Determining the Factors Predicting the Response to Anti-HER2 Therapy in HER2-Positive Breast Cancer Patients

Purpose: We aimed to identify the differently expressed genes or related pathways associated with good responses to anti-HER2 therapy and to suggest a model for predicting drug response in neoadjuvant systemic therapy with trastuzumab in HER2-positive breast cancer patients. Methods: This study was retrospectively analyzed from consecutively collected patient data. We recruited 64 women with breast cancer and categorized them into 3 groups: complete response (CR), partial response (PR), and drug resistance (DR). The final number of patients in the study was 20. RNA from 20 core needle biopsy paraffin-embedded tissues and 4 cultured cell lines (SKBR3 and BT474 breast cancer parent cells and cultured resistant cells) was extracted, reverse transcribed, and subjected to GeneChip array analysis. The obtained data were analyzed using Gene Ontology, Kyoto Gene and Genome Encyclopedia, Database for Annotation, Visualization and Integrated Discovery. Results: In total, 6,656 genes differentially expressed between trastuzumab-susceptible and trastuzumab-resistant cell lines were identified. Among these, 3,224 were upregulated and 3,432 were downregulated. Expression changes in 34 genes in several pathways were found to be related to the response to trastuzumab-containing treatment in HER2-type breast cancer, interfering with adhesion to other cells or tissues (focal adhesion) and regulating extracellular matrix interactions and phagosome action. Thus, decreased tumor invasiveness and enhanced drug effects might be the mechanisms explaining the better drug response in the CR group. Conclusions: This multigene assay-based study provides insights into breast cancer signaling and possible predictions of therapeutic response to targeted therapies such as trastuzumab.

Automated summary

This study aimed to identify differentially expressed genes and pathways associated with good responses to anti-HER2 therapy and predict drug response in HER2-positive breast cancer patients undergoing neoadjuvant systemic therapy with trastuzumab. Analysis of RNA from tissue samples and cell lines revealed 6,656 differentially expressed genes, with 3,224 upregulated and 3,432 downregulated genes in trastuzumab-resistant cell lines. Changes in expression of 34 genes in various pathways were found to be related to the response to trastuzumab-containing treatment, affecting adhesion, extracellular matrix interactions, and phagosome action. This study provides insights into breast cancer signaling and potential predictions of therapeutic response to targeted therapies.