Abstract S1-03: Pooled individual patient data analysis of stromal tumor infiltrating lymphocytes in primary triple negative breast cancer treated with anthracycline-based chemotherapy
Authors: Loi S , Drubay D , Adams S , Francis PA , Joensuu H , Dieci MV , Badve S , Demaria S , Gray R , Piccart MJ , Kellokumpa-Lehtinen P-L , Andre F , Dufaure-Gare I , Denkert C , Salgado R , Michiels S 
Published: May 2016

Background:

Retrospective analyses from individual clinical trials have suggested that host anti-tumor immunity as measured by stromal tumor infiltrating lymphocytes (TILs) is important for the outcomes of the primary triple negative breast cancer (TNBC) subgroup, but the clinical utility of TILs in day-to-day management of primary TNBC is still limited. Our objective was to conduct a pooled analysis of the clinical trials that have investigated TILs in TNBC patients treated by anthracyclines-based (A) chemotherapy regimens in order to gain a robust understanding of the prognostic value of TILs in this setting.

Material and methods:

Methods were predefined in a protocol. Eligible studies were randomized clinical trials that have evaluated the prognostic associations of TILs (evaluated in the same manner) in patients diagnosed with early stage TNBC treated with A or A plus taxanes (A+T). Cox regression models stratified by trial for invasive disease-free survival (IDFS, primary endpoint) and overall survival (OS), fitting stromal TILs as a continuous variable.

Results:

We collected individual data from 991 TNBC patients included in 6 randomized clinical trials (ECOG2197, ECOG1199, BIG2-98, FinHER, 2 from Gustave Roussy): 62% of patients were treated by A+T and 38% by A alone; 32% of patients had no nodal involvement, 43% of patients had 1-3 nodes and 25% patients more than 3 nodes involved. The average age was 49 years (range 22.6-85 yrs) and the average tumor size 3.0 cm (sd 1.7).

Across the entire data set, the average value of stromal TILs was 20% (sd 17%); 90% of patients had at least 1% stromal TILs. After adjusting for trial, stromal TILs were significantly lower with increasing tumor size (linear model, p&lt;0.0001) but not significantly associated with nodal status categories (p=0.52 and p=0.37) nor age (p=0.25). With a median follow-up of 6.6 years for IDFS and 7.3 years for OS, a total of 363 IDFS events and 273 deaths were observed. Each 10% increase in stromal TILs was associated with a 14% relative reduction in IDFS events (HR=0.86, 95% 0.80 to 0.93, p&lt;0.0001) and a 17% relative reduction in deaths (HR=0.83, 95% CI 0.76 to 0.91, p=0.0001). There was no significant evidence for heterogeneity between trials for IDFS (chi2=4.55, p=0.34) nor for OS (chi2=4.45, p=0.34).

In a multivariable analysis adjusted for age, nodal status, tumor size and chemotherapy regimen, stromal TILs added significant independent prognostic information for both IDFS and OS (likelihood chi2=17.9 for IDFS, p&lt;0.0001 and chi2=16.7 for OS, p&lt;0.0001). The adjusted hazard ratio for each 10% increase in stromal TILs was HR=0.86 (0.76-0.92) for IDFS events and HR=0.84 (0.76-0.92) for death.

Conclusion:

This large pooled individual patient data analysis confirms the strong prognostic role of stromal TILS in primary TNBC treated with A or A+T. TILs should now be strongly considered for incorporation as a stratification factor in future clinical trials enrolling TNBC patients. Given the important prognostic role of pre-existing immunity, patients with TNBC are rational candidates for immunotherapy clinical trials.

Funding:Ligue Nationale Contre le Cancer.

Citation Format: Loi S, Drubay D, Adams S, Francis PA, Joensuu H, Dieci MV, Badve S, Demaria S, Gray R, Piccart MJ, Kellokumpa-Lehtinen P-L, Andre F, Dufaure-Gare I, Denkert C, Salgado R, Michiels S. Pooled individual patient data analysis of stromal tumor infiltrating lymphocytes in primary triple negative breast cancer treated with anthracycline-based chemotherapy. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr S1-03.