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Taylor & Francis Taylor & Francis Group

EXPERT REVIEW

OF ANTICANCER THERAPY

Expert Review of Anticancer Therapy

ISSN: 1473-7140 (Print) 1744-8328 (Online) Journal homepage: www.tandfonline.com/journals/iery20

The argument for screening programs in previvors with Li-Fraumeni syndrome

Meis Omran & David Malkin

To cite this article: Meis Omran & David Malkin (2025) The argument for screening programs in previvors with Li-Fraumeni syndrome, Expert Review of Anticancer Therapy, 25:9, 1065-1074, DOI: 10.1080/14737140.2025.2522943

To link to this article: https://doi.org/10.1080/14737140.2025.2522943

Published online: 03 Jul 2025.

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The argument for screening programs in previvors with Li-Fraumeni syndrome

Meis Omran İD and David Malkin iDa,b,c a

ªDivision of Haematology/Oncology, The Hospital for Sick Children, Toronto, ON, Canada; bDepartment of Paediatrics, University of Toronto, Toronto, ON, Canada; “Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada

ABSTRACT

Introduction: Li-Fraumeni syndrome (LFS) is a cancer predisposition syndrome caused by pathogenic/ likely pathogenic germline TP53 variants. Core cancers include sarcomas, brain tumors, adrenocortical carcinoma and breast cancer. Surveillance with whole-body MRI (WBMRI) and other modalities is used for early cancer detection, regardless of the individual’s personal cancer history. With the increasing use of diagnostic multigene panels in oncology, more diverse phenotypic presentations have emerged, and subsequent cascade testing identifies more asymptomatic cancer-free individuals - ‘previvors.’

Areas covered: This review analyzes aspects of early cancer detection screening programs in asympto- matic germline TP53 variant carriers including current guidelines, specific founder variant populations, health economics and emerging strategies including liquid biopsies and wearable devices. A literature search with PubMed included publications in English until April 2025.

Expert opinion: Current guidelines recommend WBMRI in all LFS individuals, regardless of their prior cancer history, due to its demonstrated survival advantage. Guidelines for use of other modalities such as endoscopy, ultrasound or laboratory tests are less well-established. Therefore, longitudinal prospec- tive studies including all these modalities and their cancer detection rates are needed. In the future, a one-size-fits-all approach toward surveillance will be replaced by more precise patient-centered tailor- made screening programs incorporating noninvasive methods.

PLAIN LANGUAGE SUMMARY

Li-Fraumeni syndrome (LFS) is a rare inherited condition that greatly increases a person’s risk of developing cancer, often at a young age. It is caused by changes in a gene called TP53, which normally helps prevent cancer. People with LFS are more likely to develop certain cancers like bone and soft tissue cancers (sarcomas), brain tumors, adrenal gland cancer, and breast cancer. Because the risk of cancer is so high, people with LFS are offered regular screening to for early cancer detection, even in those that have never had cancer. One of the main tools for this is a type of scan called a whole-body MRI (WBMRI). Over time, more people are being diagnosed with LFS through genetic testing, including those who haven’t had cancer but carry the TP53 gene change. These individuals are sometimes called ‘previvors. ‘This review looks at the different cancer screening strategies used for people with LFS, including the current guidelines, psychosocial effects due to screening and the costs involved. It also explores new tools being studied, like blood tests (liquid biopsies) and wearable health devices that may help detect cancer earlier. Experts agree that WBMRI should be used for everyone with LFS because it has been shown to improve survival. However, there’s less agreement about how and when to use other tests like endoscopies, ultrasounds, or blood tests. More long-term studies are needed to figure out which combination of tests works best. In the future, cancer screening for people with LFS will likely become more personalized, using newer, less invasive technologies to better fit each person’s needs.

ARTICLE HISTORY Received 24 April 2025 Accepted 17 June 2025

KEYWORDS Li-Fraumeni syndrome; germline TP53; surveillance, cancer screening; cancer predisposition

1. Introduction

Li-Fraumeni syndrome (LFS; OMIM #151623) is a hereditary cancer predisposition syndrome (CPS), first described by Li and Fraumeni in 1969 [1]. LFS is characterized by a lifetime cancer risk approaching a 100%. The likelihood of cancer onset reaches 40% by age 40 and exceeds 90% by age 70; over 50% of all patients develop multiple synchronous or metachronous tumors [2]. Core tumors include adrenocortical carcinoma, early onset breast cancer, sarcomas and brain tumors [3]; however, the spectrum of tumors is wide with virtually all tumor types having been described. The underlying cause of

