| Coverage Policy Manual | |
| Policy #: | 2015009 |
| Category: | Laboratory |
| Initiated: | April 2015 |
| Last Review: | January 2024 |
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| Genetic Test: Next-Generation Sequencing for Cancer Susceptibility Panels and the Assessment of Measurable Residual Disease | |
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| Description: |
Cancer Susceptibility Panels
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 (i.e., single nucleotide polymorphisms [SNPs]), which may be associated with a low, but increased cancer risk.
Next Generation Sequencing Cancer Panels
Ambry Genetics offers the following panels:
BRCA Plus (BRCA1, BRCA2, STK11, PTEN, TP53, CDH1)
GYNPlus (BRCA1, BRCA2, PTEN, TP53, MLH1, MSH2, MSH6, EPCAM)
BreastNext (BRCA1, BRCA2, ATM, BARD1, BRIP1, MRE11A, NBN, RAD50, RAD51C, PALB2, STK11, CHEK2, PTEN, TP53, CDH1, MUTYH, NF1, RAD51D)
OvaNext (BRCA1, BRCA2, ATM, BARD1, BRIP1, MRE11A, NBN, RAD50, RAD51C, PALB2, STK11, CHEK2, PTEN, TP53, CDH1, MUTYH, MLH1, MSH2, MSH6, EPCAM, PMS2, NF1, RAD51D)
ColoNext (STK11, CHEK2, PTEN, TP53, CDH1, MUTYH, MLH1, MSH2, MSH6, EPCAM, PMS2, APC, BMPR1A, SMAD4)
PancNext (BRCA1, BRCA2, ATM, PALB2, STK1, TP53, MUTYH, MLH1, MSH2, MSH6, EPCAM, PMS2, APC,CDKN2A)
PGLNext (NF1, RET, SDHA, SDHAF2, SDHB, SDHC, SDHD,TMEM127, VHL)
RenalNext (PTEN, TP53, MLH1, MSH2, MSH6, EPCAM, PMS2, SDHA, SDHB, SDHC, SDHD,VHL, FH, FLCN, MET, MITF, TSC1, TSC2)
Cancer Next (BRCA1, BRCA2, ATM, BARD1, BRIP1, MRE11A, NBN, RAD50, RAD51C, PALB2, STK11, CHEK2, STK11, MUTYH, MLH1, MSH2, MSH6, EPCAM, PMS2, APC, BMPR1A, SMAD4, NF1, RAD51D, CDK4, CDKN2A)
GeneDx offers a number of comprehensive cancer panels that use next generation sequencing. The following is a list of available tests from GeneDx and the genes offered in each panel:
Breast/Ovarian Cancer Panel (BRCA1, BRCA2, ATM, BARD1, BRIP1, NBN, RAD51C, PALB2, STK11, CHEK2, PTEN, TP53, CDH1, MLH1, MSH2, MSH6, EPCAM, PMS2, RAD51D, XRCC2, FANCC, AXIN2)
Breast Cancer High-Risk Panel (BRCA1, BRCA2, STK11, PTEN, TP53, CDH1)
Endometrial Cancer Panel (BRCA1, BRCA2, PALB2, CHEK2, PTEN, TP53, MUTYH, MLH1, MSH2, MSH6, EPCAM, PMS2)
Lynch/Colorectal Cancer High-Risk Panel (MUTYH, MLH1, MSH2, MSH6, EPCAM, PMS2, APC)
Colorectal Cancer High-Risk Panel (ATM, STK11, CHEK2, STK11, MUTYH, MLH1, MSH2, MSH6, EPCAM, PMS2, APC, BMPR1A, SMAD4, XRCC2, AXIN2)
Pancreatic Cancer Panel (BRCA1, BRCA2, ATM, PALB2, STK11, TP53, MLH1, MSH2, MSH6, EPCAM, PMS2, APC, CDK4, CDKN2A, VHL, XRCC2)
Comprehensive Cancer Panel (BRCA1, BRCA2, ATM, BARD1, BRIP1, RAD51C, PALB2, STK11, CHEK2, PTEN, TP53, CDH1, MUTYH, MLH1, MSH2, MSH6, EPCAM, PMS2, BMPR1A, SMAD4, RAD51D, CDK4, CDKN2A, VHL, XRCC2, FANCC, AXIN2)
BeScreened™-CRC (2 protein biomarkers + teratocarcinoma derived growth factor-1 genetic expression profiling (TDGF-1, Cripto-1)
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 (Washington Uo. BROCA, 2015). 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 (Washington, Uo. ColoSeq, 2015).
