What is the treatment approach for a patient with a HER2 (Human Epidermal growth factor Receptor 2) 1+ result?

HER2 1+ Breast Cancer: Treatment Approach

HER2 1+ breast cancer is classified as HER2-negative and does not qualify for traditional HER2-targeted therapies like trastuzumab, pertuzumab, or T-DM1 in the early-stage or standard metastatic setting. 1

Classification and Terminology

• HER2 1+ by IHC is officially classified as HER2-negative according to ASCO-CAP guidelines, defined as incomplete membrane staining that is faint/barely perceptible in ≥10% of tumor cells 1

• The term "HER2-Low" (encompassing IHC 1+ or IHC 2+/ISH non-amplified) was created as shorthand for clinical trial eligibility, not because it represents a distinct biological subtype with unique prognostic implications 1

• HER2 1+ status is unstable, with close to 40% of cases switching between IHC 0 and IHC 1+ when comparing paired primary and metastatic samples 1

Treatment Recommendations by Disease Stage

Early-Stage Disease (Adjuvant/Neoadjuvant Setting)

• Do not use traditional HER2-targeted therapies (trastuzumab, pertuzumab, T-DM1, neratinib) for HER2 1+ disease in the early-stage setting 1

• Treat according to hormone receptor status:

  • If ER/PR-positive: Use standard chemotherapy regimens (if indicated by tumor size, grade, nodal status) followed by endocrine therapy 1
  • If triple-negative (ER/PR/HER2-negative): Use standard chemotherapy regimens appropriate for triple-negative breast cancer 1

Metastatic Disease Setting

• For metastatic HER2 1+ disease, trastuzumab deruxtecan is now an option based on the DESTINY-Breast04 trial, which showed benefit in patients with HER2-Low (IHC 1+ or 2+/ISH non-amplified) metastatic breast cancer 1

• Trastuzumab deruxtecan eligibility requires:

  • Metastatic disease setting 1
  • Prior treatment with at least one line of chemotherapy 1
  • IHC 1+ or 2+/ISH non-amplified result 1

• Important caveat: Emerging data from the DAISY trial suggest IHC 0 and HER2-Low cancers may have similar responses to trastuzumab deruxtecan, though this requires confirmation 1

Critical Testing and Reporting Considerations

• Pathologists must clearly distinguish IHC 0 from IHC 1+ in their reports, as this distinction determines eligibility for trastuzumab deruxtecan in the metastatic setting 1

• Consider retesting metastatic sites if the patient previously tested HER2-negative in the primary tumor but presents with disease behavior suggestive of HER2-positive or triple-negative disease 1

• Be aware of testing variability: HER2 IHC at low expression levels (0 vs 1+) is subject to preanalytic factors during tissue processing and semi-quantitative assay limitations 1

Common Pitfalls to Avoid

• Do not use traditional HER2-targeted therapies (trastuzumab, pertuzumab) for HER2 1+ disease outside of clinical trials, as these were optimized to detect overexpression/amplification 1

• Do not assume HER2 1+ is a stable result across different tumor samples or time points; consider retesting metastatic sites 1

• Do not confuse "HER2-Low" terminology with a distinct biological subtype; it is simply a trial eligibility criterion for newer antibody-drug conjugates 1

• In metastatic disease, do not overlook trastuzumab deruxtecan as an option after progression on standard chemotherapy, as this represents the only currently available HER2-directed therapy for HER2 1+ disease 1