Breast cancer

Tumor Markers in Breast Cancer – European Group on Tumor Markers Recommendations

Rafael Molina, Vivian Barak, Michael J. Duffy, Roland Einarsson, Massimo Gion, Rolf Lamerz, Marius Nap, Andrea Nicolini, György Sölétormos,Petra Stieber


·     Combination of one MUC-1 marker (e.g., CA 15-3) and CEA is the recommended serum marker panel in patients with breast cancer ([i],[ii]).
·     Tumor marker sensitivity in early stages is low and normal tumor marker serum levels do not exclude the presence of malignancy and they cannot be recommended for screening or early diagnosis. Nevertheless, tumor marker determination may complement patient staging: high levels in patients thought to have localized disease suggest the presence of unsuspected metastatic disease.
·     The sensitivity of tumor markers is significantly higher in patients with advanced disease and is related to the site of recurrence (lowest in locoregional recurrence). Abnormal CEA and CA 15.3 levels are found in 40–50 and 50–70% of patients with distant metastases. Simultaneous measurement of both markers results in increased sensitivity (i.e., approximately 80%) in patients with metastatic breast cancer ([iii],[iv]).
·     Prognosis: Preoperatively elevated levels of either CA 15.3 or CEA are associated with adverse outcome in patients with breast cancer; their use in combination with established prognostic factors is recommended ([v],[vi],[vii],[viii],[ix]).
·     Early diagnosis of recurrence: Serial CA 15.3 and CEA serum determinations are recommended for the early detection of recurrence in asymptomatic patients with breast cancer, if the detection of recurrent or metastatic disease would alter clinical management. The impact of this lead time information on patient outcome is not clear.([x],[xi],[xii],[xiii],[xiv],[xv],[xvi],[xvii])
·     Currently, there are no data available regarding the optimum frequency for the measurement of serum tumor markers in the early diagnosis of recurrent disease. However, the EGTM panel suggests the following approach during the follow-up of asymptomatic women: tumor markers should be determined every 2–4 months (according to the risk of recurrence) during the initial 5 years after diagnosis, then every 6 months during the next 3 years and at yearly intervals thereafter (i,iv,[xviii]).
·     Therapy monitoring: Biochemical changes often precede clinical or radiological signs of response or progression, potentially enabling earlier treatment decisions regarding continuation of effective therapy, discontinuation of ineffective therapy, change of therapy or more effective palliation (xvii,[xix],[xx],[xxi],[xxii]).
·     The EGTM recommends that tumor markers in patients treated with chemotherapy should be determined before every chemotherapy course. In patients treated with hormone therapy, they should be measured at least every 3 months.
·     Defining Significant Changes: The EGTM regards an increase in tumor marker concentration of at least a 25% increase over the previous value – with the second value above the reference interval – to be significant. It is recommended that such an increase be confirmed with a second specimen obtained within a month. If the continued increase is confirmed, this provides evidence of progressive disease. Similarly, confirmed decreases in serum levels of more than 50% are consistent with tumor response. The use of markers for monitoring therapy should, where possible, be used in conjunction with patient history, clinical examination and diagnostic imaging.
·     Certain treatments may cause transient increases in serum marker levels, so that increases observed shortly after treatment must always be confirmed (i,xix,[xxiii], ,[xxiv]).
·     Measurement of Serum Markers: Well-documented and relevant IQC and EQA procedures must be in place and should be followed whenever tumor markers are measured. If it is necessary to change method during serial monitoring, this must be undertaken with considerable care.


·     ER and PR should be assayed on all newly diagnosed breast cancer
·     The primary use of ER and PR is for selecting patients for treatment with hormone therapy. Patients with hormone receptor-positive tumors should be treated with some form of endocrine therapy, while receptor-negative patients should receive an alternate form of therapy ([xxv],[xxvi],[xxvii],[xxviii],[xxix]).
·     ER and PR should be measured by immunohistochemistry as recommended by American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP) ([xxx]).
·     HER-2 should be measured on all newly diagnosed breast cancer patients.
·     The primary use of HER2 is for selecting patients with breast cancer for treatment with anti-HER2 therapy (e.g., trastuzumab, lapatinib, pertuzumab or trastuzumab T-DM1).
·     HER2 should be measured as recommended by American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP) ([xxxi])
·     uPA and PAI-1 may be used for determining prognosis, especially in patients with lymph node-negative disease. Patients with low levels of both these proteins are at a relatively low risk of developing recurrent or metastatic disease and, consequently, may be able to avoid the toxic side effects and costs of adjuvant chemotherapy.([xxxii],[xxxiii],[xxxiv],[xxxv],[xxxvi])
·     ELISAs validated for both analytical and clinical performance should be used for determining these proteins. Immunohistochemistry should be used for clinical purposes. ([xxxvii])
·     Oncotype DX may be used to identify which women with early-stage, estrogen-receptor positive and lymph-node-negative breast cancer are more likely to benefit from adding chemotherapy to their hormonal treatment ([xxxviii],[xxxix],[xl]).


