The Possible Role of Anti- and Protumor-Infiltrating Lymphocytes in Pathologic Complete Response in Early Breast Cancer Patients Treated with Neoadjuvant Systemic Therapy

SIMPLE SUMMARY: Understanding the role of tumor-infiltrating lymphocytes (TILs) and their phenotype in pathologic complete response (pCR) is gaining increasing attention in cancer research. It is believed that the behavior of cancer cells is affected by the tumor microenvironment, dominated by either pro- or antitumor immune cells. In our prospective study, patients with early breast cancer started treatment with systemic therapy, followed by surgery. We assessed the probability of pCR in relation to TIL density and the proportion of two (presumably) antitumor biomarkers (CD8+ and CXCL13+) and two (presumably) protumor biomarkers (PD-1+ and FOXP3+) in TILs. In addition to confirming previous findings that a higher number of TIL correlates with a higher probability of pCR, our results paradoxically showed that a higher proportion of presumably protumor TILs could be favorable for a higher probability of pCR when considering each biomarker individually (if all four biomarkers are considered together, we cannot draw any conclusions on the direction of association between protumor TILs and pCR). Future decisions regarding neoadjuvant or adjuvant therapy may be influenced by TIL density and TIL subtypes. ABSTRACT: The tumor microenvironment, composed of pro- and antitumor immune cells, affects cancer cell behavior. We aimed to evaluate whether tumor-infiltrating lymphocyte (TIL) density and TIL subtypes in core biopsies at the diagnosis of breast cancer patients could predict a pathologic complete response (pCR; ypT0/is ypN0) from neoadjuvant systemic therapy (NST). The TIL subtypes were determined based on the proportions of presumably antitumor (CD8+, CXCL13+) and protumor (PD-1+, FOXP3+) immune cells. A prospective, noninterventional study, including 171 participants undergoing NST, was performed. The median TIL density for the entire cohort was 10% (IQR: 3.5–23.8), and 59 (35%) patients achieved pCR. TIL density was positively associated with pCR (univariately and multivariably). In the multivariable logistic regression model, TIL density was an independent predictor of pCR (p = 0.012, OR 1.27; 95% CI 1.05–1.54) when controlled for age (p = 0.232), Ki-67 (p = 0.001), node-negative status (p = 0.024), and HER2+/triple negative vs. luminal B-like subtype (p < 0.001). In our sample, higher proportions of PD-1+ TILs and FOXP3+ TILs were associated with a higher probability of pCR but the association was not statistically significant and we could not make any conclusions on the direction of associations in the model with all four biomarkers. In the exploratory multivariable analysis, we showed that only higher CD8+ TILs were associated with pCR. In conclusion, TIL density and its subtypes are associated with pCR.