Tumor-Infiltrating Lymphocytes and Prognosis: A Pooled Individual Patient Analysis of Early-Stage Triple-Negative Breast Cancers

Abstract

Purpose: The aim of the current study was to conduct a pooled analysis of studies that have investigated the prognostic value of tumor-infiltrating lymphocytes (TILs) in early-stage triple negative breast cancer (TNBC).

Methods: Participating studies had evaluated the percentage infiltration of stromally located TILs (sTILs) that were quantified in the same manner in patient diagnostic samples of early-stage TNBC treated with anthracycline-based chemotherapy with or without taxanes. Cox proportional hazards regression models stratified by trial were used for invasive disease-free survival (iDFS; primary end point), distant disease-free survival (D-DFS), and overall survival (OS), fitting sTILs as a continuous variable adjusted for clinicopathologic factors.

Results: We collected individual data from 2,148 patients from nine studies. Average age was 50 years (range, 22 to 85 years), and 33% of patients were node negative. The average value of sTILs was 23% (standard deviation, 20%), and 77% of patients had 1% or more sTILs. sTILs were significantly lower with older age ( P = .001), larger tumor size ( P = .01), more nodal involvement ( P = .02), and lower histologic grade ( P = .001). A total of 736 iDFS and 548 D-DFS events and 533 deaths were observed. In the multivariable model, sTILs added significant independent prognostic information for all end points (likelihood ratio χ², 48.9 iDFS; P < .001; χ², 55.8 D-DFS; P < .001; χ², 48.5 OS; P < .001). Each 10% increment in sTILs corresponded to an iDFS hazard ratio of 0.87 (95% CI, 0.83 to 0.91) for iDFS, 0.83 (95% CI, 0.79 to 0.88) for D-DFS, and 0.84 (95% CI, 0.79 to 0.89) for OS. In node-negative patients with sTILs ≥ 30%, 3-year iDFS was 92% (95% CI, 89% to 98%), D-DFS was 97% (95% CI, 95% to 99%), and OS was 99% (95% CI, 97% to 100%).

Conclusion: This pooled data analysis confirms the strong prognostic role of sTILs in early-stage TNBC and excellent survival of patients with high sTILs after adjuvant chemotherapy and supports the integration of sTILs in a clinicopathologic prognostic model for patients with TNBC. This model can be found at www.tilsinbreastcancer.org .

FIG 1.

Study flow chart. CP, clinicopathologic; IPD, individual participant data; iTILs, intratumoral tumor-infiltrating lymphocytes; TILs, tumor-infiltrating lymphocytes.

FIG 2.

Forest plot of the prognostic effect of the stromal tumor-infiltrating lymphocytes (TILs) variable for each 10% increment on (A) invasive disease-free survival, (B) distant disease-free survival, and (C) overall survival. Hazard ratios (HR) are derived using Cox proportional hazards regression models and presented with 95% CIs. The size of the boxes is proportional to the inverse of the variance of the estimator in each study. Cochrane Q-like test (Q) and I² statistics were used to evaluate between-study heterogeneity. BIG, Breast International Group; ECOG, Eastern Cooperative Oncology Group; FinHER, Finland Herceptin; GR, Gustave Roussy; IBCSG, International Breast Cancer Study Group; IEO, European Institute of Oncology; PACS, Protocole Adjuvant dans le Cancer du Sein.

FIG 3.

Kaplan-Meier curves of (A) invasive disease-free survival (iDFS), (B) distant disease-free survival (D-DFS), and (C) overall survival (OS) according to stromal tumor-infiltrating lymphocytes (TILs) dichotomized at the value of 30% in the entire population. Shaded areas correspond to pointwise 95% CIs. P values correspond to log-rank tests.

FIG 4.

Kaplan-Meier curves of (A) invasive disease-free survival (iDFS), (B) distant disease-free survival (D-DFS), and (C) overall survival (OS) according to nodal status and stromal tumor-infiltrating lymphocytes (TILs) dichotomized at the value of 30%. Shaded areas correspond to pointwise 95% CIs. P values correspond to log-rank tests. iDFS estimated 3-year survival for stromal TILs ≥ 30% v < 30% for node negative disease: 92% (95% CI, 0.89 to 0.96) v 88% (95% CI, 0.85 to 0.90); estimated 5-year survival: 88% (95% CI, 0.84 to 0.93) v 81% (95% CI, 0.77 to 0.84). D-DFS estimated 3-year survival for stromal TILs ≥ 30% v < 30% for node-negative disease: 97% (95% CI, 0.95 to 0.99) v 91% (95% CI, 0.88 to 0.83); estimated 5-year survival: 93% (95% CI, 0.89 to 0.96) v 87% (95% CI, 0.84 to 0.90). OS estimated 3-year survival for stromal TILs ≥ 30% v < 30% for node-negative disease: 99% (95% CI, 0.97 to 1.00) v 95% (95% CI, 0.93 to 0.97); estimated 5-year survival: 95% (95% CI, 0.92 to 0.98) v 90% (95% CI, 0.87 to 0.92).