ORIGINAL ARTICLE – BREAST ONCOLOGY Interobserver Agreement Between Pathologists Assessing Tumor- Infiltrating Lymphocytes (TILs) in Breast Cancer Using Methodology Proposed by the International TILs Working Group Shannon K. Swisher 1 , Yun Wu, MD, PhD 2 , Carlos A. Castaneda, MD 3 , Genvieve R. Lyons, MSPH 4 , Fei Yang, MD 5 , Coya Tapia, MD 5 , Xiuhong Wang, MD 2 , Sandro A. A. Casavilca, MD 6 , Roland Bassett, MS 4 , Miluska Castillo, MD 3 , Aysegul Sahin, MD 2 , and Elizabeth A. Mittendorf, MD, PhD 1 1 Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX; 2 Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX; 3 Department of Clinical Medicine, Instituto Nacional de Enfermedades Neoplasicas (INEN), Lima, Peru; 4 Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX; 5 Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX; 6 Department of Pathology, Instituto Nacional de Enfermedades Neoplasicas (INEN), Lima, Peru ABSTRACT Background. The presence of tumor-infiltrating lympho- cytes (TILs) in breast tumors is prognostic and predictive, suggesting that TILs may be an important biomarker. Recently, an international TILs working group formulated consensus recommendations for TIL evaluation. The cur- rent study was performed to determine interobserver agreement using that methodology. Methods. Tumor-infiltrating lymphocytes were assessed on a single hematoxylin and eosin (H&E)-stained slide obtained from the core biopsy of 75 triple-negative breast cancers. Four pathologists independently reviewed each slide and evaluated stromal TILs (sTILs) and intratumoral TIL (iTILs). The kappa statistic was used to estimate interobserver agreement for identification of sTILs, and the intraclass correlation coefficient (ICC) was used to esti- mate the agreement among observers for iTILs. Cases with poor agreement were reviewed to identify pathologic fac- tors that may contribute to the lack of agreement. Results. The kappa statistic for sTIL evaluation was 0.57 (standard error, 0.04). For iTILs, the ICC calculated to determine internal consistency within raters was 0.65 (95 % confidence interval [CI] 0.56–0.74; p \ 0.0001), and the ICC calculated to determine agreement among raters was 0.62 (95 % CI 0.50–0.72; p \ 0.0001). In 10 cases (13 %), there was not agreement between three of four pathologists. The pathologic features contributing to difficulty in TIL enumeration included marked individual tumor cell necrosis or apoptosis, the presence of reactive plasma cells mimicking tumor cells, plasmatoid tumor cells, and accurate quantification of TILs in specimens with focal areas of heavy immune infiltrate. Conclusion. Acceptable agreement in TIL enumeration was observed, suggesting that the proposed methodology can be used to facilitate the use of TILs as a biomarker in research and clinical trial settings. Based on the success of immunotherapeutic agents in the treatment of melanoma and lung cancer, there is growing interest in the potential for immunotherapeutic strategies in the treatment of many solid tumor types, including breast cancer. Interest in using immunotherapy to treat breast cancer has been limited historically due to the belief that breast tumors are nonimmunogenic. Recent studies, however, have shown that breast cancers, particu- larly human epidermal growth factor receptor 2 (HER2)- positive and triple-negative tumors are in fact immuno- genic, as evidenced by the presence of tumor-infiltrating Electronic supplementary material The online version of this article (doi:10.1245/s10434-016-5173-8) contains supplementary material, which is available to authorized users. Ó Society of Surgical Oncology 2016 First Received: 12 November 2015 E. A. Mittendorf, MD, PhD e-mail: eamitten@mdanderson.org Ann Surg Oncol DOI 10.1245/s10434-016-5173-8