Abstract
Background
Li Fraumeni syndrome (LFS), a rare genetic condition, poses a significant health impact due to the ∼75%-90% lifetime risk of developing cancer in affected individuals. Due to the rarity of this disease, little is known about the outcomes, clinical characteristics, and treatments of cancer for patients with LFS.
Patients and methods
We present a retrospective dataset of 57 patients from 41 families diagnosed with LFS between 1996 and 2021, with or without a concurrent cancer diagnosis, who were managed at a single cancer institution in the UK. We present the cancer types that were observed in this group, the age at cancer diagnosis, and treatment modalities for those affected with cancer, either before or after having a TP53 test to establish their LFS diagnosis.
Results
A total of 24 individuals underwent predictive testing, of which 13 were not diagnosed with cancer during the observation period. The other 33 individuals underwent diagnostic testing and had at least one cancer diagnosis each. Overall, there were 92 distinct cancer diagnoses in 44 participants, the majority being breast cancers and sarcomas. Patients were most likely to be diagnosed with LFS between the ages of 30 and 40 years. Some 75% of all cancer diagnoses were diagnosed at an early stage [TNM (tumour–node–metastasis) stage 0-2], and 19% had a recurrence, despite the early diagnosis. In total, 42% of individuals with LFS died as a result of a cancer diagnosis in our dataset, but the overall survival could not be calculated due to the short follow-up period (median 6 years, IQR 2-11 years).
Conclusions
Individuals with LFS have a high risk of cancer, cancer recurrence, and death. Larger multicentric international studies focusing on developing cohorts of specific diseases are needed to better understand disease patterns related to different pathogenic TP53 variants and inform which patients with LFS may need a more targeted and aggressive surveillance protocol.
Key words: Li Fraumeni syndrome, breast cancer, sarcoma, early diagnosis, screening, electronic patient record, service evaluation
Highlights
-
•
LFS remains a challenging disease due to the extremely high risk of developing cancer.
-
•
Despite 75% of all cancers in LFS being diagnosed early, the risk of recurrence within the early-stage cancers was 19%.
-
•
To better understand disease patterns, larger multicentric international studies focusing on cohorts of specific LFS cancers are needed.
Background
Li Fraumeni syndrome (LFS) is a rare autosomal dominant genetic condition that predisposes an individual to develop (often multiple) cancers throughout their lifetime. People with LFS are born with a pathogenic (P) or likely pathogenic (LP) germline alteration in the TP53 gene, either inherited from one of their parents or arising de novo during embryogenesis.1
It is estimated that LFS occurs in ∼1 in 5000 to 1 in 20 000 people worldwide. In the UK, LFS could affect >400-600 individuals, including children.2,3 More than 90% of women and around 75% of men with an inherited P/LP variant in the TP53 gene will develop cancer during their lifetime.4, 5, 6 The risk of cancer imparted by TP53 mutations is evident at an early age, with women in LFS families who carry such mutations having a cumulative 49% risk of developing cancer by the age of 30 years. Men with TP53 alterations have a 21% risk at the same age.7
The classic LFS diagnostic triad initially consisted of a sarcoma diagnosed before age 45 years, a first-degree relative with any cancer before age 45 years, and a relative in the same lineage, with any cancer before age 45 years or a sarcoma at any age.8, 9, 10, 11 These criteria have evolved significantly over the past 20 years, reflecting the expansion of knowledge about LFS (Supplementary Table S1, available at https://doi.org/10.1016/j.esmoop.2025.105541 – testing criteria in England).
Very few published datasets have tried to characterise the outcomes and cancer characteristics of people with LFS. One of the most studied TP53 variants is the p.337H variant, also known as the Brazilian founder mutation, because it is very common in the South of Brazil, although it has a reduced penetrance and is very rarely seen outside the Brazilian population.12, 13, 14, 15 For example, Petry and colleagues15 described the outcomes of 41 Brazilian patients with localised breast cancer on a background of LFS, the majority harbouring the p.R337H variant. In their dataset, it was shown that patients with LFS had worse outcomes and higher rates of cancer relapse, compared with non-LFS patients. In another dataset with women with LFS affected by breast cancers, those with a human epidermal growth factor receptor 2 (HER2)-positive subtype were younger at diagnosis and had predominantly positive hormone receptors and had favourable pathological responses to neoadjuvant therapies with HER2 inhibitors.16
In patients with LFS, surveillance is likely to have a significant impact on outcomes. In a series of 89 individuals with LFS from three centres in Canada and the USA, between 2004 and 2015, who either selected or declined surveillance [which included rapid whole-body magnetic resonance imaging (WB-MRI), breast imaging, brain imaging, blood tests, upper and lower endoscopies in adults], the 5-year overall survival rate was 88.8% for individuals in the surveillance group and 59.6% for those who declined.17 Therefore, national and international guidelines now recommend annual surveillance including WB-MRI.3,5
Due to the rarity of this syndrome, despite the aggressive phenotype and high risk of developing cancers, the outcomes of people with LFS and cancer characteristics are not well understood. Moreover, information about cancer diagnosis, including the rate of early versus late cancer diagnosis or the risk of recurrence in people with LFS affected by cancer, is lacking. We herein present a retrospective analysis of 57 patients with LFS from a single UK cancer centre, with or without a cancer diagnosis; we review the age at diagnosis of LFS, age at diagnosis of first and sequential cancers, rate of early versus late diagnosis of cancer as well as risk of recurrence.
