Abstract P2-08-02: Tumor-infiltrating lymphocytes (TILs) are a powerful prognostic marker in patients with triple negative breast cancer treated by induction chemotherapy with or without oral low dose cyclophosphamide-methotrexate maintenance chemotherapy (CMM)
Authors: Pruneri G , Gray KP , Vingiani A , Viale G , Curigliano G , Criscitiello C , Láng I , Thürlimann B , Goldhirsch A , Price KN , Cancello G , Munzone E , Gelber RD , Regan MM , Colleoni M 
Published: May 2016

Abstract
Background: TILs have been reported to have a prognostic role in patients with triple negative breast cancer (TNBC) receiving AC-containing regimens, but their predictive role has not been demonstrated. IBCSG Trial 22-00 is a randomized, phase III clinical trial, assessing the efficacy of low dose CMM, following standard adjuvant chemotherapy, in hormone receptor negative breast cancer. Patients were randomly assigned to treatment with adjuvant induction chemotherapy plus oral CMM for 1 year, or induction with no further treatment.
Patients and Methods: Of 724 patients enrolled in Trial 22-00 with TNBC confirmed centrally per 2013 St Gallen criteria (&lt;1% ER/PgR, Her2 negative by IHC or FISH), 672 (93%) had blocks/slides available and gave consent. TILs analysis was retrospectively performed on prospectively collected full face H&E slides, following recent TILs Working Group guidelines. The analytic cohort included 647 (96%) of the 672 samples with TILs results available. Endpoints were breast cancer free interval (BCFI) and overall survival (OS). Cox proportional hazards regression models tested for prognostic association of stromal TILs as a continuous (10% increase) or binary (&lt;50% or ≥50 TILs, lymphocyte-predominant breast cancer, LPBC) variable in univariable (UVA) and multivariable analyses (MVA) adjusted for pathological and demographic factors (age, nodal status and tumor size), and for TILs-by-treatment interaction to assess predictive associations in subgroups.
Results: The median follow-up for the cohort was 6.9 (95% CI: 6.6-7.2) years. Median TILs score was 18%, and 119 (18%) patients had ≥50% TILs. Continuous TILs score was significantly associated with improved BCFI and OS in UVA, with an estimated HR for each 10% increase in TILs score accounting for 0.87 (95%CI: 0.79-0.95, p=.003) and 0.83 (95%CI: 0.74-0.92, p&lt;.001), respectively. The MVA showed consistent results, indicating that TILs as a continuous variable was a powerful prognostic factor for BCFI (HR 0.88, 95%CI: 0.8-0-96, p=.007) and OS (HR 0.84, 95% CI:0.75-0.93, p=.001) for every 10% TILs increase, independent of age, lymph node status and tumor size. When assessed as a binary variable (LPBC vs. non LPBC), the estimated HR for BCFI was 0.56 (95%CI: 0.33-0.94, p=.03) in UVA, and 0.6 (95%CI: 0.36-1.03,p=0.06) in MVA. Patients with higher TILs (LPBC) receiving CMM had breast cancer risk reduction (HR=0.65, 95%CI: 0.22-1.91) when compared with observation, less apparent in patients with &lt;50% TILs (HR=0.94, 95%CI:0.65-1.37), although the TIL-by-treatment interaction was not statistically significant.
Conclusions: TILs are highly prognostic in patients with TNBC treated with different chemotherapy regimens. Interestingly, the risk reduction observed in CMM for patients with higher TILs suggests that TILs may predict clinical benefit from metronomic chemotherapy, a hypothesis deserving further investigation in the lymphocyte subpopulations involved in tumor immunity. The study further demonstrates the need for mandatory collection of tissue blocks from clinical trials.
Citation Format: Pruneri G, Gray KP, Vingiani A, Viale G, Curigliano G, Criscitiello C, Láng I, Thürlimann B, Goldhirsch A, Price KN, Cancello G, Munzone E, Gelber RD, Regan MM, Colleoni M. Tumor-infiltrating lymphocytes (TILs) are a powerful prognostic marker in patients with triple negative breast cancer treated by induction chemotherapy with or without oral low dose cyclophosphamide-methotrexate maintenance chemotherapy (CMM). [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 P2-08-02.