Medical Policy

Policy Num:      11.003.022
Policy Name:    Genetic Testing for Li-Fraumeni Syndrome
Policy ID:          [11.003.022]  [Ac / B / M+ / P+]  [2.04.101]

Last Review:     August 20, 2024
Next Review:     August 20, 2025
 

Related Policies:
11.003.070 - Preimplantation Genetic Testing

Genetic Testing for Li-Fraumeni Syndrome

summary

Description

Li-Fraumeni syndrome (LFS) is a cancer predisposition syndrome associated with the development of several types of tumors. The syndrome is caused by germline pathogenic variants in the TP53 gene. Testing for LFS pathogenic variants may be useful in confirming the diagnosis of LFS and/or evaluating genetic status in asymptomatic relatives of an index case.

Summary of Evidence

For individuals with suspected LFS by clinical criteria who receive genetic testing for TP53, the evidence includes case series and cross-sectional studies. Relevant outcomes include overall survival, disease-specific survival, test accuracy and validity, changes in reproductive decision making, and resource utilization. Evidence on the clinical validity of testing comes from the International Agency for Research on CancerTP53 Database that has compiled records on 891 families with LFS. For patients with suspected LFS based on clinical criteria, the clinical sensitivity ranges from 50% to 80%. No evidence was identified on clinical specificity. In individuals with suspected LFS, a positive genetic test will establish a genetic diagnosis of LFS and facilitate the overall workup for cancer susceptibility syndrome when multiple conditions are considered. Also, the presence of a documented TP53 pathogenic variant may aid in decision making for risk-reducing (prophylactic) mastectomy. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who are asymptomatic and have a close relative with a known TP53 pathogenic variant who receive targeted TP53 familial variant testing, the evidence includes case series and cross-sectional studies. Relevant outcomes include overall survival, disease-specific survival, test accuracy and validity, changes in reproductive decision making, and resource utilization. Evidence on the clinical validity of testing comes from the International Agency for Research on CancerTP53 Database that has compiled records on 891 families with LFS. In asymptomatic individuals who have a close relative with a known TP53 pathogenic variant, targeted familial variant testing can confirm or exclude the presence of the familial variant with high certainty. A positive genetic test will lead to increased surveillance for LFS-associated cancers, and a negative test will eliminate the need for enhanced surveillance. Knowledge of TP53 genetic status may also inform reproductive decision making in individuals considering offspring. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Additional Information

Not applicable.

OBJECTIVE

The objective of this evidence review is to determine whether genetic testing improves the net health outcome in individuals with suspected Li-Fraumeni syndrome and asymptomatic individuals with family members with Li-Fraumeni syndrome.

POLICY Statement

Genetic testing for TP53 may be considered medically necessary to confirm a diagnosis of Li-Fraumeni syndrome under the following conditions:

• In an individual who meets either the classic or the Chompret clinical diagnostic criteria for Li-Fraumeni syndrome, or

• In individuals with early-onset breast cancer (age of diagnosis <31 years), or

• In pediatric hypodiploid acute lymphoblastic leukemia (see Policy Guidelines).

Targeted TP53 familial variant testing may be considered medically necessary in an at-risk relative of a proband with a known TP53 pathogenic variant.

Genetic testing for a germline TP53 variant is considered investigational for all other indications (see Policy Guidelines).

POLICY GUIDELINES

The NCCN Pediatric Acute Lymphoblastic Leukemia panel considers “pediatric” to include any patient age ≤18 years, as well as adolescent and young adult (AYA) patients >18 years treated in a pediatric oncology setting; the latter could include patients up to age 30 years.

This reference medical policy addresses germline testing for TP53 and does not address somatic testing. Somatic TP53 variants found on tumor testing are common across many types of cancers. The finding of somatic TP53 variant(s) on tumor testing would support genetic counseling for assessment of risk for germline alterations associated with Li-Fraumeni Syndrome ^1,.

Genetics Nomenclature Update

The Human Genome Variation Society nomenclature is used to report information on variants found in DNA and serves as an international standard in DNA diagnostics. It is being implemented for genetic testing medical evidence review updates starting in 2017 (see Table PG1). The Society's nomenclature is recommended by the Human Variome Project, the Human Genome Organization, and by the Human Genome Variation Society itself.

