What does a HER2-negative (immunohistochemistry 1+) result indicate?

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Last updated: June 22, 2026 • View editorial policy

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HER2-Negative (IHC 1+) Interpretation

A HER2 IHC 1+ result means the breast cancer is classified as HER2-negative for protein overexpression, but importantly, patients with this result may now be eligible for trastuzumab deruxtecan (T-DXd), a newer HER2-targeted therapy that works at lower levels of HER2 expression. 1

What the Score Means Technically

HER2 IHC 1+ indicates:

  • Incomplete or faint membrane staining in >10% of invasive tumor cells 2
  • The HER2 protein is present at low levels but not overexpressed
  • This is distinct from HER2 IHC 0 (no staining or staining in ≤10% of cells)

Clinical Significance: The Treatment Paradigm Has Changed

Traditional Classification (Still Valid)

  • Both IHC 0 and IHC 1+ are classified as HER2-negative using established ASCO-CAP criteria 1
  • These patients are not eligible for traditional HER2-targeted therapies (trastuzumab, pertuzumab, T-DM1)

New Treatment Opportunity

The DESTINY-Breast04 trial fundamentally changed the landscape:

  • Patients with IHC 1+ (or IHC 2+/ISH non-amplified) showed significant survival improvement with trastuzumab deruxtecan compared to chemotherapy 1
  • This led to FDA approval of T-DXd for this population
  • The term "HER2-low" emerged to describe IHC 1+ and IHC 2+/ISH non-amplified tumors 2

Reporting Standards

Pathology reports should now include:

  1. The traditional HER2 status: "HER2-negative for protein overexpression"
  2. The specific IHC score in parentheses: (1+ staining present) 1
  3. A footnote explaining treatment eligibility for T-DXd 1

This dual reporting is critical because:

  • It maintains consistency with established HER2 classification
  • It identifies patients who may benefit from newer therapies
  • The distinction between IHC 0 and 1+ now has direct therapeutic implications 1

Important Clinical Caveats

Reproducibility Concerns

The IHC 0 versus 1+ threshold can be challenging:

  • Pathologists should examine slides at 40x magnification when discriminating between these scores 1
  • Consider second pathologist review when results are borderline (>10% of cells with incomplete membrane staining that is faint/barely perceptible) 1
  • Studies show substantial but not perfect agreement among pathologists (κ = 0.79 for HER2-low cutoff) 3

Dynamic HER2 Status

  • HER2 status can vary between biopsies during the disease course 4
  • Discordance rates of 26-44% have been observed between primary and metastatic sites 4
  • For patients with metastatic disease initially scored as IHC 0, repeat biopsies may identify HER2-low status, potentially opening treatment options 4
  • Approximately one-third of patients show HER2-low status with each additional successive biopsy 4

Not a Distinct Biological Entity

Despite the clinical importance:

  • HER2-low tumors are not a distinct molecular subtype 2
  • After correcting for hormone receptor status, minimal biological differences exist between IHC 0 and IHC 1+ tumors 2, 5
  • The biology is primarily driven by hormone receptor expression, not the low-level HER2 2

Practical Algorithm for Clinicians

For patients with HER2 IHC 1+ breast cancer:

  1. Confirm the specific IHC score is documented (not just "HER2-negative")
  2. In metastatic disease after prior therapy: Consider trastuzumab deruxtecan eligibility
  3. If initially scored as IHC 0 in metastatic setting: Consider repeat biopsy, as approximately 30% may show HER2-low on subsequent testing 4
  4. Review prior biopsies: Check if any previous samples showed IHC 1+ or 2+/ISH non-amplified 1
  5. For equivocal cases: Request pathology review or consider testing at a reference laboratory with HER2-low expertise 1

The key message: HER2 IHC 1+ is technically HER2-negative but clinically actionable in the era of antibody-drug conjugates like trastuzumab deruxtecan.

References

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Professional Medical Disclaimer

This information is intended for healthcare professionals. Any medical decision-making should rely on clinical judgment and independently verified information. The content provided herein does not replace professional discretion and should be considered supplementary to established clinical guidelines. Healthcare providers should verify all information against primary literature and current practice standards before application in patient care. Dr.Oracle assumes no liability for clinical decisions based on this content.