Skip to main content

Advertisement

SpringerLink
Log in

A review of prognostic and predictive biomarkers in breast cancer

  • Review Article
  • Published:
Clinical and Experimental Medicine Aims and scope Submit manuscript

Abstract

Breast cancer (BC) is a common cancer all over the world that affects women. BC is one of the leading causes of cancer mortality in women, which today has decreased with the advancement of technology and new diagnostic and therapeutic methods. BCs are histologically divided into in situ and invasive carcinoma, and both of them can be divided into ductal and lobular. The main function after the diagnosis of invasive breast cancer is which patient should use chemotherapy, which patient should receive adjuvant therapy, and which should not. If the decision is for adjuvant therapy, the next challenge is to identify the most appropriate treatment or combination of treatments for a particular patient. Addressing the first challenge can be helped by prognostic biomarkers, while addressing the second challenge can be done by predictive biomarkers. Among the molecular markers related to BC, ER, PR, HER2, and the Mib1/Ki-67 proliferation index are the most significant ones and are tightly confirmed in the standard care of all primary, recurrent, and metastatic BC patients. CEA and CA-15–3 antigens are the most valuable markers of serum tumors in BC patients. Determining the series of these markers helps monitor response to the treatment and early detection of recurrence or metastasis. miRNAs have been demonstrated to be intricate in mammary gland growth, proliferation, and formation of BC known to be incriminated in BC biology. By combining established prognostic factors with valid prognostic/predicted biomarkers, we can start the journey to personalized treatment for every recently diagnosed BC patient.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

AI:

Aromatase inhibitors

ASCO:

American society of clinical oncology

BC:

Breast cancer

CA:

Cancer antigen

CDK4/6:

Cyclin-dependent kinase 4/6

CEA:

Carcinoembryonic antigen

CTCs:

Circulating tumor cells

ctDNA:

Circulating tumor DNA

DCIS:

Ductal carcinoma in situ

DFS:

Disease-free survival

E2:

Estradiol 2

EGFR:

Epidermal growth factor receptor

EGTM:

European Group on Tumor Markers

ER:

Estrogen receptor

ESR:

Mutational status of ER

ET:

Endocrine therapy

HER2:

Human epidermal growth factor receptor

IHC:

Immunohistochemistry

ILC:

Infiltrating lobular carcinoma

ISH:

In situ hybridization

LCIS:

Lobular carcinoma in situ

miRNAs:

Micro-RNAs

MUC1:

Mucin-1

NCI:

National Cancer Institute

OS:

Overall survival

PET/CT:

Positron emission tomography/computed tomography

PIN1:

Protein interacting with never in mitosis A

PR:

Progesterone receptor

SERD:

Selective ER down-regulator

SERM:

Selective ER modulator

TNBC:

Triple-negative BC

UTR:

Untranslated region

VAF:

Variant allele frequency

References

  1. Ali OS, Shabayek MI, Seleem MM, Abdelaziz HG, Makhlouf DO. MicroRNAs 182 and 375 sera expression as prognostic biochemical markers in breast cancer. Clin Breast Cancer. 2018;18(6):e1373–9.

    Article  CAS  PubMed  Google Scholar 

  2. Siegel RL, Miller KD, Goding Sauer A, et al. Colorectal cancer statistics, 2020. CA Cancer J Clin. 2020;70:145–64.

    Article  PubMed  Google Scholar 

  3. American Cancer Society. Breast Cancer Facts & Figures 2019-2020. Atlanta: American Cancer Society, Inc.; 2019.

    Google Scholar 

  4. Anderson BO, Yip CH, Smith RA, et al. Guideline implementation for breast healthcare in low-income and middle-income countries: Overview of the Breast Health Global Initiative Global Summit 2007. Cancer. 2008;113(S8):2221–43.

    Article  PubMed  Google Scholar 

  5. Nicolini A, Ferrari P, Duffy MJ,. Prognostic and predictive biomarkers in breast cancer: past, present and future. Semin Cancer Biol. 2018;52(Pt 1):56–73.

    Article  CAS  PubMed  Google Scholar 

  6. Yao Y, Liu R, Gao C, et al. Identification of prognostic biomarkers for breast cancer based on miRNA and mRNA co-expression network. J Cell Biochem. 2019;120(9):15378–88.

    Article  CAS  PubMed  Google Scholar 

  7. Bertozzi S, Londero AP, Seriau L, Di Vora R, Cedolini C, Mariuzzi L. Biomarkers in Breast Cancer. In: Begum G, editor. Biomarker—Indicator of Abnormal Physiological Process. London: IntechOpen; 2018.

    Google Scholar 

  8. Khordadmehr M, Shahbazi R, Ezzati H, Jigari-Asl F, Sadreddini S, Baradaran B. Key microRNAs in the biology of breast cancer; emerging evidence in the last decade. J Cell Physiol. 2019;234(6):8316–26.

