Medical Policy

 

Subject: Genetic Testing for TP53 Mutations
Document #: GENE.00035 Publish Date:    12/12/2018
Status: Reviewed Last Review Date:    11/08/2018

Description/Scope

This document addresses genetic testing for TP53 mutations.

The TP53 gene (also known as p53) located on chromosome 17 is a tumor suppressor gene.  The protein product of the TP53 gene binds to cellular DNA and is involved in the control of the cell cycle and apoptosis (programmed cell death). 

Note: For additional information on genetic testing for malignant conditions, please refer to:

Position Statement

Medically Necessary:

Germline testing for cancer susceptibility

  1. TP53 gene mutation testing for Li-Fraumeni syndrome (LFS) is considered medically necessary when any one of criteria A through F and all of criteria G are met:
    1. The individual has a family history of known TP53 mutation; or
    2. The individual was diagnosed with sarcoma prior to age 45 years; and
      1. Has a first-degree relative who was diagnosed with cancer prior to age 45 years; and
      2. Has an additional first- or second degree relative on the same side of the family who was diagnosed with cancer prior to age 45 years, or sarcoma at any age; or
    3. The individual was diagnosed with a tumor from the LFS tumor spectrum (for example, soft tissue sarcoma, osteosarcoma, brain tumor, breast cancer, adrenocortical carcinoma, leukemia, lung bronchoalveolar cancer) prior to age 46 years; and
      1. Has at least one first-or second-degree relative with any of the above LFS spectrum tumors (other than breast cancer, if the proband has breast cancer) diagnosed prior to the age of 56 years or with multiple primaries at any age; or
    4. The individual was diagnosed with multiple tumors (except multiple breast tumors), two of which belong to LFS tumor spectrum, with the initial cancer occurring prior to age 46 years; or
    5. The individual was diagnosed with adrenocortical carcinoma, choroid plexus carcinoma or rhabdomyosarcoma of embryonal anaplastic subtype at any age, regardless of family history; or
    6. The individual was diagnosed with early onset breast cancer at age 30 years or younger; and
    7. Genetic counseling, which encompasses all of the following components, has been performed:
      1. Interpretation of family and medical histories to assess the probability of disease occurrence or recurrence; and
      2. Education about inheritance, genetic testing, disease management, prevention and resources; and
      3. Counseling to promote informed choices and adaptation to the risk or presence of a genetic condition; and
      4. Counseling for the psychological aspects of genetic testing.
  2. Prenatal or preimplantation genetic testing is considered medically necessary to establish a diagnosis of LFS in the offspring of individuals with known TP53 genetic mutation and genetic counseling, which encompasses all of the following components, has been performed:
    1. Interpretation of family and medical histories to assess the probability of disease occurrence or recurrence; and
    2. Education about inheritance, genetic testing, disease management, prevention and resources; and
    3. Counseling to promote informed choices and adaptation to the risk or presence of a genetic condition; and
    4. Counseling for the psychological aspects of genetic testing.

Somatic tumor testing

TP53 gene mutation testing is considered medically necessary for individuals diagnosed with chronic lymphocytic leukemia or hypodiploid acute lymphocytic leukemia to identify those who would benefit from treatment with chemotherapy.

Investigational and Not Medically Necessary:

TP53 gene mutation testing is considered investigational and not medically necessary in individuals not meeting the criteria above.

TP53 gene mutation testing using panels of genes (with or without next generation sequencing) is considered investigational and not medically necessary unless all components of the panel have been determined to be medically necessary based on the criteria above.  However, individual components of a panel may be considered medically necessary when criteria above are met.

Note: When a component of a genetic panel is separately identified, but a specific medical necessity statement is not found above or in another document, the criteria in GENE.00001 Genetic Testing for Cancer Susceptibility may be used to determine medical necessity.

Rationale

Li-Fraumeni syndrome (LFS)
LFS is diagnosed in individuals meeting established clinical criteria or in those who have a germline mutation in TP53 regardless of family cancer history.  At least 70% of individuals diagnosed clinically have an identifiable germline mutation in TP53, the only gene so far identified in which mutations are definitively associated with LFS.

Acquired TP53 mutations are observed in numerous tumors; however, no other inherited phenotypes are associated specifically with germline mutations involving TP53.  Somatic mutations of the TP53 gene are found in approximately 50% of all tumors.

Two forms of LFS have been identified: classic LFS and Li-Fraumeni-like syndrome (LFLS).  Several criteria sets have been developed over the years to identify individuals with classic LFS or LFLS.  Individuals with classic LFS meet the following criteria: a diagnosis of a sarcoma was made before age 45 years; a first-degree relative was diagnosed with any cancer prior to age 45 years; and an additional first- or second-degree relative was diagnosed with any form of cancer prior to age 45 years or diagnosed with sarcoma at any age (Li, 1988).  Individuals with LFLS fulfill a portion, but not all, of the above criteria.  The Birch criteria and the Eeles criteria are less stringent than the criteria for LFS and were developed to identify individuals with LFLS.  More recently, an additional set of criteria (the Chompret criteria) was developed to select individuals appropriate for genetic testing for LFS (Birch, 1994; Chompret, 2001; Eeles, 1995).

