Abstract P5-08-14: Tumor Infiltrating lymphocytes (TIL) related genomic signature associated with chemotherapy response and prognosis in subtypes of breast cancer
Authors: Kochi M , Niikura N , Iwamoto T , Bianchini G , Mizoo T , Nogami T , Shien T , Motoki T , Taira N , Masuda S , Doihara H , Fujiwara T , Tokuda Y , Matsuoka J 
Published: May 2016

Abstract
Background: Tumor infiltrating lymphocytes (TIL) in subtypes of breast cancer may provide clinically important information on chemotherapy response and prognosis. However, the standardized methodology for immunohistochemical (IHC)-TIL has not yet been established, reproducible and objective method of evaluation of TIL such as gene expression profiles is warranted. We evaluated whether IHC-TIL level was associated with gene expression profiles and whether such profiles could be used to predict chemotherapy response and prognosis according to subtypes of breast cancers.
Methods: To select TIL associated genes, we used 40 samples with both IHC-TIL information and gene expression profiling data. The degree of TIL at the edges of the tumor mass, in the tumor mass, or in the stroma surrounding the expanding mammary ducts packed by carcinoma cells was evaluated as score 0, 1, and 2, when TIL was not unrecognizable (0%), sparse (0 &lt;&lt; 50%) and dense (50% ≤), respectively. We selected 22 genes as the TIL-gene signature (GS), by comparing expression profiles between TIL score 2 and 0 tumors. We showed the associations between the TIL-GS levels and subtypes of breast cancers (Estrogen receptor: ER / Human Epidermal growth factor 2: HER2). The chemotherapy sensitivity analysis was performed on cohorts of 625 patients with stage I–III breast cancer who received neo adjuvant chemotherapy (NAC) based on Anthracycline and Taxane containing regimen. Data from 1,586 tumors were used to evaluate the association between distant metastasis free survival (DMFS) and the TIL-GS in a Kaplan-Meier analysis.
Results: The TIL-GS for ER negative (-)/HER2- and HER2 positive (+) cases were significantly higher expression level than luminal types (p-value &lt;0.001). All breast cancer subtypes except luminal-low proliferation had significantly higher differential TIL-GS level in cases with pathological complete response (pCR) after NAC than residual disease (luminal-high: p-value = 0.013, HER2+: 0.005, and ER-/HER2-: 0.016). With no adjuvant chemo or only tamoxifen treated breast cancer data set, the TIL-GS had no prognostic power in luminal cases regardless of proliferative level. In HER2+ breast cancers, cases with the high TIL-GS had significantly better prognosis than low cases (p-value =0.001), but no significance in ER-/HER2- cases (p-value = 0.621).
Conclusions: Higher TIL-gene signature of 22 genes appeared to be associated with aggressive subtypes and pCR rate (except luminal-low) of breast cancers. This approach may improve the reproducibility of assessment on tumor TIL level and thus serve the clinical applications for breast cancers.
Citation Format: Kochi M, Niikura N, Iwamoto T, Bianchini G, Mizoo T, Nogami T, Shien T, Motoki T, Taira N, Masuda S, Doihara H, Fujiwara T, Tokuda Y, Matsuoka J. Tumor Infiltrating lymphocytes (TIL) related genomic signature associated with chemotherapy response and prognosis in subtypes of 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 P5-08-14.