    Article  CAS  PubMed  Google Scholar 

  9. Nassar FJ, Nasr R, Talhouk R. MicroRNAs as biomarkers for early breast cancer diagnosis, prognosis and therapy prediction. Pharmacol Ther. 2017;172:34–49.

    Article  CAS  PubMed  Google Scholar 

  10. Sharma GN, Dave R, Sanadya J, Sharma P, Sharma K. Various types and management of breast cancer: an overview. J Adv Pharm Technol Res. 2010;1(2):109.

    PubMed  PubMed Central  Google Scholar 

  11. Bodmer M, Meier C, Krähenbühl S, Jick SS, Meier CR. Long-term metformin use is associated with decreased risk of breast cancer. Diabetes Care. 2010;33(6):1304–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Page K, Guttery DS, Fernandez-Garcia D, et al. Next generation sequencing of circulating cell-free DNA for evaluating mutations and gene amplification in metastatic breast cancer. Clin Chem. 2017;63(2):532–41.

    Article  CAS  PubMed  Google Scholar 

  13. Akram M, Iqbal M, Daniyal M, Khan AU. Awareness and current knowledge of breast cancer. Biol Res. 2017;50(1):33.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Ulaner GA, Riedl CC, Dickler MN, Jhaveri K, Pandit-Taskar N, Weber W. Molecular imaging of biomarkers in breast cancer. J Nucl Med. 2016;57(Suppl 1):53S.

    Article  CAS  PubMed  Google Scholar 

  15. Carrigan P, Krahn T. Impact of biomarkers on personalized medicine. New approaches to drug discovery. Berlin: Springer; 2015. p. 285–311.

    Book  Google Scholar 

  16. Goossens N, Nakagawa S, Sun X, Hoshida Y. Cancer biomarker discovery and validation. Transl Cancer Res. 2015;4(3):256.

    CAS  PubMed  Google Scholar 

  17. Henry NL, Hayes DF. Cancer biomarkers. Mol Oncol. 2012;6(2):140–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Paik S, Shak S, Tang G, et al. A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med. 2004;351(27):2817–26.

    Article  CAS  PubMed  Google Scholar 

  19. Porika M, Malotu N, Veldandi UK, Yadala N, Abbagani S. Evaluation of tumor markers in southern Indian breast cancer patients. Asian Pac J Cancer Prev. 2010;11(1):157–9.

    PubMed  Google Scholar 

  20. Loibl S, von Minckwitz G, Schneeweiss A, et al. PIK3CA mutations are associated with lower rates of pathologic complete response to anti-human epidermal growth factor receptor 2 (her2) therapy in primary HER2-overexpressing breast cancer. J Clin Oncol. 2014;32:3212–20.

    Article  CAS  PubMed  Google Scholar 

  21. Krop I, Johnston S, Mayer IA. The FERGI phase II study of the PI3 K inhibitor pictilisib (GDC-0941) plus fulvestrant vs. fulvestrant plus placebo in patients with ER+, aromatase inhibitor (AI)- resistant advanced or metastatic breast cancer. San Antonio Breast Cancer Symposium 2014; Abstract No. S2–02.

  22. Fasching PA, Brucker SY, Fehm TN, et al. Biomarkers in patients with metastatic breast cancer and the PRAEGNANT study network. Geburtsh Frauenheilk. 2015;75(1):41–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Zwart W, Theodorou V, Carroll JS. Estrogen receptor-positive breast cancer: a multidisciplinary challenge. Wiley Interdiscip Rev Syst Biol Med. 2011;3(2):216–30.

    Article  CAS  PubMed  Google Scholar 

  24. Kumar R, Zakharov MN, Khan SH, et al. The dynamic structure of the estrogen receptor. J Amino Acids. 2011;2011:812540.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Weigel MT, Dowsett M. Current and emerging biomarkers in breast cancer: prognosis and prediction. Endocr Relat Cancer. 2010;17(4):R245–62.

    Article  CAS  PubMed  Google Scholar 

  26. Jin C, Rajabi H, Pitroda S, Li A, et al. Cooperative interaction between the MUC1-C oncoprotein and the Rab31 GTPase in estrogen receptor-positive breast cancer cells. PLoS ONE. 2012;7(7):e39432.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Tecalco-Cruz AC, Ramírez-Jarquín JO. Mechanisms that increase stability of estrogen receptor alpha in breast cancer. Clin Breast Cancer. 2017;17(1):1–10.

    Article  CAS  PubMed  Google Scholar 

  28. Yuan S, Shi C, Liu L, Han W. MUC1-based recombinant Bacillus Calmette-Guerin vaccines as candidates for breast cancer immunotherapy. Expert Opin Biol Ther. 2010;10(7):1037–48.

    Article  CAS  PubMed  Google Scholar 

  29. Yuan S, Shi C, Ling R, Wang T, Wang H, Han W. Immunization with two recombinant Bacillus Calmette-Guerin vaccines that combine the expression of multiple tandem repeats of mucin-1 and colony stimulating-factor suppress breast tumor growth in mice. J Cancer Res Clin Oncol. 2010;136(9):1359–67.