Patients and methods
Patients and study design
We obtained ethical approval from the Royal Marsden Hospital NHS Foundation Trust Committee for Clinical Research (Service evaluation 1287/18.05.2023) to carry out this study. For this service evaluation, consent from participants was not needed because the information was curated retrospectively from de-identified, routinely collected clinical data. We searched the prospectively maintained TrakGene genetic database in the Cancer Genetic Unit (CGU) at the Royal Marsden Hospital in London, UK, to identify all patients diagnosed with LFS before January 2022. TrakGene is a clinical genetics information management systems provider and was implemented at the Royal Marsden Hospital in 2011. Individuals were carriers of a P/LP TP53 variant in all cases. Patients’ demographics, date of LFS diagnosis, cancer diagnoses, data on treatments, scans, last date of follow-up documented in the patient’s medical file, and survival were obtained from the TrakGene database and electronic patient records. We will refer to patients with an LFS diagnosis before any cancer diagnosis as the ‘predictive subgroup’. These patients usually underwent TP53 testing because they were at risk of inheriting an established familial TP53 variant. Patients who were diagnosed with LFS following a cancer diagnosis, are in the ‘diagnostic subgroup’. These patients had a cancer diagnosis and met criteria for NHS-funded constitutional TP53 testing at the time of their referral to CGU.
The pathogenicity of each TP53 variant was determined by a genetic laboratory based on the guidelines of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology for germline variant classification of the TP53 gene.18,19 Diagnostic testing was done via TP53 sequence analysis of exons 1-11 and flanking splice sites. Direct sequencing of PCR products has been carried out in both directions, and splice sites flanking these exons have been analysed with variable amounts of intron. Predictive testing was done using targeted testing for the familial variant and by Sanger sequence analysis.
Outcomes
The outcomes were age at LFS diagnosis, time from LFS diagnosis to first and subsequent cancer diagnoses, age at each cancer diagnosis, cancer characteristics, risk of recurrence, and median follow-up. The date of LFS diagnosis was the date when the laboratory issued the germline report for each case. Other data were available in the medical records, including type and duration of cancer treatments, date of cancer recurrence, and date of death, which were available in the electronic patient record. Patients had a diagnosis of predictive or diagnostic LFS when they received the genetic result based on the criteria described above. The data cut-off for all follow-up information was 1 August 2024.
Statistical analysis
The participants’ baseline characteristics were described as frequencies (percentages). We calculated the time from birth to each cancer diagnosis and LFS diagnosis to death or loss of follow-up. Statistical analysis was descriptive and carried out using Microsoft Excel and STATA SE software Version 18.0.20 Due to the observational nature of the dataset, no formal unbiased comparisons between the two subgroups (predictive and diagnostic tests) were possible. The allocation of predictive and diagnostic tests was done unbiased and reflected the different ways LFS was diagnosed. Swimmer plots were generated using STATA software, to illustrate visual timelines of ages at diagnosis of LFS and each cancer, as well as last follow-up or death.
Results
Patients’ characteristics
Fifty-seven adults with LFS from 41 unrelated families were identified (Table 1). Females represented 79% of all patients (n = 45), and males represented 21% (n = 12). All individuals were diagnosed with LFS before January 2022. The first case of LFS included in this series was diagnosed in April 1996. A total of 24 individuals underwent predictive genetic testing (predictive subgroup), and at the time of the analysis, 13 of these cases had never been diagnosed with cancer. The other 33 individuals underwent diagnostic TP53 testing due to meeting the LFS genetic testing criteria at the time of their cancer diagnosis (e.g. criteria in Supplementary Table S1, available at https://doi.org/10.1016/j.esmoop.2025.105541, and similar and evolving criteria in the years preceding this) (diagnostic subgroup) and had been diagnosed with at least one cancer before having a positive TP53 genetic test.
Table 1.
