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MP 2.04.93 Genetic Cancer Susceptibility Panels Using Next Generation Sequencing

Medical Policy    
Section
Medicine 
Subsection Last Review Status/Date
Reviewed with literature search/5:2014
Issue
5:2014
Original Policy Date
June:2013
Return to Medical Policy Index

Disclaimer

Our medical policies are designed for informational purposes only and are not an authorization, or an explanation of benefits, or a contract.  Receipt of benefits is subject to satisfaction of all terms and conditions of the coverage.  Medical technology is constantly changing, and we reserve the right to review and update our policies periodically. 


Description

 

Numerous genetic mutations are associated with certain types of hereditary cancer. Genetic testing using next generation sequencing technology allows for the analysis of multiple genes at one time (panel testing), and these panels are commercially available. The utility of these genetic panels will be reviewed, in comparison with testing for individual mutations.

Background
Genetic testing for cancer susceptibility may be approached by a focused method that involves testing for well-characterized mutations based on a clinical suspicion of which gene(s) may be the cause of the familial cancer. Panel testing involves testing for multiple mutations in multiple genes at one time.

Several companies, including Ambry Genetics and GeneDx, offer genetic testing panels that use next generation sequencing methods for hereditary cancers. Next generation sequencing refers to 1 of several methods that use massively parallel platforms to allow the sequencing of large stretches of DNA. Panel testing is potentially associated with greater efficiencies in the evaluation of genetic diseases; however, it may provide information on genetic mutations that are of unclear clinical significance or which would not lead to changes in patient management. Currently available panels do not include all genes associated with hereditary cancer syndromes. In addition, these panels do not test for variants (ie, single nucleotide polymorphisms [SNPs]), which may be associated with a low, but increased cancer risk.

Next Generation Sequencing Cancer Panels
A list of the genes that are included in these panels is given in Tables 1 and 2, followed by a brief description of each gene.

Table 1

Gene Tested

BRCAplus

GYNplus

BreastNext

OvaNext

ColoNext

PaneNext

PGLNext

RenalNext

CancerNext

BRCA1

X

X

X

X

 

X

 

 

X

BRCA2

X

X

X

X

 

X

 

 

X

ATM

 

 

X

X

 

X

 

 

X

BARD1

 

 

X

X

 

 

 

 

X

BRIP1

 

 

X

X

 

 

 

 

X

MRE11A

 

 

X

X

 

 

 

 

X

NBN

 

 

X

X

 

 

 

 

X

RAD50

 

 

X

X

 

 

 

 

X

RAD51C

 

 

X

X

 

 

 

 

X

PALB2

 

 

X

X

 

X

 

 

X

STK11

X

 

X

X

X

X

 

 

X

CHEK2

 

 

X

X

X

 

 

 

X

PTEN

X

X

X

X

X

 

 

X

X

TP53

X

X

X

X

X

X

 

X

X

CDH1

X

 

X

X

X

 

 

 

X

MUTYH

 

 

 

X

X

X

 

 

X

MLH1

 

X

 

X

X

X

 

X

X

MSH1

 

X

 

X

X

X

 

X

X

MSH6

 

X

 

X

X

X

 

X

X

EPCAM

 

X

 

X

X

X

 

X

X

PMS2

 

X

 

X

X

X

 

X

X

APC

 

 

 

 

X

X

 

 

X

BMPR1A

 

 

 

 

 

X

 

 

X

SMAD4

 

 

 

 

 

X

 

 

X

NF1

 

 

 

X

X

 

X

 

X

RAD51D

 

 

X

X

 

 

 

 

X

CDK4

 

 

 

 

 

 

 

 

X

CDKN2A

 

 

 

 

 

X

 

 

X

RET

 

 

 

 

 

 

X

 

 

SDHA

 

 

 

 

 

 

X

X

 

SDHAF2

 

 

 

 

 

 

X

 

 

SDHB

 

 

 

 

 

 

X

X

 

SDHC

 

 

 

 

 

 

X

X

 

SDHD

 

 

 

 

 

 

X

X

 

TMEM127

 

 

 

 

 

 

X

 

 

VHL

 

 

 

 

 

 

X

X

 

FH

 

 

 

 

 

 

 

X

 

FLCN

 

 

 

 

 

 

 

X

 

MET

 

 

 

 

 

 

 

X

 

MITF

 

 

 

 

 

 

 

X

 

TSC1

 

 

 

 

 

 

 

X

 

TSC2

 

 

 

 

 

 

 

X

 

GeneDx offers a number of comprehensive cancer panels that use next generation sequencing, summarized in Table 2.

