Asian Pacific Journal of Cancer Prevention

Asian Pacific Journal of Cancer Prevention (아시아태평양암예방학회)
권호 표지
DOI QR코드

DOI QR Code

Ki67 Index in Breast Cancer: Correlation with Other Prognostic Markers and Potential in Pakistani Patients

  • Haroon, Saroona (Department of Pathology and Microbiology, Aga Khan University Hospital) ;
  • Hashmi, Atif Ali (Department of Histopathology, Liaquat National Hospital and Medical College) ;
  • Khurshid, Amna (Department of Histopathology, Liaquat National Hospital and Medical College) ;
  • Kanpurwala, Muhammad Adnan (Department of Physiology, Muhammad Bin Qasim Medical and Dental College) ;
  • Mujtuba, Shafaq (Department of Histopathology, Liaquat National Hospital and Medical College) ;
  • Malik, Babar (Department of Medical Oncology, Sindh Institute of Urology and Transplantation) ;
  • Faridi, Naveen (Department of Histopathology, Liaquat National Hospital and Medical College)
  • Published : 2013.07.30
Download PDF
⟨ Previous Next ⟩

Abstract

Introduction: Breast cancer aggressiveness can be correlated with proliferation status of tumor cells, which can be ascertained with tumor grade and Ki67 indexing. However due to lack of reproducibility, the ASCO do not recommend routine use of Ki67 in determining prognosis in newly diagnosed breast cancers. We therefore aimed to determine associations of the Ki67 index with other prognostic markers like tumor size, grade, lymph node metastasis, ER, PR and HER2neu status. Methods: A total of 194 cases of newly diagnosed breast cancer were included in the study. Immunohistochemical staining for ER, PR, HER2neu and Ki67 was performed by the DAKO envision method. Associations of the Ki67 index with other prognostic factors were evaluated both as continuous and categorical variables. Results: Mean age of the patients was 51.7 years (24-90). Mean Ki67 index was 26.9% (1-90). ER, PR, HER2neu positivity was noted in 90/194 cases (46.4%), 74/194 cases (38.1%) and 110/194 cases (56.70%) respectively. Significant association was found between Ki67 and tumor grade, PR, HER2neu positivity and lymph node status, but no link was apparent with ER positivity and tumor size. There wasan inverse relation between Ki67 index and PR positivity, whereas a direct correlation was seen with HER2neu positivity. However, high Ki67 (>30%) was associated with decreased HER2neu positivity as compared to intermediate Ki67 (16-30%). The same trend was established with lymph node metastasis. Conclusion: Our study indicates that with high grade tumors, clinical utility of ki67 is greater in combination with other prognostic markers because we found that tumors with Ki67 higher than 30% have better prognostic profile compared to tumors with intermediate Ki67 level, as reflected by slightly lower frequency of lymph node metastasis and HER2neu expression. Therefore we suggest that Ki67 index should be categorized into high, intermediate and low groups when considering adjuvant chemotherapy and prognostic stratification.