The American College of Medical Genetics and Genomics and the Association for Molecular Pathology standards and guidelines for interpretation of sequence variants represent expert opinion from both organizations, in addition to the College of American Pathologists. These recommendations primarily apply to genetic tests used in clinical laboratories, including genotyping, single genes, panels, exomes, and genomes. Table PG2 shows the recommended standard terminology - "pathogenic," "likely pathogenic," "uncertain significance," "likely benign," and "benign" - to describe variants identified that cause Mendelian disorders.

Table PG1. Nomenclature to Report on Variants Found in DNA

Table PG2. ACMG-AMPStandards and Guidelines for Variant Classification

ACMG: American College of Medical Genetics and Genomics; AMP: Association for Molecular Pathology.

Genetic Counseling

Genetic counseling is primarily aimed at patients who are at risk for inherited disorders, and experts recommend formal genetic counseling in most cases when genetic testing for an inherited condition is considered. The interpretation of the results of genetic tests and the understanding of risk factors can be very difficult and complex. Therefore, genetic counseling will assist individuals in understanding the possible benefits and harms of genetic testing, including the possible impact of the information on the individual's family. Genetic counseling may alter the utilization of genetic testing substantially and may reduce inappropriate testing. Genetic counseling should be performed by an individual with experience and expertise in genetic medicine and genetic testing methods.

Coding

See the Codes table for details.

BENEFIT APPLICATION

Benefits are determined by the group contract, member benefit booklet, and/or individual subscriber certificate in effect at the time services were rendered.  Benefit products or negotiated coverages may have all or some of the services discussed in this medical policy excluded from their coverage.

BlueCard/National Account Issues

Some Plans may have contract or benefit exclusions for genetic testing.

BACKGROUND

TP53 Gene

The TP53 gene contains the genetic instructions for the production of tumor protein p53. The p53 protein is a tumor suppressor that functions as a cell cycle regulator to prevent cells from uncontrolled growth and division when there is DNA damage. Somatic (acquired) pathogenic variants are one of the most frequent alterations found in human cancers. Germline (inherited) pathogenic variants in TP53 are associated with Li-Fraumeni syndrome (LFS).

Li-Fraumeni Syndrome

Li-Fraumeni syndrome is a cancer predisposition syndrome associated with a high lifetime cumulative risk of cancer and a tendency for multiple cancers in affected individuals. The syndrome was originally described based on a retrospective analysis of families with aggressive soft tissue sarcomas in young siblings and their biologically related cousins.^1,

The tumor types most closely associated with LFS include premenopausal breast cancer, bone and soft tissue sarcomas, central nervous system (CNS) tumor, adrenocortical carcinoma, hypodiploid acute lymphoblastic leukemia, unusually early onset of other adenocarcinomas, or other childhood cancers. Sarcoma, breast cancer, adrenocortical tumors, and certain brain tumors have been referred to as the “core” cancers of LFS since they account for the majority of cancers observed in individuals with germline TP53 pathogenic and likely pathogenic variants.^2,3, Other malignancies associated with LFS include a wide variety of gastrointestinal tract, lung, skin, and thyroid cancers as well as leukemias and lymphomas.

Individuals with LFS are at increased risk of developing multiple primary tumors, with subsequent malignancies, not all being clearly related to the treatment of the previous neoplasms. The risk of developing a second tumor has been estimated at 40% to 49%.^2, In a study of 322 pathogenic variant carriers from France, Bougeard et al (2015) reported that 43% of individuals had multiple malignancies.^4,

Individuals with LFS are at increased risk of both bone and soft tissue sarcomas. Sarcomas of various histologies account for 25% of the cancers reported in people with LFS, with the most commonly reported sarcomas in an international database being rhabdomyosarcoma before age 5 years and osteosarcoma at any age.^5, Women with LFS are at greatly increased risk of developing premenopausal breast cancer, with the median age of diagnosis being 33 years of age.^2, Male breast cancer has rarely been reported in LFS families. Many types of brain tumors have been described in LFS, including astrocytomas, glioblastomas, medulloblastomas, and choroid plexus carcinomas. The median age of onset of LFS-related brain tumors is 16 years of age. Individuals with LFS are at increased risk of developing adrenocortical carcinoma. For adults, Raymond et al (2013) estimated that 6% of individuals diagnosed with adrenocortical carcinoma after age 18 years have a germline TP53 pathogenic variant.^6,

Data from M.D. Anderson Cancer Center's long-term clinical studies of LFS have shown that the risk of developing soft tissue sarcomas is greatest before the age of 10 years, brain cancer appears to occur early in childhood with a smaller peak in risk in the fourth to fifth decade of life, risk for osteosarcoma is highest during adolescence, and breast cancer risk among females with LFS starts to increase significantly around age 20 years and continues into older adulthood.^7,

Clinical Diagnosis

The diagnosis of LFS is based on an evolving set of clinical classification criteria, established using salient aspects of family history and tumor-related characteristics.^1, The first formal criteria, the classic LFS criteria, were developed in 1988 and are the most stringent used to make a clinical diagnosis of LFS.

