Endocrine therapy in estrogen receptor-low breast cancer: new evidence, persistent questions

The estrogen receptor (ER) is the most important biomarker in breast cancer, defining not only tumor biology but also systemic treatment strategies. ER-positive disease is the most common breast cancer subtype, and endocrine therapy (ET) has been, is, and will likely remain the mainstay of systemic treatment for these tumors. According to the American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP), tumors with ≥1% ER staining are classified as ER-positive. Within this group, those with 1–10% expression are categorized as ER-low (1). Although ER-low tumors represent only 2–5% of all breast cancers, the high worldwide incidence of the disease means that thousands of women are diagnosed with this subtype every year, underscoring its clinical relevance (2).

ER-low cancers have consistently demonstrated distinctive biological and clinical features. They are more frequently high-grade, highly proliferative, and lack progesterone receptor (PR) expression, sharing greater biological similarity with triple-negative breast cancers (TNBCs) than with classical ER-positive tumors. Gene expression studies confirm that most of these tumors cluster as basal-like rather than luminal (3,4). Clinically, they display higher rates of pathological complete response (pCR) to neoadjuvant chemotherapy (NAC) and an early recurrence pattern, reinforcing their resemblance to TNBC (5,6). Importantly, recent phase 3 studies have also suggested that ER-low tumors may derive consistent benefit from the addition of immunotherapy among patients with hormone receptor–positive, grade 3 disease (7,8), and real-world data have provided convergent evidence in the same direction (9). Taken together, these biological and clinical features imply that a diagnosis of ER-low breast cancer often reflects an underlying genotype and phenotype strongly associated with primary endocrine resistance. A more detailed description of the clinical, pathological, and molecular characteristics of ER-low breast cancer is beyond the scope of this editorial, but comprehensive reviews are available elsewhere (2,10).

Historically, the therapeutic paradigm has been to offer ET to all patients with ER expression ≥1%, adopting a one-size-fits-all approach regardless of the quantitative level of receptor expression. This strategy was validated by older trials that, although practice-changing, lacked refined tools to capture the biological heterogeneity of breast cancer and relied on less sensitive ER assessment methods (9). Notably, many tumors classified as ER-low in those early studies may actually correspond to ER levels greater than 10% by current standards, while cancers presently defined as ER-low might have been categorized as ER-negative in past decades. This possibility is largely explained by advances in diagnostic assays, which have become progressively more sensitive and specific over time, resulting in a shift in how tumors are classified across ER expression categories (11).

As biological and clinical evidence accumulated, skepticism grew regarding the true benefit of ET in ER-low tumors, and the appropriateness of a uniform recommendation has been questioned (2). Against this evolving background, Choong et al. recently reported findings that may be considered surprising (12). Their analysis, entitled “Endocrine Therapy Omission in Estrogen Receptor-Low (1–10%) Early-Stage Breast Cancer”, revives the debate on whether ET can indeed confer meaningful benefit in ER-low disease, warranting deeper discussion of this complex and clinically significant issue.

Using data from the National Cancer Database (NCDB), Choong et al. (12) evaluated 7,018 women with stage I–III breast cancer and ER-low expression (1–10%) who had all received chemotherapy between 2018 and 2020 (12). The median age was 55 years, and most cases involved white women with invasive ductal carcinoma harboring adverse biological features such as high histologic grade, Ki-67 ≥20%, and absence of PR expression. The majority (62%) received NAC, whereas 38% were treated in the adjuvant setting. ET was omitted within 12 months after surgery in approximately 42% of cases. Omission was more common among women with PR-negative, human epidermal growth factor receptor 2 (HER2)-negative, and highly proliferative tumors, in those treated with NAC, and in patients diagnosed during the coronavirus disease 2019 (COVID-19) pandemic year.