Keywords

References

  1. Aleskandarany MA, Rakha EA, Macmillan RD, et al (2010). MIB1/Ki-67 labelling index can classify grade 2 breast cancer into two clinically distinct subgroups. Breast Cancer Res Treat, 127, 591-9.
  2. Awadelkarim KD, Costantini RM, Osman I, Barberis MC (2012). Ki-67 Labeling Index in Primary Invasive Breast Cancer from Sudanese Patients: A Pilot Study. ISRN Pathology.
  3. Billgren AM, Tani E, Liedberg A, Skoog L, Rutqvist LE (2002). Prognostic significance of tumor cell proliferation analyzed in fine needle aspirates from primary breast cancer. Breast Cancer Res Treat, 71, 161-70. https://doi.org/10.1023/A:1013899614656
  4. Bonnefoi H, Underhill C, Iggo R, Cameron D (2009). Predictive signatures for chemotherapy sensitivity in breast cancer: are they ready for use in the clinic? Eur J Cancer, 45, 1733-43. https://doi.org/10.1016/j.ejca.2009.04.036
  5. Bottini A (2005). Cytotoxic and antiproliferative activity of the single agent epirubicin versus epirubicin plus tamoxifen as primary chemotherapy in human breast cancer: a singleinstitution phase III trial. Endocr Relat Cancer, 12, 383-92. https://doi.org/10.1677/erc.1.00945
  6. Collins LC, Botero ML, Schnitt SJ (2005). Bimodal frequency distribution of Estrogen Receptor immunohistochemical staining results in breast cancer. Am J Clin Pathol, 123, 16-20. https://doi.org/10.1309/HCF035N9WK40ETJ0
  7. Colozza M, Azambuja E, Cardoso F et al (2005). Proliferative markers as prognostic and predictive tools in early breast cancer :where are we now? Ann Oncol, 16, 1723-27. https://doi.org/10.1093/annonc/mdi352
  8. Cuzick J, Dowsett M, Wale C, et al (2009). Prognostic value of a combined ER, PgR, Ki67, HER2 immunohistochemical (IHC4) score and the comparison with the GHI recurrence score-results from TransATAC. Cancer Res, 69, 503.
  9. Dai H, vant Veer L, Lamb J, et al (2005). A cell proliferation signature is a marker ofextremely poor outcome in a subpopulation of breast cancer patients. Cancer Res, 65, 4059-66. https://doi.org/10.1158/0008-5472.CAN-04-3953
  10. Desmedt C, Sotiriou C (2006). Proliferation: the most prominent predictor of clinical outcome in breast cancer. Cell Cycle, 5, 2198-202. https://doi.org/10.4161/cc.5.19.3254
  11. Dowsett M (2006). Proliferation and apoptosis as markers of benefit in neoadjuvant endocrine therapy of breast cancer. Clin Cancer Res, 12, 1024-30. https://doi.org/10.1158/1078-0432.CCR-05-2127
  12. Dowsett M, Procter M, McCaskill-Stevens W, et al (2009). Disease-free survival according to degree of HER2 amplification for patients treated with adjuvant chemotherapy with or without 1 year of trastuzumab: the HERA trial. J Clin Oncol, 27, 2962-69. https://doi.org/10.1200/JCO.2008.19.7939
  13. Ellis LM, Fidler IJ (1996). Angiogenesis and metastasis. Eur J Cancer, 32, 2451-60. https://doi.org/10.1016/S0959-8049(96)00389-9
  14. Eppenberger U, Kueng W, Schlaeppi JM, et al (1998). Markers of tumor angiogenesis and proteolysis independently define high- and low-risk subsets of node-negative breast cancer patients. J Clin Oncol, 16, 3129-36.
  15. Fasching PA, Heusinger K, Haeberle L, et al (2011). Ki67, chemotherapy response, and prognosis in breast cancer patients receiving neoadjuvant treatment. BMC Cancer. 11, 486. https://doi.org/10.1186/1471-2407-11-486
  16. Ferguson NL, Bell J, Heidel R, et al (2013). Prognostic value of breast cancer subtypes, ki-67 proliferation index, age, and pathologic tumor characteristics on breast cancer survival in caucasian women. Breast J, 19, 22-30. https://doi.org/10.1111/tbj.12059
  17. Gerdes J, Lemke H, Baisch H, et al (1984). Cell cycle analysis of a cell proliferation-associated human nuclear antigen defined by the monoclonal antibody Ki-67. J Immunol. 133, 1710-5.
  18. Gerdes J, Schwab U, Lemke H, Stein H (1983). Production of a mouse monoclonal antibody reactive with a human nuclear antigen associated with cell proliferation. Int J Cancer, 31, 13-20. https://doi.org/10.1002/ijc.2910310104
  19. Gerdes J, Li L, Schlueter C, et al (1991). Immunobiochemical and molecular biologic characterization of the cell proliferation-associated nuclear antigen that is defined by monoclonal antibody Ki-67. Am J Pathol, 138, 867-73.
  20. Goldhirsch A, Ingle JN, Gelber RD, et al (2009). Thresholds for therapies: highlights of the St Gallen International Expert Consensus on the primary therapy of early breast cancer 2009. Ann Oncol, 20, 1319-29. https://doi.org/10.1093/annonc/mdp322
  21. Goldhirsch A, Wood WC, Coates AS, et al (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. Ann Oncol, 22,1736-47. https://doi.org/10.1093/annonc/mdr304