    Article  CAS  PubMed  Google Scholar 

  30. Li X, Li L, Zhou Q, et al. Synthesis of the novel elemonic acid derivatives as Pin1 inhibitors. Bioorg Med Chem Lett. 2014;24(24):5612–5.

    Article  CAS  PubMed  Google Scholar 

  31. Kim JH, Jung JH, Kim SH, Jeong SJ. Decursin exerts anti-cancer activity in MDA-MB-231 breast cancer cells via inhibition of the Pin1 activity and enhancement of the Pin1/p53 association. Phytother Res. 2014;28(2):238–44.

    Article  CAS  PubMed  Google Scholar 

  32. Wei S, Kozono S, Kats L, et al. Active Pin1 is a key target of all-trans retinoic acid in acute promyelocytic leukemia and breast cancer. Nat Med. 2015;21(5):457–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Kim HM, Kim C-S, Lee J-H, et al. CG0009, a novel glycogen synthase kinase 3 inhibitor, induces cell death through cyclin D1 depletion in breast cancer cells. PLoS ONE. 2013;8(4):e60383.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Fowler AM, Solodin N, Preisler-Mashek MT, Zhang P, Lee AV, Alarid ET. Increases in estrogen receptor-α concentration in breast cancer cells promote serine 118/104/106-independent AF-1 transactivation and growth in the absence of estrogen. FASEB J. 2004;18(1):81–93.

    Article  CAS  PubMed  Google Scholar 

  35. Fowler AM, Solodin NM, Valley CC, Alarid ET. Altered target gene regulation controlled by estrogen receptor-α concentration. Mol Endocrinol. 2006;20(2):291–301.

    Article  CAS  PubMed  Google Scholar 

  36. Lumachi F, Brunello A, Maruzzo M, Basso U, M.M Basso S,. Treatment of estrogen receptor-positive breast cancer. Curr Med Chem. 2013;20(5):596–604.

    Article  CAS  PubMed  Google Scholar 

  37. Kabel AM, Elkhoely AA. Ameliorative potential of fluoxetine/raloxifene combination on experimentally induced breast cancer. Tissue Cell. 2016;48(2):89–95.

    Article  CAS  PubMed  Google Scholar 

  38. Han HH, Lee SH, Kim BG, Lee JH, Kang S, Cho NH. Estrogen receptor status predicts late-onset skeletal recurrence in breast cancer patients. Medicine. 2016;95(8):e2909.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Beije N, Onstenk W, Kraan J, et al. Prognostic impact of HER2 and ER status of circulating tumor cells in metastatic breast cancer patients with a HER2-negative primary tumor. Neoplasia. 2016;18(11):647–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Gulbahce HE, Blair CK, Sweeney C, Salama ME. Quantification of estrogen receptor expression in normal breast tissue in postmenopausal women with breast cancer and association with tumor subtypes. Appl Immunohistochem Mol Morphol. 2017;25(8):548–52.

    Article  CAS  PubMed  Google Scholar 

  41. Oh H, Eliassen AH, Wang M, et al. Expression of estrogen receptor, progesterone receptor, and Ki67 in normal breast tissue in relation to subsequent risk of breast cancer. NPJ Breast Cancer. 2016;2(1):1–3.

    Article  Google Scholar 

  42. Caruana D, Wei W, Martinez-Morilla S, Rimm DL, Reisenbichler ES. Association between low estrogen receptor positive breast cancer and staining performance. NPJ Breast Cancer. 2020;6(1):1–6.

    Article  Google Scholar 

  43. Carroll J. EJE PRIZE 2016: mechanisms of oestrogen receptor (ER) gene regulation in breast cancer. Eur J Endocrinol. 2016;175(1):R41–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Bae SY, Kim S, Lee JH, et al. Poor prognosis of single hormone receptor-positive breast cancer: similar outcome as triple-negative breast cancer. BMC Cancer. 2015;15(1):138.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Ma CX, Reinert T, Chmielewska I, Ellis MJ. Mechanisms of aromatase inhibitor resistance. Nat Rev Cancer. 2015;15(5):261–75.

    Article  CAS  PubMed  Google Scholar 

  46. Jeselsohn R, Yelensky R, Buchwalter G, et al. Emergence of constitutively active estrogen receptor-α mutations in pretreated advanced estrogen receptor–positive breast cancer. Clin Cancer Res. 2014;20(7):1757–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Kumar S, Lindsay D, Chen QB, et al. Tracking plasma DNA mutation dynamics in estrogen receptor positive metastatic breast cancer with dPCR-SEQ. NPJ Breast Cancer. 2018;4(1):1–5.

    Article  CAS  Google Scholar 

  48. Schiavon G, Hrebien S, Garcia-Murillas I, et al. Analysis of ESR1 mutation in circulating tumor DNA demonstrates evolution during therapy for metastatic breast cancer. Sci Transl Med. 2015;7(313):313ra182-313ra182.