Myriad Genetics (Salt Lake City, UT) offers the myRISK™ next-generation sequencing panel, which includes testing for the following genes: APC, ATM, BARD1, BMPR1A, BRCA1, BRCA2, BRIP1, CDH1, CDK4, CDKN2A (p16INK4a and p14ARF), CHEK2, MLH1, MSH2, MSH6, MUTYH, NBN, PALB2, PMS2, PTEN, RAD51C, RAD51D, SMAD4, STK11, TP53.
Fulgent Diagnostics offers the Breast Ovarian Cancer NGS Panel: BRCA1 and BRCA2, along with cadherin 1, type1, E-cadherin (epithelial) (CDH1); partner and localizer of BRCA2 (PALB2); phosphate and tensin homolog (PTEN); serine/threonine kinase 11 (STK11); and tumor protein p53 (TP53), among others.
Lucence offers the Liquid HALLMARK next-generation sequencing assay which tests for mutations in 80 genes, fusions in 10 genes, and somatic variants: ABL1, AKT1, ALK, APC, AR, ARAF, ATM, AXL-MBIP, BAT25, BAT26, BRAF, BRCA1, BRCA2, CCND1, CCND2, CDH1, CDK6, CDKN2A, CLIP1-LTK, CREBBP, CTNNB1, CTNNB1-PLAG1, DNAJB1-PRKACA, EGFR, ERBB2, ERCC2, ERG, ESR1, ETV1, ETV4, ETV5, EZH2, FBXW7, FGFR1, FGFR2, FGFR3, FLI1, FLT3, GATA3, GNA11, GNAQ, GNAS, HNF1A, HRAS, IDH1, IDH2, JAK1, JAK2, JAK3, KEAP1, KIT, KRAS, MAP2K1, MAP2K2, MAPK1, MED12, MET, MLH1, MONO27, MTOR, MYB-NFIB, MYC, NF1, NFE2L2, NOTCH1, NR21, NR24, NR27, NRAS, NRG1, NTRK1, NTRK2, NTRK3, PAX8-FOXO1, PAX8-PPARG, PD-L1, PDGFRA, PIK3CA, PIK3R1, PPP2R1A, PTEN, PTPN11, RAF1, RB1, RET, RHEB, RHOA, RIT1, ROS1, RSPO3, SF3B1, SLC45A3, SMAD4, SMO, SPOP, SSX2, STK11, TERT Promoter, TFE3, THADA, TMPRSS2, TP53, U2AF1, VHL
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 variants 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 variants 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. Variations in these genes are estimated to confer up to a 4-fold increase in the risk for breast cancer. This pathway is also associated with a higher risk of ovarian cancer and, less often, pancreatic 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 variants 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 is a tumor suppressing gene located on chromosome 16q22.1 that encodes the cell-to-cell adhesion protein E-cadherin. Germline variants in the CDH1 gene have been associated with an increased risk of developing hereditary diffuse gastric cancer (DGC) and lobular breast cancer. A diagnosis of HDGC can be confirmed by genetic testing, although 20% to 40% of families with suspected HDGC do not have a CDH1 variant on genetic testing. Pathogenic CDH1 variants have been described in Māori families in New Zealand, and individuals of Maori ethnicity have a higher prevalence of diffuse-type gastric cancer than non-Maori New Zealanders. The estimated cumulative risk of gastric cancer for CDH1 variant carriers by age 80 years is 70% for men and 56% for women. CDH1 variants 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 variants in the APC gene, have MUTYH variants.
