Association of tumor-infiltrating lymphocytes (TILs) with clinicopathologic characteristics and prognosis in young women with HR+/HER2- breast cancer (BC).
Authors: Tesch Megan E , Guzman Arocho Yaileen D , Collins Laura C. , Heng Jan , Zheng Yue , Tayob Nabihah , Rosenberg Shoshana M. , Ruddy Kathryn Jean , Tamimi Rulla , Schapira Lidia , Peppercorn Jeffrey M. , Borges Virginia F. , Come Steven E. , Snow Craig , Mittendorf Elizabeth A. , Partridge Ann H. 
Published: June 2023

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Background: Increased TILs are associated with better prognosis in triple-negative BC, including in patients (pts) age < 40. However, the role of TILs remains unclear in HR+/HER2- BC and little data exist in young pts, in whom immune microenvironment could be altered by age-related host/tumor differences. We assessed the extent and composition of immune infiltration in HR+ tumors of young women and correlated with clinicopathologic features and survival outcomes. Methods: From a prospective cohort study of women with BC diagnosed age ≤40, we identified those with stage I-III HR+/HER2- BC and available pre-treatment (tx) tumor tissue. Multiplexed immunofluorescence was used to quantify cytotoxic T (CD8+), T helper (Th, CD3+CD8-), T regulatory (Tregs, FOXP3+CD3+) and exhausted T (PD1+CD8+) cells in stroma and tumor. Univariate analyses tested associations between clinicopathologic variables and immune markers by high or low expression, divided based on median. High vs. low TILs were evaluated in Cox regression analyses for invasive breast cancer-free survival (iBCFS), distant disease-free survival (DDFS) and overall survival (OS). Results: In 390 pts, median age was 37 years (21-40), most had grade 2 (51%), T1 (65%), N0 (63%) tumors and 67% received adjuvant chemotherapy. Black pts (n = 17) had higher expression of stromal CD8+ ( P= .010), FOXP3+CD3+ ( P= .027) and PD1+CD8+ TILs ( P= .043); intratumoral TILs did not differ by race. Older age (36-40) was associated with high expression of CD8+ ( P= .033) and PD1+CD8+ TILs ( P= .031) within stroma and CD3+CD8- TILs within tumor ( P= .046). Grade 3 tumors had higher stromal and intratumoral expression of CD3+CD8- ( P= .002; P< .001) and FOXP3+CD3+ TILs ( P= .020; P< .001). No differences in TILs were seen according to recency of pregnancy, BRCA1/2 status or T/N stage. Over a median follow up of 8 years, 85 iBCFS events, 64 DDFS events and 37 deaths occurred. High stromal expression of CD3+CD8- TILs was associated with better iBCFS (HR 0.49, P= .002) and DDFS (HR 0.57, P= .046), which remained significant when adjusted for T/N stage, grade and chemotherapy (iBCFS HR 0.41, P< .001; DDFS HR 0.45, P= .008). High stromal expression of CD3+CD8- and FOXP3+CD3+ TILs was associated with better OS (HR 0.47, P= .038) and iBCFS (HR 0.58, P= .018), respectively, on adjusted analyses only. High intratumoral expression of CD3+CD8- and FOXP3+CD3+ TILs was associated with better iBCFS (HR 0.59, P= .025; HR 0.63, P= .043) after adjustment only. Conclusions: The distribution of TIL subtypes in young women’s HR+ BC varied according to race, age and grade. High stromal and intratumoral expression of Th and Tregs was associated with improved BC outcomes. Characterization of immune cell subsets could help refine the prognostic value of TILs in HR+ BC, particularly in young pts who may benefit from individualized escalated/de-escalated tx strategies.