With respect to survival outcomes, patients who received ET had superior overall survival (OS) compared with those in whom ET was omitted. The estimated 3-year OS was 92.3% vs. 89.1%, respectively. In multivariate analyses, lack of ET remained significantly associated with worse OS [hazard ratio (HR) =1.23; 95% confidence interval (CI): 1.04–1.46]. The adverse effect was particularly evident in tumors with ER 6–10% (HR =1.42; 95% CI: 1.00–2.02), whereas no significant impact was observed among those with ER 1–5% (HR =1.15; 95% CI: 0.91–1.45). Subgroup analyses added further nuance: in the neoadjuvant setting, the omission of ET did not influence outcomes in women who achieved a pCR, but it was significantly detrimental in those with residual disease (HR =1.26; 95% CI: 1.00–1.57). By contrast, in the adjuvant chemotherapy cohort, withholding ET was not significantly associated with survival. Taken together, these results suggest that the prognostic effect of ET is most pronounced in patients with ER 6–10% tumors and in those with incomplete response to neoadjuvant therapy.

The study has important limitations, which the authors appropriately acknowledged, including its retrospective design, relatively short follow-up, and lack of granular information regarding chemotherapy regimens, type and duration of ET, and treatment adherence. In addition, because the NCDB aggregates data from more than 1,500 centers, variability in ER testing and reporting is inevitable. The relatively short follow-up of this analysis may limit the assessment of late recurrences and long-term endocrine effects, potentially leading to either underestimation of delayed benefit or disproportionate emphasis on early outcome differences. Nevertheless, this analysis represents the largest cohort of ER-low breast cancer patients reported to date. It provides compelling evidence that omission of ET may adversely impact survival, particularly in women with ER 6–10% tumors and in those with residual disease after NAC.

Retrospective analyses addressing the role of ET in ER-low breast cancer have produced conflicting results. Some cohorts suggested that ET may still confer survival benefit in this population, such as the study by Luo et al., which evaluated 16,578 women and identified 388 with hormone receptor-low tumors (1–10%); using propensity score matching, they found that omission of ET was independently associated with worse disease-free survival (13). A similar signal was observed by Bari et al., who analyzed real-world cohorts and reported that, even within the 1–10% range, higher ER levels correlated with incremental benefit from ET, supporting the notion that endocrine responsiveness exists on a continuum (14). In contrast, Wang et al. reported no significant difference in recurrence-free survival between patients who received ET and those who did not, in a multicenter Chinese cohort of 457 patients with ER-low disease, thereby questioning the efficacy of ET in this setting (15). These divergent findings illustrate the heterogeneity of ER-low tumors and the uncertainty regarding their endocrine responsiveness.

This controversy was further underscored by the large patient-level meta-analysis conducted by the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG), which included more than 16,000 women. In this analysis, patients with ER expression greater than 10% clearly benefited from adjuvant tamoxifen. In contrast, those with ER expression between 1% and 9% did not demonstrate a statistically significant improvement in disease-free survival or OS (16). The trial-level evidence showed that five years of tamoxifen reduced recurrence rates by nearly half during years 0–4 (rate ratio ~0.53) and by about one third during years 5–9 (rate ratio ~0.68), translating into a 30–35% reduction in breast cancer mortality at 15 years of follow-up. Notably, even tumors with marginal ER levels, defined by older ligand-binding assays as 10–19 fmol/mg, derived some benefit (rate ratio ~0.67). However, the analysis was not designed to specifically capture patients with very low ER expression [1–9% by current immunohistochemistry (IHC) standards], which limits its direct applicability to the contemporary ER-low population.

At the same time, novel therapeutic opportunities have emerged. Signals of benefit from immune checkpoint inhibitors in ER-low patients enrolled in phase 3 trials of hormone receptor-positive, grade 3 breast cancer further reinforce their biological overlap with triple-negative disease (7,8). However, this overlap does not preclude the possibility that a subset of ER-low tumors may retain partial endocrine sensitivity. In this context, the analysis by Choong et al. (12) is particularly noteworthy, as it challenges prevailing assumptions and suggests that ET may still hold clinical value for selected patients within this heterogeneous group. One of the most relevant insights from the NCDB analysis by Choong et al. (12) is the demonstration of heterogeneity within ER-low breast cancers. The survival benefit from ET was more evident in tumors with ER expression of 6–10%, whereas patients with ER expression of 1–5% showed no significant advantage. This observation aligns with the biological notion of a continuum, in which tumors with very low receptor expression behave almost indistinguishably from TNBC. At the same time, those closer to the 10% threshold may retain partial endocrine sensitivity. Recognizing this gradient is crucial for refining treatment strategies and informing more personalized decisions regarding the use of ET.