PALB2 germline variants have been associated with an increased risk of pancreatic and breast cancer. Familial pancreatic and/or breast cancer due to PALB2 variants are inherited in an autosomal dominant pattern.
PTEN variants are 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 variants are associated with Peutz-Jeghers 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 variants are associated with Li-Fraumeni syndrome. People with TP53 variants 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. Variants in the NF1 gene have been associated with neurofibromatosis type 1, juvenile myelomonocytic leukemia, and Watson syndrome.
RAD51D germline variants have been associated with familial breast and ovarian cancer.
CDK4 (cyclin-dependent kinase-4) is a protein-serine kinase involved in cell cycle regulation. Variants 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. Variants 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 variants are associated with risk of pheochromocytomas.
VHL germline variants are associated with Von Hippel-Lindau syndrome, an autosomal dominant familial cancer syndrome. This syndrome is associated with various malignant and benign tumors, including central nervous system tumors, renal cancers, pheochromocytomas, and pancreatic neuroendocrine tumors.
FH (fumarate hydratase) variants 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 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 variants are associated with hepatocellular carcinoma and papillary renal cell carcinoma.
MITF (microphthalmia-associated transcription factor) is a transcription factor involved in melanocyte differentiation. MITF variants lead to several auditory-pigmentary syndromes, including Waardenburg syndrome type 2 and Tietze 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. Variants 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 variants have been associated with familial adenomatous polyposis syndrome, although the phenotypes associated with AXIN2 variants 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 (Shannon, 2012).
Other mutations may be associated with intermediate penetrance and a lifetime breast cancer risk of 20% to 40% (e.g., CHEK2, APC, CDH-1). Low-penetrance mutations discovered in genome-wide association studies (e.g., 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 (e.g., 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:
The 2009 Chompret criteria for LFS / TP53 testing are as follows:
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% (Gonzalez, 2009). 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, i.e., 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 (Pilarski, 2004) 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 (Schrader, 2012). 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 (Hampel, 2009). The polyposis syndromes can be further subdivided by polyp histology, which includes the adenomatous (FAP, aFAP, and MUTYH-associated) and hamartomatous (JPS, PJS, PTEN hamartoma 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 (Vasen, 1999) 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 (FASCRS, 2015). 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 (Burke, 1997).
Measurable Residual Disease
Measurable residual disease (MRD), also known as minimal residual disease, refers to residual clonal cells in blood or bone marrow following treatment for hematologic malignancies. MRD is typically assessed by flow cytometry or polymerase chain reaction, which can detect one clonal cell in 100,000 cells. It is proposed that next-generation sequencing (NGS), which can detect one residual clonal sequence out of 1,000,000 cells, will improve health outcomes in patients who have been treated for hematologic malignancies such as acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), multiple myeloma (MM), diffuse large B-cell lymphoma (DLBCL), and mantle cell lymphoma (MCL).
There are 3 main types of hematologic malignancies: lymphomas, leukemias, and myelomas. Lymphoma begins in lymph cells of the immune system, which originate in the bone marrow and collect in lymph nodes and other tissues. Leukemia is caused by the overproduction of abnormal white blood cells in the bone marrow, which leads to a decrease in the production of red blood cells and plasma cells. The most common forms of leukemia are acute lymphoblastic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, and chronic myeloid leukemia. Multiple myeloma (MM), also called plasma myeloma, is a malignancy of plasma cells in the bone marrow. This policy addresses B-cell acute lymphoblastic leukemia, chronic lymphocytic leukemia, multiple myeloma, diffuse large B-cell lymphoma, and mantle cell lymphoma. As B-Cell acute lymphoblastic leukemia and B-Cell lymphoblastic lymphoma are generally considered clinically indistinct, reference to B-Cell acute lymphoblastic leukemia is intended to encompass both entities.
Treatment
Treatment depends on the type of malignancy and may include surgery, radiotherapy, chemotherapy, targeted therapy, plasmapheresis, biologic therapy, or hematopoietic cell transplant. Treatment of acute leukemias can lead to complete remission. Multiple myeloma and the chronic leukemias are treatable but generally incurable. Outcomes of lymphoma vary by subtype, and some forms are curable.
