Prognostic value of tumor-infiltrating lymphocytes on residual disease after primary chemotherapy for triple-negative breast cancer: a retrospective multicenter study

Abstract

Background: There is a need to develop surrogates for treatment efficacy in the neoadjuvant setting to speed-up drug development and stratify patients according to outcome. Preclinical studies showed that chemotherapy induces an antitumor immune response. In order to develop new surrogates for drug efficacy, we assessed the prognostic value of tumor-infiltrating lymphocytes (TIL) on residual disease after neoadjuvant chemotherapy (NACT) in patients with triple-negative breast cancer (TNBC).

Patients and methods: Three hundred four TNBC patients with residual disease after NACT were retrospectively identified in three different hospitals. Hematoxylin and eosin-stained slides from surgical postchemotherapy specimens were evaluated for intratumoral (It-TIL) and stromal (Str-TIL) TIL. Cases were classified as High-TIL if It-TIL and/or Str-TIL >60%.

Results: TIL were assessable for 278 cases. Continuous It-TIL and Str-TIL variables were strong prognostic factors in the multivariate model, both for metastasis-free [hazard ratio (HR) 0.86, 95% confidence interval (CI) 0.77-0.96, P = 0.01 and HR 0.85, 95% CI 0.75-0.98, P = 0.02 for Str-TIL and It-TIL, respectively] and overall survival (HR 0.86, 95% CI 0.77-0.97, P = 0.01 and HR 0.86, 95% CI 0.75-0.99, P = 0.03 for Str-TIL and It-TIL, respectively). The 5-year overall survival rate was 91% (95% CI 68% to 97%) for High-TIL patients (n = 27) and 55% (95% CI 48% to 61%) for Low-TIL patients (HR 0.19, 95% CI 0.06-0.61, log-rank P = 0.0017). The major prognostic impact of TIL was seen for patients with large tumor burden following NACT (residual tumor >2 cm and/or node metastasis). In all but one High-TIL case, It-TIL and Str-TIL values were lower on the prechemotherapy sample.

Conclusions: The presence of TIL in residual disease after NACT is associated with better prognosis in TNBC patients. This parameter may represent a new surrogate of drug efficacy to test investigational agents in the neoadjuvant setting and a new prognostic marker to select patients at high risk of relapse.

Keywords: breast cancer; neoadjuvant chemotherapy; triple negative; tumor lymphocytes.

Figures

Figure 1.

Flowchart of the study. TNBC, triple-negative breast cancer; ER, estrogen receptor; PR, progesterone receptor; TILs, tumor-infiltrating lymphocytes.

Figure 2.

Prognostic value of high lymphocytic infiltration on residual disease after neoadjuvant chemotherapy. Estimated Kaplan–Meyer curves of metastasis-free survival (A) and overall survival (B) for all patients. Estimated Kaplan–Meyer curves of metastasis-free survival for patients with node-negative and ≤2 cm residual disease (C) and for patients with node-positive and/or >2 cm residual disease (D).

Figure 3.

Tumor-infiltrating lymphocytes (TILs) changes before and after neoadjuvant chemotherapy. Intratumoral-TIL (It-TIL, A) and stromal-TIL (Str-TIL, B) level changes from diagnostic core biopsy (prechemotherapy) to surgical specimen (postchemotherapy) for patients having a High-TIL residual disease after neoadjuvant chemotherapy. Illustration of a case changing from Low-TIL (core biopsy, C) to High-TIL (residual disease, D).