Kristin Zelley

Li–Fraumeni syndrome (LFS) is caused by germline likely pathogenic/pathogenic variants in the TP53 gene which encodes the p53 tumor suppressor. LFS is a hereditary cancer predisposition syndrome (CPS) with significant lifelong multiorgan cancer risk. As one of the earliest described and less common CPS, knowledge of LFS has grown significantly over time through international collaboration. Future progress in the management of these patients is dependent upon clinical and research advances as facilitated by disease-specific patient/family meetings like the LFS Association bi-annual REACH meeting. This meeting brings together scientists, clinicians, and patients with LFS and their family members in a collaborative effort to explore challenges in the field. Major current areas of study in LFS include (i) improving our understanding of specific p53 tumor suppressive functions necessary for cancer development, (ii) developing novel classification systems for TP53 variants, (iii) exploring more precise genotype–phenotype correlations, (iv) defining the cancer spectrum to better inform risk prediction for patients, and (v) understanding the psychosocial implications of an LFS diagnosis. Areas of need were also identified, particularly the need for more precise and practical methods of cancer screening and innovative strategies for targeting the p53 pathway for cancer prevention or early tumor interception. This commentary reflects the major advances in understanding of LFS, including most up-to-date research in the field related to p53 biology, variant interpretation, and clinical care. Herein, we also review areas of late-breaking research and future directions in the field, as a “call to action” for LFS researchers and clinicians.

Li-Fraumeni syndrome (LFS) is a cancer predisposition syndrome associated with significant lifelong risk of cancer, and individuals with LFS undergo recommended screening protocols that are heavily dependent upon radiologic imaging. Recently, liquid biopsy has emerged as a potential new screening technique for LFS. In this study, we conducted a survey of adults with LFS and caregivers of children with LFS to determine interest in a clinical trial evaluating liquid biopsy as an addition to standard-of-care cancer screening. We also assessed barriers to receiving recommended screening and consequent financial toxicity. A total of 81 adults with LFS and 28 parents/guardians (“caregivers”) of children with LFS responded to the survey. Of these, the majority (93%) were interested in the addition of liquid biopsy and were willing to have additional screening as frequently as every 3 months. Although most respondents were able to complete standard-of-care cancer screening as planned, more than a third reported financial barriers to completion of screening. Other reported barriers included scheduling, transportation, and stress around screening results. Additionally, approximately one fifths of adults and one fourths of parents/caregivers reported financial toxicity, with the most prevalent being food insecurity. These results provide data for feasibility and high participant interest in a clinical trial of liquid biopsy for cancer screening in LFS. Additionally, any clinical trial will require planning around barriers to existing screening protocols.Prevention Relevance:Liquid biopsy testing for circulating tumor DNA is a promising strategy for cancer screening. Prior to a clinical trial of liquid biopsy cancer screening in LFS, this prospective survey of individuals with LFS and their caregivers assessed trial interest and barriers to current standard-of-care screening practices.

Supplemental Materials 1. Measures Developed for the purpose of this study

Pediatric gastrointestinal polyps are frequently associated with an underlying hereditary syndrome associated with multisystem manifestations and increased risk of early-onset cancer. Thus, the identification of polyps in a child should prompt evaluation with genetic testing to (1) characterize the syndrome to determine next clinical steps including surveillance recommendations, and (2) conduct cascade testing to identify affected family members. Given the considerations for pediatric genetic testing, including autonomy and psychosocial stressors associated with the early detection of a cancer risk syndrome, it is important to conduct targeted testing. Herein, we propose a stepwise approach to genetic testing in the pediatric patient with gastrointestinal polyps.

Li-Fraumeni syndrome (LFS) is a cancer predisposition syndrome associated with significant lifelong risk of cancer, and individuals with LFS undergo recommended screening protocols that are heavily dependent upon radiologic imaging. Recently, liquid biopsy has emerged as a potential new screening technique for LFS. In this study, we conducted a survey of adults with LFS and caregivers of children with LFS to determine interest in a clinical trial evaluating liquid biopsy as an addition to standard-of-care cancer screening. We also assessed barriers to receiving recommended screening and consequent financial toxicity. A total of 81 adults with LFS and 28 parents/guardians (“caregivers”) of children with LFS responded to the survey. Of these, the majority (93%) were interested in the addition of liquid biopsy and were willing to have additional screening as frequently as every 3 months. Although most respondents were able to complete standard-of-care cancer screening as planned, more than a third reported financial barriers to completion of screening. Other reported barriers included scheduling, transportation, and stress around screening results. Additionally, approximately one fifths of adults and one fourths of parents/caregivers reported financial toxicity, with the most prevalent being food insecurity. These results provide data for feasibility and high participant interest in a clinical trial of liquid biopsy for cancer screening in LFS. Additionally, any clinical trial will require planning around barriers to existing screening protocols. Prevention Relevance: Liquid biopsy testing for circulating tumor DNA is a promising strategy for cancer screening. Prior to a clinical trial of liquid biopsy cancer screening in LFS, this prospective survey of individuals with LFS and their caregivers assessed trial interest and barriers to current standard-of-care screening practices.