Classic Li-Fraumeni Syndrome

Classic LFS is defined by the presence of all of the following criteria:

• A proband with a sarcoma before 45 years of age,

• A first-degree relative with any cancer before 45 years of age, and

• A first- or second-degree relative with any cancer before 45 years of age or a sarcoma at any age.^2,3,

Chompret Criteria

Chompret et al (2001) developed criteria that have the highest positive predictive value, and that, when combined with the classic LFS criteria, provide the highest sensitivity for identifying individuals with LFS.^8, The Chompret criteria were updated in 2009 to assist in identifying families with milder phenotypes.^9, The Chompret criteria will also identify individuals with de novo TP53 pathogenic variants, whereas the classic LFS criteria require a family history.

The Chompret criteria, most recently updated in 2015, are defined as the following:

• Proband with tumor belonging to the LFS tumor spectrum (eg, soft tissue sarcoma, osteosarcoma, brain tumor, premenopausal breast cancer, adrenocortical carcinoma) before age 46 years AND at least 1, first- or second-degree relative with LFS tumor (except breast cancer if the proband has breast cancer) before age 56 years or with multiple tumors; or

• Proband with multiple tumors (except multiple breast tumors), 2 of which belong to the LFS tumor spectrum and the first of which occurred before age 46 years; or

• Patient with adrenocortical carcinoma, rhabdomyosarcoma of embryonal anaplastic subtype, or choroid plexus tumor, irrespective of family history; or

• Female proband with breast cancer before age 31 years.^4,2,3,

National Comprehensive Cancer Network guidelines recommend TP53 testing for individuals who meet classic LFS criteria and Chompret criteria.^3,

Molecular Diagnosis

Li-Fraumeni syndrome is associated with germline pathogenic variants in the TP53 gene (chromosome 17p13.1), which encodes for a ubiquitous transcription factor that is responsible for a complex set of regulatory functions that promote DNA repair and tumor suppression. TP53 is the only gene in which pathogenic variants are known to cause LFS, and no other inherited phenotypes are associated specifically with germline pathogenic variants involving TP53.^2, The presence of a TP53 variant is considered diagnostic.

Li-Fraumeni syndrome is a highly penetrant cancer syndrome, with the risks of cancer being about 80% by age 70 years.^2, It is inherited in an autosomal dominant manner. De novo germline TP53 pathogenic variants (no pathogenic variant is identified in either biologic parent) are estimated to be 7% to 20%.

Approximately 95% of pathogenic variants detected in the TP53 gene are sequence variants (small intragenic deletions and insertions and missense, nonsense, and splice site variants). Large deletions and duplications not readily detected by sequence analysis account for approximately 1% of the pathogenic variants detected.^2,

Certain genotype-phenotype correlations have been reported in families with LFS and TP53 pathogenic variants. Genotype-phenotype correlations in LFS are predictive of the age of onset of a tumor, level of risk of developing a tumor, and outcome in patients with TP53 germline pathogenic variants.^1,2,

Management

Treatment

The evaluation of cancer in an individual diagnosed with LFS should be based on personal medical history and, to some degree, the specific pattern of cancer in the family. Women with LFS who develop breast cancer are encouraged to consider bilateral mastectomies to reduce the risk of developing a second primary breast cancer and to avoid exposure to radiotherapy. Preventive measures may include risk-reducing (prophylactic) mastectomy in women, and in all patients with a TP53 pathogenic variant, avoidance of radiotherapy, because the evidence has suggested that TP53 pathogenic variants confer an increased sensitivity to ionizing radiation and the possibility of radiation-induced malignancies.

Surveillance

Li-Fraumeni syndrome confers a high risk of multiple different types of cancer, which poses challenges for establishing a comprehensive screening regimen, and many of the cancers associated with LFS do not lend themselves to early detection. There is no international consensus on the appropriate clinical surveillance strategy in individuals with LFS,^10, but, in general, the strategy includes physical examination, colonoscopy, and breast imaging. Other protocols being evaluated include additional imaging techniques and biochemical assessment. The National Comprehensive Cancer Network has consensus-based screening guidelines.

