Interaction between Molecular Subtypes and Stromal Immune Infiltration before and after Treatment in Breast Cancer Patients Treated with Neoadjuvant Chemotherapy.

Abstract

High levels of tumor-infiltrating lymphocytes (TIL) before neoadjuvant chemotherapy (NAC) are associated with higher pathologic complete response (pCR) rates and better survival in triple-negative breast cancer (TNBC) and <i>HER2</i>-positive breast cancer. We investigated the value of TIL levels by evaluating lymphocyte infiltration before and after NAC. We assessed stromal TIL levels in 716 pre- and posttreatment matched paired specimens, according to the guidelines of the International TIL Working Group. Pre-NAC TIL levels were higher in tumors for which pCR was achieved than in cases with residual disease (33.9% vs. 20.3%, <i>P</i> = 0.001). This was observed in luminal tumors and TNBCs, but not in <i>HER2</i>-positive breast cancers (<i>P</i> _Interaction = 0.001). The association between pre-NAC TIL levels and pCR was nonlinear in TNBCs (<i>P</i> = 0.005). Mean TIL levels decreased after chemotherapy completion (pre-NAC TILs: 24.1% vs. post-NAC TILs: 13.0%, <i>P</i> < 0.001). This decrease was strongly associated with high pCR rates, and the variation of TIL levels was strongly inversely correlated with pre-NAC TIL levels (<i>r</i> = -0.80, <i>P</i> < 0.001). Pre-NAC TILs and disease-free survival (DFS) were associated in a nonlinear manner (<i>P</i> < 0.001). High post-NAC TIL levels were associated with aggressive tumor characteristics and with impaired DFS in <i>HER2</i>-positive breast cancers (HR, 1.04; confidence interval, 1.02-1.06; <i>P</i> = 0.001), but not in luminal tumors or TNBCs (<i>P</i> _Interaction = 0.04). The associations of pre- and post-NAC TIL levels with response to treatment and DFS differ between breast cancer subtypes. The characterization of immune subpopulations may improve our understanding of the complex interactions between pre- or post-NAC setting, breast cancer subtype, response to treatment, and prognosis.