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

SERUM TUMOR MARKERS

·     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.

TISSUE MARKERS

·     ER and PR should be assayed on all newly diagnosed breast cancer
patients.
·     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]).

References

Breast Cancer

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