LFS - namely a germline mutation in the TP53 tumor suppres- sor gene - was identified 20 years after the first clinical description [4]. In 2011, initial outcome data from the first surveillance protocol for early cancer detection in individuals with LFS was published, utilizing annual whole-body MRI (WBMRI) as the backbone in addition to abdominal/pelvic ultrasound, breast surveillance, blood work and clinical evalua- tion [5]. In an 11-year follow-up study, it was reported that 40 asymptomatic tumors were detected in 19/59 germline TP53 carriers, in contrast to 61 symptomatic tumors found in 43 patients, with an overall survival of 88.9% in contrast to 59.6%

Article highlights

. Regardless of presence or absence of a prior cancer history, routine surveillance including whole-body MRI is a cornerstone of various current screening guidelines.

· A broader spectrum of different phenotypes is crystallizing, with possible future implications for adjusted cancer screening.

· Future studies of long-term surveillance in different cohorts are needed to assess psychosocial impact, radiologic interpretation chal- lenges, and use of endoscopy as a screening tool.

· Emerging areas include exploration of cell-free DNA, wearable tech- nologies, microbiota and metabolic signatures to streamline future cancer screening programs.

in the non-surveillance group (p = 0.0132) [6]. The increased use of multigene panels in recent years has led to the identi- fication of germline TP53 variants in families without the classic LFS spectrum of tumors [7,8], suggesting a wider phe- notypic presentation [9] than what was first described. A germline TP53 finding identified through a multigene panel typically leads to cascade testing of healthy relatives, thus increasing the number of noncancer-affected individuals harboring a TP53 variant and the need for surveillance. The term ‘previvor’ was coined by the organization Facing Our Risk of Cancer Empowered (FORCE) by combining ‘predisposition’ and ‘survivor,’ originally used to help people at increased breast cancer risk to identify with their health journeys and with each other [10].

2. Methods

Articles for this narrative review were identified through PubMed searches using the terms ‘Li-Fraumeni syndrome;’ ‘germline TP53’, ‘surveillance in cancer predisposition syn- dromes’ and ‘heritable TP53-related cancer syndrome.’ All retrieved records were screened for relevance up until April 2024, including publications in English only.

3. Current screening recommendations

3.1. Comparison of current different surveillance guidelines

The first surveillance recommendation was the so-called Toronto protocol,’ published within the context of a clinical study [5]. Following publication of a 11-year follow-up, demonstrating survival benefit for those undergoing surveil- lance in comparison to those whose tumors were diagnosed after clinical presentation without prior surveillance [6], several other clinical surveillance guidelines have been published with slight modifications of the original protocol [11-14] (Table 1). The recommendations include germline TP53 carriers with a pathogenic/likely pathogenic (P/LP) variant, regardless of whether they had had a previous cancer (Table 1). Across guidelines, there seems to be a consensus regarding recom- mendations of annual WBMRI, brain MRI, breast MRI, physical and dermatological examinations. Differences across different guidelines are reflected in both in terms of emerging data, such as in the case of incorporating prostate-specific antigen

(PSA) for early prostate cancer detection [13,14]. European guidelines do not recommend general endoscopic surveil- lance for all carriers. Instead, they suggest a case-by-case approach with consideration of family history and/or previous abdominal radiation therapy [11,12]. It is anticipated that the guidelines/recommendations will continue to evolve over time in the clinical setting, as more data becomes available from multi-institutional studies, further clarity of genotype-pheno- type correlations, and novel molecular and other approaches to early tumor detection.

4. Screening outcomes

4.1. Tumor findings in asymptomatic TP53 carriers

The Toronto Protocol was reported in 2011, using whole-body MRI (WBMRI) as the main surveillance strategy alongside abdominal-pelvic ultrasounds, breast imaging, and clinical examination [5]. MRI does not pose added ionizing radiation exposure to the patients. However, while to date, a few case reports or small case series have been published exploring the impact of therapeutic radiation exposure on second tumor risk and virtually nothing on diagnostic radiation exposure, current recommendations remain to minimize any radiation exposure [15]. As further research is pursued that considers radiation dose, field, tissue involved, underlying TP53 mutation, age, concurrent other therapies, and radiation modality, a more nuanced approach to use of diagnostic (and therapeutic) radiation will likely emerge. The first report of tumor surveil- lance in LFS patients used FDG-PET/CT on 15 asymptomatic individuals, identifying previously unknown cancers in 3/15 (20%). All three tumors were treatable: two cases of thyroid cancer (stage II and III, respectively) and one case of esopha- geal adenocarcinoma (stage IIA) [16]. However, as noted above, since germline TP53 carriers are likely more prone to develop secondary radiation-induced tumors [15], other mod- alities like WBMRI are preferred.

