Denkert C, et al. - This study was designed in order to contemplate the relevance of tumour-infiltrating lymphocytes (TILs) for chemotherapy response and prognosis in patients with triple-negative breast cancer (TNBC), HER2-positive breast cancer, and luminal–HER2-negative breast cancer. It was determined that the increased TIL concentration speculated the response to neoadjuvant chemotherapy in all molecular subtypes assessed. It correlated with a survival benefit in HER2-positive breast cancer and TNBC. On the other hand, increased TILs served as an adverse prognostic factor for survival in luminal–HER2-negative breast cancer. This, in turn, pointed towards a varied biology of the immunological infiltrate in this subtype. The following assumption was supported in this trial: Breast cancer being immunogenic could be targetable by immune-modulating therapies. The interaction of the immune system with different types of endocrine therapy necessitated additional exploration.

Methods

• Through 6 randomised trials done by the German Breast Cancer Group, patients with primary breast cancer who were treated with neoadjuvant combination chemotherapy were selected.
• A scrutiny was conducted of the pretherapeutic core biopsies from 3,771 patients for the number of stromal TILs by standardised methods, based on the guidelines of the International TIL working group.
• TILs were examined both as a continuous parameter and in three predefined groups of low (0-10% immune cells in stromal tissue within the tumour), intermediate (11-59%), and high TILs (≥60%).
• The yielded results were utilized in univariable and multivariable statistical models for investigating the link between TIL concentration and pathological complete response in all patients, and between the amount of TILs and disease-free survival and overall survival in 2,560 patients from five of the six clinical trial cohorts.

Results

• A pathological complete response (pCR) was achieved in 45 (6%) of 759 patients with low TILs, 48 (11%) of 435 with intermediate TILs, and 49 (28%) of 172 with high TILs, in the luminal-HER2-negative breast cancer subtype.
• Herein, pCR was observed in 194 (32%) of 605 patients with low TILs, 198 (39%) of 512 with intermediate TILs, and 127 (48%) of 262 with high TILs, in the HER2-positive subtype.
• It was noted that in the TNBC subtype, the achievement of pCR was reported in 80 (31%) of 260 patients with low TILs, 117 (31%) of 373 with intermediate TILs, and 136 (50%) of 273 with high TILs (p < 0.0001 for each subtype, Χ² test for trend).
• A connection was disclosed between a 10% increase in TILs with longer disease-free survival in TNBC (hazard ratio [HR] 0.93 [95% CI 0.87-0.98], p=0.011) and HER2-positive breast cancer (0.94 [0.89-0.99], p=0.017), but not in luminal-HER2-negative tumours (1.02 [0.96-1.09], p=0.46), in the univariable analysis.
• Additionally, a correlation was determined between the increase in TILs with longer overall survival in TNBC (0.92 [0.86-0.99], p=0·032).
• However, no link was revealed in HER2-positive breast cancer (0.94 [0.86-1.02], p=0.11).
• It correlated with shorter overall survival in luminal-HER2-negative tumours (1.10 [1.02-1.19], p=0.011).