Prognostic relevance of tumor‑infiltrating lymphocytes in residual tumor tissue from patients with triple‑negative breast cancer following neoadjuvant chemotherapy: A systematic review and meta‑analysis

Abstract

Further adjuvant chemotherapy treatment can provide benefits to certain patients with triple-negative breast cancer (TNBC) that fail to achieve pathological complete response (pCR) after the administration of a neoadjuvant chemotherapy (NAC) regimen. However, biomarkers suitable for identifying patients likely to experience poor prognostic outcomes after undergoing additional adjuvant chemotherapy are currently lacking. Accordingly, the present meta-analysis was conducted to explore the relationship between tumor-infiltrating lymphocytes (TILs) or TIL subtypes (CD4⁺ or CD8⁺) in residual tumor (RT) tissue following NAC and TNBC patient prognosis. Relevant studies published through March 2023 were identified in Pubmed, The Cochrane Library, Embase and Web of Science databases. After excluding irrelevant studies, data were extracted from the remaining reports, while study quality was analyzed with the Newcastle-Ottawa Scale. Subsequent analyses were performed with Stata 14.0 and Review Manager 5.3. In total, seven relevant studies incorporating 1,202 patients were identified, all of which were retrospective cohort studies. Pooled analyses demonstrated that those patients exhibiting higher levels of RT TIL infiltration following NAC exhibited significantly improved recurrence-free, metastasis-free and event-free survival (RFS/MFS/EFS) compared with patients with lower RT TIL infiltration levels, together with an improved distant recurrence-free interval (DRFI) [hazard ratio (HR)=0.52; 95% confidence interval (CI)=0.39-0.69; P<0.00001]. In addition, patients exhibiting high RT TIL infiltration exhibited improved overall survival (OS) and breast cancer-specific survival (BCSS; HR=0.49; 95% CI=0.38-0.65; P<0.00001). Additional subgroup analyses revealed that patients with higher TIL infiltration levels or TIL subtype (CD4⁺ or CD8⁺) infiltration exhibited improved RFS/MFS/EFS/DRFI as compared with patients with lower levels of overall TIL or TIL subtype (CD4⁺ or CD8⁺) infiltration in RT tissue (HR=0.35, 95% CI=0.20-0.59, P<0.0001; HR=0.49, 95% CI=0.33-0.71, P=0.0002). Consistently, the OS/BCSS of patients exhibiting high levels of overall TIL or TIL subtype (CD4⁺ or CD8⁺) infiltration was increased compared with patients with lower levels of such infiltration (HR=0.33, 95% CI=0.19-0.59, P=0.0002; HR=0.55, 95% CI=0.41-0.76, P=0.0002). These data thus demonstrate that levels of overall TIL infiltration or infiltration by CD4⁺ or CD8⁺ TILs in RT following NAC can be used as a biomarker to reliably predict prognostic outcomes in patients with TNBC, in addition to highlighting possible targets that may guide the further immunotherapeutic management of these patients.

Keywords: meta-analysis; neoadjuvant chemotherapy; residual tumors; triple-negative breast cancer; tumor-infiltrating lymphocytes.

Figure 1.

Study selection flow chart.

Figure 2.

(A) A graph presenting the risk of bias for each of the indicated items in the form of percentages of the included studies. (B) A summary of the risk of bias for each included study.

Figure 3.

(A) Forest plots representing the association between residual tumor TIL infiltration following neoadjuvant chemotherapy in patients with triple-negative breast cancer and recurrence-free, metastasis-free, event-free and distant recurrence-free interval survival. (B) Subgroup analyses of studies assessing total TILs or TIL subtypes (CD4⁺ or CD8⁺). HR, hazard ratio; CI, confidence interval; TIL, tumor-infiltrating lymphocyte.

Figure 4.

(A) Forest plots representing the association between residual tumor TIL infiltration following neoadjuvant chemotherapy and triple-negative breast cancer patient overall survival and breast cancer-specific survival. (B) Subgroup analyses of studies assessing total TILs or TIL subtypes (CD4⁺ or CD8⁺). HR, hazard ratio; CI, confidence interval; TIL, tumor-infiltrating lymphocyte.

Figure 5.

Funnel plots analyzing potential publication bias pertaining to the relationship between TIL infiltration in residual tumor tissue following neoadjuvant chemotherapy in patients with triple-negative breast cancer and their (A) recurrence-free, metastasis-free and event-free survival/distant recurrence-free interval or (B) overall survival and breast cancer-specific survival. LNHR, Logarithm of the Negative Hazard Ratio; seLN_HR, Standard Error of the Logarithm of the Negative Hazard Ratio.