The first review and meta-analysis to report on imaging findings in asymptomatic LFS individuals was published in 2017, comprising 578 individuals undergoing a baseline WBMRI from 13 cohorts in six countries. The overall estimated detection rate for new, localized primary cancers was 7% (95% CI, 5%-9%), and the rate of false-positive findings was 42.5%. However, this also included recurrence of previous cancers and incurable metastatic cancers [17]. Recently, another meta- analysis including 703 patients across 11 studies concluded that WBMRI surveillance, both at baseline and during follow- up surveillance (2-11 years of follow-up) had an estimated detection rate of 31% for any suspicious lesion, and the esti- mated cancer detection rate among these lesions was 18%. The overall cancer detection rate was 6%, with an incidence rate of 2% per WBMRI per patient [18].

4.2. Radiological challenges (interval cancers, false-negative, false-positive)

With respect to false-negative rates and interval cancers occurring between two time points of surveillance, only one study [6] reports a follow-up period spanning over more than two rounds of

Table 1. Screening recommendations for individuals with Li-Fraumeni syndrome.
Guideline
Toronto protocolERN GENTURIS [11]UKCGG [12]NCCN [13]AACR [14]
[6]
Modality WBMRI Brain MRIAnnual from birth. Annual from birth.Annual from birthª. Annual brain MRI from birth - age 50b.Annual from birth. Annual from birth, first scan with contrast.Annual from infancy. Annual from infancy.Annual from birth. Annual from birth, first scan with contrast.
Abdominal- pelvic ultrasoundAnnual from birth every 3-4 months.From birth to age 18, every 6 months.Every 3-4 months from birth-18 years.Every 3-4 months beginning in infancy for pediatric carriers.Every 3-4 months from birth-18 years, then every 6 months.
Breast*Annual mammography and breast MRI between ages 20-75℃.Annual from age 20-65 with breast MRI.Annual dedicated MRI from age 20-70 years.Age 20-29: annual breast MRI.Age 30-75: annual breast MRI and mammogram. >75 years: individualized management.From age 20: clinical examination every 6 months, annual breast MRI from age 20°, mammograms from age 30.
ColonoscopyEvery 2 years, starting from age 25 or 10 years before earliest case of CRC in the family.From age 18, every 5 years, only in certain casese.Only indicated in presence of family history of CRC or polyposis.From age 25: colonoscopy every 2-5 years".From age 25: colonoscopy every 2-5 years.
GastroscopyNo specific recommendation.No specific recommendation.HP testing and eradication if required. Endoscopy not indicated due to lack of evidence.From age 25: gastroscopy every 2-5 years".From age 25: gastroscopy every 2-5 years.
Biochemistry Leukemia ACCCBC, ESR and LDH every 3-4 months from birth. From birth to age 40, every 3-4 months9.Urine steroids from birth to age 18 if abdominal ultrasound does not allow a proper imaging of the adrenal glands.Biochemistry should only be performed if abdominal ultrasound does not allow a proper imaging of the adrenal glands.CBC with differential if prior exposure to leukemogenic agents. In case of unsatisfactory abdominal US in children: addition of blood work every 3-4 monthsh, after age 18 every 6 months.
PSAAnnual PSA from age 40. Annual dermatologic evaluation from age 18.Annual PSA from age 35. Annual dermatologic evaluation from age 18 (part of complete examination for <18 years).
Dermatological examinationAnnual dermatological evaluation from age 18 (for children, this is included in the physical examination).Annually for adults with specific attention to occurrence of basal cell carcinoma within previous radiation fields.Annual by dermatologist or general practitioner.
Physical examinationComplete physical examination every 3-4 month from birth.Children: every 6 months. Adults: annually.For children every 3-4 months'.Complete physical examination every 6-12 months beginning in infancy.Complete physical examination every 3-4 months from birth-18 years, then every 6 months. DRE from age 35 annually.

Abbreviations: AACR = American Association for Cancer Research; DRE = digital rectal examination; ERN-GENTURIS = European Reference Network (ERN) for all patients with one of the rare genetic tumor risk syndromes (GENTURIS); CBC = complete blood count; CRC = colorectal cancer; ESR = erythrocyte sedimentation rate; HP = helicobacter pylori; LDH = lactate dehydrogenase; NCCN = National Comprehensive Cancer Network; PSA = prostate-specific antigen, UKCGG = United Kingdom Cancer Genetics Group; Toronto protocol as published by Villani et al 2016.