Table 2. GeneDx Hereditary Cancer Panel Tests

 

Gene Tested

Breast/Ovarian Cancer Panel

Breast Cancer High-Risk Panel

Endometrial Cancer Panel

Lynch/Colorectal Cancer High-Risk Panel

Colorectal Cancer Panel

Pancreatic Cancer Panel

Comprehensive Cancer Panel

BRCA1

X

X

X

 

 

X

X

BRCA2

X

X

X

 

 

X

X

ATM

X

 

 

 

X

X

X

BARD1

X

 

 

 

 

 

X

BRIP1

X

 

 

 

 

 

X

MRE11A

 

 

 

 

 

 

 

NBN

X

 

 

 

 

 

 

RAD50

 

 

 

 

 

 

 

RAD51C

X

 

 

 

 

 

X

PALB2

X

 

X

 

 

X

X

STK11

X

X

 

 

X

 

X

CHEK2

X

 

X

 

X

 

X

PTEN

X

X

X

 

X

 

X

TP53

X

X

X

 

X

X

X

CDH1

X

X

 

 

X

 

X

MUTYH

 

 

X

X

X

 

X

MLH1

X

 

X

X

X

X

X

MSH2

X

 

X

X

X

X

X

MSH6

X

 

X

X

X

X

X

EPCAM

X

 

X

X

X

X

X

PMS2

X

 

X

X

X

X

X

APC

 

 

 

X

X

X

 

BMPR1A

 

 

 

 

X

 

 

SMAD4

 

 

 

 

X

 

 

RAD51D

X

 

 

 

 

 

X

CDK4

 

 

 

 

 

X

X

CDKN2A

 

 

 

 

 

X

X

VHL

 

 

 

 

 

X

X

XRCC2

X

 

 

 

X

X

X

FANCC

 

 

 

 

 

 

X

AXIN2

 

 

 

 

X

 

X

Mayo Clinic also offers a hereditary colon cancer multigene panel analysis, which includes the genes in the Ambry Genetics ColoNext, with the addition of 2 other low-risk genes (MLH3 and AXIN2). The University of Washington offers the BROCA Cancer Risk Panel, which is a next generation sequencing panel that includes the following mutations: AKT1, APC, ATM, ATR, BAP1, BARD1, BMPR1A, BRCA1, BRCA2, BRIP1, CDH1, CDK4, CDKN2A, CHEK1, CHEK2, CTNNA1, FAM175A, GALNT12, GEN1, GREM1, HOXB13, MEN1, MLH1, MRE11A, MSH2 (+EPCAM), MSH6, MUTYH, NBN, PALB2, PIK3CA, PPM1D, PMS2, POLD1, POLE, PRSS1, PTEN, RAD50, RAD51, RAD51C, RAD51D, RET, SDHB, SDHC, SDHD, SMAD4, STK11, TP53, TP53BP1, VHL, and XRCC2.(1) The University of Washington also offers the ColoSeq™ gene panel, which includes 19 genes associated with Lynch syndrome (LS, hereditary nonpolyposis colorectal cancer, HNPCC), familial adenomatous polyposis (FAP), MUTYH-
associated polyposis, (hereditary diffuse gastric cancer (HDGC), Cowden syndrome, Li-Fraumeni syndrome, Peutz-Jeghers syndrome, Muir-Torre syndrome, Turcot syndrome, and juvenile polyposis syndrome (JPS): AKT1, APC, BMPR1A, CDH1, EPCAM, GALNT12, GREM1, MLH1, MSH2, MSH6, MUTYH, PIK3CA, PMS2, POLE, POLD1, PTEN, SMAD4, STK11, and TP53.(2)

Myriad Genetics is developing a comprehensive 25-gene cancer panel that will be commercially available around July 2014.

Genes Included in Next Generation Sequencing Panels

The following is a summary of the function and disease association of major genes included in the next generation sequencing panels. This is not meant to be a comprehensive list of all genes included in all panels.

BRCA1 and BRCA2 germline mutations are associated with hereditary breast and ovarian cancer syndrome, which is associated most strongly with increased susceptibility to breast cancer at an early age, bilateral breast cancer, male breast cancer, ovarian cancer, cancer of the fallopian tube, and primary peritoneal cancer. BRCA1 and BCRA2 mutations are also associated with increased risk of other cancers, including prostate cancer, pancreatic cancer, gastrointestinal cancers, melanoma, and laryngeal cancer.

APC germline mutations are associated with FAP and attenuated FAP. FAP is an autosomal dominant colon cancer predisposition syndrome characterized by hundreds to thousands of colorectal adenomatous polyps, and accounts for about 1% of all colorectal cancers.

ATM is associated with the autosomal recessive condition ataxia-telangiectasia. This condition is characterized by progressive cerebellar ataxia with onset between the ages of 1 and 4 years, telangiectasias of the conjunctivae, oculomotor apraxia, immune defects, and cancer predisposition, particularly leukemia and lymphoma.

BARD1, BRIP1, MRE11A, NBN, RAD50, and RAD51C are genes in the Fanconi anemia-BRCA pathway. Mutations in these genes are estimated to confer up to a 4-fold increase in the risk for breast cancer.

BMPR1A and SMAD4 are genes mutated in juvenile polyposis syndrome (JPS) and account for 45% to 60% of cases of JPS. JPS is an autosomal dominant disorder that predisposes to the development of polyps in the gastrointestinal tract. Malignant transformation can occur, and the risk of gastrointestinal cancer has been estimated from 9% to 50%.

