What is the significance of having Human Epidermal growth factor Receptor 2 (HER2) positive status for a breast cancer patient?

HER2-Positive Breast Cancer: Clinical Significance

HER2-positive breast cancer identifies patients who require HER2-targeted therapy with agents like trastuzumab and pertuzumab, which reduce recurrence risk by approximately 50% and mortality by one-third, transforming what was historically an aggressive, poor-prognosis disease into one with dramatically improved survival outcomes. 1

Prognostic Significance

Without HER2-targeted treatment, HER2-positive status indicates worse prognosis:

• HER2 amplification occurs in approximately 15-20% of breast cancers and is associated with higher rates of recurrence and mortality in untreated patients 1, 2
• The HER2 gene encodes a 185-kd glycoprotein with tyrosine kinase activity that drives tumor proliferation, migration, and invasion 1
• When amplified, HER2 receptor levels increase from normal (25,000-185,000 receptors per cell) to pathologic levels (500,000-2,000 receptors per cell), creating constitutive activation of growth-promoting signaling pathways 2

Predictive Significance for Therapy Selection

HER2 status is the critical determinant for multiple treatment decisions:

HER2-Targeted Therapy Eligibility

• Trastuzumab (Herceptin) improves response rates, time to progression, and overall survival when used alone or with chemotherapy in metastatic disease 1
• Five international randomized trials demonstrated that adjuvant trastuzumab reduces recurrence risk by one-half and mortality by one-third in early-stage disease 1
• Pertuzumab combined with trastuzumab and taxane represents the preferred first-line therapy for metastatic HER2-positive disease 3, 4
• Trastuzumab deruxtecan has emerged as preferred second-line therapy after progression on trastuzumab and taxane 4

Chemotherapy Selection

• HER2 positivity predicts enhanced response to anthracycline-containing regimens, though this may be secondary to coamplification with topoisomerase II (the direct target of anthracyclines) 1
• HER2-positive tumors show relative (but not absolute) lower benefit from non-anthracycline, non-taxane chemotherapy regimens 1
• Preliminary data suggest HER2 may predict response to paclitaxel in metastatic or adjuvant settings 1

Endocrine Therapy Considerations

• HER2 positivity confers relative resistance to endocrine therapies, particularly selective estrogen receptor modulators like tamoxifen 1, 5
• In ER-positive/HER2-positive tumors, the relative benefit from antiestrogens is lower than in HER2-negative cancers, though not absolute resistance 1
• The evidence regarding aromatase inhibitors is less clear—they may not show the same degree of reduced benefit in HER2-positive disease 1

Testing Implications

Accurate HER2 determination is essential because it directly determines eligibility for life-saving targeted therapies:

• HER2 testing should be performed in CAP-accredited laboratories demonstrating 95% concordance with validated assays 6, 5
• Two primary methods exist: immunohistochemistry (IHC) detects protein overexpression, while fluorescence in situ hybridization (FISH) detects gene amplification 2, 5
• IHC 3+ (uniform intense complete membrane staining in >30% of invasive tumor cells) defines HER2-positive disease without requiring confirmatory FISH 6
• Testing must be performed on invasive cancer components, not in situ disease 6

Common Pitfalls to Avoid

Several critical testing and interpretation issues can lead to inappropriate treatment decisions:

• Circulating HER2 extracellular domain (serum HER2) is NOT recommended for clinical decision-making in any setting, despite its association with worse outcomes 1
• A small fraction of metastatic lesions show discordant HER2 status compared to the primary tumor—consider retesting metastatic tissue if HER2 status will guide therapy selection 1
• Suboptimal assay performance and interpretation remains a source of testing inaccuracy—the 2007 ASCO/CAP guidelines were developed specifically to reduce interlaboratory variability 1
• HER2 testing in early trials used specific antibodies (4D5 and CB11) with defined scoring criteria—ensure your laboratory uses validated, standardized methods 1

Treatment Sequencing in Metastatic Disease

The current evidence-based treatment algorithm for HER2-positive metastatic breast cancer:

• First-line: Trastuzumab + pertuzumab + taxane (THP) for most patients 4, 7, 8
• Second-line: Trastuzumab deruxtecan (T-DXd) is now preferred based on DESTINY-BREAST03 showing superior progression-free survival versus trastuzumab emtansine 4
• Third-line and beyond: Tucatinib + trastuzumab + capecitabine, trastuzumab emtansine (if not used second-line), or neratinib + capecitabine 4, 7, 8
• Brain metastases: Tucatinib-based combination represents a suitable option given CNS penetration 4, 8

Special Populations

Treatment modifications based on prior therapy exposure:

• Patients relapsing ≤6 months after completing adjuvant therapy, or ≤12 months after pertuzumab-based adjuvant treatment, should receive trastuzumab deruxtecan as first-line therapy for metastatic disease 4
• Patients relapsing 6-12 months after non-pertuzumab-based adjuvant treatment should receive first-line THP 4
• In hormone receptor-positive/HER2-positive disease, chemo-free anti-HER2 strategies (endocrine therapy + HER2-targeted agents) may be considered in selected patients, though this remains investigational 7