Abstract P4-15-03: Tumor-infiltrating lymphocytes in breast ductal carcinoma in situ: Correlations with tumor pathobiology in a French cohort of 495 cases (BONBIS)
Authors: Bayol B , Tixier-Deves L , Dauplat M , Kwiatkowski F , Cayre A , Abrial C , Azria D , Penault-Llorca F , Radosevic-Robin N 
Published: February 2018

Abstract
Background: Numerous studies have shown important impact of tumor-infiltrating lymphocytes (TILs) on natural or therapeutically-modified evolution of invasive breast cancer (IBC), however knowledge about TIL role in breast ductal carcinoma in situ (DCIS) is still limited. Because of the lack of reliable prognostic parameters, DCIS treatment is much less personalized than IBC therapy. BONBIS is a phase 3 French multicenter randomized trial designed to compare 2 schemes of adjuvant radiotherapy (adjRT) for DCIS (Azria et al, ASCO meeting 2011, TPS 131). It is accompanied by a translational study of DCIS pathobiology, aimed to discover predictive or prognostic biomarkers. Here we present results of TIL density (TIL-d) assessment, its correlation with pathobiology of the lesions and preliminary clues for further biomarker search in this DCIS cohort. Methods: Formalin-fixed, paraffin-embedded DCIS surgical specimens, obtained before adjRT, were prospectively collected and centrally reviewed for histology (architectural pattern, nuclear grade, proliferation, presence of necrosis), receptor status (ER, PR, HER2) and TIL-d. TIL-d was assessed on H&E-stained DCIS sections and reported as percentage of the DCIS specialized stroma area occupied by lymphocytes, lympho-plasmocytes and plasmocytes. Tumors were classified using the St Gallen 2011 criteria for IBC (PMID 21709140). For purpose of this study, the HER2+ category included all cases with HER2 protein expression scored 2+ and 3+, irrespective of the ERBB2 amplification status. Results: TIL-d was assessed in 495 cases, with distribution as follows: 0-4% TILs (D1): 85.5% (n=423); 5-9% TILs (D2): 9.3% (n=46); ≥10% TILs (D3): 5.2% (n=26). Molecular subclasses of those cases were: luminal A (LumA): 39% (n=192); luminal B (LumB): 25.5% (n=126), HER2+: 28.5% (n=141) and triple-negative (TN): 7% (n=33). TIL-d significantly correlated with molecular subclass: ≥5% TILs (D2) were found in 39.4% (13/33) TN, 22.7% (32/141) HER2+, 18.2% (23/126) LumB and only in 1% (2/192) LumA cases (p&lt;10-7). TIL-d of ≥10% (D3) was found only in 26/495 cases (5.2%) and of ≥50% only in one. Similarly to D2, D3 was most frequent in TN, and then in HER2+, LumB and LumA lesions (15%, 9.2%, 7.1%, 0.5%, resp., p&lt;10-7). TIL-d significantly correlated with 2 architectural patterns: positively with solid (38.8%, 52.2% and 60% of D1, D2 and D3 within the solid lesions, resp., p=0.03) but negatively with cribriform (53%, 32.6% and 28% of D1, D2 and D3 within the cribriform lesions, resp., p=0.0027). Finally, the presence of necrosis was significantly associated with TIL-d of ≥5% (65.7% vs 84.5%, D1 vs D2+D3, p=0.071). Due to still short follow-up, the analysis of predictive factors for survival or adjRT benefit was not performed. Conclusion: This DCIS cohort is characterized by low density of TILs. Richer infiltration by TILs (≥10%) was found, as reported in IBC, in TN and HER2+ lesions, however ≥50% TILs was an extremely rare finding. Interestingly, the LumB cases had TIL-d comparable to the HER2+ cases. The associations between ≥10% TILs and molecular subclass or with DCIS architecture will be evaluated in the future as biomarkers of adjRT impact on survival in this cohort.
Citation Format: Bayol B, Tixier-Deves L, Dauplat M, Kwiatkowski F, Cayre A, Abrial C, Azria D, Penault-Llorca F, Radosevic-Robin N. Tumor-infiltrating lymphocytes in breast ductal carcinoma in situ: Correlations with tumor pathobiology in a French cohort of 495 cases (BONBIS) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-15-03.