Abstract
IntroductionTumor infiltrating lymphocytes may indicate an immune response to cancer development, but their significance remains controversial in breast cancer. We conducted this study to assess CD8+ (cytotoxic T) lymphocyte infiltration in a large cohort of invasive early stage breast cancers, and to evaluate its prognostic effect in different breast cancer intrinsic subtypes.MethodsImmunohistochemistry for CD8 staining was performed on tissue microarrays from 3992 breast cancer patients. CD8+ tumor infiltrating lymphocytes were counted as intratumoral when in direct contact with tumor cells, and as stromal in adjacent locations. Kaplan-Meier functions and Cox proportional hazards regression models were applied to examine the associations between tumor infiltrating lymphocytes and breast cancer specific survival.ResultsAmong 3403 cases for which immunohistochemical results were obtained, CD8+ tumor infiltrating lymphocytes were identified in an intratumoral pattern in 32% and stromal pattern in 61% of the cases. In the whole cohort, the presence of intratumoral tumor-infiltrating lymphocytes was significantly correlated with young age, high grade, estrogen receptor negativity, human epidermal growth factor receptor-2 positivity and core basal intrinsic subtype, and was associated with superior breast cancer specific survival. Multivariate analysis indicated that the favorable prognostic effect of CD8+ tumor infiltrating lymphocytes was significant only in the core basal intrinsic subgroup (Hazard ratio, HR = 0.35, 95% CI = 0.23-0.54). No association with improved survival was present in those triple negative breast cancers that lack expression of basal markers (HR = 0.99, 95% CI = 0.48-2.04) nor in the other intrinsic subtypes.ConclusionsCD8+ tumor infiltrating lymphocytes are an independent prognostic factor associated with better patient survival in basal-like breast cancer, but not in non-basal triple negative breast cancers nor in other intrinsic molecular subtypes.
Highlights
Tumor infiltrating lymphocytes may indicate an immune response to cancer development, but their significance remains controversial in breast cancer
Two other studies have tested larger series: one study used a retrospective cohort of 1,334 patients with primary breast cancer diagnosed from 1987 to 1998 in the UK and showed that total CD8+ tumor-infiltrating lymphocyte (TIL) were independently associated with better survival in breast cancer [23], whereas another study with 1,953 breast cancer cases treated in the University Hospital Basel in Switzerland between 1985 and 1996 demonstrated that the independent favorable prognostic effect of total CD8 + TILs was observed only in those with estrogen receptor-negative (ER-) tumors (whereas, in univariate analyses, CD8+ TILs had an unfavorable effect on outcome in ER-positive (ER+) breast cancers) [24]
Because analytical results from all types of TILs interpretation were broadly similar, results presented in this paper are based primarily on intratumoral tumor-infiltrating lymphocyte (iTIL) analysis, which is the fastest and simplest to perform
Summary
Tumor infiltrating lymphocytes may indicate an immune response to cancer development, but their significance remains controversial in breast cancer. Two other studies have tested larger series: one study used a retrospective cohort of 1,334 patients with primary breast cancer diagnosed from 1987 to 1998 in the UK and showed that total CD8+ TILs were independently associated with better survival in breast cancer [23], whereas another study with 1,953 breast cancer cases treated in the University Hospital Basel in Switzerland between 1985 and 1996 demonstrated that the independent favorable prognostic effect of total CD8 + TILs was observed only in those with estrogen receptor-negative (ER-) tumors (whereas, in univariate analyses, CD8+ TILs had an unfavorable effect on outcome in ER-positive (ER+) breast cancers) [24]. The extent to which TILs contribute to tumor progression and clinical outcome in breast cancer has remained controversial, possibly because the effect is limited to certain subgroups of patients
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