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

Maria Gaibar,Laura Beltrán,Apolonia Novillo,Alicia Romero-Lorca,Ana Fernández-Santander

doi:10.1155/2020/6375956

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.

Highlights

Breast cancer is the most common cancer type worldwide and is considered a heterogeneous genomic disease in terms of molecular markers, prognosis, and treatments [1, 2]
In vitro and in vivo studies indicate that the presence of somatic human epidermal growth factor receptor-2 (HER2) mutations could influence the clinical outcome of HER2-positive patients under currently approved treatments (Table 1)
In vitro and in vivo studies in metastatic ER + tumors suggest that some HER2 mutations emerge as a mechanism of acquired resistance to endocrine therapy opening new options of treatments in patients with ER + metastatic breast cancer (MBC)

Summary

Introduction

Breast cancer is the most common cancer type worldwide and is considered a heterogeneous genomic disease in terms of molecular markers, prognosis, and treatments [1, 2]. Data from preclinical and clinical studies have attributed somatic mutations in HER2, a role in the constitutive expression [31,32,33] or differential regulation of HER2 that leads to resistance (primary or acquired) to antiHER2 therapy and endocrine therapy [4, 6, 10, 34,35,36]. Such mutations undermine the clinical benefits of HER2-targeted treatment in HER2-positive breast cancer patients. Our working hypothesis was that recurrent mutations in specific HER2 domains in these patients could be good biomarkers of the efficacy of anti-HER2 therapy

Methods

Findings

Pertuzumab