Testing Strategy

Given the common germline TP53 variant types associated with LFS, a possible testing strategy to optimize yield would be:

1. Sequencing of the entire TP53 coding region (exons 2 through 11). Examples of types of pathogenic variants detected by sequence analysis include small insertions and deletions (frameshift), and missense, nonsense, and splice site variants; most are missense variants.

2. Deletion and duplication analysis, which detects large deletions and duplications involving the coding region (exon 1) or promoter; these types of deletions and duplications are not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. These types of pathogenic variants account for less than 1% of those found in individuals with LFS.

Regulatory Status

Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments. Laboratories that offer laboratory-developed tests must be licensed under the Clinical Laboratory Improvement Amendments for high-complexity testing. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of this test.

RATIONALE

This evidence review was created in May 2014 and has been updated regularly with searches of the PubMed database. The most recent literature update was performed through May 10, 2024.

Evidence reviews assess whether a medical test is clinically useful. A useful test provides information to make a clinical management decision that improves the net health outcome. That is, the balance of benefits and harms is better when the test is used to manage the condition than when another test or no test is used to manage the condition.

The first step in assessing a medical test is to formulate the clinical context and purpose of the test. The test must be technically reliable, clinically valid, and clinically useful for that purpose. Evidence reviews assess the evidence on whether a test is clinically valid and clinically useful. Technical reliability is outside the scope of these reviews, and credible information on technical reliability is available from other sources.

Promotion of greater diversity and inclusion in clinical research of historically marginalized groups (e.g., People of Color [African-American, Asian, Black, Latino and Native American]; LGBTQIA (Lesbian, Gay, Bisexual, Transgender, Queer, Intersex, Asexual); Women; and People with Disabilities [Physical and Invisible]) allows policy populations to be more reflective of and findings more applicable to our diverse members. While we also strive to use inclusive language related to these groups in our policies, use of gender-specific nouns (e.g., women, men, sisters, etc.) will continue when reflective of language used in publications describing study populations

Population Reference No. 1

Testing for Suspected Li-Fraumeni Syndrome

Clinical Context and Test Purpose

The purpose of genetic testing for TP53 in individuals with suspected Li-Fraumeni syndrome (LFS) by clinical criteria is to establish the genetic diagnosis of LFS to inform management decisions such as risk-reducing (prophylactic) mastectomies in women, avoidance of radiotherapy, cancer surveillance, and aid in reproductive planning.

The question addressed in this evidence review is: In individuals with suspected LFS by clinical criteria, does genetic testing for TP53 improve the net health outcome?

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with suspected LFS by clinical criteria.

Interventions

The test being considered is genetic testing for TP53.

Comparators

The following practice is currently being used: standard clinical management without genetic testing.

Outcomes

The general outcomes of interest are overall survival, disease-specific survival, test accuracy and validity, changes in reproductive decision making, and resource utilization. The potential beneficial outcomes of primary interest include changes in management when test results are positive (ie, risk-reducing mastectomies in women, avoidance of radiotherapy, increased cancer surveillance). The time frame for outcome measures varies from several years for the development of cancers to long-term survival as a result of cancer.

Study Selection Criteria

For the evaluation of clinical validity of the test, studies that meet the following eligibility criteria were considered:

• Patient/sample clinical characteristics were described

• Patient/sample selection criteria were described.

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

Review of Evidence

Approximately 80% of families with features of LFS will have an identifiable TP53 pathogenic variant.^3, Families that have no identifiable TP53 pathogenic variant but share clinical features of LFS are more likely to have a different hereditary cancer syndrome (eg, hereditary breast-ovarian cancer syndrome).

Observational Studies

Cohorts of individuals with adrenocortical carcinoma, which is diagnostic of LFS by the Chompret criteria, have been published.^11,12,13, In a 2015 study, 88 consecutive patients with adrenocortical carcinoma were evaluated.^13, Direct sequencing of exons 2 through 11 together with multiplex ligation-dependent probe amplification was used to identify pathogenic variants. For the entire population, 50% of individuals had a pathogenic variant detected. The detection rate varied by age, with 58% of individuals younger than 12 years of age having a pathogenic variant compared with 25% of individuals between ages 12 and 20 years.

The most comprehensive source of compiled data on the clinical validity of TP53 pathogenic variants is found in the International Agency for Research on Cancer TP53 Database (R 20, July 2019), which has shown tumor types associated with TP53 germline variants (see Table 1).^14, The main tumor types associated with TP53 germline variants include breast, soft tissue, brain, adrenal gland, and bone tumor, which comprise 71% of all tumors with confirmed TP53 germline variants.

