Abstract S1-08: Prognostic associations of tumor-infiltrating lymphocytes (TIL) in metastatic HER2-positive breast cancer (BC) treated with trastuzumab and pertuzumab: A secondary analysis of the CLEOPATRA study
Authors: Luen S , Salgado R , Stephen F , Peter S , Jennifer E-W , Emma C , Astrid K , Sandra SM , Jose B , Stefan M , Sherene L 
Published: March 2017

Abstract
Background
The presence of stromal TILs (sTILs) is associated with a better prognosis with anti-HER2 therapy in primary HER2-positive BC. The prognostic value of TILs in the advanced setting with pertuzumab-based therapy is unknown.
Methods
The CLEOPATRA trial randomly assigned 808 patients with metastatic HER2-positive BC to receive pertuzumab or placebo in combination with trastuzumab and docetaxel. We evaluated %TILs using our previously described method. For concordance evaluation, 40 slides from metastatic samples were independently analysed by two pathologists. TILs were examined for associations with clinicopathological factors, progression-free survival (PFS), overall survival (OS), and treatment interactions using Cox regression models fitting sTILs as a continuous variable (per 10%) adjusting for treatment arm, age, estrogen receptor (ER) status, PIK3CA genotype, and visceral vs. non-visceral disease at screening.
Results
Tumour samples from 678 (84%) participants were available. 519 (76.5%) were archival and 155 (22.9%) were obtained fresh, ≤45 days prior to study treatment start. Median follow-up for OS was 50 months, with 519 PFS events and 358 deaths. 54% of patients were treatment naïve i.e. had not received prior chemotherapy nor trastuzumab. The median sTIL level was 10% (1-95%). sTIL evaluation was highly concordant between pathologists (R=0.93). Fresh vs. archival samples had significantly lower sTILs (10% vs 15%, p=0.0004). sTIL levels significantly differed by ethnicity (15% Asians, 10% white, 5% African-Americans, p=0.0007), but not age (p=0.26). Higher sTILs were observed in ER-negative vs. ER-positive tumors (15% vs 10%, p&lt;0.001).
In the whole cohort for PFS, higher sTIL levels trended towards a better outcome independent of treatment (adjusted HR:0.95, 95%CI:0.90-1.00, p=0.06). For OS, the prognostic effect of sTILs reached statistical significance, with each 10% increase in sTILs associated with an 11% reduction in the risk of death (adjusted HR:0.89, 95%CI:0.83-0.96, p=0.001). The prognostic effect was observed independent of treatment arm, ER status, PIK3CA genotype, prior treatment or presence of visceral disease at screening, and in both fresh and archival tissue samples.
There was no significant interaction (int) between pertuzumab and sTILs for PFS (Pint=0.4) nor OS (Pint=0.6). There were no significant interactions between pertuzumab and sTILs for OS in subgroups of PIK3CA mutated (Pint=0.2) or PIK3CA WT (Pin=0.2), nor treatment naive (Pint=0.3) vs prior treatment (Pint=0.5).
The 5-year estimates of OS according to median ≤10% vs &gt;10% sTILs in the placebo arm were 26% (95%CI:19-37) vs. 39% (95%CI:32-48), while in the pertuzumab arm 42% (95%CI:33-53) vs. 56% (95%CI:47-66) respectively.
Conclusion
In advanced HER2-positive disease, sTILs are still evident, though at lower levels, but are nevertheless significantly associated with prognosis, with effects stronger for OS than PFS. This suggests that the influence of anti-tumour immunity persists in the advanced first line setting and that enhancement by immunotherapeutic approaches could potentially further improve survival.
Citation Format: Luen S, Salgado R, Stephen F, Peter S, Jennifer E-W, Emma C, Astrid K, Sandra SM, Jose B, Stefan M, Sherene L. Prognostic associations of tumor-infiltrating lymphocytes (TIL) in metastatic HER2-positive breast cancer (BC) treated with trastuzumab and pertuzumab: A secondary analysis of the CLEOPATRA study [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr S1-08.