CAM 204101

Genetic Testing for Li-Fraumeni Syndrome

Category:Laboratory   Last Reviewed:July 2019
Department(s):Medical Affairs   Next Review:July 2020
Original Date:July 2014    

Description
Li-Fraumeni syndrome (LFS) is a cancer predisposition syndrome associated with the development of several different types of tumors. The syndrome is caused by germline mutations in the TP53 gene.

The analytic validity of TP53 mutation testing is high, and almost all of these mutations can be identified by sequence analysis. A far smaller number of mutations can be detected by deletion/duplication analysis. 

The clinical validity of TP53 mutation testing is high in that a mutation can be identified in up to 80 percent of patients who meet the clinical criteria for a diagnosis of LFS. The clinical utility of genetic testing for a TP53 mutation is high in that confirming a diagnosis in a patient with clinical criteria of LFS will lead to changes in clinical management by increasing surveillance to detect cancers known to be associated with LFS at an early and treatable stage or to address possible prophylactic measures. Most cases of LFS are inherited, and testing of at-risk relatives will identify those who should also undergo increased cancer surveillance. 

Therefore, genetic testing for TP53 mutations may be considered medically necessary to confirm a diagnosis of LFS in patients who meet either the classic or the Chompret clinical diagnostic criteria for  LFS, in a patient who has been diagnosed with breast cancer at 35 years of age or younger and in at-risk relatives of a proband with a known TP53 mutation.

Background
LFS 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 in 1969 by two physician-scientists, Frederick P. Li and Joseph F. Fraumeni, based on a retrospective analysis of families with aggressive soft tissue sarcomas in young siblings and their biologically related cousins.2 

The tumor types that are most closely associated with LFS include soft tissue sarcomas, premenopausal breast cancer, brain tumors and adrenal cortical carcinoma.1 These core cancers account for approximately 70 percent to 80 percent of all LFS-related tumors. There is less agreement about the noncore cancers, which account for the remaining 30 percent of malignancies in LFS and include a wide variety of gastrointestinal tract, genitourinary tract, lung, skin and thyroid cancers and leukemias and lymphomas.1 

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 57 percent, and the risk of a third malignancy, 38 percent.1 

Individuals with LFS are at increased risk of both bone and soft tissue sarcomas. Sarcomas of various histologies account for 25 percent 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.3 Women with LFS are at greatly increased risk of developing premenopausal breast cancer, with the median age of diagnosis being 33 years of age.1 Male breast cancer has rarely been reported in LFS families.1 Many different types of brain tumors have been described in LFS, including astrocytomas, glioblastomas, medulloblastomas and choroid plexus carcinomas.1 The median age of onset of LFS-related brain tumors is 16 years of age. Individuals with LFS are at increased risk of developing ACC. In adults, in one series, it was estimated that 6 percent of individuals diagnosed with ACC after age 18 years have a germline TP53 mutation.4

Data from M.D. Anderson Cancer Center’s long-term clinical studies of LFS showed that the risk of developing soft tissue sarcomas is greatest before the age of 10, 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 and continues into older adulthood.5 

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.2 The first formal set of criteria, the classic LFS criteria, were developed in 1988, and are the most stringent criteria used to make a clinical diagnosis of LFS.2 

Classic LFS
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 
  • A first- or second-degree relative with any cancer before 45 years of age or a sarcoma at any age1

Chompret et al. developed criteria that were shown to have the highest positive predictive value, and which, when combined with the classic LFS criteria, provide the highest sensitivity for identifying individuals with LFS.6 The Chompret criteria were updated in 2009 to assist in identifying families with milder phenotypes.7 The Chompret criteria will also identify individuals with de novo TP53 mutations, whereas the classic LFS criteria require a family history. 

Chompret Criteria

  • Proband with tumor belonging to LFS tumor spectrum (e.g., soft tissue sarcoma, osteosarcoma, brain tumor, premenopausal breast cancer, adrenocortical carcinoma, leukemia, lung bronchoalveolar cancer) before age 46 years AND at least one first- or second-degree relative with LFS tumor (except breast cancer if proband has breast cancer) before age 56 years or with multiple tumors; OR 
  • Proband with multiple tumors (except multiple breast tumors), two of which belong to LFS tumor spectrum and the first of which occurred before age 46 years; OR 
  • Patient with ACC or choroid plexus tumor, irrespective of family history

NCCN guidelines recommend TP53 analysis for individuals who meet classic LFS criteria, Chompret criteria or who have been diagnosed with early-onset breast cancer (age of diagnosis ≤ 35 years). 

