Abstract P2-07-09: Immune recurrence score (IRS) using 7 immunoregulatory protein expression can predict recurrence in stage I-III breast cancer patients
Authors: Lee D-W , Ryu HS , Lee K-H , Jin M-S , Woo G-U , Suh KJ , Yang Y , Kim H-J , Lee H-B , Kim T-Y , Moon H-G , Han W , Park IA , Noh D-Y , Im S-A 
Published: May 2019

Abstract
Background: Immune cells in the tumor microenvironment play an essential role in tumor progression and regression. However, immunologic characteristics and their prognostic role have not been clearly identified in breast cancer patients. This study aimed to evaluate the immunologic characteristics and their prognostic role in breast cancer patients.
Methods: This study enrolled pathologically proven stage I-III breast cancer patients. We performed immunohistochemical staining in stromal tumor-infiltrating lymphocytes (TILs) using 10 immune markers (PD-1, PD-L1, PD-L2, IDO, TIM3, OX40, OX40L, B7-H2, B7-H3, B7-H4) with known/possible clinical relevance. Expression of PD-1, PD-L1, and PD-L2 was also measured in adjacent tumor tissue. Intensity and proportion of the staining was measured for each immune marker. The intensity of immunohistochemical staining (IS, intensity score) was graded as follows: 0 (negative), 1 (weak), 2 (moderate), 3 (strong). The proportion of staining (PS, proportion score) was graded as follows: 0 (stain under &lt;1%), 1 (1% to 5%), 2 (5% to 10%), 3 (10 to 25%), 4 (25% to 50%), Grade 5 (&gt; 50%). Immune markers were defined as positive with one of the following; IS 1 with PS over 3, IS 2 with PS over 2, IS 3 with PS over 1.
Results: A total of 392 patients, 271 (69.1%) luminal A, 36 (9.2%) luminal B, 32 (8.2%) HER2-positive, and 53 (13.5%) triple negative breast cancers were included. In total, PD-1 was expressed by stromal TILs in 130 (33.2%) patients, PD-L1 in 47 (12.0%), PD-L2 in 109 (27.8%), B7-H2 in 225 (57.4%), B7-H3 in 227 (57.9%), B7-H4 in 106 (27.0%), TIM3 in 111 (28.3%), IDO in 96 (24.5%), OX40 in 137 (34.9%), and OX40L in 165 (42.1%). In addition, PD-L1 was expressed in 15 (3.8%) tumor tissue, PD-L2 in 237 (60.5%), and PD-1 was not expressed in tumor tissue. Each breast cancer subtype showed different immunologic characteristics. Expression of PD-1 (stromal TILs) and PD-L1 (Tumor and stromal TILS) was higher in HER2-positive and triple negative breast cancer. By contrast, expression of TIM-3, OX40, and OX40L by stromal TILs were higher in luminal A and luminal B breast cancer. In the univariate analysis, expression of B7-H3 was associated with worse DFS and expression of OX40 and B7-H4 was associated with favorable DFS. Expression of PD-L1, PD-L2, OX40L, and B7-H2 had a tendency of favorable DFS. We devised an immune recurrence score (IRS) using 7 markers with prognostic value (B7-H2, B7-H3, B7-H4, OX40, OX40L, PD-L1, and PD-L2). Patients were classified as high-risk (31 patients, 7.9%), intermediate-risk (265, 67.6%), or low-risk (96, 24.5%) according to 7 immune marker expression. In the multivariate analysis, IRS low-risk (adjusted HR, 0.14; 95% CI, 0.04 – 0.45; p = 0.001) and intermediate-risk (adjusted HR, 0.32; 95% CI, 0.16 - 0.656.42; p = 0.002) had significantly lower risk of recurrence compared with high-risk. In the subgroup analysis, the prognostic role of IRS were maintained in both luminal A patients and non-luminal A patients.
Conclusions: This study identified immunologic characteristics of breast cancer patients using 10 immune markers. In addition, we devised an IRS with 7 immune markers which may predict recurrence in stage I-III breast cancer patients.
Citation Format: Lee D-W, Ryu HS, Lee K-H, Jin M-S, Woo G-U, Suh KJ, Yang Y, Kim H-J, Lee H-B, Kim T-Y, Moon H-G, Han W, Park IA, Noh D-Y, Im S-A. Immune recurrence score (IRS) using 7 immunoregulatory protein expression can predict recurrence in stage I-III breast cancer patients [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-07-09.