Document Type : Original Article


1 Department of Internal Medicine, College of Medicine, University of Mosul, Mosul, Iraq

2 Department of Basic Sciences, College of Nursing, University of Mosul, Mosul, Iraq

3 Department of Molecular Genetics, Ibn Al-atheer Hospital, Mosul, Iraq


Background: The prognostic impact of CA15-3 level in different molecular subtypes of metastatic breast cancer is not well elucidated yet; therefore, we conducted the present study to determine the reliability of CA15-3 tumor marker in terms of monitoring therapeutic response in different molecular subtypes of breast cancer.
Method: In this prospective study, we assessed the levels of CA15-3 in 83 patients with metastatic breast cancer assessable by RECIST, who were treated and followed up in Mosul Oncology hospital during 2017 and 2018. We evaluated the mode of changes of CA15-3 level after two cycles of systemic therapy (chemotherapy, endocrine therapy, or target therapy) and analyzed the relation between CA15-3 level changes and response to therapy in different molecular subtypes of breast cancer.
Results: Herein, CA15-3 level was more frequently elevated in Luminal subtypes of metastatic breast cancer compared with that in other subtypes. Additionally, the reduction in CA15-3 level after two cycles of systemic therapy was significantly correlated with the good response and longer progression-free survival.
Conclusion: The mode of change of CA15-3 level was closely correlated with the clinical therapeutic response and survival advantage rather than the pretreatment level of CA15-3 in metastatic breast cancer. This finding revealed equivalent quality of CA15-3 with medical imaging at lower cost. Therefore, measurement of CA15-3 level at regular intervals before and after starting systemic therapy could predicate the clinical response and replace imaging examination used routinely for monitoring the responses in patients with Luminal subtypes of metastatic breast cancer.


How to cite this article:

Al Zobair AA, Hayawi MA, Al Obeidy BF. Reliability of CA15-3 tumor marker in monitoring therapeutic response in different molecular subtypes of metastatic breast cancer. Middle East J Cancer. 2022;13(3): 438-48. doi: 10.30476/mejc.2022.87357.1412.

