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Abstract
BackgroundTrastuzumab treatment for women with HER2-positive breast cancer (BC) resulted in the significant improvement of both relapse free survival (RFS) and overall survival (OS). However, many women who are classified as HER2-positive do not respond. Many studies have focused on the role of somatic mutations rather than germline polymorphisms in trastuzumab resistance.ResultsWe completed an Agena MassArray screen of 10 ERBB-family single nucleotide polymorphisms (SNPs) in 194 adjuvant trastuzumab treated HER2-positive BC patients. SNPs in EGFR genes have a significant association with RFS and OS. Patients with the minor allele of EGFR N158N had significantly worse OS (hazard ratio (HR) = 4.01, (confidence interval (CI) = 1.53– 10.69), p = 0.05) relative to those with either the heterozygous or wild-type (WT) allele. Patients with the minor allele of EGFR T903T (HR = 3.52, (CI = 1.38– 8.97), p = 0.05) had worse RFS relative to those with either the heterozygous or WT allele.Patients and methodsUsing next generation sequencing (NGS) we identified ERBB-family (EGFR, HER2, HER3 and HER4) single nucleotide polymorphisms (SNPs) that occurred in 2 or more patients of a 32 HER2-positive BC patient cohort. Agena MassArray analysis confirmed the frequency of these SNPs in 194 women with HER2-positive BC who received trastuzumab in the adjuvant setting. Using Kaplan-Meier estimates and Cox regression analysis we correlated the presence of ERBB-family SNPs with both RFS and OS.ConclusionsThe presence of germline ERBB-family SNPs may play an important role in how a patient responds to adjuvant trastuzumab, and clinical assessment of these SNPs by targeted genetic screening of patients' blood may be important to stratify patients for treatment.
Highlights
Breast cancer (BC) remains the most common form of malignancy in women with over 25% of all cancers being diagnosed as breast cancer (BC) in 2012 [1]
We identified 10 individual common ERBB-family single nucleotide polymorphisms (SNPs) present in at least 2 samples in our 194 HER2positive BC patients (Table 1). 5 of the EGFR SNPs occurred in the kinase, transmembrane or growth factor receptor (GFR) domains of the protein
Patients with the HER2 SNP I655V who were homozygous for the minor allele (G) were significantly more likely to have a worse relapse free survival (RFS) rate than those who were homozygous for the WT allele (A) or were heterozygous for the allele (A/G) (HR = 1.79 (CI = 1.00–3.19), p = 0.05, Table 1, Figure 1(A))
Summary
Breast cancer (BC) remains the most common form of malignancy in women with over 25% of all cancers being diagnosed as BC in 2012 [1]. A significant proportion of patients with the disease have tumors that initially do not respond or that acquire resistance to trastuzumab after an initial period of response [3, 4]. Whilst much focus has been targeted towards the somatic mutations in cancer, less attention has been focused on the role of germline single nucleotide polymorphisms (SNPs) and their role in cancer development and therapy response. Recent studies have identified that SNPs can be biomarkers of the likelihood of developing cancer and several have been implicated in targeted therapy response and resistance [6]. Trastuzumab treatment for women with HER2-positive breast cancer (BC) resulted in the significant improvement of both relapse free survival (RFS) and overall survival (OS). Many studies have focused on the role of somatic mutations rather than germline polymorphisms in trastuzumab resistance
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