The importance of the role of TP53 in tumor suppression is illustrated by the fact that the majority of individuals fulfilling the criteria for classic LFS (and a smaller proportion of individuals fulfilling the Birch, Eeles, or Chompret criteria) carry germline variants in the TP53 gene.  Somatic variants in TP53 are found in more than half of sporadic cancers.  

Several studies have been published demonstrating the clinical validity of genetic testing for LFS.  In order to determine the role of germline p53 mutations in genetic predisposition to childhood cancer, Chompret and colleagues (2000) sought to identify germline p53 mutations in individuals with at least one relative (first- or second-degree relative or first cousin) affected by any cancer before 46 years of age, or affected by multiple cancers.  Screening for germline p53 mutation was completed in 268 index cases among individuals fulfilling selection criteria.  Seventeen (6.3%) mutations were identified, of which 13 were inherited mutations and 4 were de novo mutations.  The risk of cancer for individuals carrying a p53 mutation was estimated using a maximum likelihood method and a program based on a survival analysis approach.  The lifetime risk of cancer development in mutation carriers was estimated to be 73% for males and nearly 100% for females.

Birch and colleagues (2001) evaluated the types and frequency of cancers associated with TP53 gene variants in 501 individuals from 8 LFLS and 20 LFS families.  Splice-site variants, nonsense variants and insertion/deletion variants occurred in 6, 3, and 3 families, respectively, while 16 families transmitted missense variants.  Tumors present in probands and first- or second-degree relatives that were used to satisfy diagnostic criteria were excluded from the analysis.  Cancers strongly associated with TP53 gene variants were: breast carcinoma, soft tissue sarcomas, osteosarcoma, brain tumors, adrenocortical carcinoma, Wilms' tumor and phyllodes tumors.  There was a moderate association for pancreatic carcinoma.  Leukemia and neuroblastoma were weakly associated.  Although breast carcinoma and sarcomas were numerically most frequent, the greatest increases relative to general population rates were in adrenocortical carcinoma and phyllodes tumors.  

Hwang and colleagues (2003) explored the cancer incidence in 56 germline p53 mutation carriers and 3201 noncarriers from 107 kindreds ascertained through individuals with childhood soft-tissue sarcoma who were treated at the University of Texas M.D. Anderson Cancer Center.  The authors systematically followed members in these kindreds for cancer incidence for more than 20 years and evaluated their p53 gene status.  The authors found a significantly higher cancer risk in female carriers than in male carriers, 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 found in the general population (SIR=0.9; 95% CI, 0.8-1.0).  The calculated SIRs indicated a greater than 100-fold higher risk of sarcoma, female breast cancer, and hematologic malignancies for the p53 mutation carriers.  The penetrance of TP53 gene variants among carriers ranged from 12% at 20 years of age to 80% at 50 years of age.

Bougeard and colleagues (2008) performed TP53 gene testing in 474 French families with a history suggestive of LFS.  The study included 232 (48.9%) families satisfying the Chompret criteria for TP53 gene testing and 242 families who fulfilled the age or tumor spectrum delineated in the Chompret criteria or they corresponded to sporadic early-onset breast cancer cases (diagnosed before age 33 and BRCA1/2 negative).  The researchers identified a germline alteration of TP53 in 82 families (17%); in 67/232 of the families meeting the Chompret criteria (29%) and in 15/242 which did not meet these criteria (6%).  Most of the alterations corresponded to missense mutations (67%).  Four families were found to have genomic deletions removing the entire TP53 locus, the promoter and the non-coding exon 1, or exons 2-10.  The mean ages of tumor onset were significantly different between individuals harboring TP53 missense mutations and other types of alterations, with missense mutations being associated with a 9 year earlier tumor onset.  The researchers concluded that these results confirm that missense mutations not only inactivate p53 but also have an additional oncogenic effect.

Mouchawar (2010) reported on the incidence of early-onset breast cancer in women diagnosed before age 30 (very early-onset) in a population-based, case control family study. A total of 52 women were eligible to be included in the portion of the study focusing on very early onset breast cancer. A BRCA mutation was identified in approximately 17% of the women (9/52) prior to the study. An additional 2 individuals (4%) were diagnosed with a TP53 mutation. The literature suggests that the majority of individuals with early onset breast cancer will have a negative BRCA test result and will require additional testing (Dite, 2003; Sorrell, 2013). The National Comprehensive Cancer Network (NCCN) clinical practice guidelines on genetic/familial assessment for individuals at high risk for breast and ovarian cancer indicate that TP53 testing can be ordered alone, concurrently with BRCA testing or other gene testing or as a follow-up after a negative BRCA test.

Gonzalez and colleagues (2009) reported on the clinical manifestations of LFS in a series of 525 individuals who were referred for genetic testing for TP53 gene mutations based upon a clinical suspicion of LFS.  The results of genetic mutation testing were correlated with clinical and familial histories.  In this study, 91 participants (17%) were found to have a TP53 mutation.  In all cases where a TP53 mutation was identified, either the proband or a family member had a history of 1 “core” malignancy (breast cancer, sarcoma, adrenocortical carcinoma or a brain tumor) prior to 50 years of age.  A total of 141 cancers were diagnosed in the 82 participants with mutations where clinical information was available.  Breast cancer was identified in 44 of the subjects with germline mutations and occurred exclusively in women.  Sarcoma was identified in 38 cases, adrenocortical carcinoma in 14 cases and brain tumors in 13 cases.  There was also a strong association of TP53 mutations with adrenocortical carcinoma and choroid plexus carcinoma. 

