Can triple‑negative breast cancer that is HER2‑low or HER2‑ultra‑low be treated with trastuzumab‑deruxtecan (Enhertu)?

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Last updated: March 8, 2026 • View editorial policy

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Yes, triple-negative breast cancer (TNBC) with HER2-low or HER2-ultralow expression can receive Enhertu (trastuzumab deruxtecan).

The FDA has approved Enhertu for HER2-low breast cancer (IHC 1+ or IHC 2+/ISH-negative) and HER2-ultralow breast cancer (IHC 0 with membrane staining in >0% to ≤10% of tumor cells) in the metastatic setting, regardless of hormone receptor status 1.

Key Eligibility Criteria

For TNBC patients to receive Enhertu, they must meet these specific requirements:

  • HER2 status: Must be HER2-low (IHC 1+ or IHC 2+/ISH-) OR HER2-ultralow (IHC 0 with membrane staining)
  • Disease stage: Unresectable or metastatic breast cancer
  • Prior treatment: Must have received prior chemotherapy for metastatic disease, OR disease recurrence during or within 6 months of completing adjuvant chemotherapy 1

Important distinction: Traditional HER2-negative (IHC 0 with completely absent membrane staining, termed "HER2-null") is NOT eligible for Enhertu based on current FDA approval 1.

Clinical Evidence Supporting Use

The DESTINY-Breast04 trial established the efficacy of Enhertu in HER2-low metastatic breast cancer, including TNBC patients 1. The DESTINY-Breast06 trial further demonstrated benefit in both HER2-low and HER2-ultralow populations 1.

In the HER2-ultralow exploratory analysis from DESTINY-Breast06:

  • Median PFS: 15.1 months with Enhertu vs 8.3 months with chemotherapy
  • Confirmed ORR: 65.7% vs 30.8%
  • Median DOR: 14.3 months 1

Critical Testing Requirements

Accurate HER2 testing is essential to distinguish between:

  1. HER2-null (IHC 0, completely absent staining) - NOT eligible
  2. HER2-ultralow (IHC 0+, faint/barely perceptible incomplete membrane staining in >0-10% of cells) - ELIGIBLE
  3. HER2-low (IHC 1+ or IHC 2+/ISH-) - ELIGIBLE

The distinction between HER2-null and HER2-ultralow requires careful pathologic evaluation, as both may be reported as "IHC 0" under older classification systems 2.

Important Clinical Considerations

Dynamic HER2 Status

HER2 expression can change over time and between different tumor sites 3. In patients with TNBC:

  • Approximately one-third of patients without prior HER2-low results demonstrate HER2-low status with each additional biopsy
  • Discordance rates between matched biopsies: 26% (core-surgical), 44% (early-metastatic), 33% (between metastatic sites) 3

Clinical implication: For patients with metastatic HER2-0 TNBC, consider repeat biopsies of metastatic sites to reassess HER2 status, as this may identify new candidates for Enhertu therapy 3, 4.

Treatment Sequencing with Other ADCs

Real-world data comparing Enhertu with sacituzumab govitecan in TNBC shows:

  • In HR-negative/HER2-null TNBC specifically, sacituzumab govitecan-first sequencing showed superior outcomes (TOT: 11.7 vs 7.4 months; OS: 19.7 vs 11.8 months) 5
  • However, this applies only to the HER2-null subset, not HER2-low or HER2-ultralow 5

Serious Safety Warnings

Enhertu carries significant risks that require careful monitoring 1:

  1. Interstitial lung disease/pneumonitis (most serious): Can be severe, life-threatening, or fatal

    • Monitor for cough, dyspnea, fever, new/worsening respiratory symptoms
    • May require corticosteroid treatment

  2. Severe neutropenia: Check white blood cell counts before each dose

    • Monitor for signs of infection, fever, chills

  3. Cardiac toxicity: Check heart function before starting treatment

    • Monitor for dyspnea, cough, fatigue, edema, irregular heartbeat

  4. Embryo-fetal toxicity:

    • Pregnancy testing required before treatment
    • Effective contraception during treatment and for 7 months after last dose (females) or 4 months (males)

Practical Algorithm for TNBC Patients

  1. Confirm metastatic/unresectable disease
  2. Obtain accurate HER2 testing using validated IHC assay (distinguish null vs ultralow vs low)
  3. If HER2-null (IHC 0, absent staining): Enhertu NOT indicated; consider sacituzumab govitecan or other chemotherapy
  4. If HER2-ultralow or HER2-low: Enhertu is an option after prior chemotherapy
  5. If initial testing shows HER2-null but patient progresses: Consider repeat biopsy of metastatic site to reassess HER2 status
  6. Before starting Enhertu: Perform cardiac function testing, pregnancy test if applicable, baseline pulmonary assessment

The key paradigm shift: TNBC is no longer uniformly "HER2-negative" - approximately one-third of TNBC cases express HER2-low or HER2-ultralow levels, making them eligible for Enhertu therapy 6, 1.

References

2
Research

International Expert Consensus Recommendations for HER2 Reporting in Breast Cancer: Focus on HER2-Low and Ultralow Categories.

Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc, 2026

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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.

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