et al. (2021) 'Prognostic significance of Ki-67 expression in breast cancer, irrespective of specimen type', Surgical Oncology, 37, p. 101540.
Liu, Y., et al. (2024) 'Optimal Ki-67 cutoff value for predicting the prognosis of patients with breast cancer', European Journal of Breast Health, 20(2), pp. 164-171.
Lo, S.S. (2022) 'Ki-67 Is Poised to Advance as a Biomarker in Early-Stage Breast Cancer', OncLive. Available at: https://www.onclive.com/view/ki-67-is-poised-to-advance-as-a-biomarker-in-early-stage-breast-cancer (Accessed: 10 November 2025).
Luporsi, E., André, F., Spyratos, F., Martin, P.M., et al. (2012) 'Ki-67: Level of evidence and methodological considerations for its role in the clinical management of breast cancer: Analytical and critical review', Breast Cancer Research and Treatment, 132, pp. 895–915.
Mactier, M. (2024) 'The association between post-operative complications, disease-recurrence and mortality in primary breast cancer', Annals of Breast Surgery, 9, p. 1.
Mayo Clinic (2024) Recurrent breast cancer. Available at: https://www.mayoclinic.org/diseases-conditions/recurrent-breast-cancer/symptoms-causes/syc-20377135 (Accessed: 10 November 2025).
Nielsen, T.O., et al. (2024) 'Digital image analysis of Ki67 in breast cancer: a head-to-head comparison of two automated methods versus manual scoring', Breast Cancer Research and Treatment, 198, pp. 333–342.
Niikura, N., Masuda, S., Kumaki, N., Xiaoyan, T., Terada, M., Terao, M., Iwamoto, T., Oshitanai, R., Morioka, T., Tuda, B., Okamura, T., Saito, Y., Suzuki, Y. and Tokuda, Y. (2014) 'Prognostic significance of the Ki67 scoring categories in breast cancer subgroups', Clinical Breast Cancer, 14(5), pp. 323-329.e3.
Page, M.J., McKenzie, J.E., Bossuyt, P.M., Boutron, I., Hoffmann, T.C., Mulrow, C.D., et al. (2021) 'The PRISMA 2020 statement: an updated guideline for reporting systematic reviews', BMJ, 372, p. n71.
Paoletti, C., Pusztai, L. and Hatzis, C. (2021) 'The clinical utility of Ki67 in breast cancer', Journal of Clinical Oncology, 39(12), pp. 1361-1365.
Park, Y.H., et al. (2023) 'Association of Ki-67 Expression With Recurrence Score and Clinical Outcomes in Patients With ER-Positive, HER2-Negative Breast Cancer With Low Recurrence Score', JAMA Network Open, 6(9), p. e2332612.
Petrelli, F., Viale, G., Cabiddu, M. and Barni, S. (2015) 'Prognostic value of different cut-off levels of Ki-67 in breast cancer: a systematic review and meta-analysis of 64,196 patients', Breast Cancer Research and Treatment, 153(3), pp. 477-491.
Poulakaki, N., Makris, G.M., Papanota, A.M., Marineli, F., Marinelis, A., Battista, M.J., Boehm, D., Psyrri, A. and Sergentanis, T.N. (2018) 'Ki-67 Expression as a Factor Predicting Recurrence of Ductal Carcinoma In Situ of the Breast: A Systematic Review and Meta-Analysis', Clinical Breast Cancer, 18(2), pp. 157-167.e6.
Saphner, T., Tormey, D.C. and Gray, R. (1996) 'Annual hazard rates of recurrence for breast cancer after primary therapy', Journal of Clinical Oncology, 14(10), pp. 2738-2746.
Scholzen, T. and Gerdes, J. (2000) 'The Ki-67 protein: from the known and the unknown', Journal of Cellular Physiology, 182(3), pp. 311-322.
Siegel, R.L., Miller, K.D., Fuchs, H.E. and Jemal, A. (2021) 'Cancer statistics, 2021', CA: A Cancer Journal for Clinicians, 71(1), pp. 7-33.
Soliman, N.A., et al. (2016) 'Clinical significance of Ki-67 index as a prognostic marker and predictor of recurrence in different molecular subtypes of breast cancer', Cancer Biology & Medicine, 13(4), pp. 496-506.
St. Gallen Consensus (2021) St. Gallen 2021 Consensus Guidelines. Available at: https://www.europadonna.org/pdf/St.Gallen-2021-Consensus-Guidelines.pdf (Accessed: 10 November 2025).
Sun, J., et al. (2023) 'The Role of Ki-67 in HR+/HER2- Breast Cancer: A Real-World Study of 956 Patients', Breast Cancer: Basic and Clinical Research, 17, p. 11782234231165467.
Tandon, A., Mon, K.S. and Lo, S.S. (2023) 'Ki-67: A Controversial Prognostic Biomarker in Early-Stage Breast Cancer? Here’s Why', ASCO Daily News. Available at: https://dailynews.ascopubs.org/do/ki-67-controversial-prognostic-biomarker-early-stage-breast-cancer-here-s-why (Accessed: 10 November 2025).
Urruticoechea, A., Smith, I.E. and Dowsett, M. (2005) 'Proliferation marker Ki-67 in early breast cancer', Journal of Clinical Oncology, 23(28), pp. 7212-7220.
Wells, G.A., Shea, B., O'Connell, D., Peterson, J., Welch, V., Losos, M. and Tugwell, P. (n.d.) The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. Available at: https://www.ohri.ca/programs/clinical_epidemiology/oxford.asp (Accessed: 10 November 2025).
Wu, Q., Ma, F., Deng, L., Luo, T., Zhao, Z., Li, Y. and Zhou, Q. (2019) 'Prognostic Value of Ki-67 in Patients With Resected Triple-Negative Breast Cancer: A Meta-Analysis', Frontiers in Oncology, 9, p. 1068.
Yang, L., et al. (2018) 'Clinical significance of Ki-67 index as a prognostic marker and predictor of recurrence in different molecular subtypes of breast cancer'. Oncology Letters, 15(4), pp. 5671–5679.
Yardi, R., Yardi, S. and Shende, S. (2024) 'Assessment of the Predictive Role of Ki-67 in Breast Cancer Patients’ Responses to Neoadjuvant Chemotherapy', European Journal of Breast Health, 20(3), pp. 248-253.
Zhu, X., et al. (2020) 'The prognostic and predictive potential of Ki-67 in triple-negative breast cancer', Scientific Reports, 10, p. 225.
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