HER2-low status as a dynamic biomarker in breast cancer: molecular and clinical correlations

Background. The majority of breast cancers (BC) are HER2-low defined by an immunohistochemical score of 1+ or 2+ with a negativefluorescence in situ hybridization (FISH) test.The prognostic significance of HER2- low BC remains controversial, but demonstrates immunosuppressive activity and disruption of the cGAS- STING pathway. Trastuzumab-deruxtecan is effective in HER2-low due to its immunomodulatory properties. The development of new HER2-targeted therapy is relevant for the correction of the immunosuppressive microenvironment. 
Objective: to study the molecular features and clinical significance of HER2-low status depending on the genetic profile of HER2-negative breast cancer. 
Material and Methods. A retrospective study (2022–2023) included 282 patients with hereditary and sporadic BC. A genetic analysis of HRR gene mutations was performed at N.N. Petrov National Research Medical Center of Oncology. TILs and pathological response were evaluated. Immunohistochemistry included antibodies to estrogen, progesterone, HER2, Ki67, CD8, CD4, CD68, and CD163 receptors. The statistical analysis was performed using IBM SPSS Statistics v.22. 
Results. Hereditary BC is often associated with HER2-zero status due to mBRCA1/2 (p<0.001), while mutations in other HRR genes are associated with HER2-low status (p<0.05). HER2-low BC is associated with the luminal A subtype, low tumor-infiltrating lymphocytes (TILs 1 score), high proportion of macrophages (CD68≥67 %) and low level of T-lymphocytes (CD4+TILs<2.5 %, CD8+TILs<6 %), which reduces the effectiveness of chemotherapy. With the luminal subtype, HER2-low does not affect diseasefree survival (DFS), but it improves DFS in women under the age of 43 years. The presence of mBRCA2 worsens survival in HER2-zero status, and mBRCA1 in HER2-low breast cancer status. HER2-low status demonstrates discordance between the primary tumor and its metastases, with a common shift from HER2- zero to HER2-low. 
Conclusion. HER2-low status is a biomarker in advanced BC that expands therapeutic options. Further development and optimization of breast cancer treatment strategies is required, taking into account the molecular profile and microenvironment of the tumor.

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