Could a New Targeted Therapy Extend Progression-Free Survival in HER2-Low Breast Cancer?

Understanding the HER2 Breast Cancer Subtype

HER2 (human epidermal growth factor receptor 2) expression in breast cancer is not simply positive or negative, but rather a spectrum:

• HER2-positive: High HER2 expression (IHC 3+ or IHC 2+/ISH+), approximately 15–20% of all breast cancers, historically treated with HER2-targeted therapies.
• HER2-low: Defined by IHC 1+ or 2+/ISH-, representing a large subset of HR+ breast cancers formerly classified as HER2-negative.
• HER2-ultralow: Tumors with IHC 0 but showing membrane staining, recently recognized as potentially actionable.

About 70% of breast cancers are HR-positive and HER2-negative, many with low-level yet therapeutically relevant HER2 expression. FDA-approved immunohistochemistry (IHC) assays are used to accurately identify patients who may be eligible for targeted ADC therapies.

Hormonal Therapy: The Backbone for HR-Positive Metastatic Breast Cancer

Hormone receptor-positive breast cancer is predominantly treated with hormonal (endocrine) therapy. The 2025 standard of care for HR+/HER2-negative metastatic breast cancer often combines:

• Endocrine therapy (ET): Agents such as aromatase inhibitors or selective estrogen receptor degraders (SERDs) like fulvestrant.
• CDK4/6 inhibitors: Such as ribociclib, which have demonstrated improved outcomes when combined with endocrine therapy by modulating tumor cell proliferation.

Treatment options after progression on initial endocrine therapy and CDK4/6 inhibitors depend on HER2 status and specific tumor characteristics.

FDA-Approved Antibody-Drug Conjugates (ADCs) for HER2-Low Metastatic Breast Cancer

Enhertu (Trastuzumab Deruxtecan)

In January 2025, the FDA approved Enhertu (fam-trastuzumab deruxtecan-nxki) for adults with unresectable or metastatic HR-positive breast cancer with HER2-low or HER2-ultralow expression who have experienced disease progression following at least one line of endocrine therapy.

• Mechanism: Enhertu is a HER2-directed ADC, combining a HER2 monoclonal antibody with a topoisomerase I inhibitor payload.
• Clinical Data: In the phase 3 DESTINY-Breast06 trial, Enhertu demonstrated improved progression-free survival compared to chemotherapy:
  • 36% reduction in the risk of disease progression or death.
  • Median progression-free survival (PFS) of 13.2 months versus 8.1 months with chemotherapy.
  • Overall response rate (ORR) of 62.6% compared to 34.4% with chemotherapy.
• Eligibility:
  • Adult patients with HR-positive, HER2-low (IHC 1+ or 2+/ISH-) or HER2-ultralow (IHC 0 with membrane staining) breast cancer.
  • Disease progression after at least one line of endocrine therapy in the metastatic setting.
  • Chemotherapy-naïve in the metastatic setting.
• Safety Profile:
  • Main risks include interstitial lung disease (ILD) reported in 11.3% of patients (including some fatal cases), nausea, fatigue, and myelosuppression.
  • Management includes careful monitoring and timely intervention for ILD.

Datopotamab Deruxtecan (Dato-DXd)

Also FDA-approved in 2025, Datopotamab deruxtecan is indicated for adults with unresectable or metastatic HR-positive, HER2-negative breast cancer after progression on both endocrine therapy and chemotherapy.

• Reported median progression-free survival was 6.9 months versus 4.9 months with chemotherapy.
• Recommended dosage: 6 mg/kg intravenous infusion every 3 weeks until disease progression or unacceptable toxicity.
• Common adverse effects include nausea, stomatitis, fatigue, and myelosuppression.

Immunotherapy Approaches in HR-Positive or HER2+ Breast Cancer

• Immunotherapy with immune checkpoint inhibitors (ICIs) such as PD-1/PD-L1 inhibitors (e.g., pembrolizumab) has established efficacy in some breast cancer subtypes like triple-negative breast cancer (TNBC).
• For HR-positive, HER2-negative or HER2-positive breast cancer, immunotherapy remains investigational as of 2025.
• Early-phase clinical trials are ongoing to evaluate ICIs combined with chemotherapy or CDK4/6 inhibitors in specific HR+ breast cancer populations.
• No PD-(L)1 inhibitor is currently FDA-approved as monotherapy or in combination specifically for HER2-positive metastatic breast cancer.
• Patients interested in immunotherapy options may consider participation in clinical trials where appropriate.

Treatment Recommendations for HER2+ Breast Cancer in 2025

1. HER2 Testing Is Essential

   • Accurate HER2 testing identifies patients who may benefit from targeted ADC therapies such as Enhertu.
   • Central testing indicates that around 85–90% of HR-positive, HER2-negative metastatic breast cancers have some actionable HER2 expression.

2. Hormonal Therapy with CDK4/6 Inhibitors as First-Line Treatment

   • Standard initial treatment in HR+/HER2-negative or HER2-low metastatic breast cancer typically combines endocrine therapy with CDK4/6 inhibitors.
   • Upon progression, treatment options should be reassessed based on HER2 status and prior therapy.

3. Enhertu as a Next-Line Option for Eligible Patients

   • Enhertu is indicated for patients with HER2-low or ultralow breast cancer who have progressed on endocrine therapy and have not received chemotherapy for metastatic disease.
   • Clinical trial data support improved progression-free survival and response rates compared to chemotherapy.
   • Detailed patient education about the risk profile, including ILD, is important.

4. Datopotamab Deruxtecan for Subsequent Lines of Therapy

   • An additional ADC option may be considered after progression on both endocrine therapy and chemotherapy in HR+/HER2− breast cancer.

5. Immunotherapy Primarily Within Clinical Trials

   • Current evidence supports immunotherapy for HER2+ breast cancer only within research settings.
   • Clinicians should inform patients about ongoing trials exploring these approaches.

6. Personalized Care and Multidisciplinary Management

   • Treatment should be individualized considering HER2 status, previous treatments, coexisting conditions, patient preferences, and functional status.
   • Multidisciplinary teams can support optimal therapy sequencing and side effect management.

Cost and Accessibility Considerations

• ADC therapies such as Enhertu and datopotamab deruxtecan are associated with substantial treatment costs.
• Insurance coverage varies, often requiring prior authorization processes.
• Financial assistance programs are available through manufacturers AstraZeneca and Daiichi Sankyo.
• Infusions are commonly administered every 3 weeks in outpatient oncology centers.
• Accurate HER2 testing helps ensure therapy is targeted to appropriate patients, supporting cost-effective use.

Ongoing Research and Future Directions

• Clinical trials are ongoing internationally to investigate:
  • Combination regimens of ADCs with immunotherapy.
  • Earlier treatment use of ADCs.
  • New hormonal agents and SERDs for HR+ breast cancer.
• Research in biomarker identification, such as tumor immune infiltration and PD-L1 expression, aims to expand immunotherapy applicability.
• The goal of future treatments continues to be improving survival and quality of life while minimizing adverse effects.

Sources

• Oncology Drugs Approved by the FDA in January 2025
• AstraZeneca Press Release: Enhertu Approved in US for Breast Cancer Post-Endocrine Therapy
• Nature Article: Immunotherapy for Hormone Receptor–Positive HER2-Negative Breast Cancer (2024)

Disclaimer: All content, including text, graphics, images and information, contained on or available through this web site is for general information purposes only. The information and materials contained in these pages and the terms, conditions and descriptions that appear, are subject to change without notice.