Abstract PS5-09: Tumour infiltrating lymphocytes of prognostic value in different molecular breast cancer subgroups and as a suggestive predictive factor for adjuvant tamoxifen benefit in premenopausal patients after 30 years follow-up
Authors: Lundgren Christine , Bendahl Pär-Ola , Ekholm Maria , Fernö Mårten , Forsare Carina , Krüger Ute , Nordenskjöld Bo , Stål Olle , Rydén Lisa 
Published: February 2021

Abstract
BACKGROUND The molecular breast cancer subgroups comprise diverse immune biology; for human epidermal growth factor receptor 2-positive (HER2+) breast cancer (BC) and triple-negative breast cancer (TNBC) abundance of tumour infiltrating lymphocytes (TILs) have been shown to indicate good prognosis and could predict pathological complete response after neoadjuvant chemotherapy. In contrast, the clinical relevance of TILs in estrogen receptor-positive/HER2-negative (ER+/HER2-) tumours is not settled. We primary aimed to analyse the prognostic effect of TILs on BC-free interval (BCFi) in premenopausal patients, stratified by molecular subgroups. The secondary aim was to investigate the predictive value of TILs on tamoxifen benefit.
METHODS Archival tissue from primary tumours was collected from patients included in the SBII:2pre trial. In this study, 564 premenopausal women were randomised between two years of adjuvant tamoxifen or no systemic treatment regardless of hormone-receptor status. TILs were scored on whole tissue sections and the tumours were divided into ER+/HER2- (n = 255), HER2+ (n = 65) and TNBC (n = 95) molecular subgroups by immunohistochemistry and in situ hybridisation (ISH). The prognostic value of TILs was evaluated in patients allocated to no systemic therapy, whose tumours were successfully scored for TILs and had IHC/ISH data for generating molecular subgroups (n = 221). All patients with ER+ tumours and successfully annotated TILs were considered for prediction of tamoxifen benefit (n = 321). The median follow-up was 28 years and the prognostic and predictive analyses were performed by cumulative incidence curves and Cox regression analyses.
RESULTS TILs were successfully scored in 477 tumours with available ER status and the proportion of low (&lt;10%), intermediate (10-49%) and high (≥50%) TILs were 52% (n = 248), 33% (n = 157) and 15% (n = 72), respectively. High infiltration of TILs was a favourable prognostic factor (univariable analysis: hazard ratioBCFi (HRBCFi) 0.40; 95% confidence interval (CI) 0.22-0.71; P = 0.002) (Table 1). The results were essentially the same in the ER+/HER2- molecular subgroup (HRBCFi 0.40; 95% CI 0.14-1.09; P = 0.07). Adjuvant tamoxifen improved prognosis in patients with ER+ tumours and TILs levels &lt;50%, (univariable analysis HRBCFi 0.63; 95% CI 0.47-0.84; P = 0.002), which was not observed in patients displaying high immune infiltration (≥50%) (HRBCFi 0.84; 95% CI (0.24-2.86); P = 0.77). However, evidence for differential effect of tamoxifen in categories of TILs, i.e. interaction, was weak.
CONCLUSIONS We demonstrate a long-term favorable prognostic value of levels of TILs in a cohort of premenopausal BC patients. This effect seems to be extended to the ER+/HER2- subgroup. A beneficial effect of tamoxifen in ER+ patients was observed in patients with tumours of low TILs infiltration as compared to patients with tumours of high immune infiltration, but we could not confirm a treatment predictive effect.
Table 1. Uni- and multivariable Cox regression analyses of BCFi and OS (control arm)Univariable*MultivariableEndpointBCFiOSBCFiOSHR (95% CI); P valueTILs, category***All molecular subgroups(n = 221)(n = 213)Low (Ref.)1.001.001.001.00Intermediate1.10 (0.78-1.54); 0.611.26 (0.88-1.80); 0.210.61 (0.40-0.93); 0.020.65 (0.41-1.02); 0.06High0.40 (0.22-0.71); 0.0020.52 (0.29-0.95); 0.030.22 (0.11-0.43); &lt;0.0010.23 (0.11-0.48); &lt;0.001ER+/HER2-(n = 136)(n = 135)Low (Ref.)1.001.001.001.00Intermediate1.02 (0.63-1.64); 0.941.02 (0.61-1.71); 0.950.69 (0.42-1.15); 0.160.65 (0.37-1.15); 0.14High0.40 (0.14-1.09); 0.070.55 (0.20-1.52); 0.250.20 (0.06-0.60); 0.0040.30 (0.10-0.96); 0.04HER2+(n = 38)(n = 35)Low (Ref.)1.001.001.001.00Intermediate1.47 (0.62-3.49); 0.391.07 (0.45-2.56); 0.880.47 (0.14-1.60); 0.230.38 (0.11-1.31); 0.13High0.28 (0.08-0.97); 0.050.27 (0.08-0.96); 0.040.06 (0.01-0.56); 0.010.05 (0.01-0.39); 0.005TNBC(n = 47)(n = 43)Low (Ref.)1.001.001.001.00Intermediate0.76 (0.31-1.87); 0.551.24 (0.49-3.14); 0.650.59 (0.21-1.67); 0.321.02 (0.34-3.11); 0.97High0.27 (0.08-0.88); 0.030.44 (0.14-1.36); 0.160.38 (0.11-1.39); 0.150.59 (0.16-2.26); 0.44*Stratified by Region**The following variables were included in multivariable analysis: age (≥40 vs.&lt;40 years), nodal status (0 vs.1-3 vs. ≥4), tumour size (&gt;20 mm vs. ≤20), NHG (1 vs. 2 vs. 3), ER (positive vs. negative), PR (positive vs. negative), HER2 (positive vs. negative), LVI (present vs. absent) and TILs (high vs. intermediate vs. low). Stratified by Region.*** TILs were categorised as low: &lt;10%, intermediate: 10-49% and high: ≥50%Abbreviations: BCFi breast cancer free-interval, OS overall survival, TILs tumour infiltrating lymphocytes, HER2 human epidermal growth factor receptor 2, TNBC triple-negative breast cancer, NHG nottingham histological grade, ER estrogen receptor, PR progesterone receptor, HR hazard ratio, CI confidence interval
Citation Format: Christine Lundgren, Pär-Ola Bendahl, Maria Ekholm, Mårten Fernö, Carina Forsare, Ute Krüger, Bo Nordenskjöld, Olle Stål, Lisa Rydén. Tumour infiltrating lymphocytes of prognostic value in different molecular breast cancer subgroups and as a suggestive predictive factor for adjuvant tamoxifen benefit in premenopausal patients after 30 years follow-up [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS5-09.