    Article  Google Scholar 

  49. Jeselsohn R, Buchwalter G, De Angelis C, Brown M, Schiff R. ESR1 mutations—a mechanism for acquired endocrine resistance in breast cancer. Nat Rev Clin Oncol. 2015;12(10):573.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Helena AY, Riely GJ, Lovly CM. Therapeutic strategies utilized in the setting of acquired resistance to EGFR tyrosine kinase inhibitors. Clin Cancer Res. 2014;20(23):5898–907.

    Article  Google Scholar 

  51. Brady SW, Zhang J, Seok D, Wang H, Yu D. Enhanced PI3K p110α signaling confers acquired lapatinib resistance that can be effectively reversed by a p110α-selective PI3K inhibitor. Mol Cancer Ther. 2014;13(1):60–70.

    Article  CAS  PubMed  Google Scholar 

  52. Rosenzweig SA. Acquired resistance to drugs targeting receptor tyrosine kinases. Biochem Pharmacol. 2012;83(8):1041–8.

    Article  CAS  PubMed  Google Scholar 

  53. Carausu M, Bidard F-C, Callens C, et al. ESR1 mutations: a new biomarker in breast cancer. Expert Rev Mol Diagn. 2019;19(7):599–611.

    Article  CAS  PubMed  Google Scholar 

  54. Toy W, Shen Y, Won H, et al. ESR1 ligand-binding domain mutations in hormone-resistant breast cancer. Nat Genet. 2013;45(12):1439.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. De Santo I, McCartney A, Migliaccio I, Di Leo A, Malorni L. The emerging role of ESR1 mutations in luminal breast cancer as a prognostic and predictive biomarker of response to endocrine therapy. Cancers. 2019;11(12):1894.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Takeshita T, Yamamoto Y, Yamamoto-Ibusuki M, et al. Clinical significance of plasma cell-free DNA mutations in PIK3CA, AKT1, and ESR1 gene according to treatment lines in ER-positive breast cancer. Mol Cancer. 2018;17(1):1–6.

    Article  Google Scholar 

  57. O’Leary B, Cutts RJ, Liu Y, et al. The genetic landscape and clonal evolution of breast cancer resistance to palbociclib plus fulvestrant in the PALOMA-3 trial. Cancer Discov. 2018;8(11):1390–403.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Reinert T, Coelho GP, Mandelli J, et al. Association of ESR1 mutations and visceral metastasis in patients with estrogen receptor-positive advanced breast cancer from Brazil. J Oncol. 2019;2019:1947215.

    Article  PubMed  PubMed Central  Google Scholar 

  59. English DP, Roque DM, Santin AD. HER2 expression beyond breast cancer: therapeutic implications for gynecologic malignancies. Mol Diagn Ther. 2013;17(2):85–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Ishikawa T, Ichikawa Y, Shimizu D, et al. The role of HER-2 in Breast Cancer. J Surg Sci. 2014;2(1):4.

    PubMed  PubMed Central  Google Scholar 

  61. Winstanley J, Cooke T, Murray G, et al. The long term prognostic significance of c-erbB-2 in primary breast cancer. Br J Cancer. 1991;63(3):447.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Krishnamurti U, Silverman JF. HER2 in breast cancer: a review and update. Adv Anat Pathol. 2014;21(2):100–7.

    Article  CAS  PubMed  Google Scholar 

  63. Cao W, Zhang B, Liu Y, et al. High-level SLP-2 expression and HER-2/neu protein expression are associated with decreased breast cancer patient survival. Am J Clin Pathol. 2007;128(3):430–6.

    Article  CAS  PubMed  Google Scholar 

  64. Reix N, Malina C, Chenard M-P, et al. A prospective study to assess the clinical utility of serum HER2 extracellular domain in breast cancer with HER2 overexpression. Breast Cancer Res Treat. 2016;160(2):249–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Dieci MV, Miglietta F, Griguolo G, Guarneri V. Biomarkers for HER2-positive metastatic breast cancer: beyond hormone receptors. Cancer Treat Rev. 2020;88:102064.

    Article  CAS  PubMed  Google Scholar 

  66. Pegram MD, Konecny GE, O’Callaghan C, Beryt M, Pietras R, Slamon DJ. Rational combinations of trastuzumab with chemotherapeutic drugs used in the treatment of breast cancer. J Natl Cancer Inst Monogr. 2004;96(10):739–49.

    Article  CAS  Google Scholar 

  67. Duffy M, Harbeck N, Nap M, et al. Clinical use of biomarkers in breast cancer: updated guidelines from the European Group on Tumor Markers (EGTM). Eur J Cancer. 2017;75:284–98.

    Article  CAS  PubMed  Google Scholar 

  68. Wu J-R, Zhao Y, Zhou X-P, Qin X. Estrogen receptor 1 and progesterone receptor are distinct biomarkers and prognostic factors in estrogen receptor-positive breast cancer: Evidence from a bioinformatic analysis. Biomed Pharmacother. 2020;121:109647.