Table 1. Tumors Associated With TP53 Germline Variants (N= 3034)

Adapted from Kratz et al (2021).14,

O'Shea et al (2018) retrospectively analyzed 123 individuals (118 women, 5 men) in Ireland undergoing full TP53 sequencing.^15, Classic criteria for LFS or Li-Fraumeni like syndrome were met by 64 (52%) individuals, none of whom was TP53-positive. Of the 59 (48%) individuals who did not meet classic criteria, 2 had pathogenic TP53 variants (3% detection rate), showing that broadened testing criteria may be beneficial. It was noted that the detection rate of this study (1.6%) was lower than those of similar studies, but the authors suggested that this might be due to the predominance of patients in this cohort with breast cancer, which has an associated lower detection rate.

Rana et al (2018) published a retrospective, single-laboratory analysis of 38,938 individuals who had undergone TP53 testing to compare different phenotype manifestations found in TP53-positive individuals identified by single-gene testing and multigene panel testing (MGPT).^16, The differences included a significantly higher median age at first cancer for MGPT TP53-positive patients (n=126) than single-gene testing TP53-positive patients (n=96; women: median age, 36 vs. 28 years; p<.001; men: median age, 40 vs. 15 years; p<.004). For breast cancer specifically, median ages were 40 years and 33 years for MGTP TP53-positive and single-gene testing TP53-positive women, respectively (p<.001). Also, fewer MGPT TP53-positive patients met LFS testing criteria. The study: (1) lacked complete family histories, (2) enrolled predominantly women with breast cancer in the MGPT cohort, (3) used improved technology permitting detection of lower levels of TP53 variants, possibly contributing to misclassification, and (4) assessed a sample too small to investigate other possible factors for phenotypic variation.

Tables 2 and 3 summarize key study characteristics and results.

Table 2. Summary of Key Observational Comparative Study Characteristics

NR: not reported.

Table 3. Summary of Key Observational Comparative Study Results

LFS: Li-Fraumeni syndrome; VUS: variants of uncertain significance.

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from randomized controlled trials.

Direct evidence for the clinical utility of genetic testing to confirm a diagnosis of LFS is lacking.

Qian et al (2018), introduced above, investigated TP53 variants in childhood ALL.^18, When comparing children with ALL to non-ALL controls, the investigators found a significantly higher prevalence of TP53 pathogenic variants in the ALL group (odds ratio, 5.2; p<.001). Furthermore, the presence of TP53 pathogenic variants in children with ALL was associated with several significant findings. These children were more likely to have hypodiploid ALL compared to those without pathogenic variants (65.4% vs. 1.2%; p<.001). Additionally, they exhibited inferior event-free survival and overall survival rates (hazard ratio, 4.2 and 3.9, respectively; both p<.001). Moreover, children with TP53 pathogenic variants had a higher risk of developing secondary cancers, with a 5-year cumulative incidence of 25.1% versus 0.7% in those without such variants (p<.001).

Chain of Evidence

Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.

Diagnostic Testing in Individuals With Suspected Li-Fraumeni Syndrome

A chain of indirect evidence was developed, which addresses 2 key questions:

1. Does use of TP53 genetic testing in individuals with suspected LFS lead to changes in clinical management (eg, increased cancer surveillance, risk-reducing [prophylactic] mastectomy)?

2. Do those management changes improve outcomes?

There are standardized diagnostic criteria based on personal, clinical, and family history. However, there are limitations to these methods of diagnosis. A detailed family history may not be complete or may not be available in many instances. Classic LFS and Chompret criteria, when used in combination, provide the greatest sensitivity to providing a clinical diagnosis of LFS. With the greater availability of genetic testing, National Comprehensive Cancer Network guidelines recommend that a positive genetic test be required for a definitive diagnosis of LFS.

Changes in Management

In most cases, treatment and management will be unaffected by negative results from genetic testing, because individuals with a strong clinical presentation for LFS with a negative genetic test are likely to be treated as presumed LFS. However, there are some situations in which genetic testing may impact management. A positive test will facilitate the workup for cancer susceptibility syndromes when multiple conditions are considered. Knowledge of pathogenic variant status may also assist in decision making for risk-reducing mastectomy by providing more definitive risk estimates. If a cancer is detected, knowledge of the presence of a TP53 variant would lead to avoidance of radiotherapy in the cancer treatment.

