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MRI Features Associated with High and Low Expression of Tumor-Infiltrating Lymphocytes: Stratified Analysis According to Molecular Subtypes1First affiliated hospital of Wenzhou Medical University, Wenzhou, China, 2University of California, Irvine, IRVINE, CA, United States, 3University of California, Irvine, Irvine, CA, United States
Synopsis
Keywords: Visualization, Breast, Cancer
Motivation: Tumor-infiltration lymphocytes (TILs) express variably in different molecular subtypes.
Goal(s): To compare the rate of high vs. low TILs and MRI features in three subtypes: Hormonal-Receptor positive, HER2 negative (HR+/HER2-), HER2+, and TN, and compare imaging features in each subtype.
Approach: The percentage of TILs of 457 breast cancers was assessed. Three radiologists reviewed MRI features.
Results: HER2+ cancers were more likely to present as non-mass enhancement (NME). In HR+, high TILs cases were more likely to present peritumoral edema. In TN, high TILs cases were more likely to present regular shapes and circumscribed margins.
Impact: TILs expression increases from HR+ to HER2+ to TN. MRI features in different molecular subtypes show substantial variations. Different models should be built for different subtypes when building MR radiomics models to predict TILs.
Introduction
TILs in breast cancer have been proven as a promising predictive and prognostic biomarker. It is a crucial component of the tumor microenvironment associated with the metabolism of tumor cells and the local immune response. Patients with cancers of high TILs are more likely to respond well to neoadjuvant therapy and immunotherapy and have improved progression-free survival. However, the quantitative assessment of TILs on pathological slides is limited by the sampling bias in the biopsied specimen and the requirement of extensive staining of a large surgical specimen. Several studies have shown that it is feasible to use MR imaging features to predict the expression level of TILs, and some have further applied radiomics analysis to build models to differentiate high vs. low TILs cases. It is known that the expression of TILs is different in different molecular subtypes; thus, the studies analyzing the mixed subtypes would be heavily dependent on the composition of subtypes, and the obtained results are not generalizable. To further investigate the association of MR imaging features with TILs and subtypes, three analyses were performed in this study: (1) Comparison of the rate of high vs. low TILs in three subtypes: Hormonal-Receptor positive, HER2 negative (HR+/HER2-), HER2 positive (HER2+), and Triple negative (TN); (2) Comparison of the MR imaging features between these three subtypes; (3) In each subtype, the comparison of imaging features between high vs. low TILs cases.Methods
A total of 457 patients with pathologically diagnosed breast cancer were included in this study. A 3.0 T MR scanner performed the breast MRI before the biopsy. The protocol included T2, DWI, and DCE-MRI. The expression of TILs was evaluated on H&E-stained slides according to the recommendations by an International TILs Working Group 2014. The percentage of TILs in the stroma adjacent to the tumor cells was assessed, stratified as low (< 10%) and high (≥ 10%). MRI features, including morphology as mass or non-mass enhancement (NME), shape, margin, internal enhancement, presence of peritumoral edema, and the DCE kinetic pattern were assessed and compared between groups.Results
Of the 241 HR+/HER2- cases, the majority 197/241 (82%) had low TILs, and only 44/241 (18%) had high TILs. There were 134 HER2+ cases, 84/134 (63%) low TILs and 50/134 (37%) high TILs. Of the 82 TN, 46/82 (56%) had low TILs, and 36/82 (44%) had high TILs. The composition of high TILs was significantly increased from HR+ to HER2+ to TN (p<0.001, Table 1). For MRI features among the three subtypes (Table 1), the size was smaller for HR+/HER2- (p<0.001); HER2+ was more likely to present as NME (p=0.031); homogeneous enhancement was only seen in HR+ (p<0.001); and the peritumoral edema was present in 45% HR+, 71% HER2+, and 80% TN (p<0.001). The MRI features between low and high TILs in each subtype are listed in Table 2. In HR+/HER2-, the peritumoral edema was more likely to be present in high TILs (31/44, 70%) than in low TILs (78/197, 40%, p<0.001). In TN, high TILs are more likely to present a regular shape (12/36, 33%) than low TILs (6/46, 13%, p=0.029); and also, high TILs are more likely to present the circumscribed margin (7/36, 19%) than low TILs (1/46, 2%, p=0.009).Discussion
It is reported that the prognostic significance of TILs in breast cancer differs according to the different molecular subtypes. The high level of TILs has a positive impact on the neoadjuvant chemotherapy response on all subtypes. Some previous studies have demonstrated that MR imaging could help distinguish breast cancers with low vs intermediate or high TILs levels. However, they did not separately analyze cases based on different molecular subtypes. In this study, the results showed the composition of high TILs was significantly increased from HR+ to HER2+ to TN subtype. The tumor size was smaller for HR+/HER2-, HER2+ was more likely to present as NME, homogeneous enhancement was primarily seen in HR+, and the peritumoral edema was mainly present in HER2+ and TN. In HR+/HER2-, peritumoral edema was likelier in high TILs than in low TILs. In TN, high TILs were more likely to present a regular shape and circumscribed margin than low TILs. Several MRI features significantly differed between high and low TILs, which may help to determine the TILs status in diagnostic MRI to assist in selecting optimal treatments. Different models should be built for different subtypes when building MR radiomics models to predict TILs.Acknowledgements
This study was supported in part by Research Incubation Project of First Affiliated Hospital of Wenzhou Medical University (No. FHY2019085), Wenzhou Science & Technology Bureau (No. Y20210232), Zhejiang Provincial Natural Science Foundation of China (LY21F020030) and Key Laboratory of Intelligent Medical Imaging of Wenzhou (No. 2021HZSY0057).References
[1]. Stanton SE, Adams S, Disis ML: Variation in the Incidence and Magnitude of Tumor-Infiltrating Lymphocytes in Breast Cancer Subtypes: A Systematic Review. JAMA Oncol 2016, 2(10):1354-1360.
[2]. Loi S, Drubay D, Adams S, Pruneri G, et al: Tumor-Infiltrating Lymphocytes and Prognosis A Pooled Individual Patient Analysis of Early-Stage Triple-Negative Breast Cancers. J Clin Oncol 2019, 37(7):559-569.
[3]. Salgado R, Denkert C, Demaria S, et al: The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014. Ann Oncol 2015, 26(2):259-271.
[4]. Ku YJ, Kim HH, Cha JH, et al: Correlation Between MRI and the Level of Tumor-Infiltrating Lymphocytes in Patients With Triple-Negative Breast Cancer. AJR Am J Roentgenol 2016, 207(5):1146-1151.
[5]. Bian T, Wu Z, Lin Q, et al: Evaluating Tumor-Infiltrating Lymphocytes in Breast Cancer Using Preoperative MRI-Based Radiomics. J Magn Reson Imaging 2022, 55(3):772-784.
[6]. Su GH, Xiao Y, Jiang L, et al: Radiomics features for assessing tumor-infiltrating lymphocytes correlate with molecular traits of triple-negative breast cancer. J Transl Med 2022, 20(1):471.
[7]. Lee HJ, Lee JE, Jeong WG, et al: HER2-Positive Breast Cancer: Association of MRI and Clinicopathologic Features With Tumor-Infiltrating Lymphocytes. AJR Am J Roentgenol 2022, 218, 258-269.
[8]. Denkert, C, von Minckwitz, G, Darb-Esfahani S, et al: Tumour-infiltrating lymphocytes and prognosis in different subtypes of breast cancer: a pooled analysis of 3771 patients treated with neoadjuvant therapy. Lancet Oncol 2018, 19, 40-50.
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