Alleles, Antineoplastic Agents, Immunological, Biomarkers, Tumor, Breast Neoplasms, Chemotherapy, Adjuvant, Female, Genotype, Germ-Line Mutation, Humans, Polymorphism, Single Nucleotide, Prognosis, Proportional Hazards Models, Receptor, ErbB-2, Trastuzumab, Treatment Outcome
This work was supported by the Irish Cancer Society Collaborative Cancer Research Centre, BREASTPREDICT Grant, CCRC13GAL (http://www.breastpredict. com), the Health Research Board (HRA/POR2012/054), NECRET, the North Eastern Cancer Research and Education Trust, and the European Commission (FP7- PEOPLE-2013-IEF - 627027 to SJF).
BACKGROUND: 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). 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.
RESULTS: We 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 METHODS: Using 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.
CONCLUSIONS: The 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.
Physics | Physiology
Toomey S, Madden SF, Furney SJ, Fan Y, McCormack M, Stapleton C, Cremona M, Cavalleri GL, Milewska M, Elster N, Carr A, Fay J, Kay EW, Kennedy S, Crown J, Gallagher WM, Hennessy BT, Eustace AJ. The impact of ERBB-family germline single nucleotide polymorphisms on survival response to adjuvant trastuzumab treatment in HER2-positive breast cancer. Oncotarget. 2016;7(46):75518-75525
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