AUTHOR=Uchida Shiro , Kojima Takaaki , Sugino Takashi 

TITLE=Clinicopathological Features, Tumor Mutational Burden, and Tumour-Infiltrating Lymphocyte Interplay in ERBB2-Mutated Breast Cancer: In Silico Analysis

JOURNAL=Pathology and Oncology Research

VOLUME=27

YEAR=2021

URL=https://www.por-journal.com/journals/pathology-and-oncology-research/articles/10.3389/pore.2021.633243

DOI=10.3389/pore.2021.633243

ISSN=1532-2807

ABSTRACT=<p>Recent evidence suggests that somatic mutations in <italic>ERBB2</italic> activate <italic>ERBB2</italic> signaling. These mutations occur at a frequency of approximately 3% in breast cancer (BC). <italic>ERBB2</italic> mutations indicate poor prognosis as they are associated with recurrence and metastasis. This study aimed to evaluate the clinicopathological features, immune infiltration levels, tumor mutational burden (TMB), and tumor-infiltrating lymphocytes (TILs) in <italic>ERBB2</italic>-mutated breast cancer (<italic>ERBB</italic>2-mutated BC) using a bioinformatic approach and publicly available datasets (i.e., TCGA-BRCA and TIMER2.0). <italic>ERBB2</italic>-mutated BCs were associated with a high histological grade. <italic>ERBB2</italic>-mutated BCs comprised invasive breast carcinoma of no special type (21/35, 60%), classic invasive lobular carcinoma (12/35, 34.3%), and pleomorphic invasive lobular carcinoma (2/35, 5.7%). A Kaplan-Meier survival curve demonstrated that <italic>ERBB2</italic>-mutated BC was associated with a significantly worse prognosis compared to <italic>ERBB2</italic> non-mutated BC (<italic>p</italic> &lt; 0.01). Furthermore, 40% (14/35) of the patients with <italic>ERBB2</italic>-mutated BC harbored <italic>CDH1</italic> mutations. Mutations at L755 and V777 accounted for 30.5% of these mutations in <italic>ERBB2</italic>-mutated BC, suggesting that these sites are mutational hot spots in BC, particularly in invasive lobular carcinoma. Of the <italic>ERBB2</italic>-mutated BCs, 8.6% were classified as TIL-high, whereas 77.1% were TILs-low; TMB significantly correlated with TILs (<italic>p</italic> &lt; 0.05). CD8<sup>+</sup> T cell infiltration levels were significantly higher in <italic>ERBB2</italic> non-mutated BC. Among <italic>ERBB2</italic>-mutated BCs, 22.9% were classified as TMB-high, which was significantly higher than the rate in the <italic>ERBB2</italic> non-mutated BC (<italic>p</italic> &lt; 0.01). These findings provide evidence for a link between <italic>ERBB2</italic> mutations and high TMB in BC.</p>