Treatments for HER2-Positive Metastatic Breast Cancer and Hormonal Therapy in 2025

New HER2-targeted therapies now extend survival beyond chemotherapy for metastatic breast cancer. This guide explains how Enhertu and advanced hormonal treatments offer personalized options to improve outcomes for patients with HER2-low and hormone receptor-positive disease.

Understanding the HER2 Breast Cancer Subtype and Treatment Considerations

HER2 is a protein receptor on breast cancer cells involved in tumor growth. Breast cancers are often categorized by HER2 status:

HER2-positive: High expression (IHC 3+ or 2+/ISH+), comprising about 15-20% of cases, often treated with HER2-targeted therapies.
HER2-low: Lower expression levels (IHC 1+ or 2+/ISH-).
HER2-ultralow: Very faint or no detectable HER2 by standard tests (IHC 0 with membrane staining).

HER2-low and HER2-ultralow are recognized as distinct categories relevant to treatment decisions, especially for hormone receptor (HR)-positive metastatic breast cancer, which accounts for approximately 70% of breast cancer cases. FDA-approved immunohistochemistry (IHC) testing is essential in accurately identifying these subtypes to guide therapy selection.

Information About Enhertu for HER2-Low Metastatic Breast Cancer

In 2025, the FDA approved Enhertu (trastuzumab deruxtecan) for adults with unresectable or metastatic HR-positive, HER2-low or HER2-ultralow breast cancer after progression on one or more endocrine therapies. Clinical studies have shown that Enhertu offers different outcomes compared to chemotherapy.

Clinical Findings from the DESTINY-Breast06 Trial

Median Progression-Free Survival (PFS): Reported as 13.2 months with Enhertu compared to 8.1 months with chemotherapy.
Objective Response Rate (ORR): Reported as 62.6% with Enhertu compared to 34.4% with chemotherapy.
Population: Chemotherapy-naïve patients with HR-positive metastatic breast cancer expressing HER2-low or HER2-ultralow levels.
Safety Profile: Observed side effects were manageable with no new safety concerns identified.

Enhertu combines a HER2 antibody with a cytotoxic agent designed to target cancer cells selectively, aiming to limit effects on normal tissues. This therapy is approved globally for multiple breast cancer indications, including HER2-positive metastatic disease after prior anti-HER2 therapy and HER2-low disease following prior systemic therapy.

Hormonal Therapy as a Treatment Approach for Hormone Receptor-Positive Breast Cancer

Hormonal (endocrine) therapy continues to be a central treatment for hormone receptor-positive (HR+) breast cancer, accounting for about two-thirds of cases. These therapies function by lowering estrogen levels or blocking estrogen receptors to slow tumor growth.

Hormonal Therapies Commonly Used in 2025

Selective Estrogen Receptor Modulators (SERMs):
Tamoxifen: Used in pre- and postmenopausal women to block estrogen receptors.
Toremifene: Similar to tamoxifen, used less frequently.
Selective Estrogen Receptor Degraders (SERDs):
Fulvestrant (injection): Degrades estrogen receptors, used particularly in advanced or metastatic disease following resistance to other endocrine therapies.
Elacestrant (oral): Newer oral SERD approved for advanced cases, including those with ESR1 mutations.
Aromatase Inhibitors (AIs):
Letrozole, anastrozole, exemestane: Reduce estrogen production post-menopause and combined with ovarian suppression in premenopausal women.
Ovarian Suppression:
Achieved through surgery, radiation, or medications (LHRH agonists like goserelin) to decrease ovarian estrogen production in premenopausal women.

Treatment Duration and Use

Hormonal therapies are usually prescribed for at least 5 years, with some patients continuing for up to 10 years depending on recurrence risk.
In metastatic cases, treatments typically continue while clinical benefit is observed.
Combination approaches, such as SERDs or AIs with ovarian suppression in premenopausal women, are used to enhance effectiveness.

Integrating HER2-Directed Therapies and Hormonal Therapy in Clinical Settings

The designation of HER2-low and ultralow breast cancer as targetable subtypes supports biomarker-driven treatment decisions. Key approaches include:

HER2 Testing:Reassessment of HER2 status at metastatic diagnosis or progression using FDA-approved IHC and ISH tests is important to determine suitability for Enhertu.
Treatment Sequencing:After progression on endocrine therapy, patients with HR-positive, HER2-low or ultralow metastatic breast cancer may consider Enhertu as an alternative to chemotherapy.
Combination Approaches:Immunotherapy combinations for HER2+ metastatic breast cancer are under evaluation in clinical trials but are not yet standard practice as of 2025.
Managing Side Effects:Side effects associated with Enhertu include gastrointestinal symptoms and possible interstitial lung disease/pneumonitis, which require careful monitoring and management, including corticosteroids and temporary treatment interruption when indicated.

The Role of Immunotherapy in HER2-Positive Metastatic Breast Cancer

As of 2025, immunotherapy combined with HER2-targeted agents is an area of active research. Clinical trials are investigating checkpoint inhibitors like durvalumab (Imfinzi) in combination with HER2-directed agents, focusing on triple-negative and HER2+ breast cancers to evaluate potential benefits. Such treatments are not yet part of routine clinical use.

Patients and healthcare providers are encouraged to review updated clinical trial results and guideline recommendations to stay informed about emerging treatment options.

Summary of Treatment Options in 2025

HER2-Positive Metastatic Breast Cancer:Enhertu is an option for HER2-low or ultralow expression metastatic breast cancer after endocrine therapy, showing reported improvements in progression-free survival and response rates compared to chemotherapy. Other established HER2-targeted agents remain options for HER2-positive metastatic disease.
Hormone Receptor-Positive Breast Cancer:Hormonal therapies, including SERMs, SERDs, aromatase inhibitors, and ovarian suppression, continue as foundational treatments for both early and metastatic disease. Oral SERDs like elacestrant are additional options for managing advanced cases with endocrine resistance.
Testing and Biomarker-Driven Therapy:Accurate HER2 and hormone receptor testing is critical to informed treatment decisions. Molecular profiling such as ESR1 mutation analysis assists in selecting specialized hormonal agents.
Future Research Directions:Immunotherapy combinations with HER2-directed ADCs show promise and are under ongoing clinical evaluation but are not standard treatment options in 2025.

The combination of hormonal therapies and targeted HER2 agents such as Enhertu offers a range of individualized treatment strategies for patients with metastatic breast cancer.

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