CHEK2 gene mutations confer an increased risk of developing several different types of cancer, including breast, prostate, colon, thyroid and kidney. CHEK2 regulates the function of BRCA1 protein in DNA repair and has been associated with familial breast cancers.

CDH1 germline mutations have been associated with lobular breast cancer in women and with hereditary diffuse gastric cancer. The estimated cumulative risk of gastric cancer for CDH1 mutation carriers by age 80 years is 67% for men and 83% for women. CDH1 mutations are associated with a lifetime risk of 39% to 52% of lobular breast cancer.

EPCAM, MLH1, MSH2, MSH6 and PMS2 are mismatch repair genes associated with LS (HNPCC). LS is estimated to cause 2% to 5% of all colon cancers. LS is associated with a significantly increased risk of several types of cancer—colon cancer (60% to 80% lifetime risk),  uterine/endometrial cancer (20% to 60% lifetime risk), gastric cancer (11% to 19% lifetime risk) and ovarian cancer (4%-13% lifetime risk).
The risk of other types of cancer, including small intestine, hepatobiliary tract, upper urinary tract and brain, are also elevated.

MUTYH germline mutations are associated with an autosomal recessive form of hereditary polyposis. It has been reported that 33% and 57% of patients with clinical FAP and attenuated FAP, respectively, who are negative for mutations in the APC gene, have MUTYH mutations.

PALB2 germline mutations have been associated with an increased risk of pancreatic and breast cancer. Familial pancreatic and/or breast cancer due to PALB2 mutations is inherited in an autosomal dominant pattern.

PTEN mutations have been associated with PTEN hamartoma tumor syndrome, which includes Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome and Proteus syndrome. CS is characterized by a high risk of developing tumors of the thyroid, breast and endometrium. Affected persons have a lifetime risk of up to 50% for breast cancer, 10% for thyroid cancer, and 5% to 10% for endometrial cancer.

STK11 germline mutations have been associated with Peutz-Jegher syndrome (PJS), an autosomal dominant disorder, with a 57% to 81% risk of developing cancer by age 70, of which gastrointestinal and breast are the most common.

TP53 has been associated with Li-Fraumeni syndrome. People with TP53 mutations have a 50% risk of developing any of the associated cancers by age 30 and a lifetime risk up to 90%, including sarcomas, breast cancer, brain tumors, and adrenal gland cancer.

NF1 (neurofibromin 1) encodes a negative regulator in the ras signal transduction pathway. Mutations in the NF1 gene have been associated with neurofibromatosis type 1, juvenile myelomonocytic leumkemia, and Watson syndrome.

RAD51D germline mutations have been associated with familial breast and ovarian cancer.

CDK4 (cyclin-dependent kinase-4) is a protein-serine kinase involved in cell cycle regulation. Mutations in this gene have been associated with a variety of cancers, particularly cutaneous melanoma.

CDKN2A (cyclin-dependent kinase inhibitor 2A) encodes proteins that act as multiple tumor suppressors through their involvement in 2 cell cycle regulatory pathways: the p53 pathway and the RB1 pathway. Mutations or deletions in CDKN2A are frequently found in multiple types of tumor cells. Germline mutations in CDKN2A have been associated with risk of melanoma, along with pancreatic and central nervous system cancers.

RET encodes a receptor tyrosine kinase; mutations in this gene have been associated with multiple endocrine neoplasia syndromes (types IIA and IIB) and medullary thyroid carcinoma.

SDHA, SDHB, SDHC, SDHD, and SDHAF2 gene products are involved in the assembly and function of one component of the mitochondrial respiratory chain. Germline mutations in these genes have been associated with the development of paragangliomas, pheochromocytomas, gastrointestinal stromal tumors, and a PTEN-negative Cowden syndrome (Cowden-like syndrome).

TMEM127 (transmembrane protein 127) germline mutations have associated with risk of pheochromocytomas.

VHL germline mutations are associated with the autosomal dominant familial cancer syndrome Von Hippel-Lindau syndrome, which is associated with a variety of malignant and benign tumors, including central nervous system tumors, renal cancers, pheochromocytomas, and pancreatic neuroendocrine tumors.

FH (fumarate hydratase) mutations have been associated with renal cell and uterine cancers.

FLCN (folliculin) acts as a tumor suppressor gene; mutations in this gene are associated with the autosomal dominant syndrome Birt-Hogg-Dube syndrome, which is characterized by hair follicle hamartomas, kidney tumors, and colorectal cancer.

MET is a proto-oncogene that acts as the hepatocyte growth factor receptor. MET mutations are associated with hepatocellular carcinoma and papillary renal cell carcinoma.

MITF (microphthalmia-associated transcription factor) is a transcription factor involved in melanocyte differentiation. MITF mutations lead to several auditory-pigmentary syndromes, including Waardenburg syndrome type 2 and Tietz syndrome. MITF variants are also associated with melanoma and renal cell carcinoma.

TSC1 (tuberous sclerosis 1) and TSC2 (tuberous sclerosis 2) encode the proteins hamartin and tuberin, which are involved in cell growth, differentiation, and proliferation. Mutations in these genes are associated with the development of tuberous sclerosis complex, an autosomal dominant syndrome characterized by skin abnormalities, developmental delay, seizures, and multiple types of cancers, including central nervous system tumors, renal tumors (including angiomyolipomas, renal cell carcinomas), and cardiac rhabdomyomas.