ªBetween birth to age 18 only if considered a high-risk variant or if the patient has received prior chemotherapy or radiotherapy. bAnnual brain MRI between from birth and onwards if the variant is considered to be high risk.

‘Or 5-10 years before the earliest case of breast cancer in the family, whichever comes first.

Breast MRI should be offered after bilateral risk-reducing mastectomy.

eOnly if the carrier has received abdominal radiotherapy or if there is a familial history of colorectal cancer.

“Or 5 years before the earliest known colon/gastric cancer in the family. In the context of having received prior abdominal radiotherapy or in the presence of a family history.

For patients who have received whole body or abdominal radiation therapy, screening is recommended to begin 5 years after end of treatment.

917-OH-progesterone, total testosterone, dehydroepiandrosterone sulfate, and androstenedione 24 h urine cortisol, if feasible. “total testosterone, dehydroepiandrosterone sulfate, and androstenedione.

“Routine physical examination is not recommended in adults (but advise of a detailed discussion on ‘red flag’ symptoms.

*Breast awareness is generally recommended from age 18 across guidelines, as well as discussions about risk-reducing mastectomy in adulthood.

screenings. While there are several reports including meta-analysis of outcomes after baseline screening [17,18], two publications report on surveillance spanning over two rounds of screenings [19,20]; thus, more longitudinal studies with several years of ongoing surveillance are needed to assess rates of false- negatives and interval cancers.

5. Psychosocial aspects of screening in previvors

Within families with LFS, there is a mixture of family members personally unaffected by cancer, having had a cancer diagno- sis and currently considered to be cancer-free, and individuals living with chronic cancer [21,22]. ‘Embodied risk’ is a concept

that has been explored in LFS, described the anticipation of illness, shared within family groups regardless of having experienced symptoms or not [23]. In addition to the psycho- social burden that could be imposed ‘simply by’ living with LFS, some studies have tried to outline the possible psycho- social impact related to repeated surveillance.

Although there are studies evaluating the psychosocial impact of surveillance with WBMRI, no study to date is specifically focused on previvors only. Most studies include a mix of both cancer affected and unaffected individuals. Study designs vary with regard to using only qualitative [24], only quantitative [25-29], and mixed methods [22] (Table 2). A small study (n = 17 of whom six were unaf- fected) reports that mean anxiety levels among the whole cohort of both affected and unaffected carriers were reduced 2 weeks after WBMRI (p = 0.025) [22]. A follow-up within the same study, including 132 carriers of whom 64

were previvors presents no significant changes over time in overall anxiety/depression, nor with distress associated with cancer or WBMRI over a four-year period [25]. These find- ings are in line with another study measuring cancer-worry levels prior to starting WBMRI surveillance and 1 year after, specifically comparing previvors (n = 28) with cancer- affected individuals (n = 32) [28]. In contrast, studies report high levels of fear of progression and distress (amongst all participants, not stratified for cancer history [27], and lower scores for anxiety within previously cancer affected in com- parison with previvors [29]. The somewhat mixed findings elucidate a complex presentation, making it difficult to fully understand the psychosocial implications of undergoing surveillance for previvors specifically.

Finally, a common theme across all the above-mentioned studies can be identified is the need for access to psychosocial support regardless of a previous cancer history, underscoring the importance of designated health care professionals with a focus on LFS specifically to alleviate distress, regardless of previous personal cancer history.

