Abstract P5-02-10: Overexpression of Indoleamine 2,3-dioxygenase 1 in HER2 positive breast cancer correlates with increase of tumor-infiltrating lymphocytes level and worse overall survival
Authors: Kim Jeeyeon , Kim Ahrong , Lee So Jeong 
Published: March 2020

Introduction: HER2+ breast cancer (BC) shows a large amount of mutation burden and high lymphocyte infiltration in the tumor. Tumor-infiltrating lymphocytes (TILs) reflect the host immune reaction against tumor cells, and TILs levels have been studied as prognostic and predictive factors in breast cancers, particularly in the triple-negative and HER2+ subtype. Conversely, tumor cells develop immunosuppressive tumor microenvironment by change the gene expression. This study evaluated the differences in expression of immune-related genes particularly involving immune evasion mechanism according to TILs level and confirmed protein expression in the tumor tissue.

Materials and Methods: This study included 167 patients with primary HER2+ BC who underwent surgery. All hematoxylin and eosin slides of the tumors were reviewed and their TILs level was recorded. All tumors were divided into high and low TILs groups with a cutoff value of 60%. RNA was extracted from formalin-fixed paraffin embedded (FFPE) block of 12 cases to determine their immune-related gene RNA expression levels using the NanoString nCounter® PanCancer Immune Profiling Panel. Among the expressed genes with significance, indoelamine-2,3-dioxygenase 1 (IDO1)expression was further evaluated by immunohistochemistry (IHC) in tissue microarray. The IDO1 expression on tumor cells and TILs was categorized as low or high.

Results: The IDO1 gene expression level was 7.1-fold higher in high-TILs group compared to low-TILs group (p=0.024). High IDO1 expression in the tumor cells and TILs by IHC analysis were related to high-TILs group (Table 1). Tumors with high IDO1 expression showed a high nuclear grade and related to worse overall survival (OS), particularly in hormone receptor-/HER2+ patients (all, p &lt; 0.05). Multivariate analysis indicated that high IDO1 expression in tumor cells was an independent poor prognostic factor for OS (p=0.045, Table 2)

Conclusion: This study demonstrated that HER2+ BC with high TILs level overexpressed IDO1 in tumor tissue. High IDO1 expression in the tumor cell is related to higher nuclear grade and poor OS in patients with HER2+ BC. In conclusion, this study showed that HER2-positive breast cancer has high immunogenicity and is related to the IDO1 immunosuppressive mechanism and related with poor OS. This result indicates that IDO1 targeted therapy may be effective in patients with HER2-positive breast cancer patients.

Table 1. Clinicopathologic features according to IDO1 expression level in HER2+ BCFactorsIDO1TC expressionIDO1TIL expressionLowHighP-value†LowHighP-value‡Age (mean, yr)51.6753.680.20254.0751.780.163Size (median, cm)3.103.350.3763.213.210.997Histologic grade (n, %)0.0540.740Low40 (44.0)22 (28.9)23 (39.0)39 (36.1)High51 (56.0)54 (71.1)36 (61.0)69 (63.9)Nuclear grade (n, %)0.040*0.523Low21 (23.1)8 (10.5)12 (20.3)17 (15.7)High70 (76.9)68 (89.5)47 (79.7)91 (84.3)Lymphovascular invasion(n, %)0.7580.257Absent48 (52.7)42 (55.3)28 (47.5)62 (57.4)Present43 (47.3)34 (44.7)31 (52.5)46 (42.6)Node metastasis(n, %)0.3500.630Absent46 (50.5)32 (42.1)26 (44.1)52 (48.1)Present45 (49.5)44 (57.9)33 (55.9)56 (51.9)AJCC 7th Stage (n, %)0.4710.853Early71 (78.0)55 (72.4)44 (74.6)82 (75.9)Advanced20 (22.0)21 (27.6)15 (25.4)26 (24.1)HR expression (n, %)0.2810.517Positive52 (57.1)37 (48.7)29 (49.2)60 (55.6)Negative39 (42.9)39 (51.3)30 (50.8)48 (44.4)TILs level (n, %)0.047*0.002*Low (≤60%)79 (86.8)56 (73.7)55 (93.2)80 (74.1)High (&gt;60%)12 (13.2)20 (26.3)4 (6.8)28 (25.9)TLSs in DCIS (n, %)0.5240.067Absent58 (63.7)44 (57.9)42 (71.2)60 (55.6)Present33 (36.3)32 (42.1)17 (28.8)48 (44.4)TLSs in invasive component (n, %)0.7440.308Absent58 (63.7)51 (67.1)42 (71.2)67 (62.0)Present33 (36.3)25 (32.9)17 (28.8)41 (38.0)Abb: IDO1TC, IDO1 in tumor cells; IDO1TIL, IDO1 in TILs; TLS, tertiary lymphoid structure

Table 2. Univariate and multivariate analysis of IDO expression for OS in HER2+ BCUnivariateMultivariateFactorsHR95% CIp-valueHR95% CIp-valueIDO1TC expression0.022*0.045*Low(ref)(ref)(ref)(ref)High3.7411.206-11.6023.2161.028-10.060IDO1TIL expression0.771Low(ref)(ref)High0.8610.313-2.368TLSs in DCIS0.036*0.079Absent(ref)(ref)(ref)(ref)Present0.2060.047-0.9050.2620.059-1.169TLSs in invasive0.364Absent(ref)(ref)Present0.5920.191-1.836Abb: OS, overall survival; HR, hazard ratio; CI, confidence interval; IDO1TC, IDO1 in tumor cells; IDO1TIL, IDO1 in TILs; TLS, tertiary lymphoid structure

Citation Format: Jeeyeon Kim, Ahrong Kim, So Jeong Lee. Overexpression of Indoleamine 2,3-dioxygenase 1 in HER2 positive breast cancer correlates with increase of tumor-infiltrating lymphocytes level and worse overall survival [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-02-10.