Demographic variables
| Demographic variables | Diagnostic n = 33 |
Predictive n = 24 |
Overall n = 57 |
|||
|---|---|---|---|---|---|---|
| n | % | n | % | n | % | |
| Female | 25 | 76 | 20 | 83 | 45 | 79 |
| Male | 8 | 24 | 4 | 17 | 12 | 21 |
| Ethnicity | ||||||
| Asian (Indian/Pakistani) | 3 | 9 | 4 | 17 | 7 | 12 |
| White | 20 | 61 | 17 | 71 | 37 | 65 |
| Other | — | — | 1 | 4 | 1 | 2 |
| Undisclosed | 10 | 30 | 2 | 8 | 12 | 21 |
| Median | IQR | Median | IQR | Median | IQR | |
| Age, years | ||||||
| At LFS diagnosis | 40 | 32-52 | 36 | 28-41 | 38 | 29-48 |
| At 1st cancer diagnosis | 32 | 18-44 | 45 | 31-53 | 33 | 24-47 |
| F/u years from LFS diagnosis | 3 | 1-8 | 10 | 6-15 | 6 | 2-11 |
| Age at death, years (n = 25) | 44 | 38-60 | 44 | 37-49 | 44 | 38-58 |
| Age at loss to f/u, years (n = 33) median (IQR) | 41 | (30-54) | 46 | (43-56) | 46 | (41-54) |
| N | N | N | ||||
| Number of new primary cancer diagnoses | 78 | 14 | 92 | |||
| Recurrence (cancers) | 14 | 2 | 16 | |||
| Number of deaths | 21 | 4 | 25 | |||
| Number at last f/u | 13 | 20 | 33 | |||
| Treatments | N | % | N | % | N | % |
| Total | 129 | — | 25 | — | 154 | — |
| Radiotherapy curative | 16 | 12 | 3 | 12 | 19 | 12 |
| Radiotherapy palliative | 10 | 7 | 3 | 12 | 13 | 8 |
| Systemic anticancer treatment | 34 | 26 | 5 | 20 | 39 | 25 |
| Surgery | 61 | 47 | 11 | 44 | 72 | 47 |
| Other | 8 | 6 | 3 | 12 | 11 | 7 |
f/u, follow-up; IQR, interquartile range; LFS, Li Fraumeni syndrome.
TP53 variants
All subjects were diagnosed with LFS based on a P or LP TP53 variant detected in their germline blood. The list of all TP53 variants, their pathogenicity, and the types of cancers associated with them is available in Table 2. There were 29 different variants, and no cases of mosaicism in this cohort.
Table 2.
TP53 variants, pathogenicity and types of cancers
| TP53 variant | Pathogenicity | Subjects (n) | Individual | Sex (male/female) | Type of test: predictive (P)/diagnostic (D) | Types of cancer (age at diagnosis of cancer or at last f/u if no cancer diagnosed, years) | Cause of death/alive at last f/u |
|---|---|---|---|---|---|---|---|
| c.1010G>A (R337H) | Pathogenic/likely pathogenic | 3 | 1 | F | D |
|
Metastatic leiomyosarcoma |
| 2 | M | D |
|
Metastatic prostate cancer | |||
| 3 | F | P |
|
Alive at last f/u | |||
| c.1024C>T | Pathogenic | 4 | 1 | F | D |
|
Alive at last f/u |
| 2 | F | P |
|
Alive at last f/u | |||
| 3 | F | D |
|
Metastatic breast cancer | |||
| 4 | F | P |
|
Alive at last f/u | |||
| c.1031T>C | Pathogenic | 1 | 1 | M | D |
|
Glioblastoma |
| c.151G>T | Likely pathogenic | 1 | 1 | F | D |
|
Metastatic carcinoma |
| c.196C>T | Pathogenic | 1 | 1 | F | P |
|
Glioblastoma NB: all three cancers were diagnosed in the same year—renal and uterine cancer detected on a one-off WB-MRI and the glioblastoma diagnosed following emergency admission with neurological symptoms |
| c.273G>A | Pathogenic | 1 | 1 | F | D |
|
Alive at last f/u |
| c.314_315delinsAT | Pathogenic | 1 | 1 | M | D |
|
Metastatic prostate cancer |
| c.375G>A | Pathogenic | 1 | 1 | F | P |
|
Alive at last f/u |
| c.377A>G | Likely pathogenic | 1 | 1 | M | P |
|
Metastatic sarcoma |
| c.422G>A | Pathogenic/likely pathogenic | 1 | 1 | F | D |
|
Patient lost to f/u following her last cancer diagnosis |
| c.455C>T | Pathogenic | 7 | 1 | M | D |
|
Alive at last f/u |
| 2 | F | D |
|
Relapse lymphoma in CNS | |||
| 3 | F | P |
|
Alive at last f/u | |||
| 4 | M | D |
|
Alive at last f/u | |||
| 5 | M | P |
|
Alive at last f/u | |||
| 6 | F | P |
|
Alive at last f/u | |||
| 7 | F | P |
|
Alive at last f/u | |||
| c.473G>A | Pathogenic/likely pathogenic | 4 | 1 | F | D |
|
Encephalopathy probably sarcoma related |
| 2 | M | D |
|
Alive at last f/u | |||
| 3 | F | P |
|
Alive at last f/u | |||
| 4 | F | P |
|
Alive at last f/u | |||
| c.524G>A | Pathogenic | 2 | 1 | F | D |
|
Metastatic leiomyosarcoma |
| 2 | M | D |
|
Glioblastoma | |||
| c.589G>A | Likely pathogenic | 2 | 1 | F | P |