Genetic testing for LFS may affect individual management in a variety of ways.  A positive test might prompt additional surveillance or consideration of a prophylactic mastectomy.  Villani and colleagues (2011) explored the feasibility and potential clinical effect of a comprehensive surveillance protocol in asymptomatic TP53 mutation carriers in families with this syndrome.  The researchers implemented a clinical surveillance protocol using frequent biochemical and imaging studies for asymptomatic TP53 mutation carriers and conducted a prospective observational study of the members of eight families with Li-Fraumeni syndrome who either chose to undergo surveillance or chose not to undergo surveillance.  The primary outcome measure was detection of new cancers while the secondary outcome measure was overall survival (OS).  Eighteen of the 33 participants agreed to undergo surveillance while the remainder of the participants did not.  The surveillance protocol included several tests, including but not limited to rapid whole-body MRI, brain MRI, abdominal ultrasound examination, and biochemical markers.  Preliminary data suggest that such a surveillance protocol may improve survival of individuals with LFS through presymptomatic detection of tumors.  Using this protocol, tumors were detected in 7 asymptomatic individuals.  At the mean follow-up time of 24 months, all 7 of these carriers were still alive.  Ten individuals who were members of the group which did not undergo surveillance developed high-grade, advanced stage tumors.  Of these 10 individuals, only 2 were alive at the end of follow-up.  OS at the 3-year interval was significantly higher for the surveillance group compared with the non-surveillance group (100% vs. 21%; p=0.016).  While this was a small study, the surveillance protocol implemented was feasible and detected asymptomatic tumors in approximately 40% of the individuals with TP53 mutations.  Additional prospective studies are needed to demonstrate the effectiveness of this protocol in individuals with LFS.

The American College of Obstetricians and Gynecologists (ACOG) recommends that individuals with a personal diagnosis of malignancies associated with Li-Fraumeni syndrome (for example, soft tissue sarcomas, osteosarcomas, premenopausal breast cancer, brain tumors, and adrenocortical carcinomas), especially with multiple family members with these types of cancer should be referred to a specialist in cancer genetics for further evaluation for Li-Fraumeni syndrome (ACOG, 2015).

Many of the cancers associated with germline mutations in TP53 do not lend themselves to early detection; therefore, surveillance recommendations are general in nature.  Current clinical guidelines for cancer surveillance in carriers of tp53 mutations focus predominantly on breast and bowel cancer for which surveillance regimens are recognized to be beneficial for conditions such as familial breast and familial bowel cancer.  According to the NCCN clinical guidelines, a surveillance schedule for TP53 mutation carriers includes but is not limited to clinical breast examination, breast MRI and mammogram in various age brackets beginning as early as 20 years of age or at the age of the earliest diagnosed breast cancer in the family.  An annual comprehensive physical examination and additional surveillance based on individual family histories is also recommended.  Women who have undergone treatment for breast cancer are advised to undergo mammography and breast MRI on the remaining breast tissue.  The need for prophylactic mastectomy should be discussed on a case by case basis.  Practitioners should educate individuals regarding the signs and symptoms of cancer and should be advised about the risk to relatives.  Annual physical examination is recommended for cancer survivors with a high index of suspicion for second malignancies and rare cancers.  Pediatricians should be aware of the risk of childhood cancers in affected families (Ballinger, 2015; NCCN, V2.2019). 

Effective surveillance methods to identify individuals who are TP53 variant carriers have proven difficult due to the wide spectrum of tumors that may occur and the fact that many of the tumors are difficult to detect early.  At the time of this review, no published guidelines for the surveillance of individuals with TP53 mutations were found which demonstrated improved health outcomes in affected individuals.  Treatment for individuals with LFS is dependent upon the type of tumor identified.  Some treatment modalities (in particular radiotherapy) are not recommended for use in individuals with LFS due to the damage it may cause to the DNA.

Some individuals diagnosed with Li-Fraumeni syndrome based upon clinical criteria do not have a detectable mutation or abnormality in TP53.  The absence of a detectable mutation may be due to mutations occurring outside of regions normally examined by genetic testing.  In these instances, the individuals may not have a germline abnormality of TP53 but may have a mutation in a gene which has not yet been identified, or may be representative of cases where the malignancy occurred by chance.

Prenatal and preimplantation genetic diagnosis for at risk pregnancies is available in the clinical setting and requires prior identification of the pathogenic germline TP53 mutation in the family.  The NCCN recommends that couples expressing the desire that their offspring not carry the familial form of the TP53 mutation receive genetic counseling and be made aware of the potential risk, benefits and limitations of prenatal and preimplantation genetic testing and reproductive options (NCCN, V2.2019). 

In summary, studies consistently demonstrate a strong correlation between TP53 genotype and a significantly increased risk of cancer and a high detection rate among individuals suspected of having LFS.  The peer-reviewed, published literature also suggests the test would be beneficial for risk assessment and the medical management of individuals with LFS.  The results of TP53 gene testing may impact future treatment decisions, influence whether at-risk individuals will receive and adhere to clinical recommendations regarding tumor screening, and potentially relieve disease-associated anxiety. 