XRCC2 encodes proteins thought to be related to the RAD51 protein product that is involved in DNA double-stranded breaks. Variants may be associated with Fanconi anemia and breast cancer.

FANCC (Fanconi-anemia complementation group C) is one of several DNA repair genes that are mutated in Fanconi anemia, which is characterized by bone marrow failure and a high predisposition to multiple types of cancer AXIN2 mutations have been associated with familial adenomatous polyposis syndrome, although the phenotypes associated with AXIN2 mutations do not appear to be well characterized.

Hereditary Cancer and Cancer Syndromes

Hereditary breast cancer. Breast cancer can be classified as sporadic, familial, or hereditary. Sporadic breast cancer accounts for 70% to 75% of cases and is thought to be due to nonhereditary causes. Familial breast cancer, in which there are more cases within a family than statistically expected, but with no specific pattern of inheritance, accounts for 15% to 25% of cases. Hereditary breast accounts for 5% to 10% of cases and is characterized by well-known susceptibility genes with apparently autosomal dominant transmission.

The “classic” inherited breast cancer syndrome is the hereditary breast and ovarian cancer [HBOC] syndrome, most of which are due to mutations in the BRCA1 and BRCA2 genes. Other hereditary cancer syndromes such as Li-Fraumeni syndrome (LFS, associated with TP53 mutations), CS (associated with PTEN mutations), PJS (associated with STK11 mutations), hereditary diffuse gastric cancer, and, possibly, LS also predispose patients, to varying degrees of risk for breast cancer. Other mutations and SNPs have also been associated with increased risk of breast cancer.

Mutations associated with breast cancer vary in their penetrance. Highly penetrant mutations in the BRCA1, BRCA2, TP53, and PTEN genes may be associated with a lifetime breast cancer risk ranging from 40% to 85%. Only about 5% to 10% of all cases of breast cancer are attributable to a highly penetrant cancer predisposition gene. In addition to breast cancer, mutations in these genes may also confer a higher risk for other cancers.(3)

Other mutations may be associated with intermediate penetrance and a lifetime breast cancer risk of 20% to 40% (eg, CHEK2, APC, CDH-1). Low-penetrance mutations discovered in genome-wide association studies (eg, SNPs), are generally common and confer a modest increase in risk, although penetrance can vary based on environmental and lifestyle factors.

An accurate and comprehensive family history of cancer is essential for identifying people who may be at risk for inherited breast cancer and should include a 3-generation family history with information on both maternal and paternal lineages. Focus should be on both the people with malignancies and also family members without a personal history of cancer. It is also important to document the presence of nonmalignant findings in the proband and the family, as some inherited cancer syndromes are also associated with other nonmalignant physical characteristics (eg, benign skin tumors in CS).

Further discussion on the diagnostic criteria of HBOC will not be addressed in this policy. Criteria for a presumptive clinical diagnosis of LFS and CS have been established.

LFS. LFS has been estimated to be involved in approximately 1% of hereditary breast cancer cases. LFS is a highly penetrant cancer syndrome associated with a high lifetime risk of cancer. People with LFS often present with certain cancers (soft tissue sarcomas, brain tumors, adrenocortical carcinomas) in early childhood and have an increased risk of developing multiple primary cancers during their lifetime.

Classic LFS is defined by the following criteria:

  • A proband with a sarcoma diagnosed before age 45 years and
  • A first-degree relative with any cancer before age 45 years and
  • A first- or second-degree relative with any cancer before age 45 years or a sarcoma at any age

The 2009 Chompret criteria for LFS / TP53 testing are as follows:

  • A proband who has:
    • A tumor belonging to the LFS tumor spectrum (soft tissue sarcoma, osteosarcoma, premenopausal breast cancer, brain tumor, adrenocortical carcinoma, leukemia, or lung bronchoalveolar cancer) before age 46 years and
    • At least one first- or second-degree relative with an LFS tumor (except breast cancer if the proband has breast cancer) before age 56 years or with multiple tumors; or
  • A 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
  • A proband who is diagnosed with adrenocortical carcinoma or choroid plexus tumor, irrespective of family history

Classic criteria for LFS have been estimated to have a positive predictive value of 56%, and a high specificity, although the sensitivity is low at approximately 40%.(4) The Chompret criteria have an estimated positive predictive value of 20% to 35%, and when incorporated as part of TP53 testing criteria in conjunction with classic LFS criteria, substantially improve the sensitivity of detecting LFS. When the Chompret criteria are added to the classic LFS criteria, the sensitivity for detected patients with TP53 mutations is approximately 95%.