Molecular Diagnosis
LFS is associated with germline mutations 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 mutations are known to cause LFS, and no other inherited phenotypes are associated specifically with germline mutations involving TP53.1 

LFS is a highly penetrant cancer syndrome, with the risks for cancer being about 50 percent by age 30 years, and 90 percent by age 60 years. 1 LFS is inherited in an autosomal dominant manner. De novo germline TP53 mutations (no mutation is identified in either biologic parent) are estimated to be 7 percent to 20 percent.

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

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

Management
Treatment
The evaluation for 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 prophylactic mastectomy in women, and in all patients with a TP53 mutation, avoidance of radiotherapy, as there is some evidence to suggest that TP53 mutations confer an increased sensitivity to ionizing radiation and the possibility of radiation-induced malignancies. 

Surveillance
LFS 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,8 but, in general, the strategy includes physical examination, colonoscopy and breast imaging. Other protocols that are being evaluated include additional imaging techniques and biochemical assessment. NCCN has consensus-based screening guidelines.

Regulatory Status
No U.S. Food and Drug Administration (FDA)-cleared molecular diagnostic tests were found. Thus, molecular evaluation is offered as a laboratory-developed test. Clinical laboratories may develop and validate tests in-house (“home-brew”) and market them as a laboratory service. Such tests must meet the general regulatory standards of the Clinical Laboratory Improvement Act (CLIA). The laboratory offering the service must be licensed by CLIA for high-complexity testing.

Policy 

  1. Genetic counseling for Li-Fraumeni Syndrome genetic testing is considered MEDICALLY NECESSARY AND IS REQUIRED .
  2. Genetic testing for TP53 mutations is considered to be MEDICALLY NECESSARY to confirm a diagnosis of Li-Fraumeni syndrome under the following conditions:
    • In a patient who meets either the classic or the Chompret clinical diagnostic criteria for Li-Fraumeni syndrome 
      1. 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
        • A first- or second-degree relative with any cancer before 45 years of age or a sarcoma at any age
      2. Chompret clinical diagnostic criteria is defined by one of the following:
        • Proband with tumor belonging to LFS tumor spectrum (e.g., soft tissue sarcoma, osteosarcoma, brain tumor, premenopausal breast cancer, adrenocortical carcinoma, leukemia, lung bronchoalveolar cancer) before age 46 years AND at least 1 first- or second-degree relative with LFS tumor (except breast cancer if proband has breast cancer) before age 56 years or with multiple tumors at any age; OR 
        • Proband with multiple tumors (except multiple breast tumors), 2 of which belong to LFS tumor spectrum and the first of which occurred before age 46
        • Patient with adrenocortical carcinoma (ACC) or choroid plexus tumor, at any age irrespective of family history
    • In women with early onset breast cancer (diagnosed at ≤30 years). The optimal strategy for confirming a TP53 mutation in a proband would be:
      1. Sequencing of the entire TP53 coding region (exons 2-11). If sequencing is negative, then:
      2. Deletion/duplication analysis
  3. Genetic testing for a TP53 mutation is considered MEDICALLY NECESSARY in a first-, second- or third-degree relative of a proband with a known TP53 mutation (see Policy Guidelines No. 1).
  4. Comprehensive genetic testing for a TP53 mutation (i.e., full sequencing of the genes and detection of large gene rearrangements) or multi-gene testing is considered MEDICALLY NECESSARY in a patient or, if unaffected, family member with highest likelihood of a mutation if there is no known familial TP53 mutation.
  5. Genetic testing for a germline TP53 mutation is considered INVESTIGATIONAL for all other indications.

