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

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.

Keywords: CD8; neoadjuvant chemotherapy; pathologic complete response; prognosis; triple-negative breast cancer; tumor-infiltrating lymphocytes.

Figure 1

ARTEMIS trial schema. Treatment-naïve patients with localized TNBC (stages I–III) undergo a pretreatment biopsy and pretreatment ultrasound and then start 4 cycles of AC chemotherapy. Patients have their tumors imaged to assess the treatment response after AC. Patients deemed to have a chemo-sensitive disease after 4 cycles of AC are recommended to undergo standard taxane-based chemotherapy. Patients predicted to be chemo-insensitive are offered therapy on clinical trials using targeted therapy in combination with chemotherapy based on the biomarker characteristics of their tumor, a ‘second hit’ strategy in the middle of NACT to overcome chemotherapy resistance. AC, doxorubicin and cyclophosphamide; ARTEMIS, a robust TNBC evaluation framework to improve survival; NACT, neoadjuvant chemotherapy; TNBC: triple-negative breast cancer.

Figure 2

The pCR rates in sTIL groups in 10% increments in 318 patients. Recursive partitioning analysis identified ≥20% for defining high sTILs in association with a pCR. The total number of patients in each sTIL group is shown on top of the corresponding column. pCR, pathologic complete response; sTIL, stromal tumor-infiltrating lymphocyte.

Figure 3

Event-free survival (EFS) and overall survival (OS) in high-sTIL and low-sTIL patients. (A) Kaplan–Meier plots of EFS between the overall-high-sTIL and overall-low-sTIL groups. (B) Kaplan–Meier plots of OS between the overall-high-sTIL and overall-low-sTIL groups. (C) Kaplan–Meier plots of EFS between the high-sTIL and low-sTIL groups, with a pCR and with RD. (D) Kaplan–Meier plots of OS between the high-sTIL and low-sTIL groups, with a pCR and with RD. pCR, pathologic complete response; RD, residual disease; sTIL, stromal tumor-infiltrating lymphocyte.

Figure 4

Comparison of T cells by whole transcriptomic sequencing (RNA-seq) between RCB 0/I (n = 64) and RCB II/III (n = 25) groups in high-sTIL patients. (A) resting CD4+ memory T cells; (B) activated CD4+ memory T cells; (C) CD8+ T cells. The horizontal bar in each plot represents the median of the scores. RCB, residual cancer burden; sTIL, stromal tumor-infiltrating lymphocytes.