Prognostic Value of Stromal Tumor-Infiltrating Lymphocytes in Young, Node-Negative, Triple-Negative Breast Cancer Patients Who Did Not Receive (neo)Adjuvant Systemic Therapy

Abstract

Purpose: Triple-negative breast cancer (TNBC) is considered aggressive, and therefore, virtually all young patients with TNBC receive (neo)adjuvant chemotherapy. Increased stromal tumor-infiltrating lymphocytes (sTILs) have been associated with a favorable prognosis in TNBC. However, whether this association holds for patients who are node-negative (N0), young (< 40 years), and chemotherapy-naïve, and thus can be used for chemotherapy de-escalation strategies, is unknown.

Methods: We selected all patients with N0 TNBC diagnosed between 1989 and 2000 from a Dutch population-based registry. Patients were age < 40 years at diagnosis and had not received (neo)adjuvant systemic therapy, as was standard practice at the time. Formalin-fixed paraffin-embedded blocks were retrieved (PALGA: Dutch Pathology Registry), and a pathology review including sTILs was performed. Patients were categorized according to sTILs (< 30%, 30%-75%, and ≥ 75%). Multivariable Cox regression was performed for overall survival, with or without sTILs as a covariate. Cumulative incidence of distant metastasis or death was analyzed in a competing risk model, with second primary tumors as competing risk.

Results: sTILs were scored for 441 patients. High sTILs (≥ 75%; 21%) translated into an excellent prognosis with a 15-year cumulative incidence of a distant metastasis or death of only 2.1% (95% CI, 0 to 5.0), whereas low sTILs (< 30%; 52%) had an unfavorable prognosis with a 15-year cumulative incidence of a distant metastasis or death of 38.4% (32.1 to 44.6). In addition, every 10% increment of sTILs decreased the risk of death by 19% (adjusted hazard ratio: 0.81; 95% CI, 0.76 to 0.87), which are an independent predictor adding prognostic information to standard clinicopathologic variables (χ² = 46.7, P < .001).

Conclusion: Chemotherapy-naïve, young patients with N0 TNBC with high sTILs (≥ 75%) have an excellent long-term prognosis. Therefore, sTILs should be considered for prospective clinical trials investigating (neo)adjuvant chemotherapy de-escalation strategies.

FIG 1.

(A) CONSORT diagram of all patients included and excluded in the PARADIGM cohort, focusing on patients with sTILs information and tumor BRCA1 status. For 336 patients with a missing subtype, at least one of ER, PR, or HER2 scores was missing. For TNBC, ER-negative and PR-negative are defined with a < 1% expression. ^aFor all analyses where T stage was used, 437 patients were included. ^bFor the analyses with tumor BRCA1 mutation status, 380 patients were used. (B) CONSORT diagram for tumor BRCA1 testing. ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; NCR, Netherlands Cancer Registry; PR, progesterone receptor; sTILs, stromal tumor-infiltrating lymphocytes; T stage, tumor stage; TNBC, triple-negative breast cancer.

FIG 2.

Kaplan-Meier curves for OS according to sTILs categories and T stage: (A) all patients, (B) patients with T1a/b/c tumors, and (C) patients with T2/3 tumors. OS, overall survival; sTILs, stromal tumor-infiltrating lymphocytes; T stage, tumor stage.

FIG 3.

Cumulative incidence functions for distant metastasis or death and second primary malignancy according to sTILs categories and T stage: (A) all patients, (B) patients with T1a/b/c tumors, and (C) patients with T2/3 tumors. Solid lines represent incidence of distant metastasis or death, and dashed lines represent the incidence of competing event. Event, distant metastasis or death; SPM, second primary malignancy; sTILs, stromal tumor-infiltrating lymphocytes; T stage, tumor stage.