Adjuvant endocrine therapy in estrogen-low breast cancer in the era of CDKI: are we at another uncertain crossroads?

Estrogen receptor-low breast cancer is defined as ER expression of 1–10% by immunohistochemistry. It occupies a debated space between luminal and triplenegative disease. The CDK4/6 inhibitors abemaciclib and ribociclib have set new standards for high-risk HR+/HER2-/early breast cancer. However, neither trial stratified patients by ER expression levels. This leaves the ER-low subgroup without dedicated prospective evidence. This review synthesizes data from adjuvant CDK4/6 inhibitor trials, clinical and molecular studies of ER-low BC, biomarker evidence, regulatory context, and chemotherapy/immunotherapy data, with specific attention to the ER-low subgroup and a structured framework for clinical decision-making. ER-low breast cancer is mostly non-luminal (about 75–80% basal-like). Its molecular features, neoadjuvant chemotherapy response rates, and survival outcomes are closer to ER-negative/triple negative breast cancer than ER-high luminal cancer. Both MONARCH E and NATALEE trials enrolled ER-low patients, using the ≥1% positivity threshold. Exploratory subgroup data suggest a numerically consistent benefit from CDK4/6 inhibitors. However, confidence intervals are wide, and formal statistical significance is not shown. PAL trials showed no benefit. This is linked to its specific pharmacology rather than a class effect. CDK4/6 inhibitor activity in ER-low disease appears to result from ERindependent RB pathway mechanisms, CCND1 amplification, and immunomodulatory effects. Frequent RB1 loss, reduced endocrine sensitivity, and cell-cycle control by CDK2/cyclin E counterbalance this activity. ER-low patients who meet high-risk trial eligibility criteria may receive adjuvant CDK4/6 inhibitors when luminal biomarkers support HR+ biology but must be counseled about the evidence gap. Molecular subtyping (PAM50), RB1 assessment, PR status, germline BRCA testing, and multidisciplinary tumor board review are mandatory. Dedicated prospective trials with ER-low as a pre-specified stratum are urgently needed.