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TP53 (Li-Fraumeni) – risk management (adult)

In this document the terms ‘male’ and ‘female’ refer to sex assigned at birth. For more information about providing individualised care refer to Resources to assist in the care of transgender individuals referred to a clinical genetics service or familial cancer centre

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Li-Fraumeni syndrome (LFS) is caused by a germline pathogenic variant in the TP53 gene and is inherited in an autosomal dominant pattern.

The care of an individual who has developed a related tumour or cancer should be individualised based on their clinical situation, their family history and the monitoring they need as part of their treatment and post-treatment follow-up.

The risk management of an individual with a pathogenic variant in two or more genes that confer a predisposition to cancer should also be individualised.

  • Individuals age 18 years and over with a pathogenic variant in TP53.
  • Individuals age 18 years and over with the Brazilian founder pathogenic variant (p.R337H) in TP53.

Exclusion criteria

  • Individuals under age 18 years with a pathogenic variant in TP53 - refer to TP53 (Li-Fraumeni) – risk management (child).
  • Individuals who tested negative for a familial TP53 pathogenic variant.
  • Untested individuals age 18 years and over at 50% risk of a known pathogenic variant in TP53.
  • Individuals diagnosed with cancer who meet classic LFS criteria but do not have a TP53 pathogenic variant. 
  • Individuals with clonal haematopoiesis of indeterminate potential (CHIP).*
  • Individuals with a variant of uncertain significance.

* CHIP is a well-recognised entity in which somatic pathogenic variants are found in cells of the blood or bone marrow, but no other criteria for haematologic neoplasia are met. Its prevalence rises with age and is roughly 10% among individuals age 70 to 80 years.r

Cancer/tumour type Risk for TP53 pathogenic variant carriers**r General population risk***
Cancer (female) 15% by age 20 years^
50% by age 30 years
75% by age 40 years
90% by age 50 years
Greater than 95% by age 60 years
See Overall survival and cancer-free survival among TP53 positive females - Figure Ar		 0.34% by age 20 years 
0.85% by age 30 years
2.4% by age 40 years 
6.1% by age 50 years 
12.5% by age 60 years 
 
Cancer (male) 25% by age 20 years^
35% by age 30 years
40% by age 40 years
60% by age 50 years
Greater than 90% by age 60 years
See Overall survival and cancer-free survival among TP53 positive males - Figure Br		 0.37% by age 20 years
0.83% by age 30 years
1.8% by age 40 years
4.2% by age 50 years
11.1% by age 60 years
 
Breast (female) 85% by age 60 years 4.7% by age 60 years (female)
Soft tissue sarcoma 50% by age 70 years 0.36% by age 70 years
Osteosarcoma  10% by age 70 years Rare
Brain  20-30% by age 70 years 0.41% by age 70 years
Colorectal  Up to 24%r 2.8% by age 70 years (male)
2.1% by age 70 years (female)
Gastric  1-16%^^r 0.4% by age 70 years
Adrenocortical carcinoma 8.7% by age 18 yearsr
Increased relative risk^^^ after age 18 years		 Rare
Others: lung, prostate, renal, melanoma, pancreatic Increased risk and/or earlier onset but not quantified Lung: 2.0% by age 70 years
Prostate: 8.5% by age 70 years
Renal: 0.82% by age 70 years 
Melanoma: 3.1% by age 70 years
Pancreatic: 0.54% by age 70 years
Risk of second primary 50% after a median of 10 years 8.1%r

** The published literature overestimates the cancer risks. These studies are based on retrospective analyses, are biased towards families with an excess of cancer diagnoses and do not exclude probands from analyses. With more TP53 testing being carried out, less penetrant LFS kindreds are being identified, which likely will lead to lower cancer risk estimates.
*** Source: Australian Institute of Health and Welfare (AIHW) 2021 Cancer Data in Australia; Canberra: AIHW. <https://www.aihw.gov.au/reports/cancer/cancer-data-in-australia/data>. (2017 data)
^ There is a bias in paediatric data based on data from childhood onset of a cancer diagnosis and TP53 PV identified. Data reported is 27-39% for females and males respectively to age 18 yearsr
^^ East Asian population
^^^ Lifetime risk of cancer has been reported to be high, but not quantified for some cancers, other than increased relative risk.

For more information see Cancer diagnosis in Li-Fraumeni syndrome (LFS) pathogenic variant carriers by age range.