Policy Guidelines 
At the present time, there are no specific, evidence-based, standardized guidelines for recommendations of which "at-risk" relatives should be tested. In relatives of an index case, the risk of having a pathologic mutation, and developing disease, is influenced by numerous factors that should be considered in evaluating risk:

  1. Proximity of relation to index case (first-, second- or third degree)
  2. Mode of inheritance of mutation (autosomal dominant versus autosomal recessive)
  3. Degree of penetrance of mutation (high, intermediate or low)
  4. Results of detailed pedigree analysis
  5. De novo mutation rate

If a proband has a TP53 mutation, the risk to the proband’s offspring of inheriting the mutation is 50 percent. If a proband has a TP53 mutation, the risk to other relatives may depend on the genetic status of the proband’s parents (that is, it is not a de novo mutation in the proband). Most TP53 mutations are inherited from 1 of a proband’s parents. After a mutation has been identified in a proband, the proband’s parent with any pertinent cancer history of family history should be tested first to establish the lineage of the mutation; otherwise, both parents should be tested. A family history could appear to be negative because of incomplete penetrance of the mutation, limited family members available for testing, early death of a parent, etc.

Rationale
This policy was created in 2014 with the most recent search of the MEDLINE database through April 28, 2015 (see Appendix Table 1 for genetic testing categories). Literature that describes the analytic validity, clinical validity and clinical utility of genetic testing for Li-Fraumeni syndrome (LFS) TP53 mutations was sought. 

Analytic Validity
Analytic validity is the technical accuracy of the test in detecting a mutation that is present or in excluding a mutation that is absent.

According to a large reference laboratory, analytic sensitivity and specificity for polymerase chain reaction sequencing for LFS TP53 testing and deletions/duplications testing by multiplex ligation-dependent probe amplification is greater than 95 percent.9   

The order of testing to optimize yield would be:

  1. sequencing of the entire TP53 coding region (exons 2-11), which detects about 95 percent of TP53 mutations in patients with LFS. Examples of types of mutations detected by sequence analysis include small deletions/duplications and missense, nonsense and splice site mutations; most are missense mutations
  2. deletion/duplication analysis, which detects large deletions/duplications involving the coding region, exon 1 or promoter; these types of deletions/duplications are not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. These types of mutations account for less than 1 percent of mutations found in individuals with LFS.

Clinical Validity
Clinical validity is the diagnostic performance of the test (sensitivity, specificity, positive and negative predictive values) in detecting clinical disease.

Approximately 80 percent of families with features of LFS will have an identifiable TP53 mutation.1 Families that have no identifiable TP53 mutation but share clinical features of LFS are more likely to have a different hereditary cancer syndrome (e.g., hereditary breast-ovarian cancer syndrome).1

Clinical Utility
Clinical utility is how the results of the diagnostic test will be used to change management of the patient and whether these changes in management lead to clinically important improvements in health outcomes.

The clinical utility of genetic testing can be considered in the following clinical situations: (1) individuals with suspected LFS, and (2) family members of individuals with LFS. These situations will be discussed separately next.

Individuals With Suspected LFS
The clinical utility for these patients depends on the ability of genetic testing to make a definitive diagnosis and for that diagnosis to lead to management changes that improve outcomes. Direct evidence for the clinical utility of genetic testing in these patients, describing how a molecular diagnosis of LFS changed patient management, is limited. However, for patients who are diagnosed with LFS by identifying a TP53 mutation, the medical management focuses on increased cancer surveillance to detect tumors at the earliest, most treatable stages.

Villani et al. conducted a prospective, observational study of members of eight LFS families who were asymptomatic TP53 carriers.10 The participants either chose to undergo or to not undergo surveillance. Surveillance included biochemical and imaging studies, which included ultrasounds, brain magnetic resonance imaging (MRI) scans and rapid total body MRI scans. The primary outcome measure was detection of new cancers, and the secondary outcome measure was overall survival. Of 33 mutation carriers that were identified, 18 underwent surveillance. The surveillance protocol detected 10 asymptomatic tumors in seven patients, which included premalignant or low-grade tumors (three low-grade gliomas, a benign thyroid tumor, one myelodysplastic syndrome) and small, high-grade tumors (two choroid plexus carcinomas, two adrenocortical carcinomas, one sarcoma). The nine solid tumors that were detected were completely resected, and the patients were in complete remission. After a median follow-up of 24 months, all of the patients who had undergone surveillance were alive. In the nonsurveillance group, 12 high-grade, high-stage tumors developed in 10 patients, of which two were alive at the end of follow-up (p=0.04 for comparison of survival in the surveillance group). Three-year overall survival in the surveillance group was 100 percent and 21 percent in the nonsurveillance group (p=0.155). 