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[ii] Bieglmayer C, Szepesi T, Kopp B, Hoffmann G, Petrik W, Guettuoche K, Grundler S, Gregorits M, Strasser M: CA15.3, MCA, CAM26, CAM29 are members of a polymorphic family of mucin-like glycoproteins. Tumor Biol 1991;12:138-148.
[iii] Gion M, Mione R, Leon AE, Lüftner D, Molina R, Possinger K, Robertson JF: CA27.29: a valuable marker for breast cancer management. A confirmatory multicentric study on 603 cases. Eur J Cancer 2001;37:355-363.
[v] Ebeling FG, Stieber P, Untch M, Ángel D, Konecny GE, Schmidt UM, Fateh-Moghadam A, Seidel D: Serum CEA and CA 15.3 as prognostic factors in primary breast cancer. Br J C 2002:86:217-222
[vi] Duffy MJ, Duggan C, Keane R, Hill ADK, McDermott E, Crown J,  O’Higgins N: High preoperative CA 15-3 concentrations predict adverse outcome in node-negative and node-positive breast cancer: a study of 600 patients with histologically confirmed breast cancer. Clin Chem 2004;50:559-563.
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[viii] Molina R, AUge Jm, Farrus B, Zanon G, Pahisa J, Muñoz M, Torne M, Filella X, Escudero JM, Fernandez P, Velasco M.  Prospective Evaluation of Carcinoembryonic Antigen (CEA) and Carbohydrate Antigen 15.3 (CA 15.3) in Patients with Primary Locoregional Breast Cancer. Clin Chem 2011;56:1148-57
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[xii] Molina R, Jo J, Zanon G, Filella X, Farrus B, Munoz M, Latre ML, Pahisa J, Velasco M, Fernandez P, Estape J, Ballesta AM: Utility of C-erbB-2 in tissue and in serum in the early diagnosis of recurrence in breast cancer patients: comparison with carcinoembryonic antigen and CA15.3. Br J Cancer 1996;74:1126-1131.
[xiii] Jager W. The early detection of disseminated (metastasized) breast cancer by serial tumour marker measurements. Eur J Cancer Prev 1993;2 Suppl 3:133-9.
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[xv] Nicolini A, Anselmi L, Michelassi C, Carpi A. Prolonged survival by 'early' salvage treatment of breast cancer patients: a retrospective 6-year study. Br J Cancer 1997;76:1106-11.
[xvi] Chan DW, Beveridge RA, Muss H, Fritsche HA, Hortobagyi G, Theriault R, Kiang D, Kennedy BJ, Eveleigh M: Use of Truquant BR Radioimmunoassay for early detection of breast cancer recurrence in patients with Stage II and Stage III disease. J Clin Oncol 1997; 15: 2322-2328.
[xvii] Molina R, Escudero JM, Muñoz M, Auge JM, Filella X. Circulating levels of HER-2/neu oncoprotein in breast cancer. Clin Chem Lab Med 2012;50:5-21
[xviii] Bast RC, Jr., Ravdin P, Hayes DF, Bates S, Fritsche H, Jr., Jessup JM, et al. 2000 update of recommendations for the use of tumor markers in breast and colorectal cancer: clinical practice guidelines of the American Society of Clinical Oncology. J Clin Oncol 2001;19:1865-78.
[xix] van Dalen A, Heering KJ, Barak V, Peretz T, Cremaschi A, Geroni P, Gion M, Saracchini S, Molina R, Namer M, Stieber P, Sturgeon C, Leonard RCF, Einarsson R: Treatment response in metastatic breast cancer. A multi-centre study comparing UICC criteria and tumor marker changes. Breast 1996;5:82-88.
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[xxi] Duffy MJ. Serum tumor markers in breast cancer: are they of clinical value? Clin Chem 2006;52:345-51.
[xxii] Carney WP, The emerging role of monitoring serum HER-2/neu oncoprotein levels in women with metastatic breast cancer. Laboratory Medicine 2003;34:58-64.
[xxiii] Hayes DF, Kiang DT, Korzum AH, Tondini C, Wood WC, Kufe DW. CA15-3 and CEA spikes during chemotherapy for metastatic breast cancer. Proc Am Soc Clin Oncol 1998;7:38.
[xxiv] Yasasever V, Dincer M, Camlica H, Karaloglu D, Dalay N. Utility of CA 15-3 and CEA in monitoring breast cancer patients with bone metastases: special emphasis on "spiking" phenomena. Clin Biochem 1997;30:53-6.