International consensus guidelines recommend comprehensive screening.rr Several comprehensive surveillance protocols have been proposed.rr The results of additional studies are awaited to clarify the optimal protocol. Surveillance ideally should be coordinated through a multidisciplinary service with expertise in LFS. Enrolment in a clinical trial evaluating screening protocols should be discussed, to allow data collection of outcomes including psychosocial impact of screening to occur.

The choice of risk management strategy should take into account current age, other health issues and age-related cancer risk. Risks and benefits of interventions should be discussed with an experienced medical professional.

The impact of lifestyle on cancer risk should be discussed e.g. exercise most days for at least 30 minutes at moderate or strenuous intensity, maintain a healthy weight, have a healthy diet, limit alcohol intake, do not smoke and avoid excessive sun exposure.

Cancer/tumour type Recommendations
Breast (female)
 		 Surgical Recommend bilateral risk-reducing mastectomy followed by self surveillance of breast arear
Surveillance Screen from age 20 years:
  • breast awareness from the age of breast development
  • annual breast MRI from age 20 years
  • other forms of imaging MMG +/- US should only be considered if unable to access MRI
  • if pregnant/lactating – consider ultrasound
Risk-reducing medication Lifetime risk is sufficient to offer risk reducing medication after careful consideration of risks and benefits. See COSA - Medications to lower the risk of breast cancer: clinician guide
Colorectal  Surveillance Consider colonoscopy every 2 to 5 years from age 20 years or younger dependent on family history
Gastric   Surveillance Consider endoscopy every 2 to 5 years from age 25 years or younger if there is a family history of gastric cancer, or those at high ethnic risk e.g. East Asian or South American background
Other H. pylori eradication
Sarcoma, other solid organ tumours Surveillance Recommend annual whole-body MRI##
Brain tumours Surveillance Recommend annual brain MRI##
Haematological cancers Surveillance No evidence of benefit for screening of asymptomatic individuals
Melanoma Surveillance Annual dermatology review from age 18 years
All Surveillance

Annual clinical review with physical examination by a designated clinician and encourage early reporting of symptoms
Prevention
  • Avoid unnecessary radiation exposure for screening or therapeutic purposes
  • Avoid (active and passive) smoking and excessive sun exposure
Education
  • Clinicians should be aware of the increased risk for rare malignancies and the increased risk of a second malignancy after a first diagnosis
  • Awareness and prompt reporting of any new symptoms

Abbreviations: MMG – mammogram (digital if available); MRI – magnetic resonance imaging; US – ultrasound.
## Because of concern about Gadolinium accumulation, first brain MRI with contrast; follow up without contrast unless needed to define new findingsr

Contraception

Combination oral contraceptive pill (OCP) use requires consideration of potential risks and benefits and alternative contraceptive strategies. A small increased risk of breast cancer has been reported for current OCP users (RR 1.2) and for up to 10 years after cessation of OCP use, regardless of family history.r The same result was found with newer formulations, including progesterone-containing implanted devices.r OCP cannot be used concurrently with breast cancer risk-reducing medications due to interactions. 

There is limited data on the effectiveness of cancer screening specifically in germline TP53 pathogenic variant carriers. Data about the utility of breast cancer and bowel cancer screening are mostly extrapolated from cancer screening studies in other groups at increased risk of these cancers. Comprehensive cancer screening protocols including whole-body MRI have shown benefit for screening, but were not randomised and are therefore subject to bias.rA meta-analysis showed 7% new, localised cancers were detected and treated with curative intent.r Issues that require clarification include defining the most appropriate screening protocol, and long term outcomes including survival benefit and psychosocial impact of intensive screening.r Enrolment in clinical trials is therefore encouraged whenever possible.

Breast

Studies have shown 37% of breast cancers are triple positive and 55% are HER2 positive among female TP53 pathogenic variant carriers. Male breast cancer has not been observed.r

Surgical

There is strong evidence that bilateral mastectomy significantly reduces breast cancer risk in high-risk women.

Surveillance

There is limited data about the utility of breast MRI screening specifically in TP53 pathogenic variant carriers. In women with an increased risk of breast cancer due to a germline BRCA1 or BRCA2 pathogenic variant, breast MRI has been shown to detect more tumours and at an earlier stage than mammogram alone.

Similarly, there is no published study evaluating potential detrimental effect of ionising radiation (mammography) used for screening purposes in TP53 pathogenic variant carriers. However, there is a concern about the cumulative risk of mammograms in very young women exposed to mammograms for a long period of time and mammograms may be more difficult to interpret in younger women with denser breasts. 

