Treatment of HER2 1+ Breast Cancer
HER2 1+ breast cancer is classified as HER2-negative and should NOT be treated with traditional HER2-targeted therapies (trastuzumab, pertuzumab, T-DM1) in the early-stage setting; however, trastuzumab deruxtecan is an effective option for metastatic HER2 1+ disease after at least one line of chemotherapy. 1
Understanding HER2 1+ Classification
HER2 1+ is defined by the American Society of Clinical Oncology (ASCO) as incomplete membrane staining that is faint/barely perceptible in ≥10% of tumor cells by immunohistochemistry (IHC), and this is classified as HER2-negative disease. 1
Critical Terminology Clarification
- The term "HER2-Low" (which includes HER2 1+ and HER2 2+/ISH non-amplified) was created specifically for clinical trial eligibility and does not represent 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
- 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
Treatment Approach by Disease Stage
Early-Stage HER2 1+ Disease
Do not use traditional HER2-targeted therapies (trastuzumab, pertuzumab, T-DM1) for HER2 1+ disease in the early-stage setting, as these agents were optimized to detect overexpression/amplification and have not demonstrated benefit in this population. 1
For ER/PR-Positive, HER2 1+ Disease:
- Use standard chemotherapy regimens appropriate for hormone receptor-positive disease followed by endocrine therapy. 1
- Consider genomic assays (Oncotype DX, MammaPrint) to guide adjuvant chemotherapy decisions. 2
- For postmenopausal women, aromatase inhibitors are recommended as first-line endocrine therapy. 2
For Triple-Negative, HER2 1+ Disease:
- Use standard chemotherapy regimens appropriate for triple-negative breast cancer. 1
- Treatment should follow triple-negative breast cancer guidelines without HER2-directed therapy. 1
Metastatic HER2 1+ Disease
Trastuzumab deruxtecan (T-DXd) is the only currently available HER2-directed therapy for HER2 1+ metastatic disease and represents a paradigm shift in treatment. 1
Eligibility Criteria for Trastuzumab Deruxtecan:
- Metastatic disease setting (not early-stage). 1
- Prior treatment with at least one line of chemotherapy for metastatic disease. 1
- IHC 1+ or 2+/ISH non-amplified result confirmed by pathology. 1
Treatment Sequencing for Metastatic Disease:
First-line therapy:
- For ER/PR-positive, HER2 1+ disease: Standard chemotherapy or endocrine therapy based on disease burden and hormone receptor status. 1, 3
- For triple-negative, HER2 1+ disease: Standard chemotherapy regimens for triple-negative breast cancer. 1
Second-line and beyond:
- After progression on at least one line of chemotherapy, trastuzumab deruxtecan should be offered based on the DESTINY-Breast04 trial, which demonstrated significant benefit in HER2-Low metastatic breast cancer. 1
Testing and Retesting Considerations
When to Consider Retesting:
ASCO and the College of American Pathologists (CAP) recommend considering retesting of metastatic sites if: 1
- The patient previously tested HER2-negative in the primary tumor
- Disease behavior is suggestive of HER2-positive or triple-negative disease
- There is clinical suspicion of receptor conversion
Technical Considerations:
HER2 IHC at low expression levels (0 vs 1+) is subject to: 1
- Preanalytic factors during tissue processing
- Semi-quantitative assay limitations
- Significant inter-observer variability
Common Pitfalls to Avoid
Do not use traditional HER2-targeted therapies (trastuzumab, pertuzumab, T-DM1) for HER2 1+ disease outside of clinical trials in the early-stage setting. 1
Do not assume HER2 1+ is a stable result across different tumor samples or time points; consider retesting metastatic sites given the 40% discordance rate. 1
Do not confuse "HER2-Low" terminology with a distinct biological subtype requiring different early-stage treatment; it is simply a trial eligibility criterion for newer antibody-drug conjugates. 1
Do not overlook trastuzumab deruxtecan as an option in metastatic disease after progression on standard chemotherapy, as this represents the only currently available HER2-directed therapy for HER2 1+ disease. 1
Do not fail to clearly document whether the result is IHC 0 versus IHC 1+ in pathology reports, as this distinction is critical for treatment eligibility. 1