What is cytokeratin 5/6 and what does a positive result indicate in an epidermal growth factor receptor (EGFR)‑positive triple‑negative breast cancer (TNBC)?

What is Cytokeratin 5/6?

Cytokeratin 5/6 (CK5/6) is an immunohistochemical marker that identifies basal/myoepithelial cells in breast tissue and serves as a defining marker for the basal-like subtype of breast cancer. 1

Biological Function and Normal Expression

• In normal breast tissue, CK5/6 is expressed exclusively in the basal/myoepithelial cell layer, while luminal epithelial cells express different cytokeratins (CK 8/18, CK 7, CK 19). 2
• CK5/6 functions as a structural protein within the cytoskeleton of basal epithelial cells and serves as a "fingerprinting" marker for tissue classification. 2

Role in Breast Cancer Classification

• CK5/6 is one of two key markers (along with EGFR) used to distinguish basal-like breast cancer from other triple-negative breast cancers. 3
• A tumor must be both triple-negative (ER−, PR−, HER2−) AND express CK5/6 and/or EGFR to be classified as basal-like; triple-negative status alone is insufficient for this classification. 3, 4
• Approximately 75% of triple-negative breast cancers express basal markers (CK5/6 and/or EGFR), meaning 25% of TNBCs lack these markers and should not be called basal-like. 3, 4

Clinical Significance in EGFR-Positive TNBC

Defining the Basal-Like Subtype

• When a triple-negative breast cancer is both EGFR-positive and CK5/6-positive, it confirms basal-like classification, which represents a distinct biological and clinical entity. 3, 4
• Basal-like tumors demonstrate significantly more aggressive pathological features compared to luminal A tumors, including:
  • Markedly elevated mitotic index (OR = 11.0,95% CI 5.6–21.7) 3, 4
  • Pronounced nuclear pleomorphism (OR = 9.7,95% CI 5.3–18.0) 3, 4
  • Higher combined histologic grade (OR = 8.3,95% CI 4.4–15.6) 3, 4
  • Increased TP53 mutation frequency (approximately 44% versus 15% in luminal A) 3, 4

Prognostic Implications

• CK5/6 expression in TNBC correlates with adverse pathological parameters and poor clinical outcomes. 5, 6
• Basal-like tumors exhibit peak recurrence risk within the first 3 years after diagnosis and sustained elevated mortality for at least 5 years. 3, 4
• In late-stage disease among African-American women, the 5-year survival rate is only approximately 14%. 3
• Research shows that basal marker-positive phenotypes have shorter disease-free intervals compared to basal marker-negative phenotypes. 6

Epidemiological Context

• The incidence of basal-like TNBC is approximately threefold higher in women of African descent compared to other populations. 3
• Among premenopausal African-American women, roughly 40% of breast cancers are basal-like, compared with 15% in postmenopausal women of the same ethnicity. 3

Diagnostic Testing Considerations

When to Test

• CK5/6 testing is required to confirm basal-like classification in a triple-negative tumor, but current guidelines do not mandate routine CK5/6 assessment in standard pathology reports. 3
• Standard pathology reports must include ER, PR, HER2, Ki-67, and histologic grade; basal markers like CK5/6 are not required by NCCN or ESMO guidelines. 3

Interpretation Pitfalls

• Do not assume all triple-negative cancers are basal-like—approximately 25% of TNBCs lack basal marker expression and represent a different biological entity. 3, 4
• Do not use triple-negative status as a surrogate for basal marker expression; direct immunohistochemical confirmation is necessary. 6
• CK5/6 expression shows significant inverse correlation with estrogen and progesterone receptor status and HER2 protein expression. 5

Therapeutic Implications

• Current guidelines do not recommend EGFR-targeted therapy as standard treatment for EGFR-positive/CK5/6-positive TNBC; such approaches should be limited to clinical trial settings. 3
• The absence of effective targeted therapies for basal-like TNBC underscores the importance of identifying this subgroup for appropriate counseling and consideration of clinical trial enrollment. 5
• Standard treatment remains cytotoxic chemotherapy, with pembrolizumab-based regimens showing improved outcomes in the neoadjuvant setting. 7

Technical Aspects

• CK5/6 immunohistochemistry demonstrates cytoplasmic staining in positive cells. 2
• In benign breast lesions, CK5/6 shows strong, diffuse staining in myoepithelial cells; in malignant lesions, positive staining is typically less intense and more focal. 2
• Research indicates variable expression rates across populations, with some South-Asian studies showing only 8% CK5/6 positivity in TNBC, suggesting potential geographic or ethnic variation. 8