Germline TP53 Testing in Breast Cancers: Why, When and How?
Manchester Centre for Genomic Medicine, Division of Evolution and Genomic Sciences, University of Manchester, Manchester M13 9WL, UK
Manchester Centre for Genomic Medicine St Mary’s Hospital, Manchester University Hospitals NHS Foundation Trust, Manchester M13 9WL, UK
Hereditary Cancer Unit, Department of Clinical Genetics, Karolinska University Hospital, SE-17176 Stockholm, Sweden
i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal
Ipatimup-Institute of Molecular Pathology and Immunology of the University of Porto, 4200-135 Porto, Portugal
Porto Comprehensive Cancer Center, 4200-072 Porto, Portugal
Department of Genetics, Rouen University Hospital, Normandy Centre for Genomic and Personalized Medicine, 76000 Rouen, France
Inserm U1245, Normandie University, UNIROUEN, Normandy Centre for Genomic and Personalized Medicine, 76183 Rouen, France
Authors to whom correspondence should be addressed.
Cancers 2020, 12(12), 3762; https://doi.org/10.3390/cancers12123762
Received: 24 November 2020 / Revised: 5 December 2020 / Accepted: 8 December 2020 / Published: 14 December 2020
(This article belongs to the Special Issue Genetic Variants Associated with Breast and Ovarian Cancer Risk)
TP53 variants detected in blood represent a main genetic cause of breast cancers occurring before 31 years of age. TP53 being included in most of the cancer gene panels, patients with breast cancer are offered germline TP53 testing, independently of the age of tumour onset and familial history. Interpretation of TP53 variants is remarkably complex, and detection of a germline disease-causing TP53 variant in a breast cancer patient has drastic medical consequences: radiotherapy contributing to the development of subsequent tumours should be, if possible, avoided. In her family, variant carriers should be offered annual follow-up, including whole-body MRI. Therefore, we consider that, in breast cancer patients, germline TP53 testing should be performed before treatment and that the decision of TP53 testing should not be systematic but based on the age of tumour onset, type of breast cancer, personal and familial history of cancer.
Germline TP53 variants represent a main genetic cause of breast cancers before 31 years of age. Development of cancer multi-gene panels has resulted in an exponential increase of germline TP53 testing in breast cancer patients. Interpretation of TP53 variants, which are mostly missense, is complex and requires excluding clonal haematopoiesis and circulating tumour DNA. In breast cancer patients harbouring germline disease-causing TP53 variants, radiotherapy contributing to the development of subsequent tumours should be, if possible, avoided and, within families, annual follow-up including whole-body MRI should be offered to carriers. We consider that, in breast cancer patients, germline TP53 testing should be performed before treatment and offered systematically only to patients with: (i) invasive breast carcinoma or ductal carcinoma in situ (DCIS) before 31; or (ii) bilateral or multifocal or HER2+ invasive breast carcinoma/DCIS or phyllode tumour before 36; or (iii) invasive breast carcinoma before 46 and another TP53 core tumour (breast cancer, soft-tissue sarcoma, osteosarcoma, central nervous system tumour, adrenocortical carcinoma); or (iv) invasive breast carcinoma before 46 and one first- or second-degree relative with a TP53 core tumour before 56. In contrast, women presenting with breast cancer after 46, without suggestive personal or familial history, should not be tested for TP53.