Contribution of genotoxic anticancer treatments to the development of multiple primary tumours in the context of germline TP53 mutations

Kasper, Edwige; Angot, Émilie; Colasse, Élodie; Nicol, Lionel; Sabourin, Jean‐Christophe; Adriouch, Sahil; Lacoume, Yann; Charbonnier, Camille; Raad, Sabine; Frébourg, Thierry; Flaman, Jean–Michel; Bougeard, Gaëlle

doi:10.1016/j.ejca.2018.06.011

Cited by 39 publications

(23 citation statements)

References 25 publications

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“…In our series, the respective role of chemotherapy and radiotherapy in the occurrence of second malignancies is not easy to evaluate. Among the 36 second malignancies, only nine arose in a radiation field, suggesting that the role of chemotherapy in the development of multiple primary tumors could be comparable with that of radiotherapy 9 . On the basis of these data, we suggest a reduction of both radio‐ and chemotherapy, whenever possible, without compromising the survival chances.…”

Section: Discussionmentioning

confidence: 73%

“…The increased risk of second malignancy after radiotherapy in patients with LFS was described a long time ago 3,26,27 . More recently, Kasper et al 9 . demonstrated the deleterious role of chemotherapy.…”

Section: Discussionmentioning

confidence: 98%

“…Due to the probable role of genotoxic treatments in the risk of second malignancies in TP53 mutation carriers, 1‐9,26,27 specific guidelines should be designed for these patients in order to reduce this risk without compromising RMS management. The increased risk of second malignancy after radiotherapy in patients with LFS was described a long time ago 3,26,27 .…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, lymphocytes from TP53 mutation carriers display a constitutive defect in the transcriptional response to DNA damaging agents. Moreover, in an LFS mouse model, chemotherapy and radiotherapy increase significantly the risk of tumor development 9 . Although these data strongly suggest a role of treatment in the pathogenesis of second malignancies in TP53 mutation carriers, specific guidelines for cancer treatment in these patients are still not available.…”

Section: Introductionmentioning

confidence: 99%

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Rhabdomyosarcoma associated with germline TP53 alteration in children and adolescents: The French experience

Pondrom

Bougeard²,

Karanian

et al. 2020

Pediatric Blood & Cancer

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Objective To describe the clinical characteristics and outcome of patients with Li‐Fraumeni–associated rhabdomyosarcoma (RMS). Method Retrospective analysis of data from 31 French patients with RMS diagnosed before the age of 20 years associated with a TP53 pathogenic germline variant. Cases were identified through the French Li‐Fraumeni database. Central histologic review was performed in 16 cases. Results The median age at diagnosis was 2.3 years, and the median follow‐up was 9.1 years (0.3‐34.8). The main tumor sites were head and neck (n = 13), extremities (n = 8), and trunk (n = 8). The local pathology report classified the 31 tumors in embryonal (n = 26), alveolar (n = 1), pleomorphic (n = 1), and spindle‐cell (n = 1) RMS (missing = 2). After histological review, anaplasia (diffuse or focal) was reported in 12/16 patients. Twenty‐five patients had localized disease, three had lymph node involvement, and three distant metastases. First‐line therapy combined surgery (n = 27), chemotherapy (n = 30), and radiotherapy (n = 14) and led to RMS control in all, but one patient. Eleven patients relapsed, and 18 patients had second malignancies. The 10‐year event‐free, progression‐free, and overall survival rates were 36% (95% CI: 20‐56), 62% (95% CI: 43‐77) and 76% (95% CI: 56‐88), respectively. The 10‐year cumulative risk of second malignancies was 40% (95% CI: 22‐60). Conclusion The high incidence of multiple primary tumors strongly influences the long‐term prognosis of RMS associated with TP53 pathogenic germline variants. Anaplastic RMS in childhood, independently of the familial history, should lead to TP53 analysis at treatment initiation to reduce, whenever possible, the burden of genotoxic drugs and radiotherapy in carriers and to ensure the early detection of second malignancies.