|
Metastatic breast cancer |
| 2 | F | P |
|
Alive at last f/u | |||
| c.638_639delinsAG | Pathogenic | 1 | 1 | F | P |
|
Alive at last f/u |
| c.638G>A | Pathogenic | 3 | 1 | F | D |
|
Lost to f/u |
| 2 | F | D |
|
Metastatic leiomyosarcoma (LFS diagnosed post-mortem) | |||
| 3 | F | P |
|
Alive at last f/u | |||
| c.659A>G | Likely pathogenic | 2 | 1 | F | D |
|
Lost to f/u |
| 2 | F | D |
|
Metastatic breast cancer | |||
| c.694A>T | Likely pathogenic | 2 | 1 | F | P |
|
Alive at last f/u |
| 2 | F | P |
|
Metastatic lung cancer | |||
| c.715A>G | Likely pathogenic | 1 | 1 | F | D |
|
Astrocytoma |
| c.733G>A | Pathogenic | 1 | 1 | F | D |
|
Alive at last f/u |
| c.745_726del9 | Likely pathogenic | 1 | 1 | F | D |
|
Metastatic myxofibrosarcoma |
| c.766A>G | Likely pathogenic in 2016, then downgraded to variant of uncertain significance in 2022 | 2 | 1 | F | P |
|
Alive at last f/u |
| 2 | F | D |
|
Metastatic pancreatic cancer | |||
| c.818G>A | Pathogenic | 6 | 1 | F | P |
|
Alive at last f/u |
| 2 | F | D |
|
Acute leukaemia | |||
| 3 | F | D |
|
Alive at last f/u | |||
| 4 | F | D |
|
Alive at last f/u | |||
| 5 | F | P |
|
Alive at last f/u | |||
| 6 | M | P |
|
Alive at last f/u | |||
| c.824G>A | Pathogenic/likely pathogenic | 1 | 1 | F | D |
|
Metastatic liposarcoma |
| c.844C>T | Pathogenic/likely pathogenic | 2 | 1 | F | D |
|
Metastatic breast cancer |
| 2 | F | D |
|
Metastatic osteosarcoma | |||
| Exon 1 deletion | Likely pathogenic | 2 | 1 | M | D |
|
Metastatic leiomyosarcoma |
| 2 | F | D |
|
Alive at last f/u | |||
| Exon 1-5 deletion | Pathogenic | 1 | 1 | F | P |
|
Alive at last f/u |
| Exon 1-11 deletion | Likely pathogenic | 1 | 1 | M | P |
|
Lost to f/u |
| Whole gene deletion | Likely pathogenic | 1 | 1 | F | D |
|
Metastatic breast cancer (LFS diagnosed post-mortem) |
Of note, the same kind of cancer can be diagnosed in two separate individuals carrying the same TP53 variant, and commas separate their ages. If there is only one person with a specific variant, each cancer diagnosis is listed separately, with the respective age at each diagnosis. For example, the person carrier of the c.1031T>C variant was diagnosed with four different cancers and had a leiomyosarcoma on each thigh diagnosed at 36 and 52 years old; the second leiomyosarcoma was considered to be a separate occurrence from the first leiomyosarcoma. Recurrences are not shown in this table, due to the short interval of follow-up, but the cause of death is shown in the last column.
CNS, central nervous system; D, diagnostic; ER, estrogen receptor; F, female; f/u, follow-up; HER2, human epidermal growth factor receptor 2; HR, hormone receptor; LFS, Li Fraumeni syndrome; M, male; MPNST, malignant peripheral nerve sheath tumour; P, predictive; PEComa, perivascular epithelioid cell tumor; WB-MRI, whole-body magnetic resonance imaging.
The TP53 c.766A>G was initially classified as LP in 2016 when two members of the same family were tested, but was then downgraded to a variant of uncertain significance in 2022. Two people were carriers of this variant in our database, and both had a diagnosis of cancer, one with bilateral breast carcinoma at the age of 72 years, and the second patient had bilateral breast cancer at the age of 34 years, then pancreatic adenocarcinoma at the age of 59 years. Although this variant is currently classified as a variant of uncertain significance, we have retained it in our database for educational purposes.
The c.1010G>A (R337H) variant was present in three unrelated individuals of different ethnic backgrounds (Polish, Pakistani, and white British). Two patients had a cancer diagnosis: the first patient had metastatic prostate cancer at the age of 55 years and renal cancer at the age of 65 years; the second patient had a leiomyosarcoma of the pelvis at the age of 33 years. The third person had a predictive test and was not diagnosed with cancer at the last follow-up when they were 48 years old.
