Breast cancers with immunohistochemical (IHC) analysis score of 1+ or 2+ with negative results on in situ hybridization (ISH) studies are defined as HER2-low.
Agents with efficacy in HER2 – low metastatic breast cancer, include trastuzumab-deruxtecan an ADC agent, and Sacituzumab govitecan also an ADC agent.
HER2-low breast cancer is a subtype that has become clinically important following recent treatment advances.
HER2(ERBB@) human epidermal growth factor receptor 2) expression is scored on a scale: 0 = no staining 1+ = faint/incomplete staining 2+ = weak-to-moderate complete staining (requires confirmatory ISH testing) 3+ = strong complete staining → classified as HER2-positive
HER2-low is defined as IHC 1+ or IHC 2+ with a negative ISH test.
These tumors were previously lumped with “HER2-negative” and treated accordingly.
HER2-low cancers account for roughly 50–60% of all breast cancers, spanning both HR-positive and triple-negative subtypes.
The distinction was largely ignored until antibody-drug conjugates (ADCs) proved active in this group.
ERBB2-low is not a distinct molecular subtype in the traditional sense — these tumors behave more like their HR+/HR− counterparts than like HER2-positive disease.
The low HER2 expression appears to be sufficient for ADC drug delivery rather than driving tumor biology directly.
Reproducibility of HER2 scoring between pathologists at the 0 vs 1+ threshold is imperfect.
The landmark DESTINY-Breast04 trial (2022) changed practice dramatically. Trastuzumab deruxtecan (T-DXd / Enhertu) showed major progression-free and overall survival benefits over standard chemotherapy in previously treated HER2-low metastatic breast cancer — leading to FDA approval and a new treatment category.
Among all patients, T-DXd demonstrated a median PFS of 9.9 months vs. 5.1 months with physician’s choice chemotherapy and median OS of 23.4 months vs. 16.8 months.
Long-term follow-up at 32 months confirmed sustained OS benefit.
DESTINY-Breast06 (DB-06) extended the benefit to an earlier line of therapy HR-positive patients who had progressed on endocrine therapy but had not yet received chemotherapy for metastatic disease.
In the HER2-low population, median PFS was 13.2 months vs. 8.1 months with an ORR of 56.5% vs. 32.2%.
Critically, this trial also included HER2-ultralow patients, who showed similar benefit (median PFS 13.2 vs. 8.3 months.
This led to the FDA’s first approval specifying the HER2-ultralow category.
HER2-low is not a distinct molecular subtype in the traditional sense — these tumors behave more like their HR+/HR− counterparts than like HER2-positive disease.
Treatment of HER2-low breast cancer depends on hormone receptor status and line of therapy:
HR-positive, HER2-low metastatic breast cancer:
First-line therapy remains endocrine therapy + CDK4/6 inhibitor (aromatase inhibitor + ribociclib preferred, category).
After endocrine therapy progression, T-DXd is now FDA-approved and NCCN-recommended for HR-positive, HER2-low or HER2-ultralow disease that has progressed on prior endocrine therapy.
After prior chemotherapy, T-DXd remains an option based on DB-04 data.
Interstitial lung disease (ILD)/pneumonitis is the most clinically significant adverse event with T-DXd, occurring in approximately 11-12% of patients, with grade 5 (fatal) events in 0.8%.
Regular monitoring is essential, and T-DXd should be used with caution in patients with a history of ILD.
Grade 3 adverse events occurred in approximately 53% of T-DXd-treated patients across trials.
HER2-low status does not currently change the management of early-stage breast cancer, as these tumors are treated according to standard HR-positive or TNBC algorithms.
Investigations into the role of T-DXd in the neoadjuvant/adjuvant setting for HER2-low disease are ongoing.
Dosing: T-DXd is administered at 5.4 mg/kg IV every 21 days until disease progression or unacceptable toxicity.