Chronic Lymphocytic Leukemia (CLL)
CLL represents approximately 1.1% of all new cancer cases in the U.S. with approximately 20,110 new cases being diagnosed and an estimated 4660 individuals dying of the disease in 2017.  CLL is characterized by the progressive accumulation of incompetent leukemic cells in the peripheral blood, lymphoid tissues and bone marrow.  In contrast to some other forms of leukemia, CLL generally progresses slowly causing few, if any, problems in its early stages.  Frequently CLL is diagnosed incidentally by blood tests that are performed during a routine physical exam.  In other cases, it is discovered as a result of the individual seeking treatment for symptoms.  There is an inherited genetic susceptibility for CLL; family members of individuals with CLL have a 6 to 9 fold increased risk of developing the disease (Eichhorst, 2015; NCCN, V5.2018; SEER, 2016).

In establishing a diagnosis of CLL, it is critical to verify that the individual has CLL and not some other lymphoproliferative disease that can mimic CLL, such as hairy cell leukemia, or leukemic manifestations of mantle cell lymphoma, marginal zone lymphoma, splenic marginal zone lymphoma with circulating villous lymphocytes, or follicular lymphoma.  According to the NCCN, International Workshop on Chronic Lymphocytic Leukemia (IWCLL) and the European Society of Medical Oncology (ESMO), the diagnosis of CLL requires the presence of at least 5x109/L B lymphocytes in the peripheral blood and the clonality of the circulating B lymphocytes should be confirmed by flow cytometry (Eichhorst, 2015; Hallek, 2008; NCCN, V5.2018). 

Several factors have been identified which provide prognostic information for CLL.  These factors include but are not limited serum markers such as beta-2 microglobulin, thymidine kinase, cytogenetic abnormalities detected by FISH (for example, del(13q), del(11q) and del(17p) and TP53 mutations.  Del(17p) and a mutation of TP53 have been identified and evaluated in individuals with CLL and are considered useful markers to provide prognostic information beyond clinical staging.  Individuals with a detectable del(17p) or a mutation of TP53 have the poorest prognosis, with a median OS of 2-5 years.  These individuals also tend to experience poorer outcomes such as shorter treatment-free interval, shorter survival (32 months) and poorer response to chemotherapy (Dohner, 2000).  

Several studies using fludarabine-based regimens have identified TP53 mutations as an independent predictor of shorter survival and decreased resistance to chemotherapy.  Zenz and colleagues (2010) conducted a randomized controlled trial in order to define the impact of TP53 mutations in CLL.  The researchers assessed TP53 mutations by denaturing high-performance liquid chromatography (exons 2 to 11) in a group of 375 individuals with a follow-up of 52.8 months (German CLL Study Group CLL4 trial; fludarabine alone and fludarabine in addition to cyclophosphamide [FC]).  The authors identified TP53 mutations in 8.5% of subjects (28 of 328 participants).  None of the participants with TP53 mutation demonstrated a complete response.  In subjects with TP53 mutation, compared with subjects without TP53 mutation, median progression-free survival (PFS; 23.3 vs 62.2 months, respectively) and OS (29.2 vs 84.6 months, respectively) were appreciably decreased (both p<0.001).  TP53 mutations in the absence of 17p deletions were found in 4.5% of participants.  PFS and OS for subjects with 17p deletion and subjects with TP53 mutation in the absence of 17p deletion were similar.  Multivariate analysis distinguished TP53 mutation as the strongest prognostic marker regarding PFS (hazard ratio [HR]=3.8; p<0.001) and OS (HR=7.2; p<0.001).  

In the prospective, randomized trial comparing FC with chlorambucil or fludarabine, researchers investigated the frequency and prognostic value of TP53 abnormalities in individuals with CLL.  The researchers analyzed a total of 529 CLL samples from the Leukemia Research Foundation Chronic Lymphocytic Leukemia 4 (LRF CLL4) trial for mutations in the TP53 gene.  TP53 mutation status was correlated with response and survival data.  Mutations of TP53 were noted in 8.5% of participants, including 87.5%who carried the 17p deletion, and conferred a poor prognosis independent of other adverse features (Gonzalez, 2011).

Stilgenbauer and colleagues (2014) conducted an analysis of the CLL8 study (a prospective, international, multicenter, randomized [1:1] first-line treatment trial comparing FC or FC with rituximab [FCR]).  Study results demonstrated that TP53, NOTCH1, and SF3B1 were mutated in 72 of 628 (11.5%), 62 of 622 (10%), and 114 of 621 (18.4%) CLL participants requiring front-line therapy, respectively.  Individuals with a mutation in TP53 experienced significantly decreased OS and PFS outcomes regardless of treatment with FC or FCR.

The NCCN (V2. 2019) recommends that all individuals diagnosed with CLL undergo TP53 sequencing prior to the initiation of treatment to direct the selection of appropriate therapy (level II A recommendation).  The ESMO guidelines provide direction regarding the role of TP53 mutation analysis in selecting appropriate treatment regimens.  With regard to treating advanced disease stage, the authors assigned level I A evidence rating for the following indications:

Treatment should only be initiated in patients with symptomatic, active disease … the presence of del(17p) or TP53 mutation without the above-mentioned conditions is not an indication for treatment.

Front-line treatment. In physically fit patients (physically active, with no major health problems, normal renal function) without TP53 deletion/mutation, FCR is the standard first-line therapy: improvement of OS has been demonstrated with this first-line chemoimmunotherapy.

