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Background: Emerging evidence indicates that estrogen receptor-low (ER-low)/human epidermal growth factor receptor 2 negative (HER2-) breast cancer (BC) may more closely resemble ER-negative (ER-zero, < 1%) rather than ER-positive disease in terms of biological and clinicopathological characteristics. In Sweden, ER-low (ER 1–9%) BC is managed as triple-negative breast cancer (TNBC) and is thus eligible for neoadjuvant chemo-immunotherapy. We aimed to investigate real-world pathological response to neoadjuvant pembrolizumab combined with chemotherapy in ER-low versus ER-zero BC patients within a Swedish population-based multi-center cohort.

Methods: BC patients with indication to receive neoadjuvant pembrolizumab in combination with chemotherapy in Sweden between 2022 and 2024 were included in the study. Clinicopathological data—including pathological complete response (pCR) status, residual cancer burden (RCB) score, stromal tumor-infiltrating lymphocytes (sTILs) levels, and routine tumor characteristics—were retrieved from laboratory information systems. Associations between categorical variables were assessed using chi-squared (χ2) tests and associations between continuous variables and ER status or pCR were analyzed using Mann–Whitney U-test.

Results: The total cohort comprised 441 TNBC cases (ER-zero n = 398; ER-low n = 43). In the ER-zero group, the pCR rate and RCB score 0–1 were 50.5% (95% CI: 45.5% to 55.5%) and 60.8% (95% CI: 55.8% to 65.6%), respectively. In the ER-low group, the corresponding values were 58.1% (95% CI: 42.1% to 73%), and 60.5% (95% CI: 44.4% to 75%), respectively. There were no statistically significant differences in either pCR rate (p = 0.46) or dichotomized RCB score (p = 0.88) between the groups. The ER-low group showed significantly higher sTILs percentage compared to the ER-zero group (median sTILs 25% versus 20%, p = 0.046). However, when sTILs were analyzed as a binary categorical variable using a 30% cut-off, no significant difference was observed (p = 0.33).

Conclusions: We observed no significant difference in pathological response to neoadjuvant chemo-immunotherapy with pembrolizumab between ER-zero and ER-low BCs. These findings support previous evidence suggesting that ER-low tumors behave more similarly to ER-zero than ER-positive.