Importantly, these findings appear to diverge from the results of the EBCTCG meta-analysis, which did not demonstrate a statistically significant benefit of ET for patients with ER expression in the 1–9% range (16). Methodological differences, population characteristics, and length of follow-up may partially explain this discrepancy. Nevertheless, the NCDB data raise the hypothesis that at least a subset of ER-low tumors—particularly those with ER expression of 6–10% expression or with residual disease after NAC—may retain some degree of endocrine responsiveness. This inconsistency between large pooled analyses and contemporary real-world data underscores the complexity of ER-low biology and, more importantly, highlights the need for prospective studies specifically designed to define the role of ET in this population.

Together, these findings emphasize a clinical dilemma between undertreatment and overtreatment. On one hand, omission of ET in patients with potential endocrine responsiveness—such as those with ER 6–10% expression or with residual disease after NAC—may compromise survival outcomes. On the other hand, prescribing ET universally to all ER-low patients risks exposing many women, particularly those with ER 1–5% tumors, to treatment-related toxicity, impaired quality of life, and adherence challenges despite uncertain benefit. This tension underscores the importance of individualized therapeutic decisions and shared patient–physician counseling.

Ultimately, the NCDB analysis underscores the pressing need for more accurate predictive tools. IHC alone may be insufficient to capture the complex biology of ER-low tumors. Integration of gene expression profiling (17), immune signatures (18), circulating tumor DNA (19), and digital pathology approaches (20) could help identify subsets of patients who are truly endocrine-sensitive. Beyond IHC, emerging molecular and immune-based tools may help refine ET decision-making in ER-low breast cancer. Gene expression analyses have shown that a substantial proportion of tumors with 1–10% ER expression cluster as basal-like rather than luminal, as demonstrated by Iwamoto et al., providing a biological rationale for their limited and heterogeneous endocrine sensitivity (3). In parallel, immune profiling studies reviewed by Griguolo et al. indicate that ER-low tumors frequently exhibit immune-enriched phenotypes and features overlapping with TNBC, which are typically associated with relative endocrine resistance. In this context, an ER-low tumor characterized by a basal-like molecular profile or an immune-enriched signature may reasonably derive minimal benefit from ET, whereas tumors retaining luminal features could still display partial endocrine responsiveness (18). Although not yet validated for routine clinical use, these tools illustrate how molecular and immune profiling could support more individualized treatment decisions in this heterogeneous population. These considerations further highlight the importance of systematically including ER-low tumors in prospective, biomarker-driven trials of ET escalation or de-escalation, as well as in studies evaluating immunotherapy strategies in the ER-low/HER2-negative setting.

In clinical practice, the key challenge is to translate this evolving and often conflicting evidence into patient-centered recommendations. The available data do not support routine omission of ET in ER-low breast cancer. Still, they also highlight the need for caution in prescribing it indiscriminately to all patients within this category. Clinicians must carefully weigh comorbidities, patient preferences, and the potential impact of ET on quality of life, particularly when the probability of benefit appears minimal. Individualized counseling, transparent discussion of uncertainties, and shared decision-making remain essential until prospective trials provide more precise guidance.

In conclusion, ER-low breast cancer is increasingly recognized as a distinct entity that lies between classical ER-positive and triple-negative disease. The available evidence remains conflicting, but recent data suggest that at least a subset of tumors may retain partial endocrine sensitivity. For now, ET should not be uniformly omitted; however, its use must be carefully weighed against the risks of toxicity, quality-of-life impact, and patient preferences. This ongoing uncertainty underscores the urgent need for prospective biomarker-driven trials to definitively establish the role of ET in this challenging subgroup.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Chinese Clinical Oncology. The article has undergone external peer review.

Peer Review File: Available at https://cco.amegroups.com/article/view/10.21037/cco-2025-aw-125/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cco.amegroups.com/article/view/10.21037/cco-2025-aw-125/coif). T.R. reports research funding from AstraZeneca, and Libbs; and speaker honoraria/advisory board of AstraZeneca, Daichi-Sankyo, Gilead, Novartis, MSD, Lilly, and Libbs. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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