In patients with relevant co-morbidity, who are usually older, but without TP53 deletion/mutation, the combination of chlorambucil plus an anti-CD20 antibody (rituximab, ofatumumab or obinutuzumab) prolongs progression-free survival (PFS) when compared with monotherapy and is therefore the standard approach (Eichhorst, 2015).

Studies have demonstrated that TP53 mutation is an independent marker of poor prognosis in patients with CLL. Genetic testing as a prognostic factor is starting to play a role in therapeutic selection.  Current guidelines recommend using TP53 mutation status as a tool to identify the most appropriate regimen for symptomatic CLL patients requiring treatment. 

TP53 Mutations in Low-hypodiploid Acute Lymphocytic Leukemia (ALL)
Although TP53 mutations are one of the most frequently observed somatic alterations in cancer, and are also common in acute myeloid leukemia, they are relatively uncommon in ALL.  In cases involving ALL, TP53 is frequently mutated in two settings: (1) relapsed and (2) low-hypodiploid ALL.  Hypodiploid ALL encompasses up to 5% of childhood ALL cases “and is stratified according to the severity of aneuploidy; with several stereotyped patterns of chromosomal loss identified: near haploidy (24–31 chromosomes), low hypodiploidy (32–39 chromosomes), and high hypodiploidy (40–44 chromosomes)” (Comeaux, 2017).  Each of these patterns of chromosomal loss is characterized by distinct genetic mutations which are not commonly found in other forms of ALL, one of the most prominent being TP53 mutations in low-hypodiploid ALL.  It has been noted that the frequency of TP53 mutations/deletions increase with age and that individuals harboring a hypodiploid ALL have a high risk of treatment failure.  Research suggests the presence of TP53 mutations/deletions is a valuable prognostic parameter for individuals with ALL and may be used as a tool to identify which individuals would benefit from chemotherapy treatment (Comeaux, 2017; Holmfeldt, 2013; Stengal, 2014).

While the TP53 alteration seems to be an essential component of the pathogenesis of low-hypodiploid ALL and has been associated with poor outcome in individuals with ALL, there are limited data regarding the functional role of TP53 alterations in leukemogenesis and drug resistance (Comeaux, 2017; Hof, 2011).  However, based on the published data and specialty consensus input, TP53 gene mutation testing may be considered appropriate for individuals diagnosed with hypodiploid acute lymphocytic leukemia in order to identify those who would benefit from treatment with chemotherapy.

Background/Overview

LFS is a rare, autosomal dominant cancer predisposition syndrome.  LFS often occurs at a young age.  It has been estimated that individuals with LFS have a 60% chance of malignancy by age 45 and a 95% chance by age 70. 

Once a TP53 mutation has been identified in a family, testing of at-risk relatives can identify those family members who also have the familial mutation.  Management for individuals with LFS may include increased surveillance for the development of cancer.  For women with LFS, breast MRIs instead of mammograms may be recommended as a means to reduce radiation exposure.  Prophylactic mastectomy rather than lumpectomy may be recommended as a preventive measure in women with a germline TP53 mutation.  Individuals with germline TP53 mutations are cautioned to avoid known carcinogens including excessive sun exposure, tobacco use, occupational exposures and excessive alcohol use.

CLL is a chronic, slowly developing form of leukemia.  In many cases, in its early stages, it produces few symptoms.  While some individuals can live with CLL without any symptoms for decades, others live for a shorter period.  Careful analysis of an individual’s blood and physical condition help to determine the stage of the disease – a crucial first step in deciding on the proper course of treatment.  Unlike people with many other types of cancer, some individuals with CLL do not benefit from early, aggressive treatment, but instead do better with careful long-term monitoring of the disease. 

Genetic testing for TP53 mutations may be carried out using a variety of technologies, including but not limited to direct sequencing and analysis as well as multiplex ligation-dependent probe amplification (MLPA).  TP53 gene testing may be performed for the purpose of diagnosis, risk assessment, and/or disease management.

ALL
ALL is a rapidly progressing type of cancer that originates in the lymphocytes of the bone marrow.  Because ALL cells typically invade the blood fairly quickly, they can metastasize to other parts of the body, including but not limited to the lymph nodes, liver, spleen, central nervous system (brain and spinal cord), and testicles (in males). Generally speaking, if not treated promptly, proliferation of leukemia cells can cause bone marrow failure and death due to anemia, hemorrhage, and/or infection within a few months.

Contemporary therapy for ALL generally involves the administration of various cytotoxic chemotherapeutic agents in several phases over several years.  Treatment is curative in more than 90% of children.  However, relapse of ALL occurs in up to 20% of children and even more frequently in adults and is often refractory to further chemotherapy.  For this reason, relapsed ALL is a leading cause of childhood cancer death (Comeaux, 2017).

Genetic Counseling
According to the National Society of Genetic Counselors (NSGC, 2006), genetic counseling is the process of assisting individuals to understand and adapt to the medical, psychological and familial ramifications of a genetic disease.  This process typically includes the guidance of a specially trained professional who:

(1) Integrates the interpretation of family and medical histories to assess the probability of disease occurrence or recurrence; and
(2) Provides education about inheritance, genetic testing, disease management, prevention and resources; and
(3) Provides counseling to promote informed choices and adaptation to the risk or presence of a genetic condition; and
(4) Provides counseling for the psychological aspects of genetic testing

Definitions

Acute lymphocytic leukemia (also known as acute lymphoblastic leukemia; ALL): A fast growing type of cancer that originates in the lymphocytes (white blood cells) in the bone marrow.