Improved Outcomes

Outcomes are improved when a definitive diagnosis is made by avoiding the need for further testing to determine whether a cancer susceptibility syndrome is present. Better estimation of risk for breast cancer improves the capacity for informed decision making regarding risk-reducing mastectomy.

Section Summary: Testing for Suspected Li-Fraumeni Syndrome

Evidence on the clinical validity for testing for TP53 pathogenic variants is provided by the International Agency for Research on Cancer TP53 Database, which includes a compilation of published studies and 891 families. The largest amount of evidence involves patients with breast, soft tissue, brain, and adrenal gland tumors, which represents 72% of all patients with tumors who have an associated TP53 germline variant. In patients who meet clinical criteria for LFS, the clinical sensitivity has been reported to range between 50% and 80%. No evidence was identified on the clinical specificity of testing. Direct evidence of the clinical utility of TP53 testing is limited. Children with TP53 pathogenic variants are prone to developing hypodiploid ALL and experiencing unfavorable treatment outcomes.An indirect chain of evidence can demonstrate clinical utility of genetic testing for TP53 variants. For diagnosis, a positive genetic test will increase the certainty of LFS, facilitate the overall workup for cancer susceptibility syndromes, eliminate or necessitate the need for increased cancer surveillance and assist in decision making for prophylactic mastectomy.

Summary of Evidence

For individuals with suspected LFS by clinical criteria who receive genetic testing for TP53, the evidence includes case series and cross-sectional studies. Relevant outcomes include overall survival, disease-specific survival, test accuracy and validity, changes in reproductive decision making, and resource utilization. Evidence on the clinical validity of testing comes from the International Agency for Research on CancerTP53 Database that has compiled records on 891 families with LFS. For patients with suspected LFS based on clinical criteria, the clinical sensitivity ranges from 50% to 80%. No evidence was identified on clinical specificity. In individuals with suspected LFS, a positive genetic test will establish a genetic diagnosis of LFS and facilitate the overall workup for cancer susceptibility syndrome when multiple conditions are considered. Also, the presence of a documented TP53 pathogenic variant may aid in decision making for risk-reducing (prophylactic) mastectomy. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Population Reference No. 2 

Testing At-Risk Relatives of a Proband with Li-Fraumeni Syndrome

Clinical Context and Test Purpose

The purpose of targeted TP53 familial variant testing of individuals who are asymptomatic and have a close relative with a known TP53 pathogenic variant is to determine the carrier status of the relative when there is a known TP53 pathogenic variant in the family. If the relative has a positive test for a known TP53 familial variant, appropriate management such as risk-reducing (prophylactic) mastectomies in women, avoidance of radiotherapy, and cancer surveillance may be initiated. If the relative has a negative test for a known TP53 familial variant, then increased cancer surveillance is not necessary.

The question addressed in this evidence review is: In individuals who are asymptomatic and have a close relative with a known TP53 pathogenic variant, does the use of targeted TP53 familial variant testing result in changes in management or outcome improvements, including, in the case of a positive result, risk-reducing mastectomies in women, avoidance of radiotherapy, necessitating or eliminating the need for increased cancer surveillance, or aid in reproductive decision making?

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals who are asymptomatic and have a close relative with a known TP53 pathogenic variant.

Interventions

The test being considered is targeted TP53 familial variant testing.

Comparators

The following practice is currently being used: standard clinical management without genetic testing.

Outcomes

The general outcomes of interest are overall survival, disease-specific survival, test accuracy and validity, changes in reproductive decision making, and resource utilization. The potential beneficial outcomes of primary interest include improved overall or disease-specific survival and reduced morbidity associated with changes in management when test results are positive (eg, risk-reducing mastectomies in women, avoidance of radiotherapy, increased cancer surveillance).

The potential harmful outcomes are those resulting from a false-positive or false-negative test result. False-positive test results can lead to inappropriate surgeries (eg, risk-reducing mastectomies in women), inappropriate avoidance of radiotherapy, or psychological harm after receiving positive test results. False-negative test results can lead to lack of risk-reducing mastectomies in women, inappropriate use of radiotherapy, or lack of increased cancer surveillance. The time frame for outcome measures varies from several years for the development of cancers to long-term survival as a result of cancer.

Study Selection Criteria

For the evaluation of clinical validity of the test, studies that meet the following eligibility criteria were considered:

• Patient/sample clinical characteristics were described

• Patient/sample selection criteria were described.