Measurable Residual Disease
Relapse is believed to be due to residual clonal cells that remain following "complete response” after induction therapy but are below the limits of detection using conventional morphologic assessment. Residual clonal cells that can be detected in the bone marrow or blood are referred to as measurable residual disease (MRD), also known as minimal residual disease. MRD assessment is typically performed by flow cytometry or polymerase chain reaction (PCR) with primers for common variants. Flow cytometry or next generation flow cytometry evaluates blasts based on the expression of characteristic antigens, while PCR assesses specific chimeric fusion gene transcripts, gene variants, and overexpressed genes. PCR is sensitive for specific targets, but clonal evolution may occur between diagnosis, treatment, remission, and relapse that can affect the detection of MRD. Next-generation sequencing (NGS) has 10- to 100-fold greater sensitivity for detecting clonal cells, depending on the amount of DNA in the sample and does not require patient-specific primers. For both PCR and NGS a baseline sample at the time of high disease load is needed to identify tumor-specific sequences. MRD with NGS is frequently used as a surrogate measure of treatment efficacy in drug development.
It is proposed that by using a highly sensitive and sequential MRD surveillance strategy, one could expect better outcomes when therapy is guided by molecular markers rather than hematologic relapse. However, some patients may have hematologic relapse despite no MRD, while others do not relapse despite residual mutation-bearing cells. Age-related clonal hematopoiesis, characterized by somatic variants in leukemia-associated genes with no associated hematologic disease, further complicates the assessment of MRD. One available test (clonoSEQ) uses both PCR and NGS to detect clonal DNA in blood and bone marrow. ClonoSEQ Clonality (ID) PCR assessment is performed when there is a high disease load (e.g., initial diagnosis or relapse) to identify dominant or “trackable” sequences associated with the malignant clone. NGS is then used to monitor the presence and level of the associated sequences in follow-up samples. As shown in below, NGS can detect clonal cells with greater sensitivity than either flow cytometry or PCR, although next-generation flow techniques have reached a detection limit of 1 in 10-5 cells, which is equal to PCR and approaches the limit of detection of NGS.
Sensitivity of Methods for Detecting Measurable Residual Disease:
Microscopy (complete response) - Detection limit of blasts per 100,000 Nucleated Cells 50,000
Multiparameter flow cytometry - Sensitivity10-4 (10 to the power of -4) Detection limit of blasts per 100,000 Nucleated Cells 10
Next-generation flow cytometry - Sensitivity10-5 (10 to the power of -5) Detection limit of blasts per 100,000 Nucleated Cells 1.0
Polymerase chain reaction - Sensitivity10-5 (10 to the power of -5) Detection limit of blasts per 100,000 Nucleated Cells1.0
Quantitative next-generation sequencing - Sensitivity10-5 (10 to the power of -5) Detection limit of blasts per 100,000 Nucleated Cells 1.0
Next-generation sequencing - Sensitivity10-6 (10 to the power of -6) Detection limit of blasts per 100,000 Nucleated Cells 0.1
Regulatory Status
Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; such tests must meet the general regulatory standards of the Clinical Laboratory Improvement Act (CLIA). Laboratories that offer laboratory-developed tests must be licensed by CLIA for high-complexity testing. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of these tests.
The clonoSEQ® Minimal Residual Disease Test is offered by Adaptive Biotechnologies. ClonoSEQ® was previously marketed as ClonoSIGHT™ (Sequenta), which was acquired by Adaptive Biotechnologies in 2015. ClonoSIGHT™ was a commercialized version of the LymphoSIGHT platform by Sequenta for clinical use in MRD detection in lymphoid cancers. In September 2018, clonoSEQ received marketing clearance from the Food and Drug Administration through the de novo classification process to detect MRD in patients with ALL or MM. In 2020, clonoSEQ received marketing clearance from the FDA to detect MRD in patients with chronic lymphocytic leukemia. clonoSEQ is available for use in other lymphoid cancers, such as diffuse large B-cell lymphoma (DLBCL), as a CLIA-validated laboratory developed test (LDT).