    Article  CAS  PubMed  Google Scholar 

  69. Daniel AR, Hagan CR, Lange CA. Progesterone receptor action: defining a role in breast cancer. Expert Rev Endocrinol Metab. 2011;6(3):359–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Mohammed H, Russell IA, Stark R, et al. Progesterone receptor modulates ERα action in breast cancer. Nature. 2015;523(7560):313–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Carroll JS, Hickey TE, Tarulli GA, Williams M, Tilley WD. Deciphering the divergent roles of progestogens in breast cancer. Nat Rev Cancer. 2017;17(1):54–64.

    Article  CAS  PubMed  Google Scholar 

  72. Elledge RM, Green S, Pugh R, et al. Estrogen receptor (ER) and progesterone receptor (PgR), by ligand-binding assay compared with ER, PgR and pS2, by immuno-histochemistry in predicting response to tamoxifen in metastatic breast cancer: a Southwest Oncology Group study. Int J Cancer. 2000;89(2):111–7.

    Article  CAS  PubMed  Google Scholar 

  73. Chen X, Yuan Y, Gu Z, Shen K. Accuracy of estrogen receptor, progesterone receptor, and HER2 status between core needle and open excision biopsy in breast cancer: a meta-analysis. Breast Cancer Res Treat. 2012;134(3):957–67.

    Article  CAS  PubMed  Google Scholar 

  74. Fang C, Cao Y, Liu X, Zeng X-T, Li Y. Serum CA125 is a predictive marker for breast cancer outcomes and correlates with molecular subtypes. Oncotarget. 2017;8(38):63963.

    Article  PubMed  PubMed Central  Google Scholar 

  75. 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 ONE. 2015;10(7):e0133830.

    Article  PubMed  PubMed Central  Google Scholar 

  76. Gold P, Freedman SO. Specific carcinoembryonic antigens of the human digestive system. J Exp Med. 1965;122(3):467–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Wu S-g, He Z-y, Zhou J, 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.

    Article  PubMed  Google Scholar 

  78. Duffy MJ, Evoy D, McDermott EW. CA 15–3: uses and limitation as a biomarker for breast cancer. Clin Chim Acta. 2010;411(23–24):1869–74.

    Article  CAS  PubMed  Google Scholar 

  79. Li J, Liu L, Feng Z, et al. Tumor markers CA15–3, CA125, CEA and breast cancer survival by molecular subtype: a cohort study. Breast Cancer. 2020:1–10.

  80. Molina R, Barak V, van Dalen A, et al. Tumor markers in breast cancer–European Group on Tumor Markers recommendations. Tumor Biol. 2005;26(6):281–93.

    Article  Google Scholar 

  81. Marić P, Ozretić P, Levanat S, Orešković S, Antunac K, Beketić-Orešković L. Tumor markers in breast cancer-evaluation of their clinical usefulness. Coll Antropol. 2011;35(1):241–7.

    PubMed  Google Scholar 

  82. Duffy MJ, Duggan C, Keane R, et al. High preoperative CA 15–3 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.

    Article  CAS  PubMed  Google Scholar 

  83. 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.

    Article  CAS  PubMed  Google Scholar 

  84. Goldhirsch A, Wood WC, Coates AS, 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 2011. Ann Oncol. 2011;22(8):1736–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Park B-W, Oh J-W, Kim J-H, et al. Preoperative CA 15–3 and CEA serum levels as predictor for breast cancer outcomes. Ann Oncol. 2008;19(4):675–81.

    Article  PubMed  Google Scholar 

  86. Molina R, Auge JM, Farrus B, et al. Prospective evaluation of carcinoembryonic antigen (CEA) and carbohydrate antigen 15.3 (CA 15.3) in patients with primary locoregional breast cancer. Clin Chem. 2010;56(7):1148–57.

    Article  CAS  PubMed  Google Scholar 

  87. Lee JS, Park S, Park JM, Cho JH, Kim SI, Park B-W. 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(3):477–84.

    Article  CAS  PubMed  Google Scholar 

  88. Lee JS, Magbanua MJM, Park JW. Circulating tumor cells in breast cancer: applications in personalized medicine. Breast Cancer Res Treat. 2016;160(3):411–24.

    Article  CAS  PubMed  Google Scholar 

  89. Smerage JB, Barlow WE, Hortobagyi GN, et al. Circulating tumor cells and response to chemotherapy in metastatic breast cancer: SWOG S0500. J Clin Oncol. 2014;32(31):3483.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Le Du F, Ueno NT, Gonzalez-Angulo AM. Breast cancer biomarkers: utility in clinical practice. Curr Breast Cancer Rep. 2013;5(4):284–92.

    Article  CAS  Google Scholar 

  91. Munzone E, Nolé F, Goldhirsch A, et al. Changes of HER2 status in circulating tumor cells compared with the primary tumor during treatment for advanced breast cancer. Clin Breast Cancer. 2010;10(5):392–7.