Supplementary Table 1 shows non-malignant findings identified on WBMRI screening in our patient cohort with corresponding patient IDs to cancer diagnoses identified on WBMRI screening.

Supplementary Table 2 outlines prior studies of initial WBMRI screening in LFS cohorts both in pediatric and adult patient populations including length of the study, number of patients with findings, and number of cancers detected.

Hereditary endocrine neoplasia syndromes comprise multiple entities associated with an increased risk for the development of endocrine and nonendocrine neoplasms and other systemic manifestations. These syndromes typically demonstrate autosomal dominant inheritance, and each syndrome is associated with a unique genetic predisposition to a distinct spectrum of tumor susceptibility. Moreover, genotype–phenotype associations within each syndrome may affect the spectrum, penetrance, and age of onset of associated tumors. As many endocrine tumors are benign and/or indolent, a careful approach to monitoring is necessary, wherein the nature, timing of initiation, and frequency of presymptomatic surveillance balance the goal of detecting tumors at a point in which intervention would limit tumor-associated morbidity against the physical, emotional, and financial burdens of surveillance. In this study, we summarize changes in knowledge and practice recommendations related to children with multiple endocrine neoplasia syndromes (types 1, 2A, 2B, 4, and 5), hyperparathyroidism–jaw tumor syndrome, and Carney complex since an initial summary in 2017. These updates reflect the evolving understanding of these complex genetic disorders and aim to improve patient care and outcomes.

Hereditary Pheochromocytoma/Paraganglioma Syndromes (HPPS) are a collection of conditions caused by variants in genes producing subunits of the succinate dehydrogenase (SDH) complex or related proteins. These conditions are characterized by substantial lifetime risks for developing pheochromocytomas, paragangliomas, and other tumors. Affected individuals who develop these tumors may experience severe, acute and chronic problems. Indeed, aggressive, malignant, and/or disseminated tumors may result in death. Tumor surveillance enables early intervention, which, in turn, should lead to improved clinical outcomes. However, the desire for intensive surveillance strategies must be balanced against medical and psychosocial risks. In 2017, consensus HPPS surveillance recommendations addressing germline predisposition to SDHA, SDHAF2, SDHB, SDHC, SDHD, MAX, TMEM127 (collectively, SDHx+) related tumors were published after the inaugural AACR Childhood Cancer Predisposition Workshop. Based on the limited available clinical data at that time, these recommendations advocated a uniform approach to tumor surveillance in HPPS. Since then, several other groups have proposed alternative consensus surveillance guidelines. Although these surveillance approaches share some common elements, including recommendations tailored to emerging differences in tumor phenotype based on underlying specific SDHx+ genes, these approaches also vary significantly amongst each other. As clinical data continue to accrue, it is critical that surveillance strategies continue to be refined to address emerging genotype-phenotype differences. In this review, we provide a brief up-to-date clinical overview of HPPS and describe recently proposed tumor surveillance regimens. We then detail our updated consensus pediatric-focused tumor surveillance recommendations from the 2023 AACR Childhood Cancer Predisposition Workshop.

PURPOSE: Relapsed high-risk neuroblastomas (NBLs) are enriched for targetable mutations in ALK and RAS-MAPK pathways, yet the prognostic effect of these aberrations and relevance of subclonal mutations at diagnosis remain undefined. We describe the spectrum and clinical significance of clonal and subclonal pathogenic alterations in high-risk NBL. METHODS: We developed a focused high-risk NBL sequencing panel including ALK , NRAS , KRAS , HRAS , BRAF , PTPN11 , TP53 , and ATRX genes for ultra-deep sequencing and applied this assay to 242 pretherapy tumors from patients enrolled on the phase III trial Children's Oncology Group ANBL0532. We assessed the effect of clonal and subclonal mutations on event-free survival (EFS) and overall survival (OS). RESULTS: ALK -activating mutations occurred in 21.5% of tumors (n = 52, 30 clonal, 22 subclonal), and 3.3% (n = 8) showed ALK amplification. EFS and OS for patients with any ALK -aberrant tumor were inferior to patients with wild-type (WT) ALK tumors (5-year OS 37.7% v 66.3%; hazard ratio [HR], 1.992; P = .0007). EFS and OS for patients with tumors harboring activating ALK mutations ≥5% variant allele frequency (VAF) were inferior to ALK WT (5-year OS 37.7% v 66.3%; HR, 1.966; P = .0041). The 5-year EFS and OS for patients with ALK -amplified tumors were 25.0%. RAS pathway mutations occurred in 7.9% of tumors (n = 19; four clonal, 15 subclonal), with EFS and OS for those with VAF ≥5% inferior to RAS-WT patients (5-year OS 19.1% v 60.0%; HR, 3.021; P = .0168). CONCLUSION: Ultra-deep sequencing of high-risk NBLs demonstrates that oncogenic aberrations are more prevalent at diagnosis than previously recognized. ALK and RAS pathway aberrations confer inferior outcomes in patients treated with contemporary therapy, emphasizing the need for novel therapeutic approaches.