Radio-induced malignancies after breast cancer postoperative radiotherapy in patients with Li-Fraumeni syndrome

Abstract

BackgroundThere are no specific recommendations for the management of breast cancer patients with germ-line p53 mutations, an exceptional genetic condition, particularly regarding postoperative radiotherapy. Preclinical data suggested that p53 mutations conferred enhanced radiosensitivity in vitro and in vivo and the few clinical observations showed that Li-Fraumeni families were at a higher risk of secondary radio-induced malignancies.MethodsWe reviewed a cohort of patients with germ-line p53 mutations who had been treated for breast cancer as the first tumor event. We assessed their outcome and the incidence of secondary radio-induced malignancies.ResultsAmong 47 documented Li-Fraumeni families treated from 1997 to 2007 at the Institut Gustave Roussy, 8 patients had been diagnosed with breast cancer as the first tumor event. Three patients had undergone conservative breast surgery followed by postoperative radiotherapy and five patients had undergone a mastectomy (3 with postoperative radiotherapy). Thus, 6/8 patients had received postoperative radiotherapy. Median follow-up was 6 years. Median age at the diagnosis of the primary breast cancer was 30 years. The histological characteristics were as follows: intraductal carcinoma in situ (n = 3), invasive ductal carcinoma (n = 4) and a phyllodes tumor (n = 1). Among the 6 patients who had received adjuvant radiotherapy, the following events had occurred: 3 ipsilateral breast recurrences, 3 contralateral breast cancers, 2 radio-induced cancers, and 3 new primaries (1 of which was an in-field thyroid cancer with atypical histology). In contrast, only one event had occurred (a contralateral breast cancer) among patients who had not received radiation therapy.ConclusionsThese observations could argue in favor of bilateral mastectomy and the avoidance of radiotherapy.

Next-generation sequencing for the diagnosis of hereditary breast and ovarian cancer using genomic capture targeting multiple candidate genes

“…In patients harbouring germline TP53 mutations, several studies have highlighted the risk of secondary tumours in the field of radiotherapy suggesting that, in a breast patient with germline TP53 mutation, radiotherapy should be avoided. [35][36][37] This is a strong additional argument justifying the inclusion of TP53 in a diagnostic NGS panel for breast cancer. Nevertheless, considering the wide LFS tumour spectrum and tumour risk in children, TP53 testing should be carefully considered and the medical implications of a positive test should be clearly explained to the patient before the test.…”

Clinical Response to a Lapatinib-Based Therapy for a Li-Fraumeni Syndrome Patient with a Novel HER2V659E Mutation

“…Nevertheless, mutations affecting the V659 residue within the transmembrane domain of HER2 have not been identifi ed in human tumors until now. Of note, the human HER2 V659E mutation necessarily implies a tandem dinucleotide change (TT>AA), a type of mutation that may arise from induced pyrimidine adducts in response to radiotherapy ( 26 ). The patient did not receive radiotherapy; however, the dinucleotide genomic alteration might have been caused by another type of irradiation, including the one from the frequent X-ray/ CT scans conducted on the patient.…”

Genetic predisposition in children with cancer – affected families' acceptance of Trio-WES

“…For instance, LFS patients are highly susceptible to radiationinduced tumorigenesis and alkylating chemotherapy and, thus, have an increased risk of developing secondary cancers [5,7].…”