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.

Figure 1

Structural domains of HER2 protein.

Figure 2

The mechanism of action of different drugs (italics and striped) on HER receptor signaling pathways. HER: human epidermal growth factor receptor; MAPK: mitogen-activated protein kinase; PI3K: phosphatidylinositol 3-kinase; Akt: serine/threonine kinase Akt, also known as PKB (protein kinase B); ECD: extracellular domain; TMD: transmembrane domain; TKD: tyrosine kinase domain.

Figure 3

Pharmacological impacts of the SNPs reviewed in this study. The sensitivity of HER2 mutants to different drugs used as anti-HER2 therapy is shown. The pharmacological products have different levels of activity against mutant HER2+ proteins in vitro. When data from in vivo studies (xenotransplant and/or breast cancer patients) were available, they were considered for the analysis. Furthermore, some mutants that have been described to be sensitive to specific inhibitors in preclinical analyses were instead found to be resistant to the same drugs; in this case, we have indicated this information as inconclusive data.

Figure 4

Schematic diagram of HER2 protein with the locations of the SNPs reviewed in this study found in HER2-positive breast cancer patients. Domains I, II, III, and IV belong to the extracellular domain (ECD); TMD: transmembrane domain; JMD: juxtamembrane domain; TKD: tyrosine kinase domain.