title: The impact of ERBB-family germline single nucleotide polymorphisms on survival response to adjuvant trastuzumab treatment in HER2-positive breast cancer.
abstract: 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.
  
  
  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.
authors: Medical Oncology Group, Department of Molecular Medicine, Royal College of Surgeons in Ireland, Ireland.
authors: Sinead
authors: S
authors: Toomey
authors: Population Health Sciences Division, Royal College of Surgeons in Ireland, Ireland.
authors: Stephen F
authors: SF
authors: Madden
authors: School of Medicine, University College Dublin, Ireland.
authors: Simon J
authors: SJ
authors: Furney
authors: University College Dublin, UCD School of Biomolecular and Biomedical Science, Conway Institute of Biomolecular and Biomedical Research, Ireland.
authors: Yue
authors: Y
authors: Fan
authors: Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Ireland.
authors: Mark
authors: M
authors: McCormack
authors: Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Ireland.
authors: Carragh
authors: C
authors: Stapleton
authors: Medical Oncology Group, Department of Molecular Medicine, Royal College of Surgeons in Ireland, Ireland.
authors: Mattia
authors: M
authors: Cremona
authors: Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Ireland.
authors: Gianpiero L
authors: GL
authors: Cavalleri
authors: Medical Oncology Group, Department of Molecular Medicine, Royal College of Surgeons in Ireland, Ireland.
authors: Malgorzata
authors: M
authors: Milewska
authors: Medical Oncology Group, Department of Molecular Medicine, Royal College of Surgeons in Ireland, Ireland.
authors: Naomi
authors: N
authors: Elster
authors: Medical Oncology Group, Department of Molecular Medicine, Royal College of Surgeons in Ireland, Ireland.
authors: Aoife
authors: A
authors: Carr
authors: Department of Histopathology, Beaumont Hospital, Dublin, Ireland.
authors: Joanna
authors: J
authors: Fay
authors: Department of Histopathology, Beaumont Hospital, Dublin, Ireland.
authors: Elaine W
authors: EW
authors: Kay
authors: St Vincent's University Hospital, Dublin Ireland.
authors: Susan
authors: S
authors: Kennedy
authors: St Vincent's University Hospital, Dublin Ireland.
authors: John
authors: J
authors: Crown
authors: University College Dublin, UCD School of Biomolecular and Biomedical Science, Conway Institute of Biomolecular and Biomedical Research, Ireland.
authors: William M
authors: WM
authors: Gallagher
authors: Medical Oncology Group, Department of Molecular Medicine, Royal College of Surgeons in Ireland, Ireland.|Department of Oncology, Beaumont Hospital, Dublin, Ireland.
authors: Bryan T
authors: BT
authors: Hennessy
authors: Medical Oncology Group, Department of Molecular Medicine, Royal College of Surgeons in Ireland, Ireland.
authors: Alex J
authors: AJ
authors: Eustace
mesh_terms: D000483:Alleles; D000074322:Antineoplastic Agents, Immunological / Q000627:therapeutic use; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality*; D017024:Chemotherapy, Adjuvant; D005260:Female; D005838:Genotype; D018095:Germ-Line Mutation; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D016016:Proportional Hazards Models; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D000068878:Trastuzumab / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D000074322:Antineoplastic Agents, Immunological; D014408:Biomarkers, Tumor; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab
keywords: ERBB-family germline mutations; high depth sequencing; single nucleotide polymorphisms; survival impact