Age at diagnosis
The median age at LFS diagnosis across both predictive and diagnostic subgroups was 38 years [interquartile range (IQR) 29-48 years]. The youngest patient was diagnosed at 17 years, and the oldest patient was diagnosed at 66 years. The median (IQR) age for LFS diagnosis in the diagnostic subgroup was 40 years (32-52 years), and in the predictive subgroup was 36 years (28-41 years). Patients were most likely to be diagnosed between the ages of 30 and 40 years (Figure 1). Each participant’s age at first cancer (or age at the last clinical follow-up data entry if no cancer) is displayed in Table 2, alongside the corresponding TP53 variant. The graph illustrates that no clear patterns of cancer diagnosis or deaths are clustered around particular variants in our population.
Figure 1.
Distribution of age in years at diagnosis of LFS for all patients. LFS, Li Fraumeni syndrome.
The median (IQR) age for the first cancer diagnosis in the diagnostic subgroup was 32 years (18-44 years). In contrast, the median age in the predictive subgroup was 45 years (31-53 years). The median overall age at first cancer diagnosis, including both predictive and diagnostic tests, was 33 years (24-47 years).
In two female patients, the diagnosis of Li Fraumeni was made post-mortem; in the first case, the diagnosis was made 1 year post-mortem on a stored DNA sample as the technology for TP53 testing became more available. In the second case, the diagnosis was made 2 months post-mortem, as the patient died of complications of her cancer before the result of the test was available.
Supplementary Figure S2, available at https://doi.org/10.1016/j.esmoop.2025.105541, illustrates the age at first cancer diagnosis or the age at last follow-up if there was no cancer diagnosis and the TP53 variant corresponding to each individual.
Risk-reducing surgeries and access to whole-body MRI
A total of 16 women underwent a risk-reducing surgery (RRS), namely, unilateral or bilateral mastectomy. In the diagnostic group, seven women had an RRS, five a bilateral mastectomy, and two a unilateral prophylactic surgery, after a diagnosis of contralateral breast cancer. Three of the five women who had a bilateral RRS had an initial breast cancer diagnosis that was treated with wide excision, then had a completion bilateral mastectomy either at LFS diagnosis or at diagnosis of contralateral breast cancer. In the predictive group, nine women underwent RRS: in all cases, a bilateral RRS mastectomy.
Five patients had a screening WB-MRI, four had one single WB-MRI from participating in a UK study,21 and only one patient had access to a routine annual WB-MRI. This patient was diagnosed with two early cancers: a bladder carcinoma and a sarcoma of the thigh.
Cancer characteristics
There were, in total, 92 distinct cancer diagnoses (excluding recurrences) in 44 participants, the majority being breast cancer (n = 29) and sarcomas (n = 29) (Figure 2). In the 35 women diagnosed with at least one cancer, breast cancer was the most frequent diagnosis (38%), followed by bone and soft tissue sarcoma (26%) and leukaemia, ovarian, and brain tumours (4% each) (Figure 3). Two of the breast cancers were malignant phyllodes, a rare and very aggressive subtype. The first cancer diagnosis in women was breast cancer in 18 cases, sarcoma in 6 cases, leukaemia or lymphoma in 3 cases, and other tumours in the remaining 8 cases.
Figure 2.
All cancer types in our LFS cohort. BCC, basal cell carcinoma; LFS, Li Fraumeni syndrome; SCC, squamous cell carcinoma.
Figure 3.
Distribution of cancers for females (n = 45) and males (n = 12). BCC, basal cell carcinoma; DLBCL, diffuse large B-cell lymphoma; LFS, Li Fraumeni syndrome; SCC, squamous cell carcinoma.
Nine men were diagnosed with a total of 17 cancers, the most common diagnosis being bone and soft tissue sarcoma (53%), followed by colorectal and prostate cancer (12% each) and brain tumours (11%). The first diagnosis of cancer in men was sarcoma in seven cases and prostate cancer in two other cases. Interestingly, all three women diagnosed with a brain tumour had an astrocytoma, whereas both men diagnosed with a brain tumour had a glioblastoma.
Most cancers were diagnosed at an early stage [TNM (tumour–node–metastases) stage 0-2] in both diagnostic and predictive subgroups. Out of 92 new diagnoses, 69 (75%) were diagnosed at an early stage (TNM stages 0-2), 18 (19.5%) were diagnosed at a late stage (TNM stages 3-4), and for 5 (5%) cancers, information about stage at diagnosis and recurrence was missing.
Surgery was the first treatment option for most cases, likely due to the higher incidence of early diagnosis in this population (Table 1). Chemotherapy (either with curative intent or palliative) was offered in 39 diagnoses of cancer.
Radiotherapy (radical or palliative) was administered to 25 patients overall. Radical, or curative, radiotherapy was used as a treatment modality in 19 patients. Thirteen patients also received palliative radiotherapy, indicating that some patients received radiotherapy on more than one occasion (Table 1). One case of radiation-induced osteosarcoma was documented in this series in a woman who received radiotherapy for the treatment of rhabdomyosarcoma. This patient was diagnosed with rhabdomyosarcoma of the left chest wall at the age of 2 years, for which she received chemotherapy, surgery and radiotherapy; she then developed a poorly differentiated advanced carcinoma of the left breast as well as a radiation-induced localised osteosarcoma of the left scapula, almost concomitantly (diagnosed 1 month apart) at 26 years old, 24 years after the initial radiotherapy.
