Effect of dose-dense adjuvant chemotherapy in patients with node-positive early breast cancer according to estrogen receptor levels: an exploratory analysis of the GIM2 trial

Background: Estrogen receptor (ER)-negative early breast cancer (eBC) generally derives greater benefit from adjuvant chemotherapy than ER-positive disease, but the predictive role of ER expression levels for dose-dense (DD) chemotherapy remains uncertain. This exploratory analysis of the GIM2 phase III trial evaluated whether ER expression influences the efficacy of DD chemotherapy in node-positive eBC. Methods: In the GIM2 trial, patients with node-positive eBC were randomized to receive anthracycline-based chemotherapy followed by paclitaxel, administered either in a DD or standard-interval schedule. ER expression was categorized as ER 0, ER-low (1–10%), ER-intermediate (11–50%), and ER-high (>50%). Associations between ER levels and invasive disease-free survival (iDFS) and overall survival (OS) were evaluated using multivariable Cox models. Treatment effects across the continuum of ER expression were explored using STEPP. Results: Among 1709 eligible patients, 150 (9%) had ER 0, 78 (4%) ER-low, 283 (17%) ER-intermediate, and 1198 (70%) ER-high tumors. After a median follow-up of 15 years (IQR 8–16), 15-year iDFS rates were 48%, 59%, 56%, and 59%, respectively (p = 0.001). Corresponding 15-year OS rates were 72%, 71%, 68%, and 75% (p < 0.001). ER expression was independently associated with both iDFS and OS; however, no significant interaction was observed between ER levels and treatment effect for either endpoint. STEPP analyses demonstrated a consistent benefit of DD chemotherapy across the spectrum of ER expression. Conclusions: ER expression levels were prognostic, but quantitative ER expression did not identify a subgroup with a clearly differential benefit from DD chemotherapy. Given the exploratory nature of this analysis and the small size of the ER-0 and ER-low subgroups, these hypothesis-generating findings are consistent with DD chemotherapy remaining an effective adjuvant treatment option for patients with node-positive eBC across the range of ER expression.