What is the role of biomarkers (biological markers) in diagnosing and managing cancer?

Cancer Biomarkers: Role in Diagnosis and Management

Cancer biomarkers serve three validated clinical purposes: predicting treatment response to specific therapies, assessing prognosis after diagnosis is established, and monitoring disease progression—but they should NOT be used for initial cancer detection or screening in asymptomatic patients. 1

Framework for Understanding Biomarker Utility

The American Society of Clinical Oncology establishes that biomarkers must meet three rigorous criteria before clinical use 1:

• Analytic validity: The test must be accurate, reliable, and reproducible across laboratories 1
• Clinical validity: The biomarker must reliably separate patients into groups with different biological or clinical outcomes 1
• Clinical utility: Using the biomarker must improve patient outcomes (survival, quality of life) compared to not using it 1

Most proposed cancer biomarkers fail at the clinical utility stage—they may correlate with disease but don't change outcomes when used to guide decisions. 1, 2

Validated Clinical Applications by Cancer Type

Breast Cancer (Strongest Evidence Base)

In early-stage breast cancer, specific biomarker assays guide adjuvant chemotherapy decisions and reduce overtreatment: 1

• ER, PR, and HER2 status must be tested on all newly diagnosed breast cancers to direct endocrine and targeted therapy 1
• Oncotype DX, EndoPredict, Prosigna, Breast Cancer Index, or uPA/PAI-1 can identify hormone receptor-positive patients who can safely avoid chemotherapy 1
• Only ONE multi-gene assay should be used per patient; if multiple tests give different results, there is no evidence for which to prioritize 1

In metastatic breast cancer, rebiopsy of accessible metastases should be performed to retest ER, PR, and HER2, as receptor status changes in 10-40% of cases: 1

• When primary and metastatic tissue show discordant results, use the metastatic tissue receptor status to guide therapy 1
• CEA, CA 15-3, and CA 27-29 may be used as adjunctive monitoring tools but never alone to make treatment decisions 1

Lung Cancer

EGFR mutation testing is mandatory in all advanced non-small cell lung cancer (NSCLC) to identify patients who benefit from targeted therapy: 1, 3

• ALK translocation testing should be performed in adenocarcinoma and never-smokers 1
• Blood tumor markers (CEA, CYFRA 21-1, NSE) should NOT be used for diagnosis or screening but may monitor treatment response after diagnosis is established 1, 3
• The American College of Chest Physicians explicitly recommends against surveillance biomarker testing outside clinical trials (Grade 2C) 1, 3

Colorectal Cancer

KRAS and NRAS mutation testing is required before starting anti-EGFR antibody therapy (cetuximab, panitumumab) in metastatic disease: 1

• Patients with KRAS or NRAS mutations will not respond to these agents and should not receive them 1
• Mismatch repair testing (Lynch syndrome) guides treatment decisions and identifies hereditary risk 1

Immunotherapy Across Cancer Types

PD-L1 expression and tumor mutational burden predict response to checkpoint inhibitors, but their clinical utility varies by cancer type and specific drug: 1

• These biomarkers require careful clinical validation for each immunotherapy agent and cancer combination 1
• A subset of patients benefit substantially from immunotherapy, but the majority do not—predictive biomarkers reduce exposure to toxicity in non-responders 1

Critical Limitations and Common Pitfalls

Why Blood Biomarkers Fail for Early Detection

Traditional serum tumor markers lack the sensitivity and specificity for cancer screening or early diagnosis: 3, 2, 4

• CEA is elevated in inflammatory conditions (COPD, smoking), liver disease, and many benign states 3
• CA-125 is elevated in endometriosis, ovarian cysts, and peritoneal inflammation 5
• PSA screening for prostate cancer remains controversial because benefits may not outweigh harms 5

The only blood-based screening test with proven mortality reduction is fecal occult blood testing (FOBT) for colorectal cancer—and this detects blood, not a molecular biomarker. 5

The Emerging Exception: Circulating Cell-Free DNA

Cell-free DNA (cfDNA) can detect cancer recurrence 2-5 months before imaging in 72-93% of cases, but this has only been shown in small studies and does not yet translate to improved survival: 3

• This temporal advantage has not been validated to change clinical outcomes 3
• cfDNA testing remains investigational and should only be used in research protocols 3

Tissue Diagnosis Always Takes Priority

When malignant cells are present in pleural fluid, pericardial fluid, or ascites, cytological examination provides definitive diagnosis with 60-90% sensitivity—blood markers cannot do this: 3

• If pleural effusion is present in suspected lung cancer, thoracentesis with cytology should be performed early as it provides the quickest definitive diagnosis 3
• Blood markers rarely provide the initial diagnostic finding in any cancer 3

Practical Clinical Algorithm

For newly diagnosed cancer patients: 1

1. Test biomarkers that predict response to specific therapies (ER/PR/HER2 in breast cancer, EGFR/ALK in lung cancer, KRAS/NRAS in colorectal cancer) 1
2. Consider prognostic multi-gene assays in early-stage breast cancer to guide chemotherapy decisions 1
3. Do NOT use blood tumor markers for initial diagnosis—prioritize tissue diagnosis through biopsy, cytology, or surgical specimen 3

For monitoring established cancer: 1, 3

1. Serial imaging remains the gold standard for detecting recurrence 1
2. Blood markers (CEA, CA 15-3, CYFRA 21-1) may be used adjunctively to support clinical decisions but never as the sole basis for changing treatment 1, 3
3. Rising tumor markers in an asymptomatic patient with stable imaging does not necessarily indicate treatment failure 1

For metastatic disease: 1

1. Rebiopsy accessible metastases to retest predictive biomarkers, as receptor status changes in a significant proportion of patients 1
2. When primary and metastatic tissue show different receptor status, preferentially use the metastatic tissue results to guide therapy 1

Quality of Life Considerations

Validated health-related quality of life (HRQOL) instruments should be used at baseline and during follow-up in patients who have undergone curative-intent therapy (Grade 2C): 1

• EORTC QLQ-C30 and disease-specific modules can monitor treatment impact on functional status 1
• This is particularly important for patients receiving aggressive treatments like stereotactic body radiation therapy or radical chemoradiation 1