Risk reducing medication

Tamoxifen and raloxifene have been shown to reduce the risk of breast cancer in high risk women, although there is no specific data for TP53 pathogenic variant carriers. The lifetime breast cancer risk is sufficient to offer risk reducing medication. See COSA - Medications to lower the risk of breast cancer: clinician guide

Radiation therapy

Breast radiation therapy is associated with development of multiple new primary cancers of breast and adjacent local tissues in TP53 pathogenic variant carriers. Therefore, radiation therapy should be avoided where possible and therapeutic mastectomy considered in preference, and mammography avoided for screening if breast MRI is available.

Colorectal cancer

Surveillance

Regular colonoscopy screening has been shown to significantly reduce bowel cancer risk in families at moderate-high risk. TP53 pathogenic variant carriers have a higher lifetime risk of developing colorectal cancer. Their risk is estimated at 2.8 times the population risk,r which is the equivalent of approximately 24% lifetime risk. Colorectal cancer also occurs at younger age (median age 40 years, compared with 71 years for sporadic colorectal cancer).r A retrospective review of 66 individuals with LFS reported initial colonoscopy findings.r Abnormalities were detected in 15 of the 31 patients who underwent colonoscopy. Cancer detection rate for colonoscopy is likely to be less than 16% as they were not performed as part of a screening study, and 2 of the 5 patients with colorectal cancer were symptomatic at the time of the procedure (personal communication). International consensus guidelines suggest that colonoscopy screening should commence at 25 years of age, or younger depending on family history. However, in this retrospective review, 4 out of 5 cancers were detected in patients less than 25 years of age,r and another study of whole-body MRI screening detected colorectal cancer in a patient 21 years of age, suggesting that screening should be considered from 20 years.

Gastric cancer

Surveillance

There is limited evidence for upper endoscopy screening for gastric cancer in LFS patients. Gastric cancer was found to occur in 15.8% of Asian patients with TP53 pathogenic variant, compared with 1% of North American and 3.6% of Europeans patients with LFS. This 8.9 times increased relative risk of gastric cancer is in excess of the 4.5 times increased risk of sporadic gastric cancer observed in Asian populations.r Although there are no studies evaluating the use of upper endoscopy in LFS patients, there is evidence that it may reduce mortality in high risk populations such as those of South East Asian and South American background.

Other cancers

The risk of cancer varies significantly by age and gender.r

See Number and type of first cancer by age group at the time of diagnosis.r

Surveillance

A recent prospective non-randomised study of comprehensive screening program including regular biochemical and imaging surveillance (MRI of the whole-body, brain and breast, and abdominal ultrasound) in germline TP53 pathogenic variant carriers reported 11 year follow-up results.r Early tumour detection through surveillance was associated with improved survival; 5- year overall survival of 88.8% (95% CI, 78.7-100) in the surveillance group vs 59.6% (95% CI, 47.2-75.2) in the non-surveillance group (p=0.0132). Other studies have documented the outcomes of baseline whole-body MRI screening.r The cancer detection rate was 6.7 to 9%, with a false positive rate of 15-87%. The higher rate of false positive with initial screening MRI is known from previous studies. Preliminary reports suggest that MRI screening, although intensive, may be accompanied by reduction in anxiety.r 

Other cancers including lung, pancreatic, renal, prostate, melanoma and haematological cancers have an increased risk compared with the general population, however, this risk is not quantified.

Prevention

TP53 pathogenic variants are believed to cause radiation sensitivity, due to impaired recognition and repair of DNA damage and there are numerous reports of second primary malignancies developing in areas previously treated with radiation therapy. Minimising radiation therapy is recommended where possible, especially if other treatment modalities with comparable cure rates are available. Similarly tests using ionising radiation should be avoided if other effective modalities are available.

There is evidence that smoking increases the risk of lung cancers in TP53 pathogenic variant carriers by 3-fold.

First degree blood relatives (parents/brothers/sisters/children) are at up to 50% risk of having inherited the pathogenic variant. More distant relatives may also be at risk of inheriting the pathogenic variant. Genetic relatives should be referred to a clinical genetics service or familial cancer centre to discuss predictive genetic testing.

Informing family members about hereditary cancer

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Bibliography

Hwang, S. J., G. Lozano, C. I. Amos, et al. 2003. "Germline p53 mutations in a cohort with childhood sarcoma: sex differences in cancer risk." Am J Hum Genet 72(4):975-983.

