Abstract P4-09-08: Tumor mutational burden in Japanese patients with triple negative breast cancer
Authors: Kurata Kanako , Kubo Makoto , Yuan Yuan , Harada Yurina , Morisaki Takafumi , Shimazaki Akiko , Hayashi Saori , Kawaji Hitomi , Kaneshiro Kazuhisa , Yamada Mai , Kai Masaya , Nakamura Masafumi 
Published: March 2020

Abstract
Background: Immune checkpoint inhibitors (ICIs) has become a new promising treatment in the field of cancer therapy. Therefore, it is important to identify predictors of effect for ICIs in breast cancers (BC). PD-L1 expression and the abundance of TILs were known to be related to tumor mutational burden (TMB). TMB is associated with clinical benefit to ICIs in patients with melanoma, lung and colon cancer. However, the significance of TMB is unclear in BC. In this study, we assessed TMB using the TruSightOncology 500 panel (TSO500) (Illumina, San Diego), which the US Food and Drug Administration had designated as a breakthrough device, and identify characteristics of higher TMB tumors in triple negative breast cancer (TNBC), one of the most clinically aggressive subtypes.
Methods: This study included 30 patients with primary TNBC underwent resection without neoadjuvant chemotherapy. DNA was extracted from FFPE tissue. Next-generation sequencing assay was performed by using the TSO500. The DNA of 523 genes for assessment of small variants, as well as biomarkers related to response to immunotherapy, such as TMB and MSI. TMB was measured in synonymous and/or non-synonymous mutation (mut) per megabase (mb). Total TMB levels were divided into three groups: low (1-5 mut/mb), intermediate (int) (6-19 mut/mb), and high (≥20 mut/mb). PD-L1 were assessed in IHC staining and PD-L1 positivity was defined as PD-L1 expression in ≥1% of tumor cells. TILs were assessed in HE staining and TILs were defined as TILs-high for ≥50% stromal TILs and TILs-low for &lt;50% stromal TILs.
Results: The median age of patients was 63 years old (range: 32-81). The median TMB was 8.56 mut/mb (2.35-14.22). Among the 30 tumors, 8 (26.7%) were TMB-low, 22 (73.3%) were TMB-int, and none was TMB-high. TMB-int tumors had more aggressive features than TMB-low tumors. In TMB-int tumors, nuclear grade 3 were 72.7%, high labeling index of Ki-67 (≥20%) were 54.5%, and PD-L1 positivity on tumor cells were 68.2%. Whereas, PD-L1 positivity were 25.0% in TMB-low tumors (p=0.03). TILs-high were 72.7% in TMB-int and TILs-low were 75.0% in TMB-low (p=0.02). Twelve patients in TMB-int (54.5%) and 1 patient in TMB-low (12.5%) were treated by anthracycline based chemotherapy as an adjuvant chemotherapy. Six patients with TMB-int had recurred within 5 years and 3 of them died. Meanwhile, no one with TMB-low had recurred and died.
Conclusions: Findings of our study demonstrated that higher TMB in TNBC might be a poor prognostic factor. We could expect this breakthrough device to be useful for the treatment strategy in patients with TNBC.
Citation Format: Kanako Kurata, Makoto Kubo, Yuan Yuan, Yurina Harada, Takafumi Morisaki, Akiko Shimazaki, Saori Hayashi, Hitomi Kawaji, Kazuhisa Kaneshiro, Mai Yamada, Masaya Kai, Masafumi Nakamura. Tumor mutational burden in Japanese patients with triple negative breast cancer [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 P4-09-08.