  22. Haerslev T, Jacobsen GK, Zedeler K (1996). Correlation of growth fraction by Ki-67 and proliferating cell nuclear antigen (PCNA) immunohistochemistry withhistopathological parameters and prognosis in primary breast carcinomas. Breast Cancer Res Treat, 37, 101-13. https://doi.org/10.1007/BF01806492
  23. Hanahan D, Weinberg RA (2000). The hallmarks of cancer. Cell, 100, 57-70. https://doi.org/10.1016/S0092-8674(00)81683-9
  24. Harris L, Fritsche H, Mennel R, et al (2007). American society of clinical oncology 2007 update of recommendations for the use of tumor markers in breast cancer. J Clin Oncol, 25, 5287-312. https://doi.org/10.1200/JCO.2007.14.2364
  25. Keshgegian AA, Cnaan A (1995). Proliferation markers in breast carcinoma. Mitotic figure count, S-phase fraction, proliferating cell nuclear antigen, Ki-67 and MIB-1. Am J Clin Pathol. 104, 42-9.
  26. Learn PA, Yeh IT, McNutt M, et al (2005). HER-2/neu expression as a predictor of response to neoadjuvant docetaxel in patients with operable breast carcinoma. Cancer, 103, 2252-60. https://doi.org/10.1002/cncr.21037
  27. Luporsi E, André F, Spyratos F, et al (2012). Ki-67: level of evidence and methodological considerations forits role inthe clinical management of breastcancer: analytical and critical review. Breast Cancer Res Treat, 132, 895-915. https://doi.org/10.1007/s10549-011-1837-z
  28. Matsubara N, Mukai H, Fujii S, Wada N (2013). Different prognostic significance of Ki-67 change between pre- and post-neoadjuvant chemotherapy in various subtypes of breast cancer. Breast Cancer Res Treat, 137, 203-12. https://doi.org/10.1007/s10549-012-2344-6
  29. Molino A, Micciolo R, Turazza M, et al (1997). Ki-67 immunostaining in 322primary breast cancers: associations with clinical and pathological variablesand prognosis. Int J Cancer, 74, 433-7. https://doi.org/10.1002/(SICI)1097-0215(19970822)74:4<433::AID-IJC12>3.0.CO;2-A
  30. Railo M, Luldin J, Haglund C, von Smitten K, Nordling S (2007). Ki-67, ER receptors, ploidy and S phase as longterm prognostic factors in T1 node-negative breast cancer. Tumour Biol, 28, 45-51. https://doi.org/10.1159/000097702
  31. Reyal F, Hajage D, Savignoni A, et al (2013). Long-term prognostic performance of Ki67 rate in early stage, pT1- pT2, pN0, invasive breast carcinoma. PLoS One, 8, 55901. https://doi.org/10.1371/journal.pone.0055901
  32. Royston P, Altman DG, Sauerbrei W (2006). Dichotomizing continuous predictors in multiple regression: a bad idea. Stat Med, 25, 127-41. https://doi.org/10.1002/sim.2331
  33. Sahin AA, Ro J, Ro JY, et al (1991). Ki-67 immunostaining in node-negative stage I/II breast carcinoma. Significant correlation with prognosis. Cancer, 68, 549-7. https://doi.org/10.1002/1097-0142(19910801)68:3<549::AID-CNCR2820680318>3.0.CO;2-J
  34. Sharifi SN, Sadeghian F, Homaei SF,Haghighi F (2006). Immunohistochemical study of cell proliferation marker (ki-67), estrogen, and progesterone receptors expression in breast carcinoma. J Birjand Uni Med Sci, 3, 38-44.
  35. Smith IE, Dowsett M, Ebbs SR, et al (2005). Neoadjuvant treatment of postmenopausal breast cancer with anastrozole, tamoxifen, or both in combination: the Immediate Preoperative Anastrozole, Tamoxifen, or Combined with Tamoxifen (IMPACT) multicenter double-blind randomized trial. J Clin Oncol, 23, 5108-16. https://doi.org/10.1200/JCO.2005.04.005
  36. Strand C, Bak M, Borgquist S, et al (2013). The combination of Ki67, histological grade and estrogen receptor status identifies a low-risk group among 1,854 chemo-naive women with N0/N1 primary breast cancer. Springerplus, 2, 111 https://doi.org/10.1186/2193-1801-2-111
  37. Trihia H, Murray S, Price K, et al (2003). Ki-67 expression in breast cancer, its association with grading systems, clinical parameters and other prognostic factors e a surrogate marker? Cancer, 97, 1321-31. https://doi.org/10.1002/cncr.11188
  38. Van Diest PJ, van der Wall E, Baak JP (2004). Prognostic value of proliferation in invasive breast cancer: a review. J Clin Pathol, 57, 675-81. https://doi.org/10.1136/jcp.2003.010777
  39. Viale G, Regan MM, Mastropasqua MG, et al (2008). Predictive value of tumor Ki-67 expression in two randomized trials of adjuvant chemoendocrine therapy for node-negative breast cancer. J Natl Cancer Inst, 100, 207-12. https://doi.org/10.1093/jnci/djm289
  40. Whitfield ML, George LK, Grant GD et al (2006). Common markers of proliferation. Nat Rev Cancer, 6, 99-106 https://doi.org/10.1038/nrc1802
  41. Wolff AC, Hammond ME, Schwartz JN, et al (2007). American society of clinical oncology/college of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol, 25, 118-45.

