Prognostic Significance of Ki-67 and p53 Immunoexpression in Breast Carcinoma Patients with Positive Axillary Lymph Nodes

  • Lalit Sharma Jawaharlal Nehru Medical College, Aligarh Muslim University, Aligarh. (U.P)-India
  • Kafil Akhtar Jawaharlal Nehru Medical College, Aligarh Muslim University, Aligarh. (U.P)-India.
  • Syed Shamshad Ahmad Jawaharlal Nehru Medical College, Aligarh Muslim University, Aligarh. (U.P)-India.
  • Atia Zakaur Rab Jawaharlal Nehru Medical College, Aligarh Muslim University, Aligarh. (U.P)-India.
Keywords: Ki-67, p53, Biomarker, Breast cancer, Positive axillary lymph nodes


Introduction: Breast carcinoma is a heterogenous disorder in which the treatment modality should be based on a risk assessment approach and only patients with higher relative risk of recurrence and distant metastasis should be the appropriate candidates for adjuvant therapy. This is where role of prognostic variables like Ki-67 and p53 immunoexpression as biomarkers of proliferative activity of tumor cells becomes important. Aims and Objectives: The aim of this study was to evaluate the significance of Ki-67 and p53 immunoexpression as prognostic biomarkers in breast carcinoma patients with positive axillary lymph nodes. Material and Methods: A total of 182 breast cancer patients were included in the study, assessed for various clinicopathological characteristics and after receiving the mastectomy/lobectomy specimen, tissue sections about 1cm thick were taken from representative areas, processed in an automated tissue processor (Histokinette) and simultaneously stained for routine hematoxylin and eosin stain along with Ki-67 and p53 immunostains and patients followed up. Results: High Ki-67 and p53 immunoexpression was significantly associated with larger tumor size, higher tumor grade, axillary lymph node metastasis, higher disease stage at presentation, lymphovascular invasion, early recurrence, shortened disease free survival and worse overall survival. Conclusions: Ki-67 and p53 immunoexpression can be used as a surrogate biomarker along with other clinicopathological characteristics in resource constrained facilities for better prediction of prognosis of breast cancer patients with positive axillary lymph nodes.

Author Biographies

Lalit Sharma, Jawaharlal Nehru Medical College, Aligarh Muslim University, Aligarh. (U.P)-India
Department of Pathology
Kafil Akhtar, Jawaharlal Nehru Medical College, Aligarh Muslim University, Aligarh. (U.P)-India.
Department of Pathology
Syed Shamshad Ahmad, Jawaharlal Nehru Medical College, Aligarh Muslim University, Aligarh. (U.P)-India.
Department of Pathology
Atia Zakaur Rab, Jawaharlal Nehru Medical College, Aligarh Muslim University, Aligarh. (U.P)-India.
Department of General Surgery


