The role of tumor-infiltrating lymphocytes (TILs) in ER+/HER2- breast cancer (BC) is debated. We evaluated the association of TILs and clinico-pathological (CP) features with distant disease-free survival (DDFS) in a large series of patients (pts) with ER+/HER2- BC.
A case-cohort was built by randomly selecting 17% of an initial cohort of 3986 pts who underwent surgery at IEO in the period 1998-2002, and for whom long-term follow-up data was available (680 pts). 307 more pts with an event were added to this cohort. TILs were assessed for these 987 cases on centralized H&E slides. TILs were considered both as continuous variable, and dichotomized in low (<5%) vs high (≥5%). DDFS was calculated from the date of surgery to the date of any first event or the date of last contact with the patient. Median f-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.
Median TILs was 2%. Higher TILs were positively associated with pN (p = 0.003), grade (p < 0.0001), peritumoral vascular invasion (p = 0.003), Ki-67 (p = 0.0001), lumB subtype (p < 0.0001), and chemotherapy (p < 0.0001), while they were inversely associated with ER (p < 0.0001) and age (p = 0.02). 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. <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 G3 tumors (p = 0.047); high TILs were associated with worse outcome in G1 tumors (p = 0.05). TILs were not associated with DDFS in the group without chemo. Instead, in the group with chemo, high TILs were associated with better DDFS (p = 0.006), particularly for ki67≥20% (p = 0.01).
High TILs in ER+/HER2- BC are significantly associated with several CP features of dismal outcome. This subgroup might be more immunogenic, thus deserving the exploration of immunotherapy approaches.
Carmen Criscitiello.
Has not received any funding.
All authors have declared no conflicts of interest.