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

Review of Evidence

See the Clinically Valid section for Testing for Suspected Li-Fraumeni Syndrome.

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from randomized controlled trials.

There is some direct evidence that enhanced screening protocols may improve outcomes. Villani et al (2011) conducted a prospective, observational study of members of 8 LFS families who were asymptomatic TP53 carriers.^17, Participants either chose or did not choose to undergo surveillance. Surveillance included biochemical and imaging studies, which included ultrasonography, brain magnetic resonance imaging, and rapid total body magnetic resonance imaging. The primary outcome measure was the detection of new cancers, and the secondary outcome measure was overall survival. Of 33 pathogenic variant carriers identified, 18 underwent surveillance. The surveillance protocol detected 10 asymptomatic tumors in 7 patients, which included premalignant or low-grade tumors (3 low-grade gliomas, 1 benign thyroid tumor, 1 myelodysplastic syndrome), and small, high-grade tumors (2 choroid plexus carcinomas, 2 adrenocortical carcinomas, 1 sarcoma). The 9 solid tumors detected were completely resected, and patients were in complete remission. After a median follow-up of 24 months, all patients who had undergone surveillance were alive. In the group without surveillance, 12 high-grade, high-stage tumors developed in 10 patients, of whom 2 were alive at the end of follow-up (p=.04 vs. survival in the surveillance group). Three-year overall survival in the surveillance group was 100% and 21% in the nonsurveillance group (p=.155). This study had an observational design that included self-selection into screening protocols, likely resulting in selection bias. Further higher quality evidence is needed to determine whether enhanced screening improves outcomes for TP53 pathogenic variant carriers.

Tables 4 and 5 summarize key study characteristics and results.

Table 4. Summary of Key Observational Comparative Study Characteristics

Table 5. Summary of Key Observational Comparative Study Results

OS: overall survival.

Chain of Evidence

Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.

Genetic testing of at-risk relatives who have family members with LFS may have clinical utility in:

• Confirming or excluding the need for cancer surveillance based on the presence or absence of a known TP53 familial variant.

• Informing the reproductive decision making process in preimplantation testing, prenatal (in utero) testing, or altering reproductive planning decisions when a known TP53 familial variant is present in a parent. Preimplantation testing is addressed elsewhere (see evidence review 4.02.05).

Testing At-Risk Relatives of Patients With Li-Fraumeni Syndrome

There is limited direct evidence on the clinical utility of genetic testing in this population. Therefore, a chain of evidence was developed, which addressed 2 key questions:

1. Does use of targeted TP53 familial variant testing in individuals with a close relative with a known TP53 pathogenic variant lead to changes in clinical management (eg, increased cancer surveillance, risk-reducing [prophylactic] mastectomy, reproductive planning)?

2. Do those management changes improve outcomes?

Changes in Management

Genetic testing of close relatives of an index case with a pathogenic variant will confirm or exclude the presence of the variant with certainty. A positive test will confer high risk for multiple malignancies, while a negative test will imply that an individual is at average risk, in the absence of other high-risk factors.

TP53 pathogenic variants have high penetrance, indicating high risk for clinical disease when a pathogenic variant is present. The multiple malignancies associated with LFS have presymptomatic phases in which early detection strategies can be implemented. The presence of a pathogenic variant will lead to enhanced screening strategies for LFS-associated malignancies. A negative genetic test will eliminate the need for enhanced screening strategies.

Improved Outcomes

Enhanced screening for breast cancer in high-risk individuals improves outcomes, and enhanced screening for lung cancer is also likely to improve outcomes. For the other LFS-associated core cancers, outcomes of screening interventions are uncertain due to the rarity of the conditions and lack of screening trials.

Section Summary: Testing At-Risk Relatives of a Proband with Li-Fraumeni Syndrome

Evidence on the clinical validity for testing for TP53 pathogenic variants is provided by the International Agency for Research on Cancer TP53 Database, which includes a compilation of published studies and 891 families. The largest amount of evidence involves patients with breast, soft tissue, brain, and adrenal gland tumors, which represents 72% of all patients with tumors who have an associated TP53 germline variant. In patients who meet clinical criteria for LFS, the clinical sensitivity has been reported to range between 50% and 80%. No evidence was identified on the clinical specificity of testing. Direct evidence of the clinical utility of TP53 testing is limited. One observational study has reported improved survival for screened patients. However, the design of this study included self-selection into screening protocols, likely resulting in selection bias. A chain of evidence can demonstrate clinical utility of genetic testing for TP53 variants. For asymptomatic family members who have a close relative with a pathogenic variant, genetic testing can confirm or exclude the presence of a variant, and direct future screening interventions that are likely to improve outcomes.