Table 2. Selected studies in psychosocial outcomes of WBMRI surveillance in LFS.
CountryPrevivors/total participants No (%)MethodsTime period
Australia (SMOC+)6/17* (35)Mixed qualitative and quantitativePrior to surveillance start - several time points during the first year
McBride et al.
[22]
Summary of key findings: no stratification for previous cancer history in the quantitative analysis. In all participants; reduction in mean anxiety two weeks after WBMRI (p= 0.025). Emerging qualitative themes identified that most participants are emotionally supported by the screening program. Some perceived screening as a burden but still wanted to continue screening, motivated by staying alive.
(SMOC+, follow- up)64/132 (48)QuantitativeMedian study time 4 years
Zaheed et al. [25]
Summary of key findings: in all carriers, not stratified for previous cancer history; no changes distress associated with WBMRI (p = 0.6) over time.in overall anxiety or depression (p = 0.2), cancer distress (p = 0.06) or
Germany6/49 (12)QuantitativeOne time point
GC-HBOC
Rippinger et al.
[26]
Summary of key findings: stratified for either 'adherence to survellance' (n = 37) or 'non-adherence to surveillance' (n = 11). Willingness to undergo surveillance was associated with satisfaction of genetic counseling and genetic testing (p = 0.019) but not by previous cancer history, sociodemographics or level of distress.
Germany47/70 (67)QuantitativeOne time point
Kiermeier et al. [27]
Summary of key findings: psychosocial support is needed regardless of having had a previous cancer or not, no significant difference was seen in the mental component score (p = 0.48). Fear of progression was seen in 48/70 (69%) and distress in 47/68 (69%).
Sweden28/60 (47)QuantitativePrior to surveillance start and 1 year efter
SWEP53 Study
Omran et al. [28]
Summary of key findings: Participants with previous cancer tend to worry more about cancer, but there were no differences in cancer-specific worry among previvors and cancer-affected after 1 year of surveillance. Both groups had a positive attitude toward surveillance
with no differences regarding perceived benefits and barriers to surveillance.
The United Kingdom29/44 (66)Quantitative (age and sex-matched population controls)Prior to surveillance start - several time points during the first year
SIGNIFY Study
Bancroft et al.
[29]
Summary of key findings: intrusive thoughts about cancer in previvors fell between preresults and 12 weeks post WBMRI (p = 0.009). Carriers with a previous cancer had lower mean scores for anxiety at 6 and 12 months in comparison to unaffected carriers, suggestive of post-traumatic growth. No clinical differences among carriers having to undergo additional imaging to investigate an unclear finding and those with normal scans.
The United States3/20 (15)QualitativeAt one time point of which 16 participants had undergone WBMRI
LEAD Program
Ross et al. [24]
Summary of key findings: all participants planned on continuing the screening program. Benefits included early detection, (n = 13), peace of mind (n = 12) amongst other variables. Most common drawbacks; logistical issues (n = 17) and negative emotions (n = 18).

*Both confirmed carriers and at risk of being carriers, confirmed in a first-degree relative.

5.2. Perceived efficacy of screening and adherence to surveillance

A study among health care professionals caring for with young TP53 carriers describes that early detection of cancers through surveillance is acknowledged among 26/29 (90%). Disadvantages included risks of screening fatigue/anxiety (23/29, 79%) and high false-positive rates (21/29, 72%) [30]. When looking at TP53 carriers themselves, adherence to sur- veillance seems to be high across studies [22,24,26], although a potential selection bias cannot be excluded without know- ing how many carriers that have been offered surveillance but declined.

6. Genotype-phenotype correlations

6.1. Founder variants and limiting surveillance to adults only

The most well-described founder variant in the context of LFS is the ‘Brazilian founder variant’ (c.1010 G>A; p.R337H), first described in 2001 among children in South/Southeastern Brazil with adrenocortical carcinomas (ACC) [31,32]. This var- iant is associated with a less severe tumor spectrum than classic LFS, affecting both children and adults. Due to the high frequency of this variant within specific regions of Brazil (0.3% [33]), newborn screening is implemented for early detec- tion of ACC [34]. Interestingly, the Brazilian founder variant seems to exhibit a different phenotype than the Classic LFS. A study comparing tumor onset in 303 adults harboring the p. R337H variant with 405 carriers of other TP53 variants (data from the NCI TP53 database) indicates a later tumor onset in individuals with the Brazilian founder (54% vs 78% at age 50, p < 0.0001). Sex differences were noted for female p.R337H carriers including higher lifetime cancer risks than males (65% vs 30% at age 50, p < 0.0001), and they were also noted to have a higher risk of second primary tumors, not observed in carriers of other TP53 variants. The authors sug- gest taking into consideration a more intensified surveillance between ages 45-60 where the cancer risk is significantly increased [35]. However, since the Brazilian founder variant predisposes to both childhood and adult tumors, the same surveillance recommendations are currently being given regardless of the variant type, until further clinical trials have been conducted.

There are several reports of a ‘Palestinian founder muta- tion’, (c.541 G>A; p.R181C), with somewhat conflicting results as to whether the variant predisposes to only adult-onset tumors or leads to a broader age spectrum [36-39]. While one group presents the occurrence of classic LFS childhood tumors (4 patients with high-grade CNS tumors) in a retrospective analysis [37], in a retrospective analysis, (Arnon et al., 2024) another comparing prevalence of child- hood tumors in p.R181H families with families matched for breast cancer at the same age without harboring a known breast cancer risk gene, could not find statistical differences in childhood tumor prevalence. The histological subtypes of the tumors in the p.R181H group were not presented, making it challenging to determine if they were within the LFS spectrum

or not [39]. Additionally, the p. R181C has been reported in the TP53 database (R21 April 2025) [40] in 65 patients globally. These reports consist of 20 different families from 5 geogra- phically distinct regions all with adult-onset cancers except 1 case of rhabdomyosarcoma at age 1 year and, subsequently, adrenocortical carcinoma and osteosarcoma at age 2 years in the same patient [6].