The National Comprehensive Cancer Network (NCCN) also considers women with early onset breast cancer (age of diagnosis younger than 30 years), with or without a family history of the core tumor types found in LFS, as another group in whom TP53 gene mutation testing may be considered. If the LFS testing criteria are met, NCCN guidelines recommend testing for the familial TP53 mutation if it is known to be present in the family. If it is not known to be present, comprehensive TP53 testing is recommended, ie, full sequencing of TP53 and deletion/duplication analysis, of a patient with breast cancer. If the patient is unaffected, testing the family member with the highest likelihood of a TP53 mutation is recommended. If a mutation is found, recommendations for management of LFS, include increased cancer surveillance and, at an earlier age, possible prophylactic surgical management, discussion of risk of relatives, and consideration of reproductive options. NCCN guidelines also state that in the situation where a person from a family with no known familial TP53 mutation undergoes testing and no mutation is found, testing for other hereditary breast syndromes should be considered if testing criteria are met.

CS. CS is a part of the PTEN hamartoma tumor syndrome (PHTS) and is the only PHTS disorder associated with a documented predisposition to malignancies. Women with CS have a high risk of benign fibrocystic disease and a lifetime risk of breast cancer estimated at 25% to 50%, with an average age of between 38 and 46 years at diagnosis. The PTEN mutation frequency in people meeting International Cowden Consortium criteria(5) for CS has been estimated to be approximately 80%. A presumptive diagnosis of PHTS is based on clinical findings; however, because of the phenotypic heterogeneity associated with the hamartoma syndromes, the diagnosis of PHTS is made only when a PTEN mutation is identified. Clinical management of breast cancer risk in patients with CS includes screening at an earlier age and possible risk-reducing surgery.

Hereditary ovarian cancer. The single greatest risk factor for ovarian cancer is a family history of disease. Breast and ovarian cancer are components of several autosomal dominant cancer syndromes. The syndromes most strongly associated with both cancers are the BRCA1 or BRCA2 mutation syndromes. Ovarian cancer has been associated with LS, basal cell nevus (Gorlin) syndrome, and multiple endocrine
neoplasia.

Hereditary colon cancer. Hereditary colon cancer syndromes are thought to account for approximately 10% of all colorectal cancers. Another 20% have a familial predilection for colorectal cancer without a clear hereditary syndrome identified.(6) The hereditary colorectal cancer syndromes can be divided into the polyposis and nonpolyposis syndromes. Although there may be polyps in the nonpolyposis syndromes, they are usually less numerous; the presence of 10 colonic polyps is used as a rough threshold when considering genetic testing for a polyposis syndrome.(7) The polyposis syndromes can be further subdivided by polyp histology, which includes the adenomatous (FAP, aFAP and MUTYH-associated) and hamartomatous (JPS, PJS, PTEN hamaratoma tumor syndrome) polyposis syndromes. The nonpolyposis syndromes include LS.

Identifying which patients should undergo genetic testing for an inherited colon cancer syndrome depends on family history and clinical manifestations. Clinical criteria are used to focus testing according to polyposis or nonpolyposis syndromes, and for adenomatous or hamartomatous type within the polyposis syndromes. If a patient presents with multiple adenomatous polyps, testing in most circumstances focuses on APC and MUTYH testing. Hamartomatous polyps could focus testing for mutations in the genes STK11/LKB1, SMAD4, BMPR1A, and/or PTEN.

Genetic testing to confirm the diagnosis of LS is usually performed on the basis of family history in those families meeting the Amsterdam criteria(8) who have tumor microsatellite instability (MSI) by immunohistochemistry on tumor tissue. Immunohistochemical testing helps identify which of the 4 MMR genes (MLH1, MSH2, MSH6, PMS2) most likely harbors a mutation. The presence of MSI in the tumor alone is not sufficient to diagnose LS because 10% to 15% of sporadic colorectal cancers exhibit MSI.

MLH1 and MSH2 germline mutations account for approximately 90% of mutations in families with LS; MSH6 mutations in about 7% to 10%; and PMS2 mutations in fewer than 5%. Genetic testing for LS is ideally performed in a stepwise manner: testing for MMR gene mutations is often limited to MLH1 and MSH2 and, if negative, then MSH6 and PMS2 testing.

Management of Polyposis Syndromes

FAP has a 100% penetrance, with polyps developing on average around the time of puberty, and the average colorectal cancer diagnosis before age 40. Endoscopic screening should begin around age 10 to 12 years, and operative intervention (colectomy) remains the definitive treatment. For attenuated FAP, colonoscopic surveillance is recommended to begin at age 20 to 30 years, or 10 years sooner than the first polyp diagnosis in the family.(9) For MUTYH-associated polyposis, colonoscopic surveillance is recommended to start at age 20 to 30 years.
Colonic surveillance in the hamartomatous polyposis syndromes includes a colonoscopy every 2 to 3 years, starting in the teens.

Management of Nonpolyposis Syndromes

People with LS have lifetime risks for cancer as follows: 52% to 82% for colorectal cancer (mean age at diagnosis, 44-61 years); 25% to 60% for endometrial cancer in women (mean age at diagnosis, 48-62 years); 6% to 13% for gastric cancer (mean age at diagnosis, 56 years); and 4% to 12% for ovarian cancer (mean age at diagnosis, 42.5 years; approximately one third are diagnosed before age 40 years). The risk for other LS-related cancers is lower, although substantially increased over that of the general population. For HNPCC or LS, colonoscopic screening should start at age 20 to 25 years. Prophylactic colectomy is based on aggressive colorectal cancer penetrance in the family. Screening and treatment for the extracolonic malignancies in HNPCC also are established.(10)

Regulatory Status

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. Ambry Genetics is CLIA licensed.