    Article  CAS  PubMed  Google Scholar 

  92. Pestrin M, Bessi S, Puglisi F, et al. Final results of a multicenter phase II clinical trial evaluating the activity of single-agent lapatinib in patients with HER2-negative metastatic breast cancer and HER2-positive circulating tumor cells. A proof-of-concept study. Breast Cancer Res Treat. 2012;134(1):283–9.

    Article  CAS  PubMed  Google Scholar 

  93. Cristofanilli M, Valero V, Mangalik A, et al. Phase II, randomized trial to compare anastrozole combined with gefitinib or placebo in postmenopausal women with hormone receptor-positive metastatic breast cancer. Clin Cancer Res. 2010;16(6):1904–14.

    Article  CAS  PubMed  Google Scholar 

  94. Nadal R, Fernandez A, Sanchez-Rovira P, et al. Biomarkers characterization of circulating tumour cells in breast cancer patients. Breast Cancer Res. 2012;14(3):1–12.

    Article  Google Scholar 

  95. Soliman NA, Yussif SM. Ki-67 as a prognostic marker according to breast cancer molecular subtype. Cancer Biol Med. 2016;13(4):496.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Penault-Llorca F, Radosevic-Robin N. Ki67 assessment in breast cancer: an update. Pathology. 2017;49(2):166–71.

    Article  CAS  PubMed  Google Scholar 

  97. Feng X, Li H, Kornaga EN, et al. Low Ki67/high ATM protein expression in malignant tumors predicts favorable prognosis in a retrospective study of early stage hormone receptor positive breast cancer. Oncotarget. 2016;7(52):85798.

    Article  PubMed  PubMed Central  Google Scholar 

  98. 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):e0172324.

    Article  PubMed  PubMed Central  Google Scholar 

  99. Clarke RB. Steroid receptors and proliferation in the human breast. Steroids. 2003;68(10–13):789–94.

    Article  CAS  PubMed  Google Scholar 

  100. Harvey JA, Santen RJ, Petroni GR, et al. Histologic changes in the breast with menopausal hormone therapy use: correlation with breast density, estrogen receptor, progesterone receptor, and proliferation indices. Menopause. 2008;15(1):67.

    Article  PubMed  PubMed Central  Google Scholar 

  101. Zhou C-j, Zhang Q-h, Zhang T-g, et al. Expression of ER, Ki-67 and cylinD1 in the pre-cancerous breast of Chinese patients. Pathol Oncol Res. 2009;15(2):153–8.

    Article  CAS  PubMed  Google Scholar 

  102. Petrelli F, Viale G, Cabiddu M, Barni S. 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 Res Treat. 2015;153(3):477–91.

    Article  PubMed  Google Scholar 

  103. Li P-J, Jin T, Luo D-H, et al. Effect of prolonged radiotherapy treatment time on survival outcomes after intensity-modulated radiation therapy in nasopharyngeal carcinoma. PLoS ONE. 2015;10(10):e0141332.

    Article  PubMed  PubMed Central  Google Scholar 

  104. Fabian CJ, Kimler BF, Zalles CM, et al. Reduction in proliferation with six months of letrozole in women on hormone replacement therapy. Breast Cancer Res Treat. 2007;106(1):75–84.

    Article  CAS  PubMed  Google Scholar 

  105. Okumura Y, Yamamoto Y, Zhang Z, et al. Identification of biomarkers in ductal carcinoma in situ of the breast with microinvasion. BMC Cancer. 2008;8(1):287.

    Article  PubMed  PubMed Central  Google Scholar 

  106. Ringberg A, Anagnostaki L, Anderson H, Idvall I, Fernö M. Cell biological factors in ductal carcinoma in situ (DCIS) of the breast-relationship to ipsilateral local recurrence and histopathological characteristics. Eur J Cancer. 2001;37(12):1514–22.

    Article  CAS  PubMed  Google Scholar 

  107. Haroon S, Hashmi AA, Khurshid A, et al. Ki67 index in breast cancer: correlation with other prognostic markers and potential in Pakistani patients. Asian Pac J Cancer Prev. 2013;14(7):4353–8.

    Article  PubMed  Google Scholar 

  108. Nishimura R, Osako T, Okumura Y, Hayashi M, Toyozumi Y, Arima N. Ki-67 as a prognostic marker according to breast cancer subtype and a predictor of recurrence time in primary breast cancer. Exp Ther Med. 2010;1(5):747–54.

    Article  PubMed  PubMed Central  Google Scholar 

  109. Ragab HM, Samy N, Afify M, Abd El Maksoud N, Shaaban HM. Assessment of Ki-67 as a potential biomarker in patients with breast cancer. J Genet Eng Biotechnol. 2018;16(2):479–84.