1. American Cancer Society. Breast Cancer Facts & Figures 2017-2018. Atlanta: Am Cancer Soc Inc 2017; 1-5.
2. Malvia S, Bagadi SA, Dubey US, Saxena S. Epidemiology of breast cancer in Indian women. Asia Pacific J Clin Oncol 2017; 13(4):289-295.
3. Murthy NS, Chaudhry K, Nadayil D, Agarwal UK, Saxena S. Changing trends in incidence of breast cancer: Indian scenario. Ind J Cancer 2009; 46(1):73-75.
4. Kim SI, Cho SH, Lee JS, Moon HG, Noh WC, Youn HJ et al. Clinical relevance of lymph node ratio in breast cancer patients with one to three positive lymph nodes. Br J Cancer 2013; 109(5):1165-1167.
5. Urruticoechea A, Smith IE, Dowsett M. Proliferation marker Ki-67 in early breast cancer. J Clin Oncol 2005; 23(28):7212-7220.
6. Gerdes J, Schwab U, Lemke H, Stein H. Production of a mouse monoclonal antibody reactive with a human nuclear antigen associated with cell proliferation. Int J Cancer 1983; 31(1):13-20.
7. Goldhirsch A, Wood WC, Coates AS, Gelber RD, Thürlimann B, Senn HJ et al. 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 2009. Ann Oncol 2011; 22(8):1736-1747.
8. Cavanaugh AH, Hempel WM, Taylor LJ, Rogalsky V, Todorov G, Rothblum LI et al. Activity of RNA polymerase I transcription factor UBF blocked by Rb gene product. Nature 1995; 374(6518):177-180.
9. Barbareschi M, Caffo O, Veronese S, Leek RD, Fina P, Fox S et al. Bcl-2 and p53 expression in node-negative breast carcinoma: a study with long-term follow-up. Hum Pathol 1996; 27(11):1149-1155.
10. Dowsett M, Nielsen TO, A’Hern R, Bartlett J, Coombes RC, Cuzick J et al. Assessment of Ki67 in breast cancer: recommendations from the International Ki67 in Breast Cancer working group. J Nat Cancer Inst 2011; 103(22):1656-1664.
11. Tan QX, Qin QH, Yang WP, Mo QG, Wei CY. Prognostic value of Ki67 expression in HR-negative breast cancer before and after neoadjuvant chemotherapy. Int J Clin Exper Pathol 2014; 7(10):6862-6863.
12. Milićević Z, Bajić V, Živković L, Kasapović J, Andjelković U, Spremo-Potparević B et al. Identification of p53 and its isoforms in human breast carcinoma cells. Sci World J 2014; 618698:10-20.
13. 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(2):539-552.
14. Yan J, Liu XL, Han LZ, Xiao G, Li NL, Deng YN et al. Relation between Ki-67, ER, PR, Her2/neu, p21, EGFR, and TOP II-α expression in invasive ductal breast cancer patients and correlations with prognosis. Asian Pac J Cancer 2015; 16(2):823-829.
15. Ohara M, Matsuura K, Akimoto E, Noma M, Nishizaka T, Kagawa N et al. Prognostic value of Ki67 and p53 in patients with estrogen receptor-positive and human epidermal growth factor receptor 2-negative breast cancer: Validation of the cut-off value of the Ki67 labeling index as a predictive factor. Mol Clin Oncol 2016; 4(4):648-654.
16. Liu S, Edgerton SM, Moore DH, Thor AD. Measures of cell turnover (proliferation and apoptosis) and their association with survival in breast cancer. Clin Cancer Res 2001; 7(6):1716-1723.
17. Madani SH, Payandeh M, Sadeghi M, Motamed H, Sadeghi E. The correlation between Ki-67 with other prognostic factors in breast cancer: A study in Iranian patients. Ind J Med Paed Oncol 2016; 37(2):95-96.
18. Pan Y, Yuan Y, Liu G, Wei Y. P53 and Ki-67 as prognostic markers in triple-negative breast cancer patients. PloS One 2017; 12(2):12-13.
19. Wojnar A, Kobierzycki C, Krolica A, Pula B, Podharska OM, Dziegeil P et al. Correlation of the Ki-67 and the MCM-2 proliferative markers with the grade of the histological malignancy(G) in ductal breast cancers. Folia Histochem Cytobiol 2010; 48(3): 442-446.
20. Xue C, Wang X, Peng R, Shi Y, Qin T. Distribution, clinicopathologic features and survival of breast cancer subtypes in Southern China. Cancer Sci 2012; 103: 1679-1687.
21. Yang P, Du CW, Kwan M, Liang SX, Zhang GJ. The impact of p53 in predicting clinical outcome of breast cancer patients with visceral metastasis. Sci Rep 2013; 3:46-47.
22. de Bono JS, Tolcher AW, Rowinsky EK. The future of cytotoxic therapy: selective cytotoxicity based on biology is the key. Breast Cancer Res 2003; 5: 154- 159
23. Tawfik K, Kimler BF, Davis MK, Fan F, Tawfik O. Ki-67 expression in axillary lymph node metastases in breast cancer is prognostically significant. Hum Pathol 2013; 44: 39-46.
24. Crabb SJ, Bajdik CD, Leung S, Speers CH, Kennecke H. Can clinically relevant prognostic subsets of breast cancer patients with four or more involved axillary lymph nodes be identified through immunohistochemical biomarkers? A tissue microarray feasibility study. Breast Cancer Res 2008;10: 6-8.
25. de Azambuja E, Cardoso F, de Castro G, Jr., Colozza M, Mano MS et al. Ki-67 as prognostic marker in early breast cancer: a meta-analysis of published studies involving 12,155 patients. Br J Cancer 2007; 96: 1504- 1513.
26. Matsubara N, Mukai H, Itoh K, Nagai S. Prognostic impact of Ki-67 overexpression in subgroups categorized according to St. Gallen with early stage breast cancer. Oncol 2011; 81: 345-352.
27. Shokouh TZ, Ezatollah A, Barand P. Interrelationships between Ki67, HER2/neu, p53, ER, and PR status and their associations with tumor grade and lymph node involvement in breast carcinoma subtypes: retrospective-observational analytical study. Med 2015; 94(32):1359-1360.
28. Jacquemier J, Charafe-Jauffret E, Monville F, Esterni B, Extra JM, Houvenaeghel G et al. Association of GATA3, P53, Ki67 status and vascular peritumoral invasion are strongly prognostic in luminal breast cancer. Breast Cancer Res 2009; 11(2):23-24.
29. Silvestrini R, Benini E, Daidone MG, Veneroni S, Boracchi P, Cappelletti V et al. p53 as an independent prognostic marker in lymph node-negative breast cancer patients. J Nat Cancer Inst 1993; 85(12):965-970.
30. Han JS, Cao D, Molberg KH, Sarode VR, Rao R, Sutton LM et al. Hormone receptor status rather than HER2 status is significantly associated with increased Ki-67 and p53 expression in triple-negative breast carcinomas, and high expression of Ki-67 but not p53 is significantly associated with axillary nodal metastasis in triple-negative and high-grade non–triple-negative breast carcinomas. Am J Clin Pathol 2011; 135(2):230-237.
31. Yamamoto M, Hosoda M, Nakano K, Jia S, Hatanaka KC, Takakuwa E et al. p53 accumulation is a strong predictor of recurrence in estrogen receptor positive breast cancer patients treated with aromatase inhibitors. Cancer Sci 2014; 105(1):81-88.
32. Payandeh M, Sadeghi M, Sadeghi E, Madani SH. Expression of p53 breast cancer in Kurdish women in the West of Iran: a reverse correlation with lymph node metastasis. Asian Pac J Cancer Prev 2016; 17(3):1261-1264.
33. Kobayashi T, Iwaya K, Moriya T, Yamasaki T, Tsuda H, Yamamoto J et al. A simple immunohistochemical panel comprising 2 conventional markers, Ki-67 and p53, is a powerful tool for predicting patient outcome in luminal-type breast cancer. BMC Clin Pathol 2013; 13(1):5-6.
34. Ross DT, Kim CY, Tang G, Bohn OL, Beck RA, Ring BZ et al. Chemosensitivity and stratification by a five monoclonal antibody immunohistochemistry test in the NSABP B14 and B20 trials. Clin Cancer Res 2008; 14(20):6602-6609.
Original Article

Most read articles by the same author(s)