Cited by

  1. Correlation between Ki67 and Histological Grade in Breast Cancer Patients Treated with Preoperative Chemotherapy vol.15, pp.23, 2015, https://doi.org/10.7314/APJCP.2014.15.23.10277
  2. Prognostic Factors in Oligodendrogliomas: a Clinical Study of Twenty-Five Consecutive Patients vol.16, pp.13, 2015, https://doi.org/10.7314/APJCP.2015.16.13.5319
  3. Ki-67 is a Valuable Prognostic Factor in Gliomas: Evidence from a Systematic Review and Meta-analysis vol.16, pp.2, 2015, https://doi.org/10.7314/APJCP.2015.16.2.411
  4. Expression of Ki67 in Papillary Thyroid Microcarcinoma and its Clinical Significance vol.16, pp.4, 2015, https://doi.org/10.7314/APJCP.2015.16.4.1605
  5. Associations and indications of Ki67 expression with clinicopathological parameters and molecular subtypes in invasive breast cancer: A population-based study pp.1792-1082, 2015, https://doi.org/10.3892/ol.2015.3461
  6. Correlations between HER2 Expression and Other Prognostic Factors in Breast Cancer: Inverse Relations with the Ki-67 Index and P53 Status vol.17, pp.3, 2016, https://doi.org/10.7314/APJCP.2016.17.3.1015
  7. Ki67 Frequency in Breast Cancers without Axillary Lymph Node Involvement and its Relation with Disease-free Survival vol.17, pp.3, 2016, https://doi.org/10.7314/APJCP.2016.17.3.1347
  8. Inflammatory and Non-inflammatory Breast Cancer: A Potential Role for Detection of Multiple Viral DNAs in Disease Progression vol.23, pp.2, 2016, https://doi.org/10.1245/s10434-015-4888-2
  9. The search for optimal cutoff points for apoptosis and proliferation rate in prognostification of early stage breast cancer patients treated with anthracyclines in adjuvant settings vol.37, pp.6, 2016, https://doi.org/10.1007/s13277-015-4646-x
  10. The antitumor effect of TIG3 in liver cancer cells is involved in ERK1/2 inhibition vol.37, pp.8, 2016, https://doi.org/10.1007/s13277-016-4998-x
  11. High KIF2A expression predicts unfavorable prognosis in diffuse large B cell lymphoma vol.96, pp.9, 2017, https://doi.org/10.1007/s00277-017-3047-1
  12. Mucoepidermoid carcinoma of the breast vol.96, pp.51, 2017, https://doi.org/10.1097/MD.0000000000009385
  13. Prognostic parameters of luminal A and luminal B intrinsic breast cancer subtypes of Pakistani patients vol.16, pp.1, 2018, https://doi.org/10.1186/s12957-017-1299-9
  14. Higher Ki67 expression in fibroblast like cells at invasive front indicates better clinical outcomes in oral squamous cell carcinoma patients vol.38, pp.6, 2018, https://doi.org/10.1042/BSR20181271
  15. Prognostic significance of p16 & p53 immunohistochemical expression in triple negative breast cancer vol.18, pp.1, 2018, https://doi.org/10.1186/s12907-018-0077-0
  16. A Machine Learning Approach for the Association of ki-67 Scoring with Prognostic Factors vol.2018, pp.1687-8469, 2018, https://doi.org/10.1155/2018/1912438
  17. Clinical and prognostic profile of Her2neu positive (non-luminal) intrinsic breast cancer subtype: comparison with Her2neu positive luminal breast cancers vol.11, pp.1, 2018, https://doi.org/10.1186/s13104-018-3677-y
  18. Cytokeratin 5/6 and cytokeratin 8/18 expression in triple negative breast cancers: clinicopathologic significance in South-Asian population vol.11, pp.1, 2018, https://doi.org/10.1186/s13104-018-3477-4
  19. The clinicopathological significance of Ki67 in papillary thyroid carcinoma: a suitable indicator? vol.16, pp.1, 2018, https://doi.org/10.1186/s12957-018-1384-8