    Article  PubMed  PubMed Central  Google Scholar 

  110. Yerushalmi R, Woods R, Ravdin PM, Hayes MM, Gelmon KA. Ki67 in breast cancer: prognostic and predictive potential. Lancet Oncol. 2010;11(2):174–83.

    Article  CAS  PubMed  Google Scholar 

  111. Eeckhoute J, Carroll JS, Geistlinger TR, Torres-Arzayus MI, Brown M. A cell-type-specific transcriptional network required for estrogen regulation of cyclin D1 and cell cycle progression in breast cancer. Genes Dev. 2006;20(18):2513–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Ortiz AB, Garcia D, Vicente Y, Palka M, Bellas C, Martin P. Prognostic significance of cyclin D1 protein expression and gene amplification in invasive breast carcinoma. PLoS ONE. 2017;12(11):e0188068.

    Article  PubMed  PubMed Central  Google Scholar 

  113. Lamb R, Lehn S, Rogerson L, Clarke RB, Landberg G. Cell cycle regulators cyclin D1 and CDK4/6 have estrogen receptor-dependent divergent functions in breast cancer migration and stem cell-like activity. Cell Cycle. 2013;12(15):2384–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Roy PG, Pratt N, Purdie CA, et al. High CCND1 amplification identifies a group of poor prognosis women with estrogen receptor positive breast cancer. Int J Cancer. 2010;127(2):355–60.

    CAS  PubMed  Google Scholar 

  115. Khordadmehr M, Shahbazi R, Sadreddini S, Baradaran B. miR-193: a new weapon against cancer. J Cell Physiol. 2019;234(10):16861–72.

    Article  CAS  PubMed  Google Scholar 

  116. Chan M, Liaw CS, Ji SM, et al. Identification of circulating microRNA signatures for breast cancer detection. Clin Cancer Res. 2013;19(16):4477–87.

    Article  CAS  PubMed  Google Scholar 

  117. Heneghan HM, Miller N, Kerin MJ. Circulating miRNA signatures: promising prognostic tools for cancer. J Clin Oncol. 2010;28(29):e573–4.

    Article  PubMed  Google Scholar 

  118. Kodahl AR, Lyng MB, Binder H, et al. Novel circulating microRNA signature as a potential non-invasive multi-marker test in ER-positive early-stage breast cancer: a case control study. Mol Oncol. 2014;8(5):874–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Shimomura A, Shiino S, Kawauchi J, et al. Novel combination of serum microRNA for detecting breast cancer in the early stage. Cancer Sci. 2016;107(3):326–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Hagrass HA, Sharaf S, Pasha HF, Tantawy EA, Mohamed RH, Kassem R. Circulating microRNAs-a new horizon in molecular diagnosis of breast cancer. Genes Cancer. 2015;6(5–6):281.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Bahmanpour Z, Sheervalilou R, Choupani J, Shekari Khaniani M, Montazeri V, Mansoori DS. A new insight on serum microRNA expression as novel biomarkers in breast cancer patients. J Cell Physiol. 2019;234(11):19199–211.

    Article  CAS  PubMed  Google Scholar 

  122. Wu Z-s, Wang C-q, Xiang R, et al. Loss of miR-133a expression associated with poor survival of breast cancer and restoration of miR-133a expression inhibited breast cancer cell growth and invasion. BMC Cancer. 2012;12(1):1–10.

    Article  Google Scholar 

  123. Wu X, Somlo G, Yu Y, et al. De novo sequencing of circulating miRNAs identifies novel markers predicting clinical outcome of locally advanced breast cancer. J Transl Med. 2012;10(1):42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Zheng R, Pan L, Gao J, et al. Prognostic value of miR-106b expression in breast cancer patients. J Surg Res. 2015;195(1):158–65.

    Article  CAS  PubMed  Google Scholar 

  125. Wang H, Tan G, Dong L, et al. Circulating MiR-125b as a marker predicting chemoresistance in breast cancer. PLoS ONE. 2012;7(4):e34210.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Hanahan D, Weinberg RA. Hallmarks of cancer: The next generation. Cell. 2011;144:646–74.

    Article  CAS  PubMed  Google Scholar 

  127. Guo H, Ding Q, Gong Y, et al. Comparison of three scoring methods using the FDA-approved 22C3 immunohistochemistry assay to evaluate PD-L1 expression in breast cancer and their association with clinicopathologic factors. Breast Cancer Res. 2020;22:69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Muenst S, Schaerli AR, Gao F, et al. Expression of programmed death ligand 1 (PD-L1) is associated with poor prognosis in human breast cancer. Breast Cancer Res Treat. 2014;146:15–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Baptista MZ, Sarian LO, Derchain SFM, Pinto GA, Vassallo J. Prognostic significance of PD-L1 and PD-L2 in breast cancer. Hum Pathol. 2016;47:78–84.

    Article  CAS  PubMed  Google Scholar 

  130. Qin T, Zeng Y, Qin G, et al. High PD-L1expression was associated with poor prognosis in 870 Chinese patients with breast cancer. Oncotarget. 2015;6:33972–81.