  1. Al Shaikh A, Braakhuis AJ, Bishop KS. The Mediterranean Diet and Breast Cancer: A Personalised Approach. Healthcare (Basel).2019; 7(3): 104. doi:10.3390/healthcare7030104.
  2. Momenimovahed Z, Salehiniya H. Cervical cancer in Iran: integrative insights of epidemiological analysis. Biomedicine (Taipei). 2018;8(3):18. doi: 10.1051/bmdcn/2018080318.
  3. Lønning PE. Breast cancer prognostication and prediction: are we making progress? Ann Oncol. 2007;18 Suppl 8:viii3-7. doi: 10.1093/annonc/mdm260.
  4. Eckhardt BL, Francis PA, Parker BS, Anderson RL. Strategies for the discovery and development of therapies for metastatic breast cancer. Nat Rev Drug Discov. 2012;11(6):479-97. doi: 10.1038/nrd2372.
  5. Kennecke H, Yerushalmi R, Woods R, Cheang MC, Voduc D, Speers CH, et al. Metastatic behavior of breast cancer subtypes. J Clin Oncol. 2010;28(20):3271-7. doi: 10.1200/JCO.2009.25.9820.
  6. Redig AJ, McAllister SS. Breast cancer as a systemic disease: a view of metastasis. J Intern Med. 2013;274(2): 113-26. doi: 10.1111/joim.12084.
  7. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6): 394-424. doi: 10.3322/caac.21492.
  8. Graham LJ, Shupe MP, Schneble EJ, Flynt FL, Clemenshaw MN, Kirkpatrick AD, et al. Current approaches and challenges in monitoring treatment responses in breast cancer. J Cancer. 2014;5(1):58-68. doi: 10.7150/jca.7047.
  9. Cheung KL, Graves CR, Robertson JF. Tumour marker measurements in the diagnosis and monitoring of breast cancer. Cancer Treat Rev. 2000;26(2):91-102. doi: 10.1053/ctrv.1999.0151.
  10. Di Gioia D, Heinemann V, Nagel D, Untch M,  Kahlert S,  Bauerfeind I, et al. Kinetics of CEA and CA15-3 correlate with treatment response in patients undergoing chemotherapy for metastatic breast cancer (MBC). Tumour Biol. 2011;32(4):777-85. doi: 10.1007/s13277-011-0180-7. Epub 2011 May 8.
  11. Shao Y, Sun X, He Y,  Liu C, Liu H. Elevated levels of serum tumor markers CEA and CA15-3 are prognostic parameters for different molecular subtypes of breast cancer. PLoS 2015;10(7):e0133830. doi: 10.1371/journal.pone.0133830. eCollection 2015.
  12. Hayes DF, Mesa-Tejada R, Papsidero L, Croghan GA, Korzun AH, Norton L, et al. Prediction of prognosis in primary breast cancer by detection of a high molecular weight mucin-like antigen using monoclonal antibodies DF3, F36/22, and CU18: a Cancer and Leukemia Group B study. J Clin Oncol. 1991;9(7):1113-1123. 1113-23. doi: 10.1200/JCO. 9.7.1113.
  13. Canizares F,  Sola J,  Perez M, Tovar I, de las heras M, Salinas J, et al. Preoperative values of CA15-3 and CEA as prognostic factors in breast cancer: a multivariate analysis. Tumour Biol. 2001;22(5):273-81.doi: 10.1159/000050627.
  14. Engstrøm M.J, Opdahl S, Hagen AI, Romundstad PR, Akslen LA, Haugen OA, et al. Molecular subtypes, histopathological grade and survival in a historic cohort of breast cancer patients. Breast Cancer Res Treat. 2013;140(3): 463-73. doi: 10.1007/s10549-013-2647-2. Epub 2013 Jul 31.
  15. 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. Ann Oncol. 2015;26(8):1533-46. doi: 10.1093/annonc/mdv221. Epub 2015 May 4.
  16. Hammond ME, Hayes DF, Dowsett M, Allred DC, Hagerty KL, Badve S, et al. American Society of Clinical Oncology/College Of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J Clin Oncol. 2010;28(16):2784-2795. doi:10.1200/JCO.2009.25.6529.
  17. Fitzgibbons PL, Murphy DA, Hammond ME, Allred DC, Valenstein Recommendations for validating estrogen and progesterone receptor immunohistochemistry assays. Arch Pathol Lab Med. 2010;134(6): 930-5. doi: 10.1043/1543-2165-134.6.930.
  18. Park S, Park S, Kim J, Ahn S, Park KH, Lee H. Assessment of Ki-67 for Predicting Effective Prognosis in Breast Cancer Subtypes. Biomed Sci Letters. 2018;24:9-14. org/10.15616/BSL.2018.24.1.9
  19. Goldhirsch A, Winer EP, Coates AS, Gelber RD, Piccart-Gebhart M,  Thürlimann B, et al. Personalizing the treatment of women with early breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2013. Ann Oncol. 2013;24(9):2206-23. doi: 10.1093/annonc/mdt303. Epub 2013 Aug 4.
  20. Gradishar WJ, Anderson BO, Aft R., Balassanian R., Blair SL, Burstein HJ, et al., editors. Breast Cancer: NCCN Clinical Practice Guidelines in Oncology. version 1. National Comprehensive Cancer Network, Inc. 2018. p.30-67.
  21. Eisenhauer EA, Therasse P,  Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-47. doi: 10.1016/j.ejca.2008.10.026
  22. Park BW, Oh JW, Kim JH, Park SH, Kim KS, Lee KS. Preoperative CA 15–3 and CEA serum levels as predictor for breast cancer outcomes. Ann Oncol. 2008; 19: 675-81. doi: 10.1093/annonc/mdm538. Epub 2007 Nov 23.
  23. Soletormos G, Nielsen D, Schioler V, Mouridsen H, Dombernowsky P. Monitoring different stages of breast cancer using tumour markers CA 15–3, CEA and TPA. Eur J Cancer. 2004; 40: 481-6. doi: 10.1016/j.ejca.2003.10.015.