To characterize cancer risk in heterozygous p53 mutation carriers, we analyzed cancer incidence in 56 germline p53 mutation carriers and 3,201 noncarriers from 107 kindreds ascertained through patients with childhood soft-tissue sarcoma who were treated at the University of Texas M. D. Anderson Cancer Center. We systematically followed members in these kindreds for cancer incidence for >20 years and evaluated their p53 gene status. We found seven kindreds with germline p53 mutations that include both missense and truncation mutation types. Kaplan-Meier analysis showed similar cancer risks between 21 missense and 35 truncation p53 mutation carriers (log-rank chi(2)=0.04; P=.84). We found a significantly higher cancer risk in female carriers than in male carriers (log-rank chi(2)=12.1; P <.001), a difference not explained by an excess of sex-specific cancer. The calculated standardized incidence ratio (SIR) showed that mutation carriers had a risk for all types of cancer that was much higher than that for the general population (SIR = 41.1; 95% confidence interval [CI] 29.9-55.0) whereas noncarriers had a risk for all types of cancer that was similar to that in the general population (SIR = 0.9; 95% CI 0.8-1.0). The calculated SIRs showed a >100-fold higher risk of sarcoma, female breast cancer, and hematologic malignancies for the p53 mutation carriers and agreed with the findings of an earlier segregation analysis based on the same cohort. These results quantitatively illustrated the spectrum of cancer risk in germline p53 mutation carriers and will provide valuable reference for the evaluation and treatment of patients with cancer.

Version 12

Date Summary of changes
15/09/2023

New eviQ cancer genetics risk management template changes applied - PDF of changes.

Version number changed to V.12.

Version 11

Date Summary of changes
13/02/2023

The following sections of the document were updated to align with the new eviQ cancer genetics risk management template:

  • Summary:
    • Template sentence updated.
  • Target population:
    • Added to exclusion criteria "Individual with a variant of uncertain significance".
  • Cancer/tumour risk management guidelines:
    • Template sentence updated. 
    • Lifestyle factors sentence moved above table.
  • Management of associated health problems:
    • Accordion title changed to "Management of associated health issues".
    • Subheading "Contraception and fertility" changed to "Contraception".

Version number increased to V.11.

Version 10

Date Summary of changes
13/05/2022

Protocol reviewed at July 2021 paediatric cancer genetics reference committee. Discussions continued via email and MS Teams. Approved for publication with the following changes made:

  • Target group:
    • Added bullet 2 re: Brazilian founder pathogenic variant (p.R337H) in TP53
    • Exclusion criteria:
      • Added 'Affected individuals who meet classic LFS criteria but do not have a TP53 pathogenic variant;
      • Added 'Individuals with clonal haematopoiesis of indeterminate potential (CHIP)'
      • Footnote re: CHIP added
  • Lifetime risk of cancer/tumour:
    • Adrenocortical carcinoma 'Increased relative risk' changed to '8.7% by age 18 years. Increased relative risk after age 18 years'
    • General population risk updated with AIHW 2017 data
  • Cancer tumour risk management guidelines:
    • Breast - Surgical: 'Offer bilateral risk reducing mastectomy especially in women <50 years...' changed to 'Recommend bilateral risk-reducing mastectomy...' 
    • Gastric - Surveillance: added 'South American background'
    • Sarcoma, other solid organ tumours - Surveillance: 'Consider annual whole-body MRI' changed to 'Recommend annual whole-body MRI'
    • Brain tumours - Surveillance: "Consider annual brain MRI' changed to 'Recommend annual brain MRI'
    • Melanoma - Surveillance: added to table
    • All - Education: added to table
  • Management of associated health problems: added to protocol
  • Evidence for risk management guidelines: reviewed and updated

Version increased to V.10. Review in 2 years.

Version 9

Date Summary of changes
20/12/2019 "Mutation" changed to "pathogenic variant" throughout document for consistency among eviQ cancer genetics protocols per agreement among the cancer genetics reference committees' chairs. Definition of "pathogenic variant" added as a pop-up. Version number increased to V.9.
18/12/2020 The following sections of the protocol were updated to align with the revised eviQ cancer genetics risk management template:
  • Summary: template sentence added
  • Lifetime risk of cancer table:
    • Heading changed to "Lifetime risk of cancer/tumour"
    • Risk for general population updated to include AIHW 2016 data
  • Cancer risk management guidelines:
    • Heading changed to "Cancer/tumour risk management guidelines"
    • Sentence added above table "The choice of risk management strategy should take into account current age, other health issues and residual cancer risk." 
    • Updated link to "COSA - Medications to lower the risk of breast cancer: clinician guide" (also updated in evidence section)
    • Other table formatting changes
  • Support and information: template wording updated
  • Website resources: added link to "COSA - Medications to lower the risk of breast cancer: clinician guide" and "COSA - Medications to lower the chance of breast cancer: information for women".

