This study provides key real-world evidence on whether patients with ER-low breast cancer should receive endocrine therapy, suggesting that endocrine therapy can significantly improve overall survival even in tumors with ER 1–10%, particularly in subgroups with residual disease and higher ER expression, offering direct guidance for clinical decision-making.
Literature Overview
This article, 'Endocrine therapy omission in estrogen receptor-low (1–10%) early-stage breast cancer,' published in the 'Journal of Clinical Oncology,' systematically investigates the use of endocrine therapy (ET) and its impact on overall survival (OS) in patients with early-stage breast cancer exhibiting low estrogen receptor expression (1–10%). Based on a retrospective cohort analysis of the National Cancer Database (NCDB), the study reveals a significant association between ET omission and increased risk of death. Further analyses indicate that this effect is more pronounced in specific subgroups, providing important evidence for treatment decisions in clinical practice for patients with ER-low tumors.Background Knowledge
Breast cancer is one of the most common malignancies in women, with approximately 70% of cases being ER-positive, typically recommended for 5–10 years of adjuvant endocrine therapy. However, tumors with low ER expression (1–10%) exhibit biological behavior more similar to triple-negative breast cancer (TNBC), and the sensitivity to endocrine therapy remains controversial. Although current ER testing standards have been lowered to ≥1%, uncertainty persists in clinical practice regarding whether patients with low ER expression should receive ET. International guidelines lack consistent recommendations on ET use for these patients, and some studies even suggest using ER≥10% as the positivity threshold. This uncertainty leads to heterogeneous treatment decisions, with some patients potentially being denied potential survival benefits due to misclassification as 'low responders.' This study addresses this clinical dilemma by aiming to clarify the real-world survival impact of ET in ER-low breast cancer using large-scale real-world data, providing evidence to support precision treatment.
Research Methods and Experiments
The study conducted a retrospective cohort analysis using the NCDB (2018–2020), including 7,018 patients with stage I–III ER-low breast cancer who received chemotherapy, defined as immunohistochemical (IHC) ER expression of 1–10%. The primary exposure was initiation of ET within 12 months postsurgery, with OS analyzed using time-dependent Cox regression models. The study performed multivariable adjustments to control for confounding factors and conducted subgroup analyses stratified by pathologic response to neoadjuvant chemotherapy (NAC) (pCR vs. RD) and ER expression levels (1–5% vs. 6–10%). Statistical methods rigorously controlled for immortal time bias to ensure robust results.Key Conclusions and Perspectives
Research Significance and Prospects
This study provides critical real-world evidence for the clinical management of ER-low breast cancer, challenging the traditional notion that 'ER-low equals endocrine-insensitive.' The findings support the active use of ET in patients with residual disease after chemotherapy or those with ER expression close to 10%, potentially yielding survival benefits. Future prospective studies are needed to validate ET benefits in these subgroups and to explore the prognostic and predictive value of gene expression profiles (e.g., PAM50) or multigene assays (e.g., Oncotype DX) in ER-low populations to enable more precise individualized treatment. Additionally, the role of intensified endocrine strategies, such as combining CDK4/6 inhibitors, in high-risk ER-low patients warrants further investigation.
Conclusion
This study confirms through large-scale real-world data that in patients with early-stage breast cancer exhibiting low ER expression, omission of endocrine therapy is significantly associated with worse overall survival, particularly in subgroups with residual disease after neoadjuvant chemotherapy or higher ER expression levels (6–10%). These findings emphasize that even in ER-low tumors, the endocrine pathway may still play an important role, and endocrine therapy should not be readily abandoned. From a translational perspective, this study provides clear decision support for clinicians: for ER-low patients receiving chemotherapy, a comprehensive assessment of pathologic response and ER expression levels should be performed, and endocrine therapy should be actively considered, especially in high-risk subgroups. Future integration of molecular subtyping and dynamic biomarker monitoring holds promise for further optimizing treatment strategies and improving long-term survival in ER-low breast cancer. This study lays an important foundation for refining current breast cancer treatment guidelines and advancing precision medicine in borderline populations.