Family Members
When a TP53 mutation has been identified in a proband, testing of at-risk relatives can identify those who also have the mutation and have LFS. These individuals need initial evaluation and ongoing surveillance. 

Section Summary
Direct evidence of the clinical utility of TP53 testing is limited. However, the clinical utility of genetic testing for TP53 mutations is that genetic testing can confirm the diagnosis in patients with clinical signs and symptoms of LFS and in at-risk family members. Management changes include increased surveillance and possible prophylactic measures for the cancers that are associated with this syndrome. 

Ongoing and Unpublished Clinical Trials
A search of ClinicalTrials.gov in April 2015 did not identify any ongoing or unpublished trials that would likely influence this policy.

Summary of Evidence
The analytic validity of TP53 mutation testing is high, and almost all of these mutations can be identified by sequence analysis. A far smaller number of mutations can be detected by deletion/duplication analysis. 

The clinical validity of TP53 mutation testing is high in that a mutation can be identified in up to 80 percent of patients who meet the clinical criteria for a diagnosis of Li-Fraumeni Syndrome (LFS). 

The clinical utility of genetic testing for a TP53 mutation is high in that confirming a diagnosis in a patient with clinical criteria of LFS will lead to changes in clinical management by increasing surveillance to detect cancers known to be associated with LFS at an early and treatable stage, or to address possible prophylactic measures. Most cases of LFS are inherited, and testing of at-risk relatives will identify those who should also undergo increased cancer surveillance. 

Therefore, genetic testing for TP53 mutations may be considered medically necessary to confirm a diagnosis of LFS in patients who meet either the classic or the Chompret clinical diagnostic criteria for LFS, in a patient who has been diagnosed with breast cancer at 35 years of age or younger and in at-risk relatives of a proband with a known TP53 mutation.

Practice Guidelines and Position Statements
National Comprehensive Cancer Network guidelines Genetic/Familial High-Risk Assessment: Breast and Ovarian (v.2.2014)11 recommend the following for LFS management:

Breast cancer risk, women: 

  • Breast awareness starting at age 18 years. 
  • Clinical breast exam every six-12 months, starting at age 20-25 years or five-10 years before the earliest known breast cancer in the family.
  • Breast screening: Discuss risk-reducing mastectomy and counsel regarding degree of protection and cancer risk, and reconstruction options. 
    • Age 20-29 years, annual breast MRI [magnetic resonance imaging] screening (preferred) or mammogram if MRI is unavailable or individualized based on earliest age of onset in family. 
    • Age >30-75 years, annual mammogram and breast MRI screening. 
    • Age >75 years, management considered on an individual basis.
  • Address psychosocial, social and quality-of-life aspects of risk-reducing mastectomy.

Other cancer risks: 

  • Annual comprehensive physical exam with high index of suspicion for the cancers associated with LFS. 
  • Consider colonoscopy every two-five years, starting no later than 25 years of age. 
  • Therapeutic radiation therapy for cancer treatment should be avoided when possible. 
  • Discuss option to participate in novel screening approaches using technologies.

For relatives: 

  • Advise about possible inherited cancer risk to relatives, options for risk assessment and management. 
  • Recommend genetic counseling and consideration of genetic testing for at-risk relatives. 