Policy

Genetic cancer susceptibility panels using next generation sequencing are considered investigational.

 


Policy Guidelines

Although genetic cancer susceptibility panels using next generation sequencing are considered investigational, ther may be individual components of the panel that are medically necessary.

There are no specific codes for molecular pathology testing by panels. If the specific analyte is listed in CPT codes 81200-81355 or 81400-81408, the specific CPT code would be reported. If the specific analyte is not listed in the more specific CPT codes, unlisted code 81479 would be reported. The unlisted code would be reported once to represent all of the unlisted analytes in the panel.

Benefit Application

BlueCard/National Account Issues

No applicable information.


Rationale 

Literature Review

This policy was created in April 2013, with a review of the literature, and has been updated periodically with literaure reviews, most recently through April 7, 2014.

Analytic Validity (technical accuracy of the test in detecting a mutation that is present or in excluding a mutation that is absent). According to Ambry Genetics, the analytical sensitivity for the 22 genes analyzed on their cancer susceptibility panels by next generation sequencing is 96% to 99%. According to the GeneDx website, their comprehensive cancer susceptibility panel has greater than 99% sensitivity in detecting mutations identifiable by sequencing or array comparative genomic hybridization.(11) This analytic sensitivity approaches that of direct sequencing of individual genes.

To determine whether next generation sequencing would enable accurate identification of inherited mutations for breast and ovarian cancer, Walsh et al developed a genomic assay to capture, sequence, and detect all mutations in 21 genes, (which included 19 of the genes on the BreastNext and OvaNext panels).(12) Constitutional genomic DNA from persons with known inherited mutations, was hybridized to custom oligonucleotides and then sequenced. The analysis was carried out blindly as to the mutation in each sample. All single nucleotide substitutions, small insertions and deletions, and large duplications and deletions were detected. There were no false positive results.

Clinical Validity (diagnostic performance of the test—sensitivity, specificity, positive and negative predictive values)

The published literature provides no guidance for the assessment of the clinical validity of panel testing for cancer susceptibility with next generation sequencing, and the usual approach to establishing the clinical validity for genetic testing is difficult to apply to panel testing.

Although it may be possible to evaluate the clinical validity of sequencing of individual genes found on these panels, the clinical validity of next generation sequencing for cancer susceptibility panels, which include mutations associated with an unknown or variable cancer risk, are of uncertain clinical validity.

For genetic susceptibility to cancer, clinical validity can be considered on the following levels:

  1. Does a positive test identify a person as having an increased risk of developing cancer?
  2. If so, how high is the risk of cancer associated with a positive test?

The likelihood that someone with a positive test result will develop cancer is affected not only by the presence of the gene mutation, but also by other modifying factors that can affect the penetrance of the mutation (eg, environmental exposures, personal behaviors) or by the presence or absence of mutations in other genes.

Clinical Utility (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)

Medical Policy Reference Manual Policy No. 2.04.92, General Approach to Evaluating the Utility of Genetic Panels, outlines criteria that can be used to evaluate the clinical utility of cancer panels. The following criteria can be used to evaluate the clinical utility of cancer susceptibility panel testing:

  • Does panel testing offer substantial advantages in efficiency compared with sequential analysis of individual genes?
  • Is decision making based on potential results of panel testing well-defined?
    • Do positive results on panel testing result in changes in cancer susceptibility that are clinically important?
    • Does this change in cancer susceptibility lead to changes in management that result in health outcome benefits for the patient being tested?
  • Is the impact of ancillary information provided by panel testing well-defined?
    • What is the probability that ancillary information leads to further testing or management changes that may have either a positive or a negative impact on the patient being tested?

Identifying a person with a genetic mutation that confers a high risk of developing cancer could lead to changes in clinical management and improved health outcomes. There are well-defined clinical guidelines on the management of patients who are identified as having a high-risk hereditary cancer syndrome. Changes in clinical management could include modifications in cancer surveillance, specific risk-reducing measures (eg, prophylactic surgery), and treatment guidance (eg, avoidance of certain exposures). In addition, other at-risk family members could be identified.

On the other hand, identifying mutations that have intermediate or low penetrance is of limited clinical utility. Clinical management guidelines for patients found to have one of these mutations are not well-defined. In addition, there is a potential for harm, in that the diagnosis of an intermediate- or low-risk mutation may lead to undue psychological stress and unnecessary prophylactic surgical intervention.