[xxv] Elledge RM, Green S, Pugh R, Allred DC, Clark GM, Hill J, et al. Estrogen receptor (ER) and progesterone receptor (PgR), by ligandbinding assay compared with ER, PgR and pS2, by immunohistochemistry in predicting response to tamoxifen in metastatic breast cancer: a Southwest Oncology Group Study. Int J Cancer 2000;89:111-7.
[xxvi] Barnes DM, Harris WH, Smith P, Millis RR, Rubens RD. Immunohistochemical determination of oestrogen receptor: comparison of different methods of assessment of staining and correlation with clinical outcome of breast cancer patients. Br J Cancer 1996;74:1445-51.
[xxvii] Pertschuk LP, Feldman JG, Kim YD, Braithwaite L, Schneider F, Braverman AS, Axiotis C. Estrogen receptor immunocytochemistry in paraffin embedded tissues with ER1D5 predicts breast cancer endocrine response more accurately than H222Sp gamma in frozen sections or
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[xxviii] Fisher ER, Anderson S, Dean S, Dabbs D, Fisher B, Siderits R, et al. Solving the dilemma of the immunohistochemical and other methods used for scoring estrogen receptor and progesterone receptor in patients with invasive breast carcinoma. Cancer 2005;103:164-73.
[xxix]Bernard-Marty C, Cardoso F, Piccart MJ. Facts and controversies in systemic treatment of metastatic breast cancer. Oncologist 2004;9:617-32.
[xxx] Hammond E 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;28:2784-95.
[xxxi]  Wolf et al. 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 2007;25:118-45.
[xxxii] Look MP,van Putten WL, Duffy MJ, Harbeck N, Christensen IJ, Thomssen C, et al. Pooled analysis of prognostic impact of urokinase-type plasminogen activator and its inhibitor PAI-1 in 8377 breast cancer patients. J Natl Cancer Inst 2002;94:116-28.
[xxxiii] Janicke F, Prechtl A, Thomssen C, Harbeck N, Meisner C, Untch M, et al. Randomized adjuvant chemotherapy trial in high-risk, lymph nodenegative breast cancer patients identified by urokinase-type plasminogen activator and plasminogen activator inhibitor type 1. J Natl Cancer Inst
[xxxiv] Duffy MJ. Urokinase plasminogen activator and its inhibitor, PAI-1, as prognostic markers in breast cancer: from pilot to level 1 evidence studies. Clin Chem 2002;48:1194-7.
[xxxv] Sweep CG, Geurts-Moespot J, Grebenschikov N, de Witte JH, Heuvel JJ, Schmitt M, et al. External quality assessment of trans-European multicentre antigen determinations (enzyme-linked immunosorbent assay) of urokinase-type plasminogen activator (uPA) and its type 1 inhibitor (PAI-1) in human breast cancer tissue extracts. Br J Cancer1998;78:1434-41.
[xxxvi] Harbeck N, Kates RE, Look MP, Meijer-van Gelder ME, Klijn JG, Kruger A, et al. Enhanced benefit from adjuvant chemotherapy in breast cancer patients classified high-risk according to urokinase-typeplasminogen activator (uPA) and plasminogen activator inhibitor type 1 (n = 3424). Cancer Res 2002;62:4617-22.
[xxxvii] Janicke F, Pache L, Schmitt M, Ulm K, Thomssen C, Prechtl A, Graeff H. Both the cytosols and detergent extracts of breast cancer tissues are suited to evaluate the prognostic impact of the urokinase-type plasminogen activator and its inhibitor, plasminogen activator inhibitor type 1. Cancer Res 1994;54:2527-30.
[xxxviii] Paik S, Shak S, Tang G, Kim C, Baker J, Cronin M, et al. A multi-gene assay to predict recurrence of tamoxifen-treated node-negative breast cancer. N Engl J Med 2005;347:2817-26.
[xxxix] Gianni L, Zambetti M, Clark K, Baker J, Cronin M, Wu J, et al. Gene expression profiles in paraffin-embedded core biopsy tissue predict response to chemotherapy in women with locally advanced breast cancer.J Clin Oncol 2005;23:7265-77.
[xl] Paik S, Tang G, Shak S, Kim C, Baker J, Kim W, et al. Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer. J Clin Oncol 2006;24:3726-34.

Breast Cancer

Clinical use of biomarkers in breast cancer: Updated guidelines from the European Group on Tumor Markers (EGTM)

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