Chronic lymphocytic leukemia: A type of cancer in which the bone marrow produces abnormal leukocytes (white blood cells).

Germ cell: An ovum or a sperm cell or one of its precursors.

Germline mutation: Any detectable and heritable change in the lineage of germ cells.  Mutations in these cells are transmitted to offspring, while, on the other hand, somatic mutations are not inherited.

Leukemia: A type of cancer affecting the blood and bone marrow.

Proband: The affected individual who serves as the starting point for the genetic study of a family.

Somatic cells: Cells that make up the body of an organism with the exception of germ cells.

Coding

 

The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When services may be Medically Necessary when criteria are met:

CPT

 

81404

Molecular pathology procedure, Level 5 (eg, 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)  [when specified as the following]:

  • TP53 (tumor protein 53) (eg, tumor samples), targeted sequence analysis of 2-5 exons

81405

Molecular pathology procedure, Level 6 (eg, analysis of 6-10 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 11-25 exons, regionally targeted  cytogenomic array analysis)  [when specified as the following]:

  • TP53 (tumor protein 53) (eg, Li-Fraumeni syndrome, tumor samples), full gene sequence or targeted sequence analysis of >5 exons

 

 

ICD-10 Diagnosis

 

 

C00.0-C96.9

Malignant neoplasms

 

Z15.01-Z15.09

Genetic susceptibility to malignant neoplasm

 

Z80.0-Z80.9

Family history of primary malignant neoplasm

 

Z85.00-Z85.9

Personal history of malignant neoplasm

 

When services are Investigational and Not Medically Necessary:
For the procedure and diagnosis codes listed above when criteria are not met or for all other indications not listed, or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

When services are also Investigational and Not Medically Necessary:
When the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

CPT

 

81445

Targeted genomic sequence analysis panel, solid organ neoplasm, DNA analysis, and RNA analylsis when performed, 5-50 genes (eg, ALK, BRAF, CDKN2A, EGFR, ERBB2, KIT, KRAS, NRAS, MET, PDGFRA, PDGFRB, PGR, PIK3CA, PTEN, RET), interrogation for sequence variants and copy number variants or rearrangements, if performed

81455

Targeted genomic sequence analysis panel, solid organ or hematolymphoid neoplasm, DNA analysis, and RNA analysis when performed, 51 or greater genes (eg, ALK, BRAF, CDKN2A, CEBPA, DNMT3A, EGFR, ERBB2, EZH2, FLT3, IDH1, IDH2, JAK2, KIT, KRAS, MLL, NPM1, NRAS, MET, NOTCH1, PDGFRA, PDGFRB, PGR, PIK3CA, PTEN, RET), interrogation for sequence variants and copy number variants or rearrangements, if performed

 

 

ICD-10 Diagnosis

 

Z15.01

Genetic susceptibility to malignant neoplasm of breast [Li Fraumeni syndrome]

Z15.09

Genetic susceptibility to other malignant neoplasm

References

Peer Reviewed Publications:

  1. Avigad S, Peleg D, Barel D, et al. Prenatal diagnosis in Li-Fraumeni syndrome. J Pediatr Hematol Oncol. 2004; 26(9):541-545.
  2. Baliakas P, Hadzidimitriou A, Sutton LA, et al. Recurrent mutations refine prognosis in chronic lymphocytic leukemia. Leukemia. 2015; 29(2):329-336.
  3. Ballinger ML, Mitchell G, Thomas DM. Surveillance recommendations for patients with germline TP53 mutations. Curr Opin Oncol. 2015; 27(4):332-337.
  4. Birch JM, Alston RD, McNally RJ, et al. Relative frequency and morphology of cancers in carriers of germline TP53 mutations. Oncogene. 2001; 20(34):4621-4628.
  5. Birch JM, Hartley AL, Tricker KJ, et al. Prevalence and diversity of constitutional mutations in the p53 gene among 21 Li-Fraumeni families. Cancer Res. 1994; 54(5):1298-1304.
  6. Bougeard G, Renaux-Petel M, Flaman JM, et al. Revisiting Li-Fraumeni Syndrome from TP53 mutation carriers. J Clin Oncol. 2015; 33(21):2345-2352.
  7. Bougeard G, Sesboue R, Baert-Desurmont S, et al. Molecular basis of the Li-Fraumeni syndrome: an update from the French LFS families. J Med Genet. 2008; 45(8):535-538. 
  8. Brooks GA, Stopfer JE, Erlichman J, et al. Childhood cancer in families with and without BRCA1 or BRCA2 mutations ascertained at a high-risk breast cancer clinic. Cancer Biol Ther. 2006; 5(9):1098-1102.
  9. Chompret A, Brugieres L, Ronsin M, et al. P53 germline mutations in childhood cancers and cancer risk for carrier individuals. Br J Cancer. 2000; 82(12):1932-1937.
  10. Comeaux EQ, Mullighan CG. TP53 Mutations in hypodiploid acute lymphoblastic leukemia. Cold Spring Harb Perspect Med. 2017; 7(3).
  11. Custodio G, Parise GA, Kiesel Filho N, et al. Impact of neonatal screening and surveillance for the TP53 R337H mutation on early detection of childhood adrenocortical tumors. J Clin Oncol. 2013; 31(20):2619-2626.
  12. Dite GS, Jenkins MA, Southey MC, et al. Familial risks, early-onset breast cancer, and BRCA1 and BRCA2 germline mutations. J Natl Cancer Inst. 2003; 95(6):448-457.
  13. Dohner H, Stilgenbauer S, Benner A, et al. Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med. 2000; 343(26):1910-1916.
  14. Eeles RA. Germline mutations in the TP53 gene. Cancer Surv. 1995; 25:101-124.
  15. Evans DG, Wu CL, Birch JM. BRCA2: a cause of Li-Fraumeni-like syndrome. J Med Genet. 2008; 45(1):62-63.
  16. Gonzalez D, Martinez P, Wade R, et al. Mutational status of the TP53 gene as a predictor of response and survival in patients with chronic lymphocytic leukemia: results from the LRF CLL4 trial. J Clin Oncol. 2011; 29(16):2223-2229.
  17. Gonzalez KD, Buzin CH, Noltner KA, et al. High frequency of de novo mutations in Li-Fraumeni syndrome. J Med Genet. 2009; 46(10):689-693.
  18. Gonzalez KD, Noltner KA, Buzin CH, et al. Beyond Li Fraumeni Syndrome: clinical characteristics of families with p53 germline mutations. J Clin Oncol. 2009; 27(8):1250-1256.
  19. Hallek M, Fischer K, Fingerle-Rowson G, et al. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet. 2010; 376(9747):1164-1174.
  20. Hisada M, Garber JE, Fung CY, et al. Multiple primary cancers in families with Li-Fraumeni syndrome. J Natl Cancer Inst. 1998; 90(8):606-611.
  21. Hof J, Krentz S, van Schewick C, et al. Mutations and deletions of the TP53 gene predict nonresponse to treatment and poor outcome in first relapse of childhood acute lymphoblastic leukemia. J Clin Oncol. 2011; 29(23):3185-3193.
  22. Holmfeldt L, Wei L, Diaz-Flores E, et al. The genomic landscape of hypodiploid acute lymphoblastic leukemia. Nat Genet. 2013; 45(3):242-252.
  23. 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. 2003; 72(4):975-983.
  24. Kast K, Rhiem K, Wappenschmidt B, et al.; German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC). Prevalence of BRCA1/2 germline mutations in 21 401 families with breast and ovarian cancer. J Med Genet. 2016; 53(7):465-471.
  25. Li FP, Fraumeni JF Jr, Mulvihill JJ, et al. A cancer family syndrome in twenty-four kindreds. Cancer Res. 1988; 48(18):5358-5362.
  26. Lin PH, Kuo WH, Huang AC, et al. Multiple gene sequencing for risk assessment in patients with early-onset or familial breast cancer. Oncotarget. 2016; 7(7):8310-8320.
  27. Masciari S, Van den Abbeele AD, Diller LR, et al. F18-fluorodeoxyglucose-positron emission tomography/computed tomography screening in Li-Fraumeni syndrome. JAMA. 2008; 299(11):1315-1319.
  28. Mouchawar J, Korch C, Byers T, et al. Population-based estimate of the contribution of TP53 mutations to subgroups of early-onset breast cancer: Australian Breast Cancer Family Study. Cancer Res. 2010; 70(12):4795-4800.
  29. Prochazkova K, Foretova L, Sedlacek Z. A rare tumor and an ethical dilemma in a family with a germline TP53 mutation. Cancer Genet Cytogenet. 2008; 180(1):65-69.
  30. 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. 2013; 17(1):31-47.
  31. Stengel A, Schnittger S, Weissmann S, et al. TP53 mutations occur in 15.7% of ALL and are associated with MYC-rearrangement, low hypodiploidy, and a poor prognosis. Blood. 2014; 124(2):251-258.
  32. Stilgenbauer S, Schnaiter A, Paschka P, et al. Gene mutations and treatment outcome in chronic lymphocytic leukemia: results from the CLL8 trial. Blood. 2014; 123(21):3247-3254.
  33. Tinat J, Bougeard G, Baert-Desurmont S, et al. 2009 version of the Chompret criteria for Li Fraumeni syndrome. J Clin Oncol. 2009; 27(26):e108-109.
  34. 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. 2011; 12(6):559-567.
  35. Zenz T, Eichhorst B, Busch R, et al. TP53 mutation and survival in chronic lymphocytic leukemia. J Clin Oncol. 2010; 28(29):4473-4479.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. American Board of Genetic Counselors. Practice-Based Competencies for Genetic Counselors. Available at: http://gceducation.org/Documents/ACGC%20Core%20Competencies%20Brochure_15_Web.pdf. Accessed on October 9, 2018.
  2. American College of Obstetricians and Gynecologists (ACOG). Hereditary cancer syndromes and risk assessment. Committee Opinion No. 634. Obstet Gynecol 2015; 125:1538-1543. Reaffirmed 2017.
  3. Eichhorst B, Robak T, Montserrat E, et al. Chronic lymphocytic leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2015; 26 Suppl 5:v78-84.
  4. Hallek M, Cheson BD, Catovsky D, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood. 2008; 111(12):5446-556.
  5. Hampel H, Bennett RL, Buchanan A, et al; Guideline Development Group, American College of Medical Genetics and Genomics Professional Practice and Guidelines Committee and National Society of Genetic Counselors Practice Guidelines Committee. A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. Genet Med. 2015; 17(1):70-87. Available at: https://www.acmg.net/docs/ACMG_Practice_Guideline_Referral_Indications_for_cancer_predisposition.pdf. Accessed on October 10, 2018.
  6. Lancaster JM, Powell CB, Chen LM, Richardson DL; SGO Clinical Practice Committee. Society of Gynecologic Oncology statement on risk assessment for inherited gynecologic cancer women with germline mutations in the cancer susceptibility genes, BRCA1 or BRCA2, associated with hereditary predispositions. Gynecol Oncol. 2015; 136(1):3-7.
  7. National Library of Medicine (NLM). Genetics Home Reference: Li-Fraumeni syndrome. Reviewed January, 2007. Available at: http://ghr.nlm.nih.gov/condition/li-fraumeni-syndrome. Accessed on October 9, 2018.
  8. National Society of Genetic Counselors' Definition Task Force, Resta R, Biesecker BB, et al. A new definition of Genetic Counseling: National Society of Genetic Counselors' Task Force report. J Genet Couns. 2006; 5(2):77-83.
  9. NCCN Clinical Practice Guidelines in Oncology™. © 2018 National Comprehensive Cancer Network, Inc. For additional information visit the NCCN website: http://www.nccn.org.index.asp. Accessed on October 8, 2018:
    • Acute Lymphoblastic Leukemia. V1.2018. Revised March 12, 2018.
    • Acute Myeloid Leukemia.V2.2018. Revised August 1, 2018.
    • Breast Cancer Risk Reduction. V2.2018. Revised April 23, 2018.  
    • Chronic Lymphocytic Leukemia/ Small Lymphocytic Lymphoma. V2.2019. Revised October 5, 2018.
    • Genetic/Familial High-Risk Assessment: Breast and Ovarian. V2.2019. Revised July 30, 2018.
    • Myelodysplastic Syndromes. V1.2019. Revised July 16, 2018.
  10. SEER Cancer Statistics Factsheets: Chronic Lymphocytic Leukemia. National Cancer Institute. Bethesda, MD. Available at: http://seer.cancer.gov/statfacts/html/clyl.html. Accessed on October 9, 2018.
Websites for Additional Information
  1. American Cancer Society. What is chronic lymphocytic leukemia? Last revised: May 10, 2018. Available at: http://www.cancer.org/cancer/leukemia-chroniclymphocyticcll/detailedguide/leukemia-chronic-lymphocytic-what-is-cll. Accessed on October 10, 2018. 
  2. National Cancer Institute. Chronic Lymphocytic Leukemia Treatment. Updated May 18, 2018. Available at: https://www.cancer.gov/types/leukemia/patient/cll-treatment-pdq. Accessed on October 9, 2018.
Index

