What is the best treatment for breast cancer (Ca mammae) with low Human Epidermal growth factor Receptor 2 (HER2) expression, positive Estrogen Receptor (ER) status, and positive Progesterone Receptor (PR) status?

From the Guidelines

For HER2-low, ER-positive, PR-positive breast cancer, the best treatment is endocrine therapy, with aromatase inhibitors (AIs) such as anastrozole, letrozole, or exemestane being the preferred first-line option for postmenopausal women, as recommended by the 2021 ASCO guideline update 1.

Treatment Approach

The treatment approach should take into account the biology of the tumor and the menopausal status of the patient, with careful attention paid to ovarian production of estrogen 1.

• For postmenopausal women, AIs are recommended as first-line endocrine therapy (ET) 1.
• For premenopausal women, ovarian suppression or ablation in combination with hormonal therapy is recommended, with guidelines for postmenopausal women used to guide the choice of hormone treatment 1.
• The choice of second-line hormonal therapy should consider prior treatment exposure and response to previous ET 1.
• Sequential hormonal therapy should be offered to patients with endocrine-responsive disease 1.

Specific Treatment Options

• AIs such as anastrozole (1mg daily), letrozole (2.5mg daily), or exemestane (25mg daily) are recommended for 5-10 years, depending on menopausal status 1.
• Fulvestrant may be offered in combination with a nonsteroidal AI for patients with metastatic breast cancer (MBC) without prior exposure to adjuvant ET, using a loading dose followed by 500 mg every 28 days 1.
• Exemestane and everolimus may be offered to postmenopausal women with HR-positive MBC progressing on prior treatment with nonsteroidal AIs, either before or after treatment with fulvestrant, as progression-free survival (PFS) is improved compared with exemestane alone 1.

Treatment Duration and Monitoring

• Treatment should be given until there is unequivocal evidence of disease progression, as documented by imaging, clinical examination, or disease-related symptoms 1.
• Tumor markers or circulating tumor cells should not be used as the sole criteria for determining progression 1.

From the FDA Drug Label

Among women with ER positive or unknown breast cancer and positive nodes who received about 5 years of treatment, overall survival at 10 years was 61.4% for tamoxifen vs. 50.5% for control (logrank 2p < 0.00001). The recurrence-free rate at 10 years was 59.7% for tamoxifen vs. 44.5% for control (logrank 2p < 0. 00001). Among women with ER positive or unknown breast cancer and negative nodes who received about 5 years of treatment, overall survival at 10 years was 78.9% for tamoxifen vs. 73.3% for control (logrank 2p < 0.00001). The recurrence-free rate at 10 years was 79.2% for tamoxifen vs. 64.3% for control (logrank 2p < 0. 00001).

For a patient with Ca mammae that is Her2 low, ER positive, and PR positive, the best treatment option is likely hormone therapy.

• Tamoxifen is a suitable option for patients with ER-positive breast cancer, as it has been shown to improve overall survival and reduce the risk of recurrence in these patients 2.
• Letrozole may also be considered, as it has been shown to be effective in the treatment of ER-positive breast cancer, particularly in postmenopausal women 3. However, the choice between these two options should be based on individual patient factors and medical history.

From the Research

Treatment Options for Ca Mammae HER2 Low, ER Positive, PR Positive

• The treatment for Ca mammae HER2 low, ER positive, PR positive breast cancer is a complex issue, and several factors need to be considered, including the stage of the disease, the patient's overall health, and the presence of any other health conditions 4.
• According to a study published in 2024, the emergence of novel anti-HER2 antibody-drug conjugate (ADC) has brought promising approaches for HER2-low breast cancer treatment, and trastuzumab deruxtecan (T-Dxd) has shown efficacy and safety in HER2-low breast cancer at different treatment settings 4.
• Another study published in 2025 proposed the use of adjuvant oral metronomic chemotherapy after surgery at an early stage in HER-2 and hormone-positive local breast cancer, where effective treatment options are available, such as anti-HER2 therapy, anti-hormonal therapy, radiotherapy, and immunotherapy 5.
• For hormone receptor-positive, HER2-negative early breast cancer, adjuvant endocrine therapy is a crucial component of treatment, and the choice of endocrine therapy agent and duration of treatment should be individualized based on patient characteristics and tumor biology 6.
• A study published in 2019 found that ER+/HER2+ breast cancer has different metastatic patterns and better survival than ER-/HER2+ breast cancer, and patients with ER-/HER2+ breast cancer may require more aggressive treatment 7.
• In terms of second-line endocrine therapy, a study published in 2025 found that palbociclib rechallenge with an alternative endocrine therapy did not significantly improve progression-free survival compared with endocrine therapy alone in patients with hormone receptor-positive/HER2-negative advanced breast cancer progressing on a first-line palbociclib-based endocrine therapy regimen 8.

Key Considerations

• The treatment of Ca mammae HER2 low, ER positive, PR positive breast cancer should be individualized based on patient characteristics, tumor biology, and the presence of any other health conditions.
• A multidisciplinary approach, including surgery, radiation therapy, and systemic therapy, may be necessary to achieve optimal outcomes.
• The use of novel anti-HER2 antibody-drug conjugate (ADC) and other targeted therapies may offer promising approaches for HER2-low breast cancer treatment.
• Adjuvant endocrine therapy is a crucial component of treatment for hormone receptor-positive, HER2-negative early breast cancer, and the choice of endocrine therapy agent and duration of treatment should be individualized based on patient characteristics and tumor biology.