Association of tumor infiltrating lymphocyte quantity with survival in patients (pts) with metastatic breast cancer (MBC) receiving microtubule-targeting agents: Post hoc analysis CALGB 40502 (Alliance).
Authors: Stover Daniel G. , Salgado Roberto , Savenkov Oleksandr , Ballman Karla V. , Magbanua Mark Jesus Mendoza , Loi Sherene , Mayer Erica L. , Vater Mark , Glover Kristyn , Watson Mark A , Wen Yujia , Symmans W. Fraser Fraser , Perou Charles , Carey Lisa A. , Partridge Ann H. , Rugo Hope S. 
Published: June 2023

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Background: Stromal tumor infiltrating lymphocyte (sTIL) quantity is prognostic in primary breast cancer, yet MBC is characterized by lower sTILs. No study has definitively evaluated the association of sTIL quantity with survival outcome in the metastatic (met) setting without checkpoint blockade. CALGB (Alliance) 40502 was a randomized phase 3 trial of 799 MBC pts receiving first-line chemotherapy, comparing paclitaxel, nab-paclitaxel or ixabepilone with or without bevacizumab. We hypothesized that sTILs quantity is associated with outcome in MBC. Methods: 582 submitted hematoxylin and eosin slide images from 443 unique pts were evaluable for sTILs in accordance with International TILs Working Group methods. Analysis of sTILs was based on most recent available tissue, with 161/443 (36.3%) having recurrent/met tissue. Using prespecified thresholds of <5% (low) vs ≥5% (high) for sTIL distribution in the met setting, associations between sTILs low/high or as a continuous variable were evaluated with baseline characteristics and outcome. The primary objective was to evaluate the association of sTILs with progression-free survival (PFS) and overall survival (OS), with chemotherapy arm as a covariate. Results: High sTILs were more frequent among pts with hormone receptor (HR)-negative disease (64% HRneg vs 34% HRpos, p<0.001), with no significant association with treatment arm, age, menopausal status, race/ethnicity, or body mass index (BMI). Among all evaluable slides, mean sTILs were higher for primary tumors than met (mean 13.3% primary vs 8.4% met, p=3e-4). Among non-lymph node met sites, sTILs ranged from 1.3% (bone) to 9.5% (lung). Among 100 unique pts with paired primary and met slides, the primary had significantly greater mean sTILs (10.5% vs 7.7%, p=0.008). For the primary objective, Cox proportional hazard model of sTILs low vs high was significantly associated with worse PFS (HR 1.34; 95% CI 1.1-1.63, p=0.004) and OS (HR 1.32; 95% CI 1.07-1.63, p=0.009) when controlling for treatment arm. When controlling for both treatment arm and HR status, association of sTILs low vs high demonstrated similar trends but did not reach statistical significance for PFS (HR 1.2; 95% CI 0.97-1.47, p=0.09) or OS (HR 1.14; 95% CI 0.91-1.43, p=0.2). There was no significant interaction between sTILs and chemotherapy arm (all p-interaction >0.05). Conclusions: Immune activation measured by sTILs is significantly lower in met tumors than primary breast cancer and varies by met site. In this trial, sTILs were associated with progression-free and overall survival in chemotherapy-treated MBC, with a trend toward independent value adjusted for other prognostic features. Clinical trial information: NCT00785291 .