Another female patient received total body irradiation at the age of 17 years for the treatment of a B-cell acute lymphoblastic leukaemia. This patient has developed four other cancers during her lifetime (multifocal left buttock leiomyosarcoma, melanoma, breast cancer, and uterine leiomyosarcoma) before being lost to follow-up at the age of 32 years. Another patient developed squamous cell carcinoma at a previous site of radiotherapy for a sarcoma.
Eleven patients received other treatments, including autologous stem cell transplant for a diffuse large B-cell lymphoma, bone marrow transplant for B-cell acute lymphoblastic leukaemia, imiquimod and fluorouracil cream for superficial skin cancer (basal cell carcinoma, n = 2), active surveillance for chronic lymphocytic leukaemia, active surveillance for renal cell carcinoma, zoledronic acid and denosumab for treatment of bone metastases (n = 3), steroids adjuvant after resection of adrenocortical carcinoma, and local ablation of bladder cancer.
Overall, 33 patients were diagnosed first with cancer, followed by LFS diagnosis (diagnostic subgroup) and 24 people underwent predictive testing (predictive subgroup) and were not affected by cancer at the time of their LFS diagnosis; 11 people with predictive testing were diagnosed with 14 cancers by the time of data cut (ranging from 1 to 3). One-third of all cancers were breast cancer (all in women), one-third were sarcomas, and the other third were all the other subtypes of cancer described in our manuscript, which is consistent with most LFS cases described in the literature.7
Children with LFS are usually managed in highly specialised paediatric centres and were not included in this cohort; however, some people diagnosed with LFS in adulthood had a childhood cancer, and those cancers were included in this analysis.
Risk of recurrence
A total of 13 early-stage cancers (19%) had a recurrence, 1 in the predictive and 12 in the diagnostic subgroups (Table 1). Overall, the median duration of follow-up since diagnosis of LFS was 6 years. The median follow-up was 3 years for the predictive subgroup and 10 years for the diagnostic subgroup, increasing the chances of detecting a recurrence in the diagnostic subgroup (Table 1).
Overall survival
Overall survival for both groups (predictive/diagnostic) could not be calculated reliably, due to a short follow-up interval (median 6 years, IQR 2-11 years).
Discussion
In this retrospective analysis, we described the outcomes of 57 men and women with a diagnosis of LFS, affected or not by a cancer diagnosis at their last follow-up, managed or followed at the Royal Marsden NHS Foundation Trust, a tertiary cancer centre in London, UK. Routine genetic testing for LFS became available in the UK in the mid-1990s; however, for many years, most geneticists hesitated to test patients for TP53 mutation, even those fulfilling diagnostic criteria for LFS, because of a lack of cancer screening modalities to then offer those with confirmatory germline test results.3 More recently, as more genetic groups have provided clear guidance for subsequent cancer screening options, LFS individuals are increasingly offered more comprehensive cancer screening options, including whole-body and dedicated brain MRIs.
We separated our patients into two subgroups: one subgroup where patients were tested for LFS after being diagnosed with cancer and fulfilled testing LFS criteria at the time of their clinical review; and a second subgroup where LFS was predictive, meaning that those individuals had a family member diagnosed with LFS, and underwent LFS testing without having a cancer diagnosis by the time of their test. We wanted to describe the outcomes of each subgroup due to the different ways LFS was diagnosed, especially to describe the cancers diagnosed and staging at diagnosis. Our results suggested, although no formal statistical comparison was made, that both subgroups had similar rates of early versus late detection of cancer, likely explained by the fact that, historically, even if LFS people were diagnosed with LFS, they still could not access extensive surveillance programmes, as these were not available until recent years.
Most cancers detected in LFS individuals were early stages (TNM 0-2), which allowed for a more radical approach, including resection and radiotherapy. Once the TP53 status was known, however, radiotherapy was given in fewer cases. This shift in treatment was because of the risk of radiation-induced sarcomas; however, only one case of radiation-induced sarcoma was documented in our series, but we described in our manuscript another striking case of likely radiation-induced malignancies in a woman who received whole-body irradiation in childhood and developed four invasive cancers in her lifetime before the age of 32 years.