    Article  PubMed  PubMed Central  Google Scholar 

  131. Sabatier R, Finetti P, Mamessier E, et al. Prognostic and predictive value of PDL1 expression in breast cancer. Oncotarget. 2014;6:5449–64.

    Article  PubMed Central  Google Scholar 

  132. Schmid P, Adams S, Rugo HS, et al. Atezolizumaband nab-paclitaxel in advanced triple-negative breast cancer. N Engl J Med. 2018;379:2108–21.

    Article  CAS  PubMed  Google Scholar 

  133. Wimberly H, Brown JR, Schalper K, et al. PD-L1 expression correlates with tumor-infiltrating lymphocytes and response to neoadjuvant chemotherapy in breast cancer. Cancer Immunol Res. 2015;3:326–32.

    Article  CAS  PubMed  Google Scholar 

  134. Salgado R, Denkert C, DeMaria S, et al. The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by anInternational TILs Working Group 2014. Ann Oncol. 2015;26:259–71.

    Article  CAS  PubMed  Google Scholar 

  135. Denkert C, Wienert S, Poterie A, et al. Standardized evaluation of tumor-infiltrating lymphocytes in breast cancer: Results of the ring studies of the international immuno-oncology biomarker working group. Mod Pathol. 2016;29:1155–64.

    Article  CAS  PubMed  Google Scholar 

  136. Denkert C, Von Minckwitz G, Darb-Esfahani S, et al. Tumour-infiltrating lymphocytes and prognosis in different subtypes of breast cancer: a pooled analysis of 3771patients treated with neoadjuvant therapy. Lancet Oncol. 2018;19:40–50.

    Article  PubMed  Google Scholar 

  137. Skriver SK, Jensen MB, Knoop AS, Ejlertsen B, Laenkholm AV. Tumour-infiltrating lymphocytes and response toneoadjuvant letrozole in patients with early oestrogen receptor-positive breast cancer: Analysis from a nationwide phase II DBCGtrial. Breast Cancer Res. 2020;22:46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Harris L, Fritsche H, Mennel R, et al. American Society of Clinical Oncology 2007 update of recommendations for the use of tumor markers in breast cancer. J Clin Oncol. 2007;25(33):5287–312.

    Article  CAS  PubMed  Google Scholar 

  139. Zervoudis S, Peitsidis P, Iatrakis G, et al. Increased levels of tumor markers in the follow-up of 400 patients with breast cancer without recurrence or metastasis: interpretation of false-positive results. J BUON. 2007;12(4):487.

    CAS  PubMed  Google Scholar 

  140. Barrington SF, Mikhaeel NG, Kostakoglu L, et al. Role of imaging in the staging and response assessment of lymphoma: consensus of the International Conference on Malignant Lymphomas Imaging Working Group. J Clin Oncol. 2014;32(27):3048.

    Article  PubMed  PubMed Central  Google Scholar 

  141. van den Abbeele AD, Badawi RD. Use of positron emission tomography in oncology and its potential role to assess response to imatinib mesylate therapy in gastrointestinal stromal tumors (GISTs). Eur J Cancer. 2002;38:S60–5.

    Article  PubMed  Google Scholar 

  142. Burzykowski T, Buyse M, Piccart-Gebhart MJ, et al. Evaluation of tumor response, disease control, progression-free survival, and time to progression as potential surrogate end points in metastatic breast cancer. J Clin Oncol. 2008;26(12):1987–92.

    Article  CAS  PubMed  Google Scholar 

  143. Niikura N, Liu J, Hayashi N, et al. Loss of human epidermal growth factor receptor 2 (HER2) expression in metastatic sites of HER2-overexpressing primary breast tumors. J Clin Oncol. 2012;30(6):593.

    Article  PubMed  Google Scholar 

  144. Hoefnagel LD, van de Vijver MJ, van Slooten H-J, et al. Receptor conversion in distant breast cancer metastases. Breast Cancer Res. 2010;12(5):1–9.

    Article  Google Scholar 

Download references

Funding

The authors did not receive support from any organization for the submitted review.

Author information

Authors and Affiliations

  1. Department of Medical Physics, Iran University of Medical Sciences, Tehran, Iran

    Elaheh Tarighati

  2. School of Paramedicine, Shahroud University of Medical Sciences, Shahroud, Iran

    Hadi Keivan

  3. Radiation Applications Research School, Nuclear Science and Technology Research Institute, P.O. Box: 14395-836, Tehran, Iran

    Hojjat Mahani

Authors
  1. Elaheh Tarighati
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hadi Keivan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hojjat Mahani
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hojjat Mahani.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

Not applicable.

Informed consent

Not applicable.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tarighati, E., Keivan, H. & Mahani, H. A review of prognostic and predictive biomarkers in breast cancer. Clin Exp Med 23, 1–16 (2023). https://doi.org/10.1007/s10238-021-00781-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10238-021-00781-1

Keywords

Search

Navigation