Level of estrogen receptor expression, histological grade, and computationally assessed stromal TILs on pre-treatment biopsies predict pathological complete response to neoadjuvant chemotherapy in ER-positive/HER2-negative breast cancer

Estrogen receptor-positive (ER+), HER2-negative (HER2-) breast cancer (BC) is the most common BC subtype. Patients with this subtype rarely achieve pathological complete response (pCR) after neoadjuvant chemotherapy (NACT), and the population most likely to benefit remains unclear. This highlights the need to identify reliable markers of response, particularly in the context of emerging chemoimmunotherapy strategies. We retrospectively included 415 patients diagnosed with ER+/HER2- BC between 2016 and 2020 from three Danish pathology departments. We analysed associations between standard clinicopathological variables and computationally assessed stromal tumor-infiltrating lymphocytes (sTILs) with response rates and long-term outcomes. To define clinically useful cut-offs, we performed threshold analysis for ER-expression and sTIL levels. The pCR rate in the study population was 6.3%, while pCR/RCB-I was observed in 15.9% of all patients. Lower ER-expression, higher grade, and higher computational sTILs were associated with greater odds of achieving pCR and good response. Threshold analysis revealed optimal cut-off points of 60% for ER expression and 20% for sTILs. Patients with simultaneously high-grade, high sTILs, and ER < 60% were the most likely to achieve good response to NACT (pCR rate 44%, pCR/RCB-I rate 62%), while patients with low-grade, low sTILs, and high ER-expression achieved pCR in only 1% and pCR/RCB-I in 11% of cases. Response to NACT is strongly influenced by ER expression, tumor grade, and sTIL levels. Composite profiles combining these factors can help identify patients most likely to achieve meaningful response, while also highlighting subgroups with low benefit where alternative treatment strategies may be more appropriate.