Abstract S1-02: Lymphocytic infiltration in invasive lobular breast cancer
Authors: Desmedt C , Salgado R , Buisseret L , Zoppoli G , Fornili M , Van den Eynden G , Garaud S , Gundem G , Rothé F , Brown D , Kheddoumi N , Rouas G , Galant C , Bertucci F , Piccart M , Campbell P , Viale G , Larsimont D , Willard-Gallo K , Biganzoli E , Pruneri G , Sotiriou C 
Published: May 2016

Abstract
Background: The presence and prognostic value of tumor infiltrating lymphocytes (TILs) in invasive breast carcinoma has been demonstrated in several studies, especially in the triple-negative and HER2-positive subtypes. So far, TILs have not been investigated with sufficient detail in invasive lobular breast cancer (ILBC). Here we therefore aimed at: first, assessing the distribution of stromal TILs in ILBC; second, correlating the presence of TILs with standard clinical and pathological markers; third, exploring associations of TILs with recurrent genomic alterations; and, fourth, comparing the lymphocytic composition of ER-positive/HER2-negative lobular to ER-positive/HER2-negative ductal tumors.
Material and methods: The percentage of stromal TILs was independently assessed according to Salgado et al. (Ann Oncol 2015) by three pathologists on full-face hematoxylin and eosin slides in a well-annotated retrospective series of 614 primary ILBCs previously characterized at the genomic level. The median value of TILs was used for the analyses. For the association analyses, we focused on the more homogeneous group of ER-positive/HER2-negative ILBC (555/614). Breast cancer-free interval was used as survival endpoint and the analyses were censored at 12 years of follow-up. The comparison of the lymphocytic composition (relative percentage of CD45+ TILs which are CD4+, CD8+ or CD19+) was assessed by FACS in a separate prospective cohort of 51 ER-positive/HER2-negative lobular and 112 ER-positive/HER2-negative ductal tumors.
Results: The intraclass correlation coefficient between the three pathologists was 0.71 (95%CI:0.65-0.76). The median percentage of stromal TILs was 5% and the interquartile range 5-10%, with only 9% of the samples having ≥ 20%. Greater numbers of TILs were significantly associated with younger age at diagnosis, axillary lymph node involvement, high proliferative tumors as assessed by Ki67, and with the mixed non-classic ILBC subtypes. Greater numbers of TILs were associated with worse prognosis (HR=1.22; 95%CI:1.07-1.38, p=0.003) only in the unadjusted analysis, as it lost significance after adjustment for standard clinical and pathological variables. Greater numbers of TILs were observed in tumors harboring ARID1A, BRCA2, KMT2C and TP53 mutations, as well as chr3p21.31 and chr8q24.23 (PTK2) loss; whereas lower numbers were observed in tumors with ERBB3 mutations as well as chr7p and chr11q14.1 (PAK1) gains. There were no significant differences in the relative proportion of CD4+, CD8+ or CD19+ lymphocytes between ER-positive/HER2-negative lobular and ductal tumors.
Conclusion: In this work, which reports to our knowledge on the largest series of ILBC ever assessed for TILs, we showed that most ILBCs were characterized by low lymphocytic infiltration. Besides the association of TILs with clinical and pathological features of ILBC patients, we found that higher TIL levels were observed in the presence of specific mutations and copy number alterations. Higher numbers of TILs were associated with worse prognosis at the univariate analysis. Finally, based on the assessed markers, we have no evidence of differential lymphocytic composition between ER-positive/HER2-negative lobular and ductal tumors.
Citation Format: Desmedt C, Salgado R, Buisseret L, Zoppoli G, Fornili M, Van den Eynden G, Garaud S, Gundem G, Rothé F, Brown D, Kheddoumi N, Rouas G, Galant C, Bertucci F, Piccart M, Campbell P, Viale G, Larsimont D, Willard-Gallo K, Biganzoli E, Pruneri G, Sotiriou C. Lymphocytic infiltration in invasive lobular breast cancer. [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 S1-02.