Akira I Hida1,2, Takahiro Watanabe3, Yasuaki Sagara4, Masahiro Kashiwaba4, Yoshiaki Sagara4, Kenjiro Aogi5, Yasuyo Ohi6, Akihide Tanimoto7. 1. Department of Pathology, Field of Oncology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan. ahida@matsuyama-shimin-hsp.or.jp. 2. Department of Pathology, Matsuyama Shimin Hospital, 2-6-5 Otemachi, Matsuyama, Ehime, 790-0067, Japan. ahida@matsuyama-shimin-hsp.or.jp. 3. Department of Pathology, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan. 4. Department of Breast Surgical Oncology, Hakuaikai Sagara Hospital, Kagoshima, Japan. 5. Department of Breast Oncology, National Hospital Organization Shikoku Cancer Center, Matsuyama, Ehime, Japan. 6. Department of Pathology, Hakuaikai Sagara Hospital, Kagoshima, Japan. 7. Department of Pathology, Field of Oncology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
Abstract
PURPOSE: High-density tumor-infiltrating lymphocytes (TILs) are a prognostic marker for triple-negative breast cancer (TNBC). However, lymphocytic infiltration is heterogeneous in its pattern. We aimed to explore the utility of TIL distribution patterns against TIL density for predicting TNBC prognosis and chemotherapeutic effects. METHODS: Primary invasive TNBC cases were retrieved from a single institutional cohort, and archived samples were reviewed by two board-certificated pathologists. We used 154 consecutive surgical specimens from patients with standard adjuvant therapy, and 80 biopsies taken before primary systemic chemotherapy. The average density of stromal TILs was scored at 10% intervals, while the distribution pattern of TILs was evaluated as diffuse or non-diffuse. The association between TILs and prognosis or pathological complete response (pCR) was statistically analyzed. RESULTS: A diffuse pattern of TILs at primary surgery correlated with better prognosis (relapse-free survival [RFS], hazard ratio [HR] 3.71, 95% confidence interval [CI] 1.60-8.57; overall survival [OS], HR 3.87, 95% CI 1.46-10.27), as well as high TIL density (≥ 50%; RFS, HR 4.51, 95% CI 2.06-9.90; OS, HR 3.28, 95% CI 1.32-8.14). Diffuse TIL pattern and nodal status were independent prognostic factors in multivariate analysis. Diffuse TIL pattern upon biopsy was associated with higher pCR rate (diffuse, 46%; non-diffuse, 21%; P = 0.032). All high TIL cases had diffuse patterns and the best outcome. Interobserver concordance was moderate (k = 0.53-0.55; distribution pattern) to good (weighted k = 0.67-0.69; density), and it was faster to assess the distribution pattern than to assess the density of TIL. CONCLUSIONS: Showing similar clinical impacts to the TIL density, diffuse TILs could be a predictive marker for better prognosis and higher pCR. The assessment of TIL distribution pattern is simple, faster, and practical. Heterogeneous tumor immunity may contribute to further stratification of TNBC treatment.
PURPOSE: High-density tumor-infiltrating lymphocytes (TILs) are a prognostic marker for triple-negative breast cancer (TNBC). However, lymphocytic infiltration is heterogeneous in its pattern. We aimed to explore the utility of TIL distribution patterns against TIL density for predicting TNBC prognosis and chemotherapeutic effects. METHODS:Primary invasive TNBC cases were retrieved from a single institutional cohort, and archived samples were reviewed by two board-certificated pathologists. We used 154 consecutive surgical specimens from patients with standard adjuvant therapy, and 80 biopsies taken before primary systemic chemotherapy. The average density of stromal TILs was scored at 10% intervals, while the distribution pattern of TILs was evaluated as diffuse or non-diffuse. The association between TILs and prognosis or pathological complete response (pCR) was statistically analyzed. RESULTS: A diffuse pattern of TILs at primary surgery correlated with better prognosis (relapse-free survival [RFS], hazard ratio [HR] 3.71, 95% confidence interval [CI] 1.60-8.57; overall survival [OS], HR 3.87, 95% CI 1.46-10.27), as well as high TIL density (≥ 50%; RFS, HR 4.51, 95% CI 2.06-9.90; OS, HR 3.28, 95% CI 1.32-8.14). Diffuse TIL pattern and nodal status were independent prognostic factors in multivariate analysis. Diffuse TIL pattern upon biopsy was associated with higher pCR rate (diffuse, 46%; non-diffuse, 21%; P = 0.032). All high TIL cases had diffuse patterns and the best outcome. Interobserver concordance was moderate (k = 0.53-0.55; distribution pattern) to good (weighted k = 0.67-0.69; density), and it was faster to assess the distribution pattern than to assess the density of TIL. CONCLUSIONS: Showing similar clinical impacts to the TIL density, diffuse TILs could be a predictive marker for better prognosis and higher pCR. The assessment of TIL distribution pattern is simple, faster, and practical. Heterogeneous tumor immunity may contribute to further stratification of TNBC treatment.
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Authors: Zuzana Kos; Elvire Roblin; Rim S Kim; Stefan Michiels; Brandon D Gallas; Weijie Chen; Koen K van de Vijver; Shom Goel; Sylvia Adams; Sandra Demaria; Giuseppe Viale; Torsten O Nielsen; Sunil S Badve; W Fraser Symmans; Christos Sotiriou; David L Rimm; Stephen Hewitt; Carsten Denkert; Sibylle Loibl; Stephen J Luen; John M S Bartlett; Peter Savas; Giancarlo Pruneri; Deborah A Dillon; Maggie Chon U Cheang; Andrew Tutt; Jacqueline A Hall; Marleen Kok; Hugo M Horlings; Anant Madabhushi; Jeroen van der Laak; Francesco Ciompi; Anne-Vibeke Laenkholm; Enrique Bellolio; Tina Gruosso; Stephen B Fox; Juan Carlos Araya; Giuseppe Floris; Jan Hudeček; Leonie Voorwerk; Andrew H Beck; Jen Kerner; Denis Larsimont; Sabine Declercq; Gert Van den Eynden; Lajos Pusztai; Anna Ehinger; Wentao Yang; Khalid AbdulJabbar; Yinyin Yuan; Rajendra Singh; Crispin Hiley; Maise Al Bakir; Alexander J Lazar; Stephen Naber; Stephan Wienert; Miluska Castillo; Giuseppe Curigliano; Maria-Vittoria Dieci; Fabrice André; Charles Swanton; Jorge Reis-Filho; Joseph Sparano; Eva Balslev; I-Chun Chen; Elisabeth Ida Specht Stovgaard; Katherine Pogue-Geile; Kim R M Blenman; Frédérique Penault-Llorca; Stuart Schnitt; Sunil R Lakhani; Anne Vincent-Salomon; Federico Rojo; Jeremy P Braybrooke; Matthew G Hanna; M Teresa Soler-Monsó; Daniel Bethmann; Carlos A Castaneda; Karen Willard-Gallo; Ashish Sharma; Huang-Chun Lien; Susan Fineberg; Jeppe Thagaard; Laura Comerma; Paula Gonzalez-Ericsson; Edi Brogi; Sherene Loi; Joel Saltz; Frederick Klaushen; Lee Cooper; Mohamed Amgad; David A Moore; Roberto Salgado Journal: NPJ Breast Cancer Date: 2020-05-12