title: Risk algorithms that include pathology adjustment for HER2 amplification need to make further downward adjustments in likelihood scores.
abstract: To assess the need for adjustment in the likelihood of germline BRCA1/2 mutations in women with HER2+ breast cancers. We analysed primary mutation screens on women with breast cancer with unequivocal HER2 overexpression and assessed the likelihood of BRCA1/BRCA2 mutations by age, oestrogen receptor status and Manchester score. Of 1111 primary BRCA screens with confirmed HER2 status only 4/161 (2.5%) of women with HER2 amplification had a BRCA1 mutation identified and 5/161 (3.1%) a BRCA2 mutation. The pathology adjusted Manchester score between 10 and 19% and 20%+ thresholds resulted in a detection rate of only 6.5 and 15% respectively. BOADICEA examples appeared to make even less downward adjustment. There is a very low detection rate of BRCA1 and BRCA2 mutations in women with HER2 amplified breast cancers. The Manchester score and BOADICEA do not make sufficient downward adjustment for HER2 amplification. For unaffected women, assessment of breast cancer risk and BRCA1/2 probability should take into account the pathology of the most relevant close relative. Unaffected women undergoing mutation testing for BRCA1/2 should be advised that there is limited reassurance from a negative test result if their close relative had a HER2+ breast cancer.
authors: Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester Academic Health Sciences Centre (MAHSC), Institute of Human Development, University of Manchester, Manchester, M13 9WL, UK. gareth.evans@cmft.nhs.uk.|Genesis Breast Cancer Prevention Centre, University Hospital of South Manchester NHS Trust, Wythenshawe, Manchester, M23 9LT, UK. gareth.evans@cmft.nhs.uk.|Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester Academic Health Sciences Centre (MAHSC), Central Manchester University Hospitals NHS Foundation Trust, Manchester, M13 9WL, UK. gareth.evans@cmft.nhs.uk.|Manchester Breast Centre, School of Molecular and Clinical Cancer Sciences, The University of Manchester, Manchester, M20 4BX, UK. gareth.evans@cmft.nhs.uk.
authors: D G
authors: DG
authors: Evans
authors: Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester Academic Health Sciences Centre (MAHSC), Institute of Human Development, University of Manchester, Manchester, M13 9WL, UK.|Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester Academic Health Sciences Centre (MAHSC), Central Manchester University Hospitals NHS Foundation Trust, Manchester, M13 9WL, UK.
authors: E R
authors: ER
authors: Woodward
authors: Genesis Breast Cancer Prevention Centre, University Hospital of South Manchester NHS Trust, Wythenshawe, Manchester, M23 9LT, UK.|Manchester Breast Centre, School of Molecular and Clinical Cancer Sciences, The University of Manchester, Manchester, M20 4BX, UK.|Department of Medical Oncology, The Christie, Manchester, M20 4BX, UK.
authors: S J
authors: SJ
authors: Howell
authors: Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester Academic Health Sciences Centre (MAHSC), Central Manchester University Hospitals NHS Foundation Trust, Manchester, M13 9WL, UK.
authors: S
authors: S
authors: Verhoef
authors: Genesis Breast Cancer Prevention Centre, University Hospital of South Manchester NHS Trust, Wythenshawe, Manchester, M23 9LT, UK.|Manchester Breast Centre, School of Molecular and Clinical Cancer Sciences, The University of Manchester, Manchester, M20 4BX, UK.
authors: A
authors: A
authors: Howell
authors: Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester Academic Health Sciences Centre (MAHSC), Central Manchester University Hospitals NHS Foundation Trust, Manchester, M13 9WL, UK.
authors: F
authors: F
authors: Lalloo
mesh_terms: D000328:Adult; D000367:Age Factors; D000465:Algorithms; D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein / Q000235:genetics*; D001940:Breast / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000175:diagnosis / Q000235:genetics / Q000473:pathology*; D055088:Early Detection of Cancer / Q000379:methods; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D005820:Genetic Testing; D018095:Germ-Line Mutation; D006801:Humans; D008875:Middle Aged; D010375:Pedigree; D011336:Probability; D011446:Prospective Studies; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000378:metabolism; D012189:Retrospective Studies; D018570:Risk Assessment / Q000379:methods
chemical_list: D019313:BRCA1 Protein; D024682:BRCA2 Protein; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; C492913:BRCA1 protein, human; C551750:BRCA2 protein, human; C508053:ERBB2 protein, human
keywords: BRCA1; BRCA2; Breast cancer; HER2; Manchester score; Oestrogen