Payal P. Khincha

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.

Consensus classification of hereditary hematologic malignancies

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

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.

TP53 germline pathogenic variants are among the most significant genetic causes of cancer across all age groups. Current TP53 variant classification guidelines are designed to identify high-penetrance TP53 variants that lead to a phenotype called Li-Fraumeni syndrome. However, they are insufficient to accurately classify variants conferring atypical penetrance. These atypical penetrance variants are disease-causing, but the phenotype is often attenuated. Using current TP53 variant classification guidelines, atypical penetrance variants are not properly recognized, leading to suboptimal management of individuals carrying such variants. We highlight the need to develop strategies to consistently identify atypical penetrance disease-causing germline TP53 variants including development of variant classification specifications tailored to distinguish such variants, and to define the associated cancer spectrum and age-related risks. These studies will inform modifications to the existing standard risk management recommendations.

Li-Fraumeni syndrome (LFS) is an inherited condition associated with high multi-organ cancer risks from birth. Young adults (YAs; 18–39 years) with LFS experience psychosocial challenges that may negatively affect health-related quality of life (HRQOL). This study aimed to describe a specific psychosocial challenge, concerns about the consequences of LFS (CC-LFS), and investigate relationships among CC-LFS and HRQOL among YAs. An online survey assessed CC-LFS and HRQOL among YAs with LFS enrolled in a National Cancer Institute study. Regression analyses examined relationships between CC-LFS and HRQOL scores, adjusted for age, cancer, and history of mental health challenges. Of 37 total respondents (78% female; M _age = 31 years), 51% had a cancer history. Many reported past mental health challenges, including emotional problems (70%), depression/anxiety disorders (68%), and suicidal ideation (43%). Mean scores for mental ( M = 65.8), physical ( M = 67.5), and general ( M = 63.9) HRQOL were lower than in the general population. Higher CC-LFS scores ( M = 31/50, SD = 7.2) were associated with lower scores for each HRQOL domain. Adjusting for covariates, higher CC-LFS scores were associated with lower physical HRQOL (β = −0.491, 95% CI −0.76, −0.22, p < 0.001) and general HRQOL (β = −0.466, 95% CI −0.77, −0.16, p = 0.004), but not mental HRQOL ( p = 0.102). CC-LFS accounted for significant proportions of unique variance in general ( R ² _adj = 17.7%, p = 0.004) and physical HRQOL ( R ² _adj = 20.4%, p < 0.001). Findings suggest YAs with LFS may experience substantial concerns, mental health challenges, and diminished HRQOL. Concerns about LFS consequences appear to be a psychosocial risk factor that clinicians and researchers might address through targeted interventions to improve YAs’ psychosocial health.

Li-Fraumeni syndrome (LFS) is an early-onset cancer syndrome caused by pathogenic germline TP53 variants. Adolescents and young adults (AYAs) with LFS may have challenges navigating new romantic partnerships given the significant effects of LFS on multiple life domains that also affect partners (e.g., reproductive decision-making). Disclosing LFS-related information to new partners may be especially difficult given the uncertainty, complexity, and chronicity of LFS. This qualitative-descriptive study aimed to explore AYAs’ LFS disclosure decisions and experiences in new romantic partnerships. Participants were individuals with LFS aged 15–39 years at enrollment in a National Cancer Institute study. The analytic sample included 33 AYAs who completed at least one telephone interview. Greene’s disclosure decision-making model guided thematic analysis. Participants were mostly female (67%) and married/in a long-term relationship (58%), with mean age 29 years and ≥ 1 primary cancer (61%). Key factors in LFS disclosure decision-making included perceived relevancy to partners (e.g., future children’s genetic risk), partner traits (e.g., trustworthiness), and relationship quality (e.g., closeness). AYAs described LFS disclosures in new partnerships as a process. Disclosing LFS diagnosis often occurred early to fulfill a sense of moral obligation and emotionally self-protect from future rejection, while subsequent LFS disclosures depended on relationship quality and the topic’s emotional valence or complexity. Partners often earned AYAs’ trust by demonstrating a willingness to learn about and try to understand LFS. Clinicians and LFS communities could support AYAs by providing opportunities to discuss, normalize, and ameliorate challenges with LFS disclosures in new romantic partnerships (e.g., peer support groups, psychotherapy).

Li–Fraumeni syndrome (LFS) is an autosomal dominant cancer predisposition condition characterized by a high lifetime risk for a wide spectrum of malignancies associated with germline pathogenic/likely pathogenic variants in the TP53 tumor suppressor gene. Secondary malignant neoplasms are particularly common. Early cancer detection through surveillance enables early intervention and leads to improved clinical outcomes with reduced tumor-related mortality and treatment-related morbidity. Since the 2017 publication of LFS tumor surveillance guidelines from the inaugural American Association for Cancer Research Childhood Cancer Predisposition Workshop, understanding the genotype–phenotype relationships in LFS has evolved, and adaptations of the guidelines have been implemented in institutions worldwide. The “Toronto Protocol” remains the current standard for lifelong surveillance; however, as outlined in this perspective, modifications should be considered about the use of certain modalities to target organs in an age-dependent manner. The Working Group’s recommendations have also been extended to include a more detailed outline for surveillance in the adult TP53 pathogenic/likely pathogenic variant carrier population, based on the recognition that early education of both practitioners and patients on what to expect after the transition from childhood/adolescence to young adulthood is important in preparing them for changes in surveillance strategies. In this perspective, we provide an up-to-date clinical overview of LFS and present our updated consensus tumor surveillance recommendations from the 2023 American Association for Cancer Research Childhood Cancer Predisposition Workshop.