A limited body of literature exists on the potential clinical utility of available next generation sequencing cancer panels. In 2014, in an industry-sponsored study, Cragun et al reported the prevalence of clinically significant mutations and variants of uncertain significance among patients who underwent ColoNext panel testing.(13) For the period included in the study (March 2012-March 2013), the ColoNext test included the MLH1, MSH2, MSH6, PMS2, EPCAM, BMPR1, SMAD4, STK11, APC, MUTYH, CHEK2, TP53, PTEN, and CDH1 genes; alterations were classified as follows: (1) pathogenic mutation; (2) variant, likely pathogenic; (3) variant, unknown significance; (4) variant, likely benign; and (5) benign. Data was analyzed for 586 patients whose ColoNext testing results and associated clinical data were maintained in a database by Ambry Genetics. Sixty-one patients (10.4%) had genetic alterations consistent with pathogenic mutations or likely pathogenic variants; after 8 patients with only CHEK2 or one MUTYH mutation were removed, 42 patients (7.2%) were considered to have actionable mutations. One hundred eighteen patients (20.1%) had at least 1 variant of uncertain significance, including 14 patients who had at least 1 variant of uncertain significance in addition to a pathologic mutation. Of the 42 patients with a pathologic mutation, most (30 patients, 71%) clearly met NCCN guidelines for syndrome-based testing, screening, or diagnosis, based on the available clinical and family history. The authors note that, “The reality remains that syndrome based testing would have been sufficient to identify the majority of patients with deleterious mutations. Consequently, the optimal and most cost-effective use of panel-based testing as a first-tier test vs a second tier test (i.e. after syndrome-based testing is negative), remains to be determined.”

Mauer et al reported a single academic center’s genetics program’s experience with next generation sequencing panels for cancer susceptibility.(14) The authors conducted a retrospective review of the outcomes and clinical indications for the ordering of Ambry’s next generation sequencing panels (BreastNext, OvaNext, ColoNext, CancerNext) for patients seen for cancer genetics counseling from April 2012 to January 2013. Of 1521 new patients seen for cancer genetics counseling, 1233 (81.1%) had genetic testing. Sixty of these patients (4.9% of total) had a next generation sequencing panel ordered, 54 of which were ordered as a second-tier test after single-gene testing was performed. Ten tests were cancelled due to out-of-pocket costs or previously identified mutations. Of the 50 tests obtained, 5 were found to have a deleterious result (10%; compared with 131 [10.6%] of the 1233 single-gene tests ordered at the same center during the study time frame). The authors report that of the 50 completed tests, 30 (60%) did not affect management decisions, 15 (30%) introduced uncertainty regarding the patients’ cancer risks, and 5 (10%) directly influenced management decisions.

Genetic cancer susceptibility panels using next generation sequencing for breast cancer, ovarian cancer, colon cancer or multiple cancer types (eg, BreastNext, OvaNext, ColoNext CancerNext, respectively) include mutations associated with varying risk of developing cancer. Therefore, these panels are of limited utility in that they may identify a clinically actionable mutation/syndrome, but could also identify a mutation for which there are no well-established guidelines or actionable level of risk associated with it. In addition, high rates of variants of uncertain significance have been reported with the use of these panels.(15)

Ongoing Clinical Trials
A search of online database ClinicalTrials.gov on May 1, 2014, identified the following ongoing studies using next generation sequencing panels currently enrolling patients: 

  • Ohio Colorectal Cancer Prevention Initiative (OCCPI) (NCT01850654) – This is a nonrandomized study designed to determine the incidence of LS in Ohio and to evaluate outcomes for patients who undergo genetic testing for conditions that increase colorectal cancer risk, including next generation panel testing. Enrollment is planned for 4000 subjects; the planned study completion date is September 2017.

Summary
The use of next generation sequencing has made it possible to simultaneously test for multiple mutations. Commercially available cancer susceptibility mutation panels address multiple specific types of cancer that may have a hereditary component, including breast, ovarian, endometrial, pancreatic, and renal cancers, and paragangliomas. Comprehensive panels are also available that include mutations for a wide variety of cancers. The mutations included in these panels are associated with varying levels of risk of developing cancer, and only some of the mutations are associated with well-defined cancer syndromes which have established clinical management guidelines.

Management guidelines for syndromes with high penetrance in appropriate patient populations have clinical utility in that they inform clinical decision making and result in the prevention of adverse health outcomes. Clinical management recommendations for the inherited conditions associated with low to intermediate penetrance are not standardized, and the clinical utility of genetic testing for these mutations is uncertain and could potentially lead to harm. In addition, high rates of variants of uncertain significance have been reported with the use of these panels.

Therefore, the use of genetic cancer susceptibility panels using next generation sequencing for breast, ovarian, colon and multiple cancer types is considered investigational.

Practice Guidelines and Position Statements
In a 2010 policy statement update on genetic and genomic testing for cancer susceptibility, the American Society of Clinical Oncology (ASCO) stated that testing for high-penetrance mutations in appropriate populations has clinical utility in that they inform clinical decision making and facilitate the prevention or amelioration of adverse health outcomes but that genetic testing for intermediate-penetrance mutations are of uncertain clinical utility because the cancer risk associated with the mutation is generally too small to form an appropriate basis for clinical decision making.(16) ASCO recommends that genetic tests with uncertain clinical utility (low-to-moderate penetrance mutations) be administered in the context of clinical trials.