Version 8

Date Summary of changes
20/12/2010 Approved.
23/06/2011 Link to diagnostic clinical criteria for Li-Fraumeni.
11/11/2011 Lifetime risk of cancer table updated to include lifetime risk of cancer for males and females.
Chemoprevention changed to current terminology risk-reducing medication.
26/09/2012

Discussed at the April 19, 2012, cancer genetics reference committee meeting and the following changes made:

  • Target group - updated for adult (>18 years). 
  • Exclusion criteria - updated to exclude children ( <18 years).
  • Lifetime risk of cancer - table updated - relative risk added, to breast, sarcoma, brain - various and adrenocoritical carcinoma and colon cancer.
  • Cancer risk management guidelines - Breast - surgical and risk-reducing medications recommendations updated.
  • Evidence for risk management guidelines - Breast - Surveillance - no evidence:
    - about the utility of breast MRI screening  specifically in TP53 mutation carriers.
    - about a detrimental effect of ionising radiation (mammography) used for screening purposes  in TP53 mutation carriers added.
  • New section added on radiation therapy.
  • Other cancers - Surveillance section updated.
    - Prevention sentence added - Avoid treating with radiotherapy if other treatment modalities with comparable cure rates are available. 
31/07/2015 Link to AGSA changed to Genetic Alliance Australia.
7/10/2015 Discussed at March 6, 2013, reference committee meeting and the following changes made:
  • Summary - TP53 testing criteria ACI link added.
  • Target group - updated.
  • Exclusion criteria - updated.
  • Lifetime risk of cancer - references updated.
  • Cancer risk management guidelines:
    • summary paragraph added
    • general recommendations added 
    • recommendations updated.
  • Evidence for risk management - wording and references updated.
  • Support and information - referral sentence updated.
  • References - updated.
07/01/2016 Sentence added to Risk Management template: "The impact of lifestyle on cancer risk should be discussed".
14/04/2016 Sentence added to Risk Management template: "This risk management guideline has been developed for individuals who have NOT been diagnosed with a relevant cancer/tumour.  The care of affected individuals should be individualised based on their clinical situation, and the monitoring they need as part of their treatment and post-treatment follow up". 
13/02/2017

Protocol reviewed at cancer genetics reference committee meeting on 20 October 2016 and the following changes made:

  • Title - changed to Risk Management for adults with a TP53 Mutation 
  • Target group - updated
  • Lifetime risk of cancer - updated
  • Cancer risk management guidelines - updated
  • Evidence for risk management guidelines - updated
  • References - updated.

Changed to Version 5. For review in 1 year. 
31/05/2017 Transferred to new eviQ website. Version number changed to V.6.
29/01/2019 Link changed from Cancer Australia Risk-reducing medication resource to COSA medication to lower the risk of breast cancer: clinician guide as per consensus at November 2018 RCM. Version kept at V.6.
20/02/2019

Protocol reviewed at the May 2018 RC meeting and discussions continued over email.  Version number increased to V.7 and the following sections were amended:

  • Target population - untested individuals >18 years at 50% risk of a known pathogenic mutation in TP53 moved to exclusion criteria
  • Lifetime risk of cancer - general population comparison data decreased to 70 years and figures updated accordingly.  Link to ACI 3501 Cancer diagnosis in LFS mutation carriers by age range added. 
  • Cancer risk management guidelines - colorectal cancer surveillance commencement age decreased from 25 years to 20 years, those at high ethic risk of gastric cancer added to surveillance endoscopy recommendation, and eradication of H.pylori, recommendations for surveillance for sarcoma, other solid organ tumours, brain tumours, and haematological cancers added updated, comment re gadolinium added as footnote to table.
  • Evidence - updated as per recommendations
  • References - updated
28/08/2019 Protocol title changed from 'Risk management for adults with a TP53 mutation' to 'TP53 (Li-Fraumeni) – risk management (adult)' in accordance with Cancer Genetics Reference Committees' consensus. Version number increased to V.8.

The information contained in this document is based on the highest level of available evidence and consensus of the eviQ reference committee regarding their views of currently accepted approaches to care or treatment. Any clinician seeking to apply or consult this document is expected to use independent clinical judgement in the context of individual clinical circumstances to determine any patient's care or treatment. While eviQ endeavours to link to reliable sources that provide accurate information, eviQ and the Cancer Institute NSW do not endorse or accept responsibility for the accuracy, currency, reliability or correctness of the content of linked external information sources. Use is subject to eviQ’s disclaimer available at www.eviQ.org.au

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https://www.eviq.org.au/p/749

10 Sep 2024