In a patient with triple‑negative breast cancer (ER‑negative, PR‑negative, HER2‑negative) that is EGFR‑positive on immunohistochemistry, what does this indicate and how should it affect treatment?

EGFR-Positive Triple-Negative Breast Cancer: Clinical Significance and Treatment Implications

EGFR positivity in triple-negative breast cancer identifies a basal-like subtype with more aggressive behavior and poorer prognosis, but current guidelines do not recommend routine EGFR testing or EGFR-targeted therapy as standard treatment outside of clinical trials. 1

What EGFR Positivity Indicates

Basal-Like Subtype Classification

• EGFR expression (along with cytokeratin 5/6) defines the basal-like subtype within triple-negative breast cancer, which accounts for approximately 75% of TNBC cases. 2
• The remaining 25% of triple-negative tumors lack basal marker expression and should not be classified as basal-like, making EGFR testing useful for subtype distinction. 2
• EGFR positivity correlates strongly with CK5/6 expression, and either marker can reliably identify basal-like tumors. 3

Prognostic Implications

• EGFR-positive TNBC demonstrates significantly worse outcomes, including:
  • Poor overall survival (OS) and disease-free survival (DFS) 4
  • Higher rates of axillary lymph node metastasis 4
  • Increased risk of distant metastases 5
  • Higher tumor grade 4, 6
• EGFR expression is associated with unfavorable response to neoadjuvant chemotherapy. 4
• High intratumoral EGFR expression levels correlate with both nodal and distant metastatic disease in basal-like TNBC. 5

Pathological Characteristics

• EGFR-positive basal-like TNBC exhibits markedly elevated mitotic index (OR 11.0), pronounced nuclear pleomorphism (OR 9.7), and higher combined histologic grade (OR 8.3) compared to luminal A tumors. 2
• TP53 mutations occur in approximately 44% of basal-like tumors versus 15% in luminal A tumors. 2
• Tumor necrosis is significantly associated with basal marker (EGFR/CK5/6) expression. 7

How This Should Affect Treatment

Standard Treatment Approach

• Despite EGFR positivity, current ESMO and NCCN guidelines do not include EGFR status in routine pathological assessment requirements for breast cancer. 1
• The standard pathological report should include ER, PR, HER2, Ki-67, and histologic grade, but EGFR is not mandated. 1
• Cytotoxic chemotherapy remains the standard treatment for TNBC regardless of EGFR status, as effective endocrine or HER2-directed therapies are absent. 2

Potential for EGFR-Targeted Therapy

• EGFR-targeted therapy may be a promising option for TNBC patients with chemotherapy resistance, but this remains investigational. 4
• Multiple studies suggest EGFR-targeted therapeutic strategies could potentially benefit TNBC patients given the high frequency of EGFR expression (51-86% of cases). 3, 6, 7
• However, EGFR-targeted therapy is not currently recommended as standard treatment and should only be considered within clinical trial settings.

Risk Stratification

• EGFR positivity identifies patients at higher risk for:
  • Chemotherapy resistance 4
  • Early recurrence (peak within first 3 years) 2
  • Nodal and distant metastases 5
• These patients warrant closer surveillance and consideration for clinical trial enrollment.

Common Pitfalls to Avoid

• Do not assume all triple-negative tumors are basal-like: approximately 25% lack EGFR/CK5/6 expression and have different biological behavior. 2, 7
• Do not use EGFR status alone to withhold standard chemotherapy: despite poor prognostic implications, chemotherapy remains the backbone of treatment. 2
• Do not prescribe EGFR-targeted therapy outside clinical trials: while biologically rational, efficacy data are insufficient to support routine use. 4, 6
• EGFR positivity should not be conflated with treatment eligibility for EGFR inhibitors used in other cancers—breast cancer EGFR biology differs from lung cancer. 4

Practical Clinical Algorithm

1. Confirm triple-negative status (ER-negative, PR-negative, HER2-negative) per standard guidelines. 1
2. Consider EGFR/CK5/6 testing if available to identify basal-like subtype for prognostic information. 2, 3
3. Proceed with standard chemotherapy regardless of EGFR status. 2
4. Counsel patients with EGFR-positive tumors about higher recurrence risk and need for vigilant follow-up. 4, 5
5. Evaluate eligibility for clinical trials investigating EGFR-targeted agents, particularly if chemotherapy-resistant disease develops. 4, 6