Prognostic Impact of High Baseline Stromal Tumor-Infiltrating Lymphocytes in the Absence of Pathologic Complete Response in Early-Stage Triple-Negative Breast Cancer

SIMPLE SUMMARY: High stromal tumor-infiltrating lymphocytes (sTILs) are associated with an improved pathologic complete response (pCR) and survival in triple-negative breast cancer (TNBC). We hypothesized that high baseline sTILs would have a favorable prognostic impact in TNBC patients without a pCR. In this study of 318 early-stage TNBC patients in a prospective clinical trial, event-free survival (EFS) in patients without a pCR was not significantly different between those with high sTILs and those with low sTILs (p = 0.7). Therefore, high baseline sTILs do not confer a benefit in EFS in the absence of a pCR. RNA-seq analysis predicted more CD8+ T cells in the high-sTIL group with favorable EFS compared with the high-sTIL group with unfavorable EFS, suggesting the type of lymphocytes within the TIL fraction may be an important parameter to consider for de-escalation strategies. The implications of our findings in the setting of immune checkpoint inhibitor therapy remain to be investigated. ABSTRACT: High stromal tumor-infiltrating lymphocytes (sTILs) are associated with an improved pathologic complete response (pCR) and survival in triple-negative breast cancer (TNBC). We hypothesized that high baseline sTILs would have a favorable prognostic impact in TNBC patients without a pCR after neoadjuvant chemotherapy (NACT). In this prospective NACT study, pretreatment biopsies from 318 patients with early-stage TNBC were evaluated for sTILs. Recursive partitioning analysis (RPA) was applied to search for the sTIL cutoff best associated with a pCR. With ≥20% sTILs identified as the optimal cutoff, 33% patients had high sTILs (pCR rate 64%) and 67% had low sTILs (pCR rate 29%). Patients were stratified according to the sTIL cutoff (low vs. high) and response to NACT (pCR vs. residual disease (RD)). The primary endpoint was event-free survival (EFS), with hazard ratios calculated using the Cox proportional hazards regression model and the 3-year restricted mean survival time (RMST) as primary measures. Within the high-sTIL group, EFS was better in patients with a pCR compared with those with RD (HR 0.05; 95% CI 0.01–0.39; p = 0.004). The difference in the 3-year RMST for EFS between the two groups was 5.6 months (95% CI 2.3–8.8; p = 0.001). However, among patients with RD, EFS was not significantly different between those with high sTILs and those with low sTILs (p = 0.7). RNA-seq analysis predicted more CD8+ T cells in the high-sTIL group with favorable EFS compared with the high-sTIL group with unfavorable EFS. This study did not demonstrate that high baseline sTILs confer a benefit in EFS in the absence of a pCR.