Rethinking Treatment Priorities in Estrogen Receptor–Low Breast Cancer

To the Editor:

Choong et al¹ evaluated the benefit of endocrine therapy (ET) in early-stage, estrogen receptor (ER)–low breast cancer using the National Cancer Database (NCDB). With the replacement of ligand-binding assays with immunohistochemistry in the 1990s, there was initially no consensus threshold for positivity. The 2010 ASCO/CAP Guidelines on Estrogen and Progesterone Receptor Testing in Breast Cancer recommended a cut point of ≥1% to define ER-positive disease, but adjuvant ET has not been clearly shown to prevent distant recurrence in cases with low ER expression. Multiple studies of large cohorts with long-term follow-up have demonstrated that ER-low breast cancer acts similar to ER-negative disease and does not appear to benefit from ET.^2–4 An analysis of 38,560 patients with breast cancer in the Munich Cancer Registry found no significant benefit of ET in recurrence or survival in ER-low and ER-negative tumors at 15 years.⁴ Conversely, Choong et al¹ found that omitting adjuvant ET was associated with worse overall survival in stage I to III, ER-low breast cancer.

The effect size of this benefit was substantial, with a 42% higher risk of all-cause mortality at 3 years in individuals with ER-low–expressing breast tumors (6%-10% ER positivity) who did not receive ET. However, using NCDB to compare survival between patients who do and who do not receive adjuvant therapy is challenging as fit patients are treated more aggressively, which inflates the survival benefit seen with aggressive treatment. As such, the impact of treatment on survival from NCDB often conflicts with findings from randomized trials. For example, one study found a significant benefit of chemotherapy in postmenopausal women with a 21-gene recurrence score between 11 and 25, in direct conflict with the results from TAILORx and RxPONDER.^5,6 Another study reported a 10-year survival advantage of chemotherapy in women 50 years and younger, with node-negative disease and an intermediate 21-gene recurrence score (4.6%),⁷ which was more than double what was observed (1.8%) in the TAILORx trial.⁵ Because of NCDB's limitations, investigators are unable to fully account for unmeasured factors that affect both treatment receipt/omission and patient mortality in retrospective analyses.

In addition, the survival benefit of ET in ER-low disease was solely driven by patients with residual disease (RD) after neoadjuvant chemotherapy. In fact, this study suggests no benefit in patients treated in the adjuvant setting. This raises an additional question—why would ET benefit only patients who had RD after chemotherapy? Only a single ER status is recorded in the NCDB, and per the Standards for Oncology Registry Entry guidelines,⁸ it is recommended that ER status is recorded from a pretreatment biopsy. However, in many centers, ER status will be recorded on samples with RD for cases with borderline (ie, ER-low) results on the pretreatment biopsy. This could lead to a scenario where patients who received ET in the postneoadjuvant setting were selected based on RD with higher levels of ER expression than seen in the pretreatment biopsy, and these cases would both respond more readily to ET and carry a more favorable prognosis.

Historically, patients with ER-low breast cancer have been excluded from randomized trials for triple-negative breast cancer. This has caused real challenges for patients with ER-low disease. For example, despite the clear benefit of neoadjuvant immunotherapy for locally advanced ER-low disease,^9,10 we have encountered issues with insurance approval because of the formal inclusion criteria of KEYNOTE-522. Now, trials for early-stage, triple-negative disease are expanding eligibility, and patients with ER-low tumors and RD after neoadjuvant therapy may be eligible for treatment with Trop2-targeting antibody-drug conjugates per the ongoing ASCENT-05 (ClinicalTrials.gov identifier: NCT05633654) and TROPION-Breast04 (ClinicalTrials.gov identifier: NCT06112379) trials. Of course, ET can, outside of trials, be administered either sequentially or concurrently with adjuvant chemotherapy or antibody-drug conjugates. However, CDK4/6 inhibitors, which are now standard therapy for high-risk ER-positive disease, would be challenging to combine with other therapies and may not benefit basal-like ER-low tumors.¹¹ Among patients with ER-low tumors, where endocrine responsiveness is uncertain, it will be important to prioritize the most effective systemic therapies. Furthermore, any potential benefit of ET must be carefully weighed against its side effects and impact on quality of life,¹² particularly for patients who have already experienced significant toxicity from intensive neoadjuvant chemotherapy.

In summary, we applaud the authors' comprehensive analysis, but we come to a different conclusion. In the adjuvant setting, ET does not appear to improve survival in ER-low disease. The limited benefit of ET should be carefully weighed against the potential for side effects, with consideration given to alternative, more effective options.