Distribution and molecular drivers of the 21-gene recurrence score in early breast cancer with low, intermediate, and high estrogen receptor expression

BackgroundEstrogen receptor (ER)-low human epidermal growth factor receptor 2 (HER2)-negative breast cancer shares similar pathological and molecular features with triple-negative breast cancer, yet the utility of the 21-gene assay in this population remains uncertain. This study aimed to evaluate the distribution and molecular drivers of the 21-gene recurrence score (RS) in early breast cancer with low, intermediate, and high ER expression.MethodsER-positive, HER2-negative early breast cancer patients with 21-gene testing results from Shanghai Jiao Tong University Breast Cancer Database (2009-2022) were included. Eligible patients were categorized into three groups: ER-low (1-9%), ER-intermediate (10-50%), and ER-high (>50%). Chi-square and Kruskal-Wallis tests were conducted to compare the 21-gene RS and expression profiles among these groups. Spearman correlation and linear variance decomposition were performed to assess the associations between RS and its constituent gene modules.ResultsA total of 4754 patients were included (ER‑low: 70, 1.5%; ER‑intermediate: 129, 2.7%; ER‑high: 4555, 95.8%). Mean RS values were 39, 32, and 24 in the three groups, with RS >25 observed in 72.9%, 62.8%, and 42.5% of patients, respectively (P < 0.001).. Among patients with ER-low tumors, the rates of RS >25 were 62.5% and 81.6% for those ≤50 or >50 years, 66.7% and 83.3% for those with low or high clinical risk, and 61.6% and 87.1% for those with PR-positive or PR-negative diseases, respectively. Notably, 90.6% younger patients had RS >15 in the ER-low group. Expression of ESR1 (P < 0.001), PGR (P < 0.001), BCL2 (P = 0.035), SCUBE2 (P < 0.001) from the ER module, and STMY3 (P = 0.001) from the invasion module were significantly lower in ER-low than in ER-high. Only, the proliferation module had a modest correlation with RS among patients with ER-low tumors (R = 0.34, P = 0.0076). Variance decomposition showed that the four modules explained only 8.83% of RS variance in ER‑low tumors (7.38% from proliferation), compared with 48.74% (42.93% from ER module) in ER‑high and 28.97% (21.94% from ER module) in ER‑intermediate tumors.ConclusionsThe 21-gene RS was higher in ER-low breast cancer patients, particularly among those ≤50 years, with high clinical risk or PR-negative diseases. RS was only moderately correlated with proliferation features and minimally determined by any of the four module components in ER-low tumors. These findings are exploratory and require further validation in larger cohorts.