A possible Swedish founder variant (c.542 G>A; p.R181H) has also been proposed in a retrospective, nationwide review of all known TP53 variants in Sweden. This variant seems to predispose mainly to breast cancer (observed in 14 families with a ‘breast cancer only’ phenotype and in four families with a Chompret phenotype). No cases of childhood cancers were found in families with p.R181H, suggesting that this variant mainly predisposes to breast cancer, without an increased risk of childhood tumors, although confirmation is needed from larger cohorts from other countries as well [41].

To date, it is still recommended that the same type of surveillance strategy as is used more broadly should be applied regardless of variant type for all of these founder variants, until more clinical data emerges that more confi- dently validates these initial findings and guides the clinician to refine the surveillance in an age- or tumor type-dependent manner.

7. Health economics from an organizational and individual view

Substantial evolution of new and emerging costly medica- tions in the field of oncology has sparked the debate of cost-effectiveness and financial toxicity in relation to patient outcomes and public health care funding [42]. Although this is often discussed in the context of cancer diagnosis and subsequent treatment within the general population, a specific facet to address is the financial cost within high- risk populations such as LFS. Early tumor detection through surveillance has been evaluated and reported in a few pub- lished studies. In Brazil, with its higher incidence of the R337H variant, a large proportion of the population does not have access to screening in accordance with the Toronto guidelines, particularly including WBMRI. Using a Markov decision analytic model to compare costs and yielded life years in carriers of the Brazilian founder variant, the incremental cost-effectiveness ratio (ICER) was calcu- lated for both men and women with and without surveil- lance. For women, the ICER was 4.185 per addi- tional life year (26.3 life years in surveillance vs. 23.5 in the non-surveillance group [43]. Limitations to this study include that it is not feasible to consider personal and indirect costs such as work absence or travel costs, which have been addressed in two different studies on different populations outside Brazil. A similar study simulated the proposed cost-effectiveness in a United States health care setting, with the same conclusion of cost-effectiveness in favor of surveillance (27 life years gained vs 23 life years for the surveillance and non-surveillance group, respectively)

[44]. The direct and indirect costs are highly dependent on the country of residence in addition to the individual differ- ences in access to care from private insurance. In a study of 20 individuals with LFS in Virginia (USA), 63% reported worry about their future financial situation because of LFS, and 65% agreed that even with insurance, their share of the associated healthcare costs was too high, although an asso- ciation of skipping surveillance in relation to the share of insurance costs could not be found. It should be noted that all patients were insured and 75% held at least a bachelor’s degree, thus probably reflecting a homogenous, highly edu- cated population that may not be accurately reflective of the general population [45]. Another study conducted in Sweden on 60 individuals could not identify financial cost as a barrier to surveillance participation, likely a reflection of different health care funding model. The surveillance procedures within the study were accessible for TP53 car- riers enrolled in the study at no additional cost reflected on the individual and thus not dependent on access to private insurance [28].

8. Blood work as surveillance

Current surveillance recommendations include the use of blood work for screening for certain cancers, including plasma-fractionated metanephrines for ACC and complete blood counts (CBC) for leukemia’s (although with some varia- tions among the different protocols (Table 1)). Limitations include the fact that CBCs are generally unhelpful in early detection of leukemia although downward trends in hemoglo- bin or platelet counts, or aberrant white cell counts may be indicators of other non-leukemic pathology. The majority of ACCs secrete glucocorticoid or mineralocorticoids [46] which makes these assays particularly valuable for detection of ACC (which most typically occurs in very young children). Non- specific biomarkers including lactic dehydrogenase (LDH) and erythrocyte sedimentation rate (ESR) are more likely to be increased in the setting of a manifest cancer rather than an asymptomatic one, and both tests might be elevated due to many other biological processes and diseases [47,48]. Interestingly, PSA has emerged as a biomarker, not originally included in the first surveillance protocol [5]. A recent study identified an increased relative prostate cancer risk of 9.1 in comparison to US population controls, with a median age of diagnosis of 56 with 44% (25/58 patients) having a Gleason score of ≥8 and 29% (10/34 patients) with advanced disease at diagnosis, with an enrichment for attenuated germline TP53 variants. This suggests considering the addition of annual PSA screening for men with at least 10 years of life expectancy years of age, due to the increased risk of aggressive prostate cancer in germline TP53 variant carriers [49].