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

References

  1. Schneider K, Zelley K, Nichols KE, Garber J. Li-Fraumeni Syndrome. In: Pagon RA, Adam MP, Bird TD, et al., eds. GeneReviews. Seattle (WA) 1993.
  2. Sorrell AD, Espenschied CR, Culver JO, Weitzel JN. Tumor protein p53 (TP53) testing and Li-Fraumeni syndrome : current status of clinical applications and future directions. Mol Diagn Ther. Feb 2013;17(1):31-47. PMID 23355100
  3. Ognjanovic S, Olivier M, Bergemann TL, Hainaut P. Sarcomas in TP53 germline mutation carriers: a review of the IARC TP53 database. Cancer. Mar 1 2012;118(5):1387-1396. PMID 21837677
  4. Raymond VM, Else T, Everett JN, Long JM, Gruber SB, Hammer GD. Prevalence of germline TP53 mutations in a prospective series of unselected patients with adrenocortical carcinoma. J Clin Endocrinol Metab. Jan 2013;98(1):E119-125. PMID 23175693
  5. Hwang SJ, Lozano G, Amos CI, Strong LC. Germline p53 mutations in a cohort with childhood sarcoma: sex differences in cancer risk. Am J Hum Genet. Apr 2003;72(4):975-983. PMID 12610779
  6. Chompret A, Abel A, Stoppa-Lyonnet D, et al. Sensitivity and predictive value of criteria for p53 germline mutation screening. J Med Genet. Jan 2001;38(1):43-47. PMID 11332399
  7. Gonzalez KD, Noltner KA, Buzin CH, et al. Beyond Li Fraumeni Syndrome: clinical characteristics of families with p53 germline mutations. J Clin Oncol. Mar 10 2009;27(8):1250-1256. PMID 19204208
  8. Mai PL, Malkin D, Garber JE, et al. Li-Fraumeni syndrome: report of a clinical research workshop and creation of a research consortium. Cancer Genet. Oct 2012;205(10):479-487. PMID 22939227
  9. http://ltd.aruplab.com/Tests/Pub/2009302. Accessed March, 2015
  10. Villani A, Tabori U, Schiffman J, et al. Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: a prospective observational study. Lancet Oncol. Jun 2011;12(6):559-567. PMID 21601526
  11. National Comprehensive Cancer Network (NCCN). Genetic/Familial High-Risk Assessment Breast and Ovarian v2.2014. http://www.nccn.org/professionals/physician_gls/pdf/genetics_screening.pdf. Accessed March, 2015.

Coding Section

Codes Number Description
CPT 81404 

Molecular pathology procedure, Level 5 (e.g., analysis of 2-5 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 6-10 exons, or characterization of a dynamic mutation disorder/triplet repeat by Southern blot analysis).

  81407

Molecular pathology procedure, Level 8 Multi-gene testing, (i.e. full sequencing of the genes and detection of large gene rearrangements) or multi-gene testing 

ICD-9-Diagnosis V84.01

Genetic susceptibility to malignant neoplasm of breast (includes Li-Fraumeni syndrome)

ICD-10-CM (effecitve 10/01/15) Z15.01

Genetic susceptibility to malignant neoplasm of breast (includes Li-Fraumeni syndrome)

ICD-10-PCS (effective 10/01/15)  

Not applicable. ICD-10-PCS codes are only used for inpatient services. There are no ICD procedure codes for laboratory tests.

Type of Service    
Place of Service    

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive. 

Appendix

Appendix Table 1. Categories of Genetic Testing Addressed in Policy No. 204101

Category Addressed
  Yes No

1. Testing of an affected individual’s germline to benefit the individual

   
    1a. Diagnostic X  
    1b. Prognostic   X
    1c. Therapeutic   X

2. Testing cancer cells from an affected individual to benefit the individual

   
    2a. Diagnostic   X
    2b. Prognostic   X
    2c. Therapeutic   X

3. Testing an asymptomatic individual to determine future risk of disease

X  

4. Testing of an affected individual’s germline to benefit family members

X  

5. Reproductive testing

   
    5a. Carrier testing: preconception   X
    5b. Carrier testing: prenatal   X
    5c. In utero testing: aneuploidy   X
    5d. In utero testing: mutations   X
    5e. In utero testing: other   X
    5f. Preimplantation testing with in vitro fertilization   X

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross and Blue Shield Association technology assessment program (TEC) and other non-affiliated technology evaluation centers, reference to federal regulations, other plan medical policies andaccredited national guidelines.

"Current Procedural Terminology© American Medical Association.  All Rights Reserved" 

History From 2014 Forward     

07/12/2019 

Annual review, no change to policy intent. 

07/23/2018 

Annual review. Adding language regarding genetic counseling and testing for TP53 mutations. No other changes to policy intent. 

07/19/2017 

Annual review, updating policy and guidelines to give clearer direction on medical necessity. No other changes made.

04/25/2017 

Updated category to Laboratory. No other changes 

07/01/2016 

Annual review, no change to policy intent. 

01/04/2016 

Updated CPT code. No change to intent of policy. 

07/01/2015 

Annual review, no change to policy intent. Updating background, description, rationale and references. Added coding and Appendix 1.

07/07/2014

New Policy.


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