In this cohort, women represented 79% of all patients, and men were the remaining 21% of individuals. Interestingly, most LFS cohorts described a predominance of women; maybe because of the very young onset of breast cancer, women are more likely to be diagnosed with LFS based on the current LFS testing criteria. Another finding in our series was that for two men with LFS (harbouring the c.1010G>A and c.314_315delInsAT variants), prostate cancer was their first cancer diagnosis at the ages of 61 and 55 years. Prostate cancer has only relatively recently been recognised as part of the LFS phenotypic spectrum.22
Patients with LFS are not often enrolled in prospective research studies due to their rarity, the lack of designated studies for patients with LFS and also due to their complex management, especially after being diagnosed with cancer. With increasing access to whole-genome sequencing and direct-to-consumer (DTC) germline testing, the number of people diagnosed with LFS is expected to rise significantly in the near future. To increase awareness, there are multiple educational initiatives at national level, including the flagship ‘just in time’ GeNotes resource from the NHS England Genomic Education Programme (https://www.genomicseducation.hee.nhs.uk/genotes/) and a joint initiative by the Royal College of Radiologists and Association of Cancer Physicians to develop tumour specific resources with a focus on genomics as well as educational initiatives through each local genomics laboratory hub and genomics medicine service alliance. It is recognised that patients with LFS should be managed in national specialist clinics, with access to WB-MRI, experienced radiologists, sarcoma and brain tumour oncologists, and genetic specialists and psychologists, but funding for such services may be challenging to secure.
The limitations of this study include the small number of subjects, due to the rarity of this syndrome; the short follow-up interval, especially for individuals diagnosed since 2020; and the heterogeneity of cancers, which makes it difficult to draw conclusions on cancer-specific outcomes. For this, multicentric international studies focusing on developing large cohorts of specific diseases are needed, taking the example from large cohorts of breast cancer patients with LFS.16,23
Therefore, more research is urgently needed to better understand disease patterns related to different P/LP TP53 variants and inform which patients with LFS may need a more targeted and aggressive surveillance protocol. To enhance access to test information and develop a research data source, some international centres are developing genetic registries, allowing for affected individuals or genetic professionals to add information about the affected population, genetic variant, and clinical information.24
Acknowledgements
The authors acknowledge funding from the Royal Marsden Cancer Charity, the National Institute for Health Research (NIHR) Biomedical Research Centre at the Royal Marsden NHS Foundation Trust and the Institute of Cancer Research.
Funding
The work was supported by a Small Business Research Initiative (SBRI) Healthcare Cancer grant (Grant number SBRICO1P3031).
Disclosure
RWL: is funded by the Royal Marsden NIHR BRC, Royal Marsden Cancer Charity. Received compensation for time spent in a secondment role for the NHS England lung health check programme and as National Specialty Lead for the NIHR (to the institution). Received research funding from Cancer Research UK (CRUK), Innovate UK (co-funded by GE Healthcare, Roche Diagnostics, Optellum, Elliptica, and RNA Guardian); SBRI (including as a co-applicant with QURE.AI), RM Partners Cancer Alliance; and NIHR (including co-applicant in grants with Optellum). Received honoraria, speaker/advisory fees, and/or hospitality/travel expenses from CRUK, Roche Diagnostics, Johnson & Johnson, Guardant, AstraZeneca, and King Faisal Hospital, Saudi Arabia; undertakes private practice. TMV: honoraria: Servier, AstraZeneca. RE: honoraria from GU-ASCO, Janssen, University of Chicago, Dana Farber Cancer Institute USA as a speaker. Educational honorarium from Bayer and Ipsen, member of external expert committee to Astra Zeneca UK and Member of Active Surveillance Movember Committee. She is a member of the SAB of Our Future Health. She undertakes private practice as a sole trader at The Royal Marsden NHS Foundation Trust and 90 Sloane Street SW1X 9PQ and 280 Kings Road SW3 4NX, London, UK. AG: honoraria/advisory board: AstraZeneca, GSK, MSD, Roche. All other authors have declared no conflicts of interest.