  24. Lee JS, Park S, Park JM, Cho JH, Kim SI, Park BW. Elevated levels of serum tumor markers CA 15–3 and CEA are prognostic factors for diagnosis of metastatic breast cancers. Breast Cancer Res Treat. 2013; 141:477-84. doi: 10.1007/s10549-013-2695-7.
  25. Colomer R, Ruibal A, Genolla J, Rubio D, Del Campo JM, Bodi R and Salvador L: Circulating CA 15-3 levels in the postsurgical follow-up of breast cancer patients and in nonmalignant diseases. Breast Cancer Res Treat. 1989; 13: 123-33. doi: 10.1007/BF01806524.
  26. Cardoso F, Costa A, Norton L, Senkus E, Aapro M, André F, et al. ESO-ESMO 2nd international consensus guidelines for advanced breast cancer (ABC2).Breast.2014;23(5):489-502. doi:10.1016/j.breast.2014.08.009. Epub 2014 Sep 20.
  27. Molina R, Barak V, van Dalen A, Duffy MJ, Einarsson R, Gion M, et al. Tumor markers in breast cancer: European Group of Tumor Markers (EGTM) recommendations. Tumor Biol. 2005;26(6):281-93.doi: 10.1159/000089260.
  28. Fleisher M, Dnistrian AM, Sturgeon CM, Lamerz R, Wittliff J., editors. Practice guidelines and recommendations for use of tumor markers in the clinic. In: Diamindis EP, Fritsche H, Scharwtz MK, Chan DW, eds. Tumor markers, physiology, pathobiology, technology and clinical applications. Chicago: AACC Press; 2002. p.33-63.
  29. Cheung KL, Graves CR, Robertson JF. Tumour marker measurements in the diagnosis and monitoring of breast cancer. Cancer Treat Rev. 2000;26(2):91-102. doi: 10.1053/ctrv.1999.0151.
  30. Bliss P, Fisken J, Roulsten J, Leonard RC. An assessment of the clinical usefulness of two serum markers, CA15 3 and HMFG2 in localized and metastatic breast cancer. Dis Markers. 1993;11:45-8.  doi: 10.1155/1993/413530.
  31. Darwish IA, Wani TA, Khalil NY, Blake DA. Novel automated flow-based immunosensor for real-time measurement of the breast cancer biomarker CA15-3 in serum. Talanta. 2012;97:499-504. doi: 10.1016/j.talanta.2012.05.005. Epub 2012 May 16.
  32. Kim HS, Park YH, Park MJ, Chang MH, Jun HJ, Kim KH, et al. Clinical significance of a serum CA15-3 surge and the usefulness of CA15-3 kinetics in monitoring chemotherapy response in patients with metastatic breast cancer. Breast Cancer Res Treat. 2009;118:89-97. doi: 10.1007/s10549-009-0377-2. Epub 2009 Mar 26.
  33. Laessig D, Nagel D, Heinemann V, Untch M, Kahlert S, Bauerfeind I et al. Importance of CEA and CA 15–3 during disease progression in metastatic breast cancer patients. Anticancer Res. 2007; 27(4A):1963-8. PMID: 17649806
  34. Berruti A, Tampellini M, Torta M, Buniva T, Gorzegno G and Dogliotti L: Prognostic value in predicting overall survival of two mucinous markers: CA 15-3 and CA 125 in breast cancer patients at first relapse of disease. Eur J Cancer. 1994; 30A(14):2082-4. doi: 10.1016/0959-8049(94)00356-a.
  35. He ZY, Xun Li X, Chen QS, Sun JY, Li FY, Wu SG, Lin HX. Elevated serum carcinoembryonic antigen and CA15-3 levels and the risk of site-specific metastases in metastatic breast cancer. Transl Cancer Res. 2016;5(5):529-537. doi: 21037/tcr.2016.08.39
  36. Geraghty JG, Coveney EC, Sherry F, O'Higgins NJ, Duffy MJ. CA 15-3 in patients with locoregional and metastatic breast carcinoma. Cancer.1992;70(12): 2831-4.doi:10.1002/1097-0142(19921215)70:12<2831::aid-cncr2820701218>;2-8.
  1. YangY, Zhang H, Zhang M, Meng Q, Cai L, Zhang Elevation of serum CEA and CA15‑3 levels during antitumor therapy predicts poor therapeutic response in advanced breast cancer patients. Oncol Lett. 2017; 14(6):7549-7556.  doi: 10.3892/ol.2017.7164. Epub 2017 Oct 10.
  2. Mozzezy N, Farahay TZ, Oloomi M, Bouzari S. Relationship between serum CA15-3 and CEA  level and clinicopathological parameter in breast cancer. Ascian Pac J cancer Prev. 2014;15(4):1685-8. doi: 10.7314/apjcp.2014.15.4.1685.
  3. Sinha P, Kumari R, Kumar M, Ranjan RK, Kumar U. Correlation of Ca15-3 and CEA in Different Molecular Subtypes of Metastatic Breast Cancer. International Journal of Research and Review. 2019;6(8):203-208.
  4. Koboldt D, Fulton R, McLellan M, Schmidt H, Kalicki-Veizer J, McMichael JF, et al. Comprehensive molecular portraits of human breast tumours. Nature. 2012;490(7418):61-70. doi: 10.1038/nature11412. Epub 2012 Sep 23.
  5. Duffy MJ, Duggan C, Keane R, Hill ADK, McDermott E, Crown J, et al. High preoperative CA15-3 concentrations predict adverse outcome in node-negative and node-positive breast cancer: study of 600 patients with histologically confirmed breast cancer. Clin Chem. 2004;50(3):559-63. doi: 10.1373/clinchem.2003.025288. Epub 2004 Jan 15
  6. Kumpulainen EJ, Keskikuru RJ, Johansson RT. Serum tumor marker CA 15.3 and stage are the two most powerful predictors of survival in primary breast cancer. Breast Cancer Res Treat. 2002;76(2):95-102. doi: 10.1023/a:1020514925143.
  7. Wu SG,  He ZY ,  Zhou J, Sun JY ,  Li FY, Lin Q , et al. Serum levels of CEA and CA15-3 in different molecular subtypes and prognostic value in Chinese breast cancer. Breast. 2014;23(1):88-93.