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Section: Discussionmentioning

confidence: 73%

Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Rhabdomyosarcoma associated with germline TP53 alteration in children and adolescents: The French experience

Pondrom

Bougeard²,

Karanian

et al. 2020

Pediatric Blood & Cancer

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“…The demonstration of the contribution of radiotherapy and conventional chemotherapy to the development of subsequent primary tumours in these carriers came from consistent observations of sequential development of multiple tumours after treatment by chemo- or radiotherapy of a first tumour and the development of tumours within the radiotherapy field [ 6 ]. A cause-effect was strongly supported by studies of the impact of chemo- and radiotherapy in lymphocytes with wild-type or mutant TP53 genotype and LFS mouse models [ 37 ]. Therefore, in cancer patients, testing for disease-causing TP53 variants must absolutely take place before starting treatment and if a disease-causing TP53 variant is found, priority should be given to surgical or ablative treatments, avoiding radiotherapy when possible and using preferably non-genotoxic chemotherapies.…”

Section: Introductionmentioning

confidence: 99%

Guidelines for the Li–Fraumeni and heritable TP53-related cancer syndromes

et al. 2020

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Fifty years after the recognition of the Li–Fraumeni syndrome (LFS), our perception of cancers related to germline alterations of TP53 has drastically changed: (i) germline TP53 alterations are often identified among children with cancers, in particular soft-tissue sarcomas, adrenocortical carcinomas, central nervous system tumours, or among adult females with early breast cancers, without familial history. This justifies the expansion of the LFS concept to a wider cancer predisposition syndrome designated heritable TP53-related cancer (hTP53rc) syndrome; (ii) the interpretation of germline TP53 variants remains challenging and should integrate epidemiological, phenotypical, bioinformatics prediction, and functional data; (iii) the penetrance of germline disease-causing TP53 variants is variable, depending both on the type of variant (dominant-negative variants being associated with a higher cancer risk) and on modifying factors; (iv) whole-body MRI (WBMRI) allows early detection of tumours in variant carriers and (v) in cancer patients with germline disease-causing TP53 variants, radiotherapy, and conventional genotoxic chemotherapy contribute to the development of subsequent primary tumours. It is critical to perform TP53 testing before the initiation of treatment in order to avoid in carriers, if possible, radiotherapy and genotoxic chemotherapies. In children, the recommendations are to perform clinical examination and abdominal ultrasound every 6 months, annual WBMRI and brain MRI from the first year of life, if the TP53 variant is known to be associated with childhood cancers. In adults, the surveillance should include every year clinical examination, WBMRI, breast MRI in females from 20 until 65 years and brain MRI until 50 years.

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Phenotype analysis of families with TP53 germline variants at the Center for Familial Breast and Ovarian Cancer, Cologne

Kast,

Rhiem,

Larsen

et al. 2024

Cancer Medicine

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PurposeTumor protein p53 (TP53) pathogenic variant (PV) carriers are identified during genetic testing for hereditary causes of cancer. PVs in TP53 are associated with the Li‐Fraumeni syndrome (LFS), and thus, surveillance and preventive measures are important for TP53 PV carriers. However, the penetrance of TP53 PVs can be low if the Chompret criteria are not fulfilled. In this study, we compared the phenotypic characteristics of families that did and did not fulfill the LFS criteria according to Chompret.MethodsThe German Consortium for Hereditary Breast and Ovarian Cancer (GC‐HBOC) database was used to identify index patients with a likely pathogenic/pathogenic TP53 variant and their family members. The study investigated the type of variant, pedigree, age of onset, number of primary tumors, and histological type of BC.ResultsTP53 PV were present in the index cases of 35 families, 57% (20/35) of which fulfilled the Chompret criteria. The median age of onset at first BC diagnosis was lower in families that fulfilled the Chompret criteria compared to those who did not. Four of all diseased individuals were minors (4%; 4/105) when malignancy was first diagnosed. Sarcomas and brain tumors occurred in 10% (10/105) and in 7% (7/105) of all diseased persons, respectively. BC was the most frequently occurring first tumor (60%; 62/105) and additional malignancy (45%; 20/44) in this cohort. Subsequent malignancies developed in 31% (20/65) of the individuals who fulfilled the Chompret criteria compared with 15% (6/40) of those who did not.ConclusionThe tumor spectrum and age of onset found in this study showed that tumors other than BC had low disease penetrance in TP53 PV carriers identified using the GC‐HBOC criteria for genetic testing.

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Contribution of genotoxic anticancer treatments to the development of multiple primary tumours in the context of germline TP53 mutations

Cited by 39 publications

References 25 publications

Rhabdomyosarcoma associated with germline TP53 alteration in children and adolescents: The French experience

Rhabdomyosarcoma associated with germline TP53 alteration in children and adolescents: The French experience

Guidelines for the Li–Fraumeni and heritable TP53-related cancer syndromes

Phenotype analysis of families with TP53 germline variants at the Center for Familial Breast and Ovarian Cancer, Cologne

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