9. Endoscopic surveillance

As demonstrated by the different guidelines and recommen- dations for surveillance summarized in Table 1, there is a discrepancy with regard to the use of endoscopic surveil- lance for early detection of colorectal cancer (CRC) and gastric cancer. Endoscopy offers a unique advantage not only as

a surveillance tool but also as has the advantage of providing a diagnostic and sometimes treatment tool at the same time through biopsies and polypectomies. To date, there is a lack of large, longitudinal studies on endoscopic surveillance in the setting of LFS for an evaluation of the findings of premalig- nant and malignant lesions.

9.1. Upper gastrointestinal cancer

Incidence and population risks for upper gastrointestinal can- cer varies widely globally. Worldwide, general population cumulative risks of developing gastric cancer (up to age 74) is 1.53% in men and 0.67% in women [50]. A recent study estimated age-cumulative cancer risks of first cancers up to age 60 by using pedigrees from three countries and 147 LFS families (4,208 individuals, of whom 741 were genotyped). The estimated risk of gastric cancer in this study reached 4%, but it is of note that the study relied on pedigree information and did not confirm cancer diagnoses further [51]. Another study extracted data from the R20 IARC database in 2020, noted similar findings of 3.9% of upper gastrointestinal (GI) cancers in TP53 carriers. They also reported on endoscopic surveillance outcomes from a single center, without invasive cancer but a relatively short follow-up time between 2018 and 2020 [52]. A retrospective chart review of 35 LFS individuals from Australia spanning 2000-2023, reports on two asymptomatic patients in their 30s with carcinoma in situ eligible for curative treatment. These patients did not have a family history sug- gestive of GI cancer, or prior abdominal radiation therapy. Premalignant lesions were identified in five patients [53]. Special screening considerations might be needed in popula- tions with a higher incidence of gastric cancer in the popula- tion, such as Japan [54].

9.2. Colorectal cancer

Similar to upper GI cancer, incidence and population risks for CRC cancer vary globally (10-fold differences) [50], with an estimated population risk from birth to death of about 4% in the United States [55]. Estimated cancer risks among LFS individuals from birth to age 60 suggests a 12% risk, based on pedigree data [51]. Early-onset CRC (<40 years) have been described in retrospective cohorts; a multicentre study reports 1.3% (6 patients) carrying germline TP53 variants, of which two were of biological uncertain significance [56]. Another single- center study reports 4 patients (4.3%) being diagnosed with a CRC before age 35, and 28 patients (1.4%) when reviewing IARC data [57].

10. Future directions and ongoing studies

10.1. ctDNA

The ‘Toronto’ protocol has been in use for many years and relies on tumors large enough (at least approximately 1 cm) to be detected by imaging. In recent years, efforts have been made to incorporate so-called ‘liquid biopsies’ into surveillance, with the aim to screen for tumors that are not detected with imaging. In 2017, the CHARM (cfDNA in

Hereditary and High-Risk Malignancies) Consortium was founded to assess the clinical validity of cell-free (cfDNA) in not only LFS, but also other hereditary cancer predisposi- tion syndromes [58]. The first proof-of-principal study using a multimodal liquid biopsy assay demonstrated an increased detection rate of cancer in germline TP53 carriers prior to diagnosis within the clinical imaging surveillance program [59]. Among cancer-free germline TP53 carriers, the positive predictive value was 54.2% (26/48) and the nega- tive predictive value was 95.4% (41/43) when combining findings from genomic, fragmentomic, and methylomic ana- lyses in LFS patients who had cancer at the time of the blood draw. Of note, 30.1% (22/73) of cancer-free germline TP53 carriers showed a cancer-associated signal by ctDNA analysis but without a subsequent clinical finding, at least over the follow-up period of the study. Although clinical validation in larger cohorts is needed, this study represents a glimpse into the future in which a multi-modal screening approach incorporating far less invasive procedures as a complement to traditional imaging for early cancer detec- tion. It could also have implications toward a more perso- nalized cancer screening, instead of a ‘one-model-fits-all- strategy’ as the case have been with WBMRI, particularly as aspects of the assay are refined to identify specific tumor types (as was demonstrated using a breast cancer methyla- tion signature).