SUPPLEMENTAL INFORMATION

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Practice Guidelines and Position Statements

Guidelines or position statements will be considered for inclusion in ‘Supplemental Information’ if they were issued by, or jointly by, a US professional society, an international society with US representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

National Comprehensive Cancer Network

The National Comprehensive Cancer Network (NCCN) guidelines on genetic or familial high-risk assessment of breast, ovarian, and pancreatic cancer (v.3.2024 ) indicate that, in general, testing criteria for high-penetrance breast and/or ovarian cancer susceptibility genes specifically includes "BRCA1, BRCA2, CDH1, PALB2, PTEN, and TP53 " (CRIT- 2). ^3, This is followed by more detailed discussions of TP53 testing that are specifically focused on its association with Li-Fraumeni syndrome (LFS) and include the following testing criteria recommendations (CRIT- 7):

• Individual from a family with a known TP53 pathogenic/likely pathogenic variant;

• Individual who meets either the classic or the Chompret clinical diagnostic criteria for LFS, including those with breast cancer before 31 years of age;

• Pediatric hypodiploid acute lymphoblastic leukemia;

• Affected individual with pathogenic/likely pathogenic variant identified on tumor genomic testing that may have implications if also identified on germline testing.

The guidelines further state that somatic pathogenic or likely pathogenic variants in TP53 would not indicate the need for germline testing unless the clinical/family history is consistent with a pathogenic or likely pathogenic variant in the germline.

American Association for Cancer Research

In 2017, the American Association for Cancer Research published recommendations for cancer screening and surveillance for patients with LFS.^20, Genetic counseling and clinical TP53 testing should be strongly considered in the following clinical situations:

"(i)...proband with an LFS spectrum tumor … prior to age 46 and at least one first- or second-degree relative with an LFS tumor … before the age of 56 years or with multiple tumors, (ii) … proband with multiple malignancies (except two breast cancers), of which at least 2 belong to the LFS spectrum, before age 46; (iii) … patients with rare tumors such as ACC, choroid plexus carcinoma, or embryonal anaplastic subtype rhabdomyosarcoma independent of family history; and (iv) breast cancer before age 31 years."

Cancer surveillance has been shown to improve overall survival for surveillance and nonsurveillance groups and should be offered as soon as either clinical or molecular diagnosis of LFS is established. The following surveillance protocols were recommended for children (birth to age 18) and adults.

For children:

• Complete physical examination every 3 to 4 months and full neurologic assessment;

• Prompt assessment with primary care physician for any medical concerns;

• Abdominal and pelvic ultrasound every 3 to 4 months;

• Annual brain magnetic resonance imaging (MRI);

• Annual whole-body MRI (WBMRI).

For adults:

• Complete physical examination every 6 months;

• Prompt assessment with primary care physician for any medical concerns;

• Breast awareness (age 18 years onward);

• Clinical breast examination twice per year (age 20 years onward);

• Annual breast MRI screening (ages 20 to 75);

• Consider risk-reducing bilateral mastectomy;

• Annual brain MRI (age 18 years onward);

• Annual WBMRI;

• Abdominal and pelvic ultrasound every 12 months;

• Upper endoscopy and colonoscopy every 2 to 5 years (age 25 years onward);

• Annual dermatologic examination.

U.S. Preventive Services Task Force Recommendations

No U.S. Preventive Services Task Force recommendations for LFS have been identified.

Medicare National Coverage

There is no national coverage determination. In the absence of a national coverage determination, coverage decisions are left to the discretion of local Medicare carriers.

Ongoing and Unpublished Clinical Trials

Some currently unpublished trials that might influence this review are listed in Table 6.

Table 6. Summary of Key Trials

NCT: national clinical trial.*last update on clinicaltrials.gov website: May 2023 ; no estimated completion date listed.

REFERENCES

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2. Schneider K, Zelley K, Nichols KE, et al. Li-Fraumeni Syndrome. In: Pagon RA, Adam MP, Bird TD, et al., eds. GeneReviews. Seattle, WA: University of Washington; 2013.
3. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment Breast and Ovarian. Version 3.2024. https://www.nccn.org/professionals/physician_gls/pdf/genetics_bop.pdf. Accessed May 09, 2024.
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