A retrospective study proposes that the optimal cutoff for classifying oestrogen receptor (ER) status in HER2-positive breast cancer treated with neoadjuvant therapy is 50%, rather than the lower values often used. Patients above that threshold would form a clinically and biologically distinct subgroup with poorer response to standard therapy.
What was already known
ER-positive, HER2-positive breast cancer shows significantly lower rates of pathological complete response (pCR) to neoadjuvant HER2-targeted therapies than ER-negative, HER2-positive disease. Until now, however, the optimal ER-positivity cutoff for clinically meaningful patient stratification had not been defined.
What this work adds
The authors analysed a retrospective cohort of 741 HER2-positive breast cancer patients treated with neoadjuvant chemotherapy plus dual HER2 blockade (trastuzumab and pertuzumab) at the Sun Yat-sen University Cancer Center. The optimal ER cutoff for predicting pCR was determined by ROC analysis with the Youden index and validated by bootstrap resampling (1,000 iterations). Transcriptomic data from the TCGA and SCAN-B cohorts were analysed to characterise biological differences between ER subgroups, drug response was predicted with the oncoPredict algorithm, and cancer dependency was assessed using DepMap CRISPR screening data.
Main results
ER positivity of ≥50% was identified as the optimal predictive cutoff (bootstrap 95% CI: 25.0%-77.5%) and was an independent predictor of significantly lower pCR rates in multivariate analysis (OR = 0.27; 95% CI: 0.19-0.40). The authors note that this subgroup shows lower HER2 and CD16A expression, with convergent transcriptomic and functional evidence of ESR1-CCND1 axis activation.
What it means
The authors conclude that ER ≥50% positivity defines a clinically and biologically distinct HER2-positive subgroup with poor response to standard neoadjuvant therapy and predicted resistance to antibody-drug conjugates (ADCs). The evidence on ESR1-CCND1 axis activation would provide mechanistic support for combining CDK4/6 inhibitors with endocrine and anti-HER2 therapies to improve outcomes in this resistant subgroup. These are research findings requiring prospective validation before translation into practice; they do not by themselves imply a change in an individual’s treatment.
Reference: Du T, Lin M, Liang G, Wang Y, Wu H, Zhao Z, et al. Optimizing the ER Cutoff in HER2-Positive Breast Cancer: ER ≥ 50% Predicts Low pCR Rates and Resistance to Antibody-Drug Conjugates in the Neoadjuvant Setting. Cancer Medicine, 2026. DOI/link
