Somatic Mutations in HER2 and Implications for Current Treatment Paradigms in HER2-Positive Breast Cancer

Abstract

In one of every four or five cases of breast cancer, the human epidermal growth factor receptor-2 (HER2) gene is overexpressed. These carcinomas are known as HER2-positive. HER2 overexpression is linked to an aggressive phenotype and a lower rate of disease-free and overall survival. Drugs such as trastuzumab, pertuzumab, lapatinib, neratinib, and the more recent afatinib target the deregulation of HER2 expression. Some authors have attributed somatic mutations in HER2, a role in resistance to anti-HER2 therapy as differential regulation of HER2 has been observed among patients. Recently, studies in metastatic ER + tumors suggest that some HER2 mutations emerge as a mechanism of acquired resistance to endocrine therapy. In an effort to identify possible biomarkers of the efficacy of anti-HER2 therapy, we here review the known single-nucleotide polymorphisms (SNPs) of the HER2 gene found in HER2-positive breast cancer patients and their relationship with clinical outcomes. Information was recompiled on 11 somatic HER2 SNPs. Seven polymorphisms are located in the tyrosine kinase domain region of the gene contrasting with the low number of mutations found in extracellular and transmembrane areas. HER2-positive patients carrying S310F, S310Y, R678Q, D769H, or I767M mutations seem good candidates for anti-HER2 therapy as they show favorable outcomes and a good response to current pharmacological treatments. Carrying the L755S or D769Y mutation could also confer benefits when receiving neratinib or afatinib. By contrast, patients with mutations L755S, V842I, K753I, or D769Y do not seem to benefit from trastuzumab. Resistance to lapatinib has been reported in patients with L755S, V842I, and K753I. These data suggest that exploring HER2 SNPs in each patient could help individualize anti-HER2 therapies. Advances in our understanding of the genetics of the HER2 gene and its relations with the efficacy of anti-HER2 treatments are needed to improve the outcomes of patients with this aggressive breast cancer.

Comparative analysis of drug response and gene profiling of HER2-targeted tyrosine kinase inhibitors

“… 32 Previous studies have shown that neratinib has greater activity than lapatinib in HER2 -amplified and HER2 -mutant models. 6 , 15 Our study confirms this finding across multiple cancer types (Fig. 1 ) and provides data showing that neratinib is more effective than tucatinib in HER2 -amplified breast cancer cell lines and in HER-altered cancer cell lines regardless of tumour tissue type (Supplementary Table S1 ).…”

“…Three of the HER2 mutations in the cell line panel (S310F, R678Q, V842I) occur in known HER2 hotspots associated with sensitivity to HER2-targeted agents. 15 The T798I mutation present in two cell lines is a ‘gatekeeper’ mutation that is reported to confer resistance to neratinib. 40 Against this background, neratinib displayed nanomolar anti-proliferative activity against all HER2 -mutant cell lines tested, proving more potent than lapatinib or tucatinib.…”

“… 14 Mutations in HER2 have also been linked to differential sensitivity to lapatinib and neratinib and resistance to trastuzumab. 15 This study aims to provide a direct comparison of anti-proliferative activity of the three TKIs clinically approved for HER2+ breast cancer and assess the activity of lapatinib, neratinib, and tucatinib across multiple cancer types in a 115 cell line panel to identify novel potential biomarkers of TKI response outside of HER2 amplification. Novel predictive drug response biomarkers were identified through cross-analysis of drug response with mutation, copy number variation, and gene expression data.…”

Role of Chromodomain-Helicase-DNA-Binding Protein 4 (CHD4) in Breast Cancer

“…This classification system helps oncologists prescribe the most appropriate treatment, i.e. , endocrine therapy, chemotherapy (alone or combined), and/or HER2-targeted therapy ( 2 , 5 , 6 ). Being able to predict tumor behavior avoids over-treating patients likely to respond well, while those less likely to do so can be given more aggressive treatment ( 7 – 10 ).…”

Molecular intrinsic versus clinical subtyping in breast cancer: A comprehensive review

“…This subpopulation may not be detected with IHC and FISH, and so the potential therapeutic opportunities may be missed. The clinical evidence supporting the use of HER2‐targeted therapy in specific HER2 mutated cancers is underway and the clinical trials can be reviewed elsewhere 94,95 …”