Cancer Precision-Prevention trial of Metformin in adults with Li Fraumeni syndrome (MILI) undergoing yearly MRI surveillance: a randomised controlled trial protocol.

BACKGROUND: Li-Fraumeni syndrome (LFS) is a rare autosomal dominant disease caused by inherited or de novo germline pathogenic variants in TP53. Individuals with LFS have a 70-100% lifetime risk of developing cancer. The current standard of care involves annual surveillance with whole-body and brain MRI (WB-MRI) and clinical review; however, there are no chemoprevention agents licensed for individuals with LFS. Preclinical studies in LFS murine models show that the anti-diabetic drug metformin is chemopreventive and, in a pilot intervention trial, short-term use of metformin was well-tolerated in adults with LFS. However, metformin's mechanism of anticancer activity in this context is unclear. METHODS: Metformin in adults with Li-Fraumeni syndrome (MILI) is a Precision-Prevention phase II open-labelled unblinded randomised clinical trial in which 224 adults aged ≥ 16 years with LFS are randomised 1:1 to oral metformin (up to 2 mg daily) plus annual MRI surveillance or annual MRI surveillance alone for up to 5 years. The primary endpoint is to compare cumulative cancer-free survival up to 5 years (60 months) from randomisation between the intervention (metformin) and control (no metformin) arms. Secondary endpoints include a comparison of cumulative tumour-free survival at 5 years, overall survival at 5 years and clinical characteristics of emerging cancers between trial arms. Safety, toxicity and acceptability of metformin; impact of metformin on quality of life; and impact of baseline lifestyle risk factors on cancer incidence will be assessed. Exploratory end-points will evaluate the mechanism of action of metformin as a cancer preventative, identify biomarkers of response or carcinogenesis and assess WB-MRI performance as a diagnostic tool for detecting cancers in participants with LFS by assessing yield and diagnostic accuracy of WB-MRI. DISCUSSION: Alongside a parallel MILI study being conducted by collaborators at the National Cancer Institute (NCI), MILI is the first prevention trial to be conducted in this high-risk group. The MILI study provides a unique opportunity to evaluate the efficacy of metformin as a chemopreventive alongside exploring its mechanism of anticancer action and the biological process of mutated P53-driven tumourigenesis. TRIAL REGISTRATION: ISRCTN16699730. Registered on 28 November 2022. URL: https://www.isrctn.com/ EudraCT/CTIS number 2022-000165-41.

SEOM clinical guideline on heritable TP53-related cancer syndrome (2022)

Li-Fraumeni syndrome is caused by heterozygous germline pathogenic variants in the TP53 gene. It involves a high risk of a variety of malignant tumors in childhood and adulthood, the main ones being premenopausal breast cancer, soft tissue sarcomas and osteosarcomas, central nervous system tumors, and adrenocortical carcinomas. The variability of the associated clinical manifestations, which do not always fit the classic criteria of Li-Fraumeni syndrome, has led the concept of SLF to extend to a more overarching cancer predisposition syndrome, termed hereditable TP53-related cancer syndrome (hTP53rc). However, prospective studies are needed to assess genotype–phenotype characteristics, as well as to evaluate and validate risk-adjusted recommendations. This guideline aims to establish the basis for interpreting pathogenic variants in the TP53 gene and provide recommendations for effective screening and prevention of associated cancers in carrier individuals (AU)

Inhibiting mitochondrial respiration prevents cancer in a mouse model of Li-Fraumeni syndrome.

Li-Fraumeni syndrome (LFS) is a cancer predisposition disorder caused by germline mutations in TP53 that can lead to increased mitochondrial metabolism in patients. However, the implications of altered mitochondrial function for tumorigenesis in LFS are unclear. Here, we have reported that genetic or pharmacologic disruption of mitochondrial respiration improves cancer-free survival in a mouse model of LFS that expresses mutant p53. Mechanistically, inhibition of mitochondrial function increased autophagy and decreased the aberrant proliferation signaling caused by mutant p53. In a pilot study, LFS patients treated with metformin exhibited decreases in mitochondrial activity concomitant with activation of antiproliferation signaling, thus reproducing the effects of disrupting mitochondrial function observed in LFS mice. These observations indicate that a commonly prescribed diabetic medicine can restrain mitochondrial metabolism and tumorigenesis in an LFS model, supporting its further consideration for cancer prevention in LFS patients.

Hereditary cancer syndromes as model systems for chemopreventive agent development.

