Can Hormonal Therapy Be Omitted in Estrogen Receptor–Low Positive Breast Cancer?

Estrogen Receptor–Low Positive Breast Cancer

Hormonal (endocrine) therapy is a cornerstone of breast cancer treatment, particularly for patients with estrogen receptor (ER)-positive disease. In recent years, however, tumors with estrogen receptor staining of 1–10% on immunohistochemistry (IHC) , known as estrogen receptor–low (ER-low) tumors, have prompted debate about their biological and clinical characteristics. Could the benefit of hormonal therapy be uncertain in this group?

On April 11, 2025, Journal of Clinical Oncology published a large study in which Choong and colleagues sought to answer this question. They examined how omitting hormonal therapy affected survival outcomes in patients with early-stage breast cancer and low estrogen receptor expression.

Study Design

• Data source: The National Cancer Database. A retrospective analysis. 

• Patient population: Patients with high-risk stage I–III breast cancer and estrogen receptor expression of 1–10%

• Treatment: Patients receiving (neo)adjuvant chemotherapy who did or did not start hormonal therapy

• Important detail: All patients had early-stage disease but were classified as high risk.

Key Findings

Patient Numbers and General Characteristics

• A total of 10362 patients were analyzed.

• Of these, 7018 patients received chemotherapy and were included in the study.

Rate of Not Starting Hormonal Therapy

• At 12 months of follow-up, 42% had not started hormonal therapy .

• Not starting hormonal therapy was more common in the following groups:

  • Progesterone receptor (PR)-negative tumors

  • HER2-negative tumors

  • Higher tumor grade (grade 2–3)

  • Ki67 proliferation index ≥ 20% tumors

  • Neoadjuvant chemotherapy recipients

• All these findings were statistically significant (P < 0.001).

Survival Outcomes

• Median follow-up: 3 years

• Total number of deaths: 586

• In multivariable analyses, omission of hormonal therapywas associated with a 23% increase in the risk of death:

  • Hazard ratio (HR): 1.23 (confidence interval [CI]: 1.04–1,46; P = 0.02)

• Risk differed according to estrogen receptor expression:

  • ER 6–10%: The risk of death increased by 42% (HR: 1.42; CI: 1.00–2.02; P = 0.048)

  • ER 1–5%: No significant increase in the risk of death was found (HR: 1.15; CI: 0.91–1.45; P = 0.24)

Findings in Patients Receiving Neoadjuvant Chemotherapy

• 4377 patients (62%) received neoadjuvant chemotherapy.

• Among patients with residual disease after neoadjuvant treatment, omitting hormonal therapy was associated with poorer survival:

  • With residual disease: HR = 1.26 (CI: 1.00–1.57; P = 0.046)

• However, in patients achieving a pathological complete response (pCR) , omitting hormonal therapy did not affect survival:

  • HR = 1.06 (CI: 0.62–1.80; P = 0.84)

Interpretation

In early-stage breast cancer with low estrogen receptor expression, omitting hormonal therapy is associated, particularly in patients with residual disease after neoadjuvant chemotherapy and those with estrogen receptor expression of 6–10% , with substantially poorer overall survival .

Until prospective data are available, the potential benefits of hormonal therapy must be considered in this patient group.

The study's numerical findings convey a critical message:

• Even with estrogen receptor expression of 1–10% , omitting hormonal therapy may have a negative effect on survival.

• Especially in patients with ER 6–10% and in cases where residual disease is detected, the risk of death increases significantly .

In clinical practice, therefore, for this group of patients with low estrogen receptor expression, actively recommending hormonal therapy and informing patients about the potential benefits of treatment are of great importance.