A small amount of primary breast cancer shows high tumor mutation burden that may benefit from immune checkpoint inhibitor therapy

Background: Targeted therapy using immune checkpoint inhibitors (ICIs) is a major breakthrough in cancer treatment in the last decade. ICIs like PD1 or PD-L1 antibodies have been shown to be quite effective in cancer like melanoma. However, in most other tumor types including breast cancer, the situation is not as optimistic. Only a small percentage of those patients respond to ICIs therapy. This highlights the importance of identifying biomarkers to predict which patients may benefit from such treatment. Tumor Mutation Burden (TMB) has been shown to be a sensitive marker for ICI treatment. This study is to investigate whether TBM could be used as a biomarker for breast cancer treatment. Methods: We reviewed next generation sequencing studies of breast cancer. Two such studies with raw data provided were included in our analysis. One study entitled METABRIC performed targeted sequencing of 173 cancer-related genes in around 2500 primary breast cancer tissues. The other study was from TCGA breast cancer project, which performed Whole Exome Sequencing (WES) of around 1000 primary breast cancer samples. Mutation data were downloaded from public data deposit. The number of mutations per sample was calculated. TBM was calculated by divide the coverage in million base pair from that of the total mutation counts. Results: In METABRIC study, 17272 mutations were identified in 2369 samples, with a median of 7 mutations per sample (95% CI: 6 ˜ 7). The median TMB of METABRIC dataset was 5.8 SNVs/Mb (95% CI: 5 ˜ 5.8). Totally 30 out 2369 (1.3%) samples had a TMB equal or large than 20 SNVs/Mb. In another cohort from TCGA breast cancer study using WES technology, 90172 mutations were identified in 977 samples, with a median of 44 mutations per sample (95% CI: 39 ˜ 50). The median TMB was 1 SNVs/Mb (95% CI: 0.9 ˜ 1.1). Totally 13 out 977 (1.3%) samples had a TMB equal or large than 20 SNVs/Mb. Conclusions: Breast cancer shows middle to low mutation burden compared to other cancer types. Around 1.3% of breast cancer has quite high TMB of at least 20 SNVs/Mb, which may be qualified for immune checkpoint inhibitors therapy. Our study indicates that TMB may be incorporated as a standard test for late stage breast cancer patients in the clinical practice. Keywords: Breast cancer, Tumor Mutation Burden, Whole exome sequencing, Targeted sequencing, Immune checkpoint Citation Format: Wang J, Chen W, Jiang Z, Lin X, Qin T, Yang X, Liu T, Hu H, Li Z, Xie D, Yao H, Song E. A small amount of primary breast cancer shows high tumor mutation burden that may benefit from immune checkpoint inhibitor therapy [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-04-11.