Association between CD8+ Tumor Infiltrating Lymphocytes and the Clinical Outcome of Patients with Operable Breast Cancer Treated with Adjuvant Dose-Dense Chemotherapy—A 10 Year Follow-Up Report of a Hellenic Cooperative Oncology Group Observational Study

SIMPLE SUMMARY: Tumor-infiltrating lymphocytes (TILs) have been reported to contribute to breast cancer (BC) prognosis. The aim of our study was to investigate the prognostic impact of CD8+ TILs and their subtypes in patients with early breast cancer treated with sequential, dose-dense adjuvant chemotherapy. Tumors of 627 patients were examined for total (t), stromal (s), and intratumoral (i) CD8 lymphocyte density (counts/mm(2)). Our results showed that high expression of sCD8, iCD8, and tCD8 correlated with higher Ki67, TILs density, ER/PgR negativity, and higher histological grade. We confirmed that patients with high iCD8+ and tCD8+ TILs had longer DFS and OS, as compared to those with low counts/mm(2). Survival benefit was retained when adjusting for classical clinical and pathological characteristics, but was not correlated to specific BC subtype. More data are needed to empower the prognostic role of TILs and establish their use in clinical practice. ABSTRACT: Tumor-infiltrating lymphocytes (TILs) contribute to breast cancer (BC) prognosis. We investigated the prognostic impact of CD8+ TILs in patients with early breast cancer treated with adjuvant chemotherapy in a large observational clinical trial. Along with a 10 year follow-up, considering the efficacy and safety, we report the results of the translational part of our study. We examined the patients’ tumors for total (t), stromal (s), and intratumoral (i) CD8 lymphocyte density (counts/mm(2)) on tissue-microarray cores. The impact of CD8+ TILs counts on DFS and OS, and its correlation with breast cancer subtypes and standard clinicopathological parameters, were investigated, along with efficacy and safety data. Among the 928 eligible patients, 627 had available CD8+ data. Of which, 24.9% had a high expression of sCD8, iCD8, and total CD8, which were correlated with higher Ki67, TILs density, ER/PgR negativity, and higher histological grade. The 5year DFS and OS rates were 86.1% and 91.4%, respectively. Patients with high iCD8 and tCD8 had longer DFS and OS compared to those with low counts/mm(2) (DFS: HR = 0.58, p = 0.011 and HR = 0.65, p = 0.034 and OS: HR = 0.63, p = 0.043 and HR = 0.58, p = 0.020, respectively). Upon adjustment for clinicopathological parameters, iCD8 and tCD8 retained their favorable prognostic significance for DFS and OS, whereas high sCD8 was only prognostic for DFS. Menopausal status, tumor size, and nodal status retained their prognostic significance in all examined multivariate models. CD8+ TILs, and especially their intratumoral subset, represent a potential favorable prognostic factor in early BC.