Abstract P2-08-11: Tumor infiltrating lymphocytes (TILs) in ER+/HER2- breast cancer
Authors: Criscitiello C , Vingiani A , Maisonneuve P , Viale G , Esposito A , Viale G , Curigliano G 
Published: May 2019

Abstract
Background: The prognostic role of tumor-infiltrating lymphocytes (TILs) in ER+/HER2- breast cancer (BC) is debated. We evaluated the association of TILs and clinico-pathological features with distant disease-free survival (DDFS) in a large series of patients (pts) with ER+/HER2- BC treated at a single Institution.
Methods: This case-cohort study was constructed using data from a previous mono-institutional study(Maisonneuve, BCR 2014). The initial cohort of 9415 pts included all women who underwent breast surgery for early ER+/HER2- BC at IEO. Then, the cohort was restricted to 3986 pts who underwent surgery in the period 1998-2002, and for whom long-term follow-up data was available. A case-cohort was built by randomly selecting approximately 17% of the above cohort (680 pts). 307 additional pts with an event (distant metastasis or death due to BC) were added to this cohort. TILs were assessed for these 987 cases on centralized H&E-stained slides according to recommendations (Salgado, Ann Onc 2015). TILs were considered both as continuous variable, and dichotomized in low (&lt;5%) vs high (≥5%). The main outcome was DDFS and was calculated from the date of surgery to the date of any first event or the date of last contact with the patient. Median follow-up was 7.5 years (0.1-10). Differences between BC subtypes were assessed using the log-rank test. Univariable and multivariable Cox proportional hazards regression with inverse sub-cohort sampling probability weighting were used to evaluate the risk across groups. Analyses were carried out with the SAS software version 9.4 (Cary NC).
Results: Median TILs was 2% (Q1-Q3 1-4%). Higher TILs were positively associated with pN (p=0.003), tumor grade (p&lt;0.0001), peritumoral vascular invasion (PVI) (p=0.003), Ki-67 (p=0.0001), luminal B subtype (p&lt;0.0001), and chemotherapy (p&lt;0.0001), while they were inversely associated with ER expression (p&lt;0.0001) and age (p=0.02). There was no association with type of endocrine therapy. In multivariable regression analysis, only Ki-67 expression retained significant association with TILs. Age and ER showed a trend towards negative association with TILs. In univariate Cox regression, TILs expression (≥5% vs. &lt;5%) was not associated with DDFS (HR 1.08, 95% CI 0.80-1.46, p=0.62). At stratified cox exploratory analyses, we found an association between high TILs and low risk in very young women (p=0.03) and grade 3 tumors (p=0.047); conversely high TILs were associated with worse outcome in grade 1 tumors (p=0.05). We evaluated TILs by treatment group (chemo vs no chemo). TILs were not associated with DDFS in the group that did not receive chemotherapy. Instead, in the group treated with adjuvant chemotherapy, high TILs were associated with better DDFS (HR 0.52, 95%CI 0.33-0.83, p=0.006), particularly in the group with ki67≥20% (HR 0.50, 95%CI 0.29-0.86, p=0.01).
Conclusion: High TILs in ER+/HER2- BC are significantly associated with several clinico-pathological features of dismal outcome. In this group, treatment escalation might be worthy. Our findings suggest that this subgroup might be more immunogenic, thus deserving the exploration of immunotherapy approaches. The prognostic value of TILs seems to be different in patients treated with or without chemotherapy.
Citation Format: Criscitiello C, Vingiani A, Maisonneuve P, Viale G, Esposito A, Viale G, Curigliano G. Tumor infiltrating lymphocytes (TILs) in ER+/HER2- breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-08-11.