Research in chemoprevention has undergone a shift in emphasis for pragmatic reasons from large, phase III randomized studies to earlier phase studies focused on safety, mechanisms, and utilization of surrogate endpoints such as biomarkers instead of cancer incidence. This transition permits trials to be conducted in smaller populations and at substantially reduced costs while still yielding valuable information. This article will summarize some of the current chemoprevention challenges and the justification for the use of animal models to facilitate identification and testing of chemopreventive agents as illustrated though four inherited cancer syndromes. Preclinical models of inherited cancer syndromes serve as prototypical systems in which chemopreventive agents can be developed for ultimate application to both the sporadic and inherited cancer settings.

Hereditary gastrointestinal cancer.

Gastrointestinal (GI) cancer, including gastric and colorectal cancer, is a major cause of death worldwide. A substantial proportion of patients with GI cancer have a familial history, and several causative genes have been identified. Gene carriers with these hereditary GI syndromes often harbor several kinds of cancer at an early age, and genetic testing and specific surveillance may save their lives through early detection. Gastroenterologists and GI surgeons should be familiar with these syndromes, even though they are not always associated with a high penetrance of GI cancer. In this review, we provide an overview and discuss the diagnosis, genetic testing, and management of four major hereditary GI cancers: familial adenomatous polyposis, Lynch syndrome, hereditary diffuse gastric cancer, and Li-Fraumeni syndrome.

Hereditary breast cancer: an update on risk assessment and genetic testing in 2015.

The last 5 years have brought significant innovation and advancement in the genetics of breast cancer. This clinical opinion aims to summarize and update current approaches to the care of women at risk for a hereditary predisposition to breast cancer. Implications of the BRCA mutation and several other hereditary syndromes will be discussed. Risk assessment and criteria for referral to cancer genetic professionals as well as high-risk screening and prophylactic options will be reviewed. Finally, the newly available genetic cancer panels and implications of mutations in some of these lesser known genes will be discussed. As the field of cancer genetics continues to evolve, the education of medical students, residents, and faculty will be paramount to identify appropriate candidates for genetic counseling and testing in conjunction with cancer genetic professionals.

[New knowledge of Li-Fraumeni syndrome].

Li-Fraumeni syndrome(LFS)is the autosomal-dominant familial cancer predisposition syndrome. The criteria for it have already been defined, and most patients with this syndrome have been identified with germline mutations in the p53 tumor suppressor gene(TP53). More recently, the feasibility and potential clinical effect of a comprehensive surveillance of asymptomatic TP53 mutation carriers of this syndrome are being shown. However, the prevention and treatment recommendations for cancer, and the support system for LFS, are insufficient. In the future, patients with this syndrome require more developed medical treatment because they and their families have profound medical issues and psychosocial distress.

[Li-Fraumeni syndrome - a proposal of complex prevention care for carriers of TP53 mutation with total-body MRI]. / Li-Fraumeni syndrom - návrh komplexní preventivní péce o nosice TP53 mutace s pouzitím celotelové magnetické rezonance.

Li-Fraumeni syndrome (LFS) is one of the most serious hereditary cancer syndromes with high risk of malignancy already in childhood. Adrenocortical carcinoma, brain tumor, leukemia, sarcoma are the most frequent malignancies in children. Early breast cancer, brain tumor, sarcoma, skin cancer, gastrointestinal, lung, gynecological, hematological and other malignancies can be seen in adults. Predictive testing in families with detected LFS and TP53 mutation is offered from the age of 18 for various reasons. One of the most important reasons is a very limited effectivity of prevention especially in children, also the possible risk of psychological harm to the child and his family caused by the diagnosis of this syndrome. Progress in diagnostic methods, especially total body MRI, enables to propose preventive care for early cancer diagnoses for children and adults. Biochemical tests, ultrasound, MRI may improve survival of these high risk individuals and support the possibility of predictive testing in children.

Hereditary breast and ovarian cancer (HBOC): clinical features and counseling for BRCA1 and BRCA2, Lynch syndrome, Cowden syndrome, and Li-Fraumeni syndrome.

This article provides an overview of the molecular changes associated with inherited gynecologic malignancies and the incorporation of this information in the counseling of individuals at increased risk for developing malignancies, as well as conventional and emerging approaches to the screening of the general population. Cancer genetic counseling and its role in women's health care is examined. The focus is hereditary breast and ovarian cancer; however, cancer predisposition caused by genes other than BRCA1 and BRCA2 is also considered. The aim is to provide a foundation for counseling based on fundamental knowledge of the genes and their clinical consequences. The reader is then guided through the mechanics of risk assessment for individual patients, concluding with the psychosocial implications of counseling.

Evaluation of a decision aid for families considering p53 genetic counseling and testing.