10.2. Wearables

The use of wearable digital health technologies and mobile apps for fast, real-time data collection of biometrics is a rapidly evolving field, with the potential of being an addition to already established surveillance strategies for individuals at risk of developing cancer. An LFS cohort of 49 individuals was included in a feasibility study including both cancer affected and unaffected family members and contained both a wearable device and a study app invol- ving daily and intermittent surveys, as well as active tasks. Adherence to the wearable device was higher than in-app activities such as completing daily surveys, and 45/49 (91.8%) of the study population remained enrolled at study completion after 6 months [60]. To further explore the clinical utility of the collection of various biometric datapoints, studies focusing on how the possible addition of wearable-collected data could be used in conjunction to conventional screening modalities. There is also a need for ongoing patient-centered involvement during the develop- ment of these devices and apps, as well as exploration of the impact of returning data to the patient and the inter- pretation of the same.

10.3. Predicting age of tumor onset

Biomarkers such as those derived from metabolic assess- ments in skin-derived fibroblasts [61] and microbiota [62] are being investigated as tools for predicting cancer onset. Although still limited to mouse models, the approach of using noninvasive strategies to explore cancer risks and

possible treatment modifications pose an exciting field to be further explored.

10.4. Newborn screening

Attitudes and willingness toward newborn screening (NBS) for underlying CPS in general, and LFS in particular remain largely unknown, and could potentially vary among different coun- tries, access to health care and different health care systems in general. A study from Germany concluded that the uptake of whole-exome sequencing of parent-child trios in children and adolescents with a newly diagnosed cancer was very high 83/ 94 (88.3%) [63]. The finding of an LFS variant in a newborn and subsequent enrollment in a surveillance program have been explored in a model designed to look at the cost-effectiveness of NBS screening for LFS in the US. With the inclusion of cancer occurrence before age 20 years and without consider- ing further impact of cancer risk reduction in the family or adult-onset cancers, a proposed reduction of cancer-related deaths was 7.2% and a 40% probability that TP53-NBS screen- ing would be cost-effective given a $100 000 per life-year gained willingness-to-pay threshold [64]. Furthermore, identi- fying an LFS variant in a newborn does not only imply a specific risk of childhood tumors but also for adult-onset cancers given that approximately 75% of all LFS variants are thought to be inherited [65]. Therefore, detecting an LFS- causing variant in a newborn could also have implications for the family with regard to genetic counseling and cascade testing. Thus, this should also be a point of exploration while designing future studies to further clarify the feasibility of newborn screening in the context of LFS. In summary, before the implementation of universal NBS for cancer predisposition syndromes like LFS, there is a need to outline not only the cost-effectiveness of interventions but also the clinical utility and attitudes among different general populations toward NBS screening.

11. Conclusion

Since the start of surveillance of LFS individuals with and without previous cancer history within a research setting, clinical surveillance protocols have emerged world-wide with slight alterations, mainly on the use of endoscopic procedures and the frequency of different imaging modalities. Until more data emerge, possibly suggestive of and differentiating between different phenotypes being useful in a clinical set- ting, current guidelines support offering pre-symptomatic can- cer screening in individuals with a likely pathogenic/ pathogenic TP53 variant.

12. Expert opinion

The first reports of a clinical syndrome are usually defined by the most severe phenotype. Over the years, a broader pic- ture has emerged including varying phenotypic presenta- tions and cancer risks associated outside of the classic LFS core tumor spectrum. At the time, whole-body MRI was not routinely used in a surveillance setting and represented a bold new strategy. Since then, the use of PSA has been

suggested to be added to the original protocol, and new studies investigating wearables and ctDNA might add to the current imaging-dependent surveillance strategies. In today’s frontline of health care, emerging fields include the use of metabolic biomarkers and microbiota as predictors of tumor onset, and the possibility to tailor surveillance in accordance with predictions. However, until more is known about the different phenotypic variations among LFS, it is still too early to stratify for a more personalized approach. Clarity regard- ing the effect of DNA damaging oncological treatments like chemotherapy and radiotherapy is needed, as to not risk withholding effective treatment strategies. In addition to studies aiming at further exploring phenotypes and treat- ments effects, future research should also be directed toward identifying less invasive, financially toxic and time- consuming surveillance, in addition to the development of drugs aimed at reducing the cancer incidence. To ensure sufficiently large cohorts and more easily interpreted data, international collaborations including longitudinal prospec- tive studies are needed.

Funding

This work is supported in part by a New Frontiers Program Project grant from the Terry Fox Research Institute with funds from the Terry Fox Foundation [grant #1081]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Declaration of interest

D Malkin holds the CIBC Children’s Foundation Chair in Child Health Research, and M Omran is supported in part by the Jeffrey Brock Cancer Genetics Research Fellowship. The authors have no other relevant affilia- tions or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosure

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

ORCID

Meis Omran @ http://orcid.org/0000-0001-5485-6566 David Malkin iD http://orcid.org/0000-0001-5752-9763

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