title: Genetic testing in a cohort of young patients with HER2-amplified breast cancer.
abstract: BACKGROUND
  Young age at diagnosis for breast cancer raises the question of genetic susceptibility. We explored breast cancer susceptibility genes testing on ≤40-year-old patients with HER2-amplified invasive breast cancer.
  
  
  METHODS
  Patients were selected from a large UK cohort study. The inclusion criterion was age ≤40 at diagnosis with confirmed HER2-amplified breast cancer. The probability of finding a BRCA gene mutation was calculated based on family history. Genetic testing used was either clinical testing for BRCA1 and BRCA2, with a subset also tested for TP53 mutations, or research-based testing using a typical panel comprising 17 breast cancer susceptibility genes (CSGs) including BRCA1, BRCA2 and TP53.
  
  
  RESULTS
  Of the 591 eligible patients, clinical testing results were available for 133 cases and an additional 263 cases had panel testing results. BRCA testing across 396 cases found 8 BRCA2 (2%) and 6 BRCA1 (2%) pathogenic mutations. Of the 304 patients tested for TP53 mutations, overall 9 (3%) had deleterious TP53 mutations. Of the 396 patients, 101 (26%) met clinical criteria for BRCA testing (≥10% probability), among whom 11% had pathogenic BRCA mutations (6 BRCA2, 5 BRCA1). Where the probability was calculated to be <10%, only 4 of 295 (1%) patients had BRCA mutations. Among the 59 patients who had TP53 testing meeting the 10% threshold, 7 had mutations (12%). Likely functionally deleterious mutations in 14 lower penetrance CSGs were present in 12 of 263 (5%) panel-tested patients.
  
  
  CONCLUSIONS
  Patients aged <41 at diagnosis with HER2+ breast cancer and no family history of breast cancer can be reassured that they have a low chance of being a high-risk gene carrier. If there is a strong family history, not only BRCA but also TP53 gene testing should be considered. The clinical utility of testing lower penetrance CSGs remains unclear.
authors.affiliation: Faculty of Medicine and Cancer Sciences, University of Southampton, Southampton, UK d.m.eccles@soton.ac.uk.
authors.forename: D M
authors.initials: DM
authors.lastname: Eccles
authors.affiliation: Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Australia Cancer Biology Research Center Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: N
authors.initials: N
authors.lastname: Li
authors.affiliation: Faculty of Medicine and Cancer Sciences, University of Southampton, Southampton, UK.
authors.forename: R
authors.initials: R
authors.lastname: Handwerker
authors.affiliation: Faculty of Medicine and Cancer Sciences, University of Southampton, Southampton, UK.
authors.forename: T
authors.initials: T
authors.lastname: Maishman
authors.affiliation: Faculty of Medicine and Cancer Sciences, University of Southampton, Southampton, UK.
authors.forename: E R
authors.initials: ER
authors.lastname: Copson
authors.affiliation: Faculty of Medicine and Cancer Sciences, University of Southampton, Southampton, UK.
authors.forename: L T
authors.initials: LT
authors.lastname: Durcan
authors.affiliation: Faculty of Medicine and Cancer Sciences, University of Southampton, Southampton, UK.
authors.forename: S M
authors.initials: SM
authors.lastname: Gerty
authors.affiliation: Barts Cancer Institute (CRUK) and Centre for Tumour Biology, Queen Mary University of London, London.
authors.forename: L
authors.initials: L
authors.lastname: Jones
authors.affiliation: Genomic Medicine Institute of Human Development, University of Manchester and St Mary's Hospital, Manchester, UK.
authors.forename: D G
authors.initials: DG
authors.lastname: Evans
authors.affiliation: Barts Cancer Institute (CRUK) and Centre for Tumour Biology, Queen Mary University of London, London.
authors.forename: L
authors.initials: L
authors.lastname: Haywood
authors.affiliation: Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Australia Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia.
authors.forename: I
authors.initials: I
authors.lastname: Campbell
mesh_terms: D000328:Adult; D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D006801:Humans; D011446:Prospective Studies; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D055815:Young Adult
chemical_list: D019313:BRCA1 Protein; D024682:BRCA2 Protein; D018719:Erb-b2 Receptor Tyrosine Kinases; D016159:Tumor Suppressor Protein p53; C495901:TP53 protein, human; C508053:ERBB2 protein, human
keywords: HER2 positive; breast cancer; gene panel; genetic testing; young onset