National Comprehensive Cancer Network (NCCN) guidelines on genetic/familial high-risk assessment for breast and ovarian cancer (v1.2014).(17) state that next generation sequencing gene panels for hereditary breast, ovarian and other cancers have limitations including an unknown percentage of variants of unknown significance, uncertainty of level of risk associated with most of the genes on the panel, and lack clear guidelines on the risk management of carriers of some of the mutations on the
panel. The guidelines also state, “Because of the complexity and limited data regarding their clinical utility, hereditary multigene cancer panels should only be ordered in consultation with a cancer genetics professional.” The most recent NCCN guidelines on genetic/familial high risk assessment for colorectal cancer (v1.2014) does not address next generation sequencing gene panels.(18)

Medicare National Coverage
There is no national coverage determination (NCD). In the absence of an NCD, coverage decisions are left to the discretion of local Medicare carriers.

References:

  1. University of Washington. BROCA -- Cancer Risk Panel. Available online at:
    http://web.labmed.washington.edu/tests/genetics/BROCA#BROCA_Gene_List. Last accessed
    April, 2014.
  2. University of Washington. ColoSeq -- Lynch and Polyposis Syndrome Panel. Available online at: http://tests.labmed.washington.edu/COLOSEQ. Last accessed April, 2014.
  3. Shannon KM, Chittenden A. Genetic testing by cancer site: breast. Cancer J 2012; 18(4):310-9.
  4. 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):1250-6.
  5. Pilarski R, Eng C. Will the real Cowden syndrome please stand up (again)? Expanding mutational and clinical spectra of the PTEN hamartoma tumour syndrome. J Med Genet 2004; 41(5):323-6.
  6. Schrader K, Offit K, Stadler ZK. Genetic testing in gastrointestinal cancers: a case-based approach. Oncology (Williston Park) 2012; 26(5):433-6, 38, 44-6 passim.
  7. Hampel H. Genetic testing for hereditary colorectal cancer. Surg Oncol Clin N Am 2009; 18(4):687-703.
  8. Vasen HF, Watson P, Mecklin JP et al. New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC. Gastroenterology 1999; 116(6):1453-6.
  9. Available online at:
    http://www.fascrs.org/physicians
    . Last accessed May, 2014.
  10. Burke W, Petersen G, Lynch P et al. Recommendations for follow-up care of individuals with an inherited predisposition to cancer. I. Hereditary nonpolyposis colon cancer. Cancer Genetics Studies Consortium. JAMA 1997; 277(11):915-9.
  11. GeneDx. Test Information Sheet -- OncoGene Dx: Comprehensive Cancer Panel. 2014. Available online at: http://www.genedx.com/test-catalog/available-tests/comprehensive-cancer-panel/. Last accessed April,
    2014.
  12. Walsh T, Lee MK, Casadei S et al. Detection of inherited mutations for breast and ovarian cancer using genomic capture and massively parallel sequencing. Proc Natl Acad Sci U S A 2010;107(28):12629-33.
  13. Cragun D, Radford C, Dolinsky JS et al. Panel-based testing for inherited colorectal cancer: a descriptive study of clinical testing performed by a US laboratory. Clin Genet 2014.
  14. Mauer CB, Pirzadeh-Miller SM, Robinson LD et al. The integration of next-generation sequencing panels in the clinical cancer genetics practice: an institutional experience. Genet Med 2013.
  15. Available online at: http://www.ambrygen.com/sites/default/files/pdfs/ACMG%20shared%20slides.pdf. Last accessed May, 2014.
  16. Robson ME, Storm CD, Weitzel J et al. American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility. J Clin Oncol 2010; 28(5):893-901.
  17. National Comprehensive Cancer Network. Genetic/Familial High Risk Assessment: Breast and Ovarian -- Version 1.2014. 2014. Available online at: http://www.nccn.org/professionals/physician_gls/pdf/genetics_screening.pdf. Last accessed April,
    2014.
  18. National Comprehensive Cancer Network. Genetic/Familial High Risk Assessment: Colorectal --Version 1:2014. 2014. Available online at:
    http://www.nccn.org/professionals/physician_gls/pdf/genetics_colon.pdf. Last accessed April,
    2014. 

Codes

Number

Description

CPT    See Policy Guidelines
ICD-9 Diagnosis     Diagnosis coding would depend on the condition for which the testing is being performed, if the test is being performed as screening or carrier testing, and any family history of the condition
ICD-10-CM (effective 10/1/15)   See note on diagnosis coding above.
ICD-10-PCS (effective 10/1/15)    Not applicable. ICD-10-PCS codes are only used for inpatient services. There are no ICD procedure codes for laboratory tests.

 


Index
Genetic Testing, Cancer Susceptibility Panels

Policy History
Date Action Reason
6/13/13 Add to Medicine: Pathology/Laboratory Policy created with literature review through March 30, 2013. Policy statement that cancer susceptibility testing using next generation sequencing panel testing for inherited breast, ovary, colon and various types of cancer is investigational.
5/22/14 Replace policy Policy updated with literature review through April 7, 2014;
references 1, 2, 11, 13-14, and 18 added. Policy statement unchanged.