PURPOSE: Li-Fraumeni syndrome (LFS) is associated with p53 germline mutations, and carriers are at increased risk for multiple primary cancers. We evaluated outcomes following the administration of a video-based decision aid (DA) prior to clinical p53 genetic counseling and testing among persons who had previously participated in cancer genetics research. METHODS: Fifty-seven individuals at risk for a known p53 mutation completed baseline and post-DA measures of psychological outcomes, plus knowledge and attitudes regarding p53 genetic testing. Counseling and testing uptake also was recorded. RESULTS: At baseline, multivariate analysis showed that greater testing intention was associated with lower decisional conflict (P < 0.01). Compared with baseline data, multivariate analyses of post-DA outcomes showed that knowledge about LFS and genetic testing increased and decisional conflict related to testing decreased (P < 0.001). Mean cancer worries scores decreased among all participants (P < 0.001), and mean depression scores decreased for males (P < 0.05). Thirty-nine (68%) completed pre-test genetic counseling and 23 (40%) subsequently gave a blood sample for clinical genetic testing. CONCLUSION: This intervention was useful as an initial outreach and educational method for families considering p53 genetic testing, and may improve knowledge about LFS as well as psychological outcomes.

Mutaçäo do gene p53 induzindo predisposiçäo genética ao câncer: relato de um caso da síndrome de Li-Fraumeni / P53 gene mutation inducing hereditary cancer predisposition: case report of Li-Fraumeni syndrome

A síndrome de Li-Fraumeni é uma síndrome de predisposiçäo familiar ao câncer, caracterizada pela presença de múltiplos tumores, tais como sarcomas, carcinomas de mama, tumores cerebrais e leucemia. O caso relatado é de uma paciente feminina de 37 anos, que apresenta uma significativa história familiar de câncer, bem como história pessoal de seis diferentes tumores primários (um de cólon, um nevus displásico, um de ovário e três de mama). O sequenciamento do gene supressor de tumor p53 em seus linfócitos presentes no sangue periférico revelou uma mutaçäo do aminoácido triptofano (TGG) para um códon de parada prematuro (TAG), no nucleotídeo 437 do códon 146 do éxon 5 deste gene. As implicaçöes clínicas, preventivas e éticas deste caso säo também abordadas.

Factores de riesgo asociados a sarcomas de partes blandas pediátricos / Risk factors associated to pediatric soft tissue sarcomas

Fundamento: El objetivo de este artículo es divulgar entre los pediatras los principales factores de riesgo (FR) asociados a los sarcomas de partes blandas (SPB) para facilitar su diagnóstico precoz y prevención. Material y método: Revisión sistemática bibliográfica de los últimos 30 años obtenida principalmente del Medline y complementada en el Science Citation Index y Embase sobre los FR asociados a los SPB pediátricos. Se han seleccionado los trabajos más importantes y de sus referencias se han recuperado los más relevantes de los años previos a la búsqueda. Resultados: Los SPB abarcan a un grupo heterogéneo de neoplasias, que constituyen el 7,4 por ciento de todos los cánceres durante las primeras dos décadas de la vida. Los dos tipos histológicos más frecuentes son el Rabdomiosarcoma (40 por ciento) y el Fibrosarcoma (30 por ciento). Estudios epidemiológicos, clínicos, inmunológicos, virológicos y genéticos han identificado diversos FR que condicionan un mayor riesgo de presentar SPB durante la época pediátrica y adulta. Los principales FR son A) Constitucionales: 1. Lesiones benignas precursoras; 2. Síndromes genéticos (Síndrome de LiFraumeni, Retinoblastoma, Neurofibromatosis Tipo 1, Síndrome de Gardner, y otros síndromes); 3. Inmunodeficiencias; y 4. Otros factores constitucionales. B) Medioambientales: 1. Radiaciones ionizantes y no ionizantes; 2. Exposiciones ocupacionales; 3. Fármacos; y 4. Otros factores medioambientales (consumo parental de tabaco, marihuana y cocaína). Conclusiones: 1. La mayoría de las causas de los SPB son todavía desconocidas. 2. Entre los FR constitucionales destacan el Síndrome de Li-Fraumeni, la Neurofibromatosis Tipo 1 y las Inmunodeficiencias. 3. Los factores medioambientales más importantes son las radiaciones ionizantes; exposiciones ocupacionales a herbicidas, dioxinas y cloruro de vinilo; y el consumo de drogas recreacionales (tabaco, marihuana y cocaína) en los progenitores. 4. La población pediátrica de alto riesgo para desarrollar SPB debe ser monitorizada con métodos de diagnóstico por imagen que eviten las radiaciones ionizantes. 5. La investigación de otros FR es fundamental para conocer mejor la biología y etiología de los SPB y conseguir una prevención eficaz (AU)