Li-Fraumeni
Low-hypodiploid Acute Lymphocytic (Lymphoblastic) Leukemia
TP53 (tp53)

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

Document History

Status

Date

Action

Reviewed

11/08/2018

Medical Policy & Technology Assessment Committee (MPTAC) review.

Reviewed

10/31/2018

Hematology/Oncology Subcommittee review. Updated Description, Rationale and References sections.

Revised

01/25/2018

MPTAC review.

Revised

01/17/2018

Hematology/Oncology Subcommittee review. Revised medically necessary statement to include subtitles Germline testing for cancer susceptibility and Somatic tumor testing. Revised medically necessary statement for germline testing to include the diagnosis of rhabdomyoscarcoma of embryonal anaplastic subtype; and to remove step requirement (negative BRCA test) and lower the cutoff age to 30 from 35 for early onset breast cancer. Removed genetic counseling requirement for somatic tumor testing. The document header wording updated from “Current Effective Date” to “Publish Date.” Updated Rationale and References sections.

Revised

05/04/2017

MPTAC review.

Revised

05/03/2017

Hematology/Oncology Subcommittee review. Revised medically necessary section of the Position Statement to include criteria for genetic counseling and criteria for individuals diagnosed with hypodiploid acute lymphocytic leukemia. Updated Background/Overview, References, Index and History sections.

Revised

11/03/2016

MPTAC review.

Revised

11/02/2016

Hematology/Oncology Subcommittee review. Title changed to Genetic Testing for TP53 Mutations. Addition of a new position statement which indicates genetic testing and associated genetic counseling is considered medically necessary for individuals diagnosed with chronic lymphocytic leukemia to identify those who would benefit from treatment with chemotherapy. Updated formatting in the “Position Statement” section. Updated Review date, Rationale, References and History sections.

Revised

11/05/2015

MPTAC review.

Revised

11/04/2015

Hematology/Oncology Subcommittee review. In the Position Statement section, changed “e.g.” to “for example”. Updated Review date, Rationale, References and History sections. Updated Coding section with 01/01/2016 CPT descriptor changes for 81445, 81455; removed ICD-9 codes.

Reviewed

11/13/2014

MPTAC review.

Reviewed

11/12/2014

Hematology/Oncology Subcommittee review. Updated Review date, Rationale, References and History section. Updated Coding section with 01/01/2015 CPT changes.

New

02/13/2014

MPTAC review. Initial document development.