What are some common breast cancer markers, such as Carbohydrate Antigen (CA) 15-3 and Human Epidermal growth factor Receptor 2 (HER2), and how do they relate to prognosis and survival?

Breast Cancer Markers: Definitions and Prognostic Significance

CA 15-3 (Carbohydrate Antigen 15-3)

CA 15-3 is the reference standard serum tumor marker for breast cancer, primarily used for monitoring treatment response in metastatic disease—not for screening or diagnosis. 1

What CA 15-3 Measures

• CA 15-3 is a mucin glycoprotein epitope shed into the bloodstream by breast cancer cells 1
• Normal reference range: <30 units/L 2
• Elevated levels correlate with disease stage and tumor burden 1

Prognostic Significance and Survival Impact

Preoperative CA 15-3 >30 units/L predicts significantly shorter overall survival, independent of tumor size, lymph node status, and patient age. 2

• High preoperative CA 15-3 (>50 kU/L) indicates advanced disease and necessitates immediate metastatic workup before treatment planning 1
• Patients with initially elevated CA 15-3 that remains high despite treatment have treatment failure and very poor prognosis 1
• CA 15-3 predicts adverse outcome in both node-negative and node-positive disease, regardless of ER status, age, or adjuvant therapy type 2

Critical Clinical Applications

Use CA 15-3 for monitoring treatment response in metastatic breast cancer alongside clinical examination and imaging—never as the sole criterion for therapy changes. 3

• CA 15-3 detects metastatic recurrence 5-6 months before clinical symptoms with Level A evidence 1
• However, early detection of metastases does not improve overall survival or quality of life 1, 3
• In patients without measurable disease on imaging, rising CA 15-3 indicates treatment failure and prompts therapy modification 3
• Sensitivity for detecting primary breast cancer is only 31%, making it unsuitable for screening 3

Technical Requirements

• All measurements must be performed in the same laboratory using identical assay techniques, as results vary significantly between methods 1, 3
• Establish baseline pretreatment CA 15-3 as the reference value for future comparisons 1

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HER2 (Human Epidermal Growth Factor Receptor 2)

HER2 is a tissue-based prognostic and predictive marker that determines eligibility for trastuzumab therapy and predicts treatment response in breast cancer. 4, 5

What HER2 Measures

• HER2 is a transmembrane tyrosine kinase receptor encoded by the HER2 (c-erbB-2) oncogene 6, 5
• Overexpression occurs in approximately 20-30% of breast cancers 4
• Testing performed on tumor tissue via immunohistochemistry (IHC) scored as 0,1+, 2+, or 3+, with FISH confirmation for 2+ cases 4

Prognostic and Predictive Significance

HER2 3+ or FISH-positive tumors treated with trastuzumab plus chemotherapy show significantly longer time to progression (7.2 vs 4.5 months), higher response rates (45% vs 29%), and improved overall survival (25.1 vs 20.3 months) compared to chemotherapy alone. 4

• HER2 overexpression without treatment indicates aggressive disease and poor prognosis 5
• Treatment benefits are largely limited to patients with highest HER2 expression (3+ by IHC or FISH-positive) 4
• In HER2 3+ patients, trastuzumab reduces risk of disease progression by 58% (relative risk 0.42) and mortality by 30% (relative risk 0.70) 4
• HER2 2+ patients without FISH amplification show minimal benefit from trastuzumab (relative risk for progression 0.76) 4

Serum HER2 (Soluble HER2)

• The extracellular domain of HER2 can be shed into blood and measured as a serum marker 6, 7
• Serum HER2 is elevated in 52.7% of patients with metastatic breast cancer 6
• Serum HER2 shows no difference between healthy individuals and localized breast cancer patients, limiting its utility for early detection 6
• Combining serum HER2 with CA 15-3 increases sensitivity to 90% for detecting metastatic disease 6
• Serum HER2 may be useful for detecting recurrence and monitoring disease progression 6, 7

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CEA (Carcinoembryonic Antigen)

CEA is a secondary serum marker for breast cancer, less sensitive than CA 15-3, used as an alternative when CA 15-3 remains normal despite clinical progression. 1, 8

Clinical Utility

• CEA is elevated in 31.8% of patients with recurrent or advanced breast cancer 7
• CA 15-3 is superior to CEA for breast cancer monitoring 1, 8
• Use CEA only when CA 15-3 remains normal but clinical disease progression is evident 1
• Do not routinely combine CEA with CA 15-3, as this increases cost without improving clinical decision-making 1, 3

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Other Markers Under Evaluation

Alternative Mucin Glycoproteins

• CA 27.29, CA 549, CA M26, and CA M29 are alternative markers to CA 15-3 1, 8
• None have been shown superior to CA 15-3 1
• These may be used instead of CA 15-3, but never in combination 1

Tissue-Based Markers

• Estrogen receptor (ER) and progesterone receptor (PR) are essential for determining hormonal therapy eligibility 5
• BRCA1 and BRCA2 genes identify patients at high risk for hereditary breast cancer 5
• Urokinase plasminogen activator and inhibitor assess prognosis in lymph node-negative patients 5

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Critical Pitfalls to Avoid

• Never use CA 15-3 for screening or diagnosis due to low sensitivity (31%) in early disease 3
• Never use tumor markers as the sole criterion for changing therapy—always correlate with clinical and radiographic findings 3
• Do not order multiple tumor markers simultaneously, as this does not improve clinical outcomes 1, 3
• Early detection of metastases via CA 15-3 does not improve survival or quality of life, so routine surveillance after curative treatment is not recommended 1, 3