Supplementary data
References
- 1.Arango-Ibañez J.P., Parra-Lara L.G., Zambrano Á.R., Rodríguez-Rojas L.X. Li-Fraumeni syndrome presenting with de novo TP53 mutation, severe phenotype and advanced paternal age: a case report. Hered Cancer Clin Pract. 2024;22(1):1–5. doi: 10.1186/s13053-023-00272-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Hwang S.J., Lozano G., Amos C.I., Strong L.C. Germline p53 mutations in a cohort with childhood sarcoma: sex differences in cancer risk. Am J Hum Genet. 2003;72(4):975–983. doi: 10.1086/374567. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Hanson H., Brady A.F., Crawford G., et al. UKCGG Consensus Group guidelines for the management of patients with constitutional TP53 pathogenic variants. J Med Genet. 2020;58(2):135–139. doi: 10.1136/jmedgenet-2020-106876. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Ferreira A.M., Brondani V.B., Helena V.P., et al. Clinical spectrum of Li-Fraumeni syndrome/Li-Fraumeni-like syndrome in Brazilian individuals with the TP53 p.R337H mutation. J Steroid Biochem Mol Biol. 2019;190:250–255. doi: 10.1016/j.jsbmb.2019.04.011. [DOI] [PubMed] [Google Scholar]
- 5.Kratz C.P., Achatz M.I., Brugieres L., et al. Cancer screening recommendations for individuals with Li-Fraumeni syndrome. Clin Cancer Res. 2017;23(11):e38–e45. doi: 10.1158/1078-0432.CCR-17-0408. [DOI] [PubMed] [Google Scholar]
- 6.Mai P.L., Best A.F., Peters J.A., et al. Risks of first and subsequent cancers among TP53 mutation carriers in the National Cancer Institute Li-Fraumeni syndrome cohort. Cancer. 2016;122(23):3673–3681. doi: 10.1002/cncr.30248. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.McBride K.A., Ballinger M.L., Killick E., et al. Li-Fraumeni syndrome: cancer risk assessment and clinical management. Nat Rev Clin Oncol. 2014;11(5):260–271. doi: 10.1038/nrclinonc.2014.41. [DOI] [PubMed] [Google Scholar]
- 8.Sorrell A.D., Espenschied C.R., Culver J.O., Weitzel J.N. Tumor protein p53 (TP53) testing and Li-Fraumeni syndrome: current status of clinical applications and future directions. Mol Diagn Ther. 2013;17(1):31–47. doi: 10.1007/s40291-013-0020-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Birch J.M., Hartley A.L., Tricker K.J., et al. Prevalence and diversity of constitutional mutations in the p53 gene among 21 Li-Fraumeni families. Cancer Res. 1994;54(5):1298–1304. [PubMed] [Google Scholar]
- 10.Eeles R.A. Germline mutations in the TP53 gene. Cancer Surv. 1995;25:101–124. [PubMed] [Google Scholar]
- 11.Varley J.M., McGown G., Thorncroft M., et al. Germ-line mutations of TP53 in Li-Fraumeni families: an extended study of 39 families. Cancer Res. 1997;57(15):3245–3252. [PubMed] [Google Scholar]
- 12.Lalli E., Zambetti G.P., Ribeiro R.C., Figueiredo B.C. Cancer associated to low-penetrance TP53 variants: insights from p.R337H. Trends Cancer. 2025;11(6):499–502. doi: 10.1016/j.trecan.2025.04.003. [DOI] [PubMed] [Google Scholar]
- 13.Oliveira L.J.C., Rodrigues A.M., Fernandes C.B., et al. A portrait of germline pathogenic variants in high and moderate penetrance breast cancer genes in Brazil. Front Oncol. 2024;14 doi: 10.3389/fonc.2024.1495605. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Corrêa T.S., Asprino P.F., de Oliveira E.S.C., et al. TP53 p.R337H germline variant among women at risk of hereditary breast cancer in a public health system of Midwest Brazil. Genes. 2024;15(7):928. doi: 10.3390/genes15070928. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Petry V., Bonadio R.C., Testa L., et al. A matched case-control study of the prognosis of early breast cancer in patients with Li-Fraumeni syndrome (BREAST TP53) Breast. 2023;68:157–162. doi: 10.1016/j.breast.2023.02.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Bottosso M., Sandoval R.L., Verret B., et al. HER2 status and response to neoadjuvant anti-HER2 treatment among patients with breast cancer and Li-Fraumeni syndrome. Eur J Cancer. 2024;211 doi: 10.1016/j.ejca.2024.114307. [DOI] [PubMed] [Google Scholar]
- 17.Villani A., Shore A., Wasserman J.D., et al. Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: 11 year follow-up of a prospective observational study. Lancet Oncol. 2016;17(9):1295–1305. doi: 10.1016/S1470-2045(16)30249-2. [DOI] [PubMed] [Google Scholar]
- 18.Fortuno C., Lee K., Olivier M., et al. Specifications of the ACMG/AMP variant interpretation guidelines for germline TP53 variants. Hum Mutat. 2021;42(3):223–236. doi: 10.1002/humu.24152. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Richards S., Aziz N., Bale S., et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405–424. doi: 10.1038/gim.2015.30. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.StataCorp . StataCorp LLC; College Station, TX: 2025. Stata Statistical Software: Release 18. [Google Scholar]
- 21.Saya S., Killick E., Thomas S., et al. Baseline results from the UK SIGNIFY study: a whole-body MRI screening study in TP53 mutation carriers and matched controls. Fam Cancer. 2017;16(3):433–440. doi: 10.1007/s10689-017-9965-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Maxwell K.N., Cheng H.H., Powers J., et al. Inherited TP53 variants and risk of prostate cancer. Eur Urol. 2022;81(3):243–250. doi: 10.1016/j.eururo.2021.10.036. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Sandoval R.L., Bottosso M., Tianyu L., et al. TP53-associated early breast cancer: new observations from a large cohort. J Natl Cancer Inst. 2024;116(8):1246–1254. doi: 10.1093/jnci/djae074. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Rubinstein W.S., Maglott D.R., Lee J.M., et al. The NIH genetic testing registry: a new, centralized database of genetic tests to enable access to comprehensive information and improve transparency. Nucleic Acids Res. 2013;41(Database issue):D925–D935. doi: 10.1093/nar/gks1173. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.