Coding
Effective in 2015, there are CPT codes for genomic sequencing procedures (or “next generation sequencing” panels). If the panel meets the requirements listed in the code descriptor, the following codes may be used:
81435: Hereditary colon cancer syndromes (e.g., Lynch syndrome, familial adenomatosis polyposis); genomic sequence analysis panel, must include analysis of at least 7 genes, including APC, CHEK2, MLH1, MSH2, MSH6, MUTYH, and PMS2
81436: duplication/deletion gene analysis panel, must include analysis of at least 8 genes, including APC, MLH1, MSH2, MSH6, PMS2, EPCAM, CHEK2, and MUTYH
81445: Targeted genomic sequence analysis panel, solid organ neoplasm, DNA analysis, 5-50 genes (e.g., 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
81450: Targeted genomic sequence analysis panel, hematolymphoid neoplasm or disorder, DNA and RNA analysis when performed, 5-50 genes (e.g., BRAF, CEBPA, DNMT3A, EZH2, FLT3, IDH1, IDH2, JAK2, KRAS, KIT, MLL, NRAS, NPM1, NOTCH1), interrogation for sequence variants, and copy number variants or rearrangements, or isoform expression or mRNA expression levels, if performed
81455: Targeted genomic sequence analysis panel, solid organ or hematolymphoid neoplasm, DNA and RNA analysis when performed, 51 or greater genes (e.g., 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
Prior to 2015 there were no specific codes for molecular pathology testing by panels. During that time and currently if the panel does not meet the criteria in the specific code descriptors, 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.
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Policy/ Coverage: |
Effective January 2023
In general, genetic cancer susceptibility panels are not covered, however, when coverage criteria of this policy or other policies are met (see policies 1998051, 2004038, 2014013, 2015004, 2015002, 2013010), limited genetic cancer susceptibility panels, including only the gene variants for which a given member qualifies, meets primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Next-generation sequencing (e.g., clonoSEQ) to detect measurable residual disease (MRD) at a threshold of 10-4 (10 to the power of -4) as an alternative test in individuals with acute lymphoblastic leukemia meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
Next-generation sequencing (e.g., clonoSEQ) to detect MRD at a threshold of 10-4 (10 to the power of -4) as an alternative test in individuals with chronic lymphocytic leukemia meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
Next-generation sequencing (e.g., clonoSEQ) to detect MRD at a threshold of 10-5 (10 to the power of -5) as an alternative test in individuals with multiple myeloma meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Next-generation sequencing (e.g., clonoSEQ) to detect measurable residual disease (MRD) at a threshold of less than 10-4 (10 to the power of -4) in individuals with acute lymphoblastic leukemia does not meet member benefit certificate primary coverage criteria.
For members with contracts without primary coverage criteria, next-generation sequencing (e.g., clonoSEQ) to detect measurable residual disease (MRD) at a threshold of less than 10-4 (10 to the power of -4) in individuals with acute lymphoblastic leukemia is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Next-generation sequencing (e.g., clonoSEQ) to detect measurable residual disease (MRD) at a threshold of less than 10-4 (10 to the power of -4) in individuals with chronic lymphocytic leukemia does not meet member benefit certificate primary coverage criteria.
For members with contracts without primary coverage criteria, next-generation sequencing (e.g., clonoSEQ) to detect measurable residual disease (MRD) at a threshold of less than 10-4 (10 to the power of -4) in individuals with chronic lymphocytic leukemia is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Next-generation sequencing (e.g., clonoSEQ) to detect measurable residual disease (MRD) at a threshold of less than 10-5 (10 to the power of -5) in individuals with multiple myeloma does not meet member benefit certificate primary coverage criteria.
For members with contracts without primary coverage criteria, next-generation sequencing (e.g., clonoSEQ) to detect measurable residual disease (MRD) at a threshold of less than 10-5 (10 to the power of -5) in individuals with multiple myeloma is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
General genetic cancer susceptibility panels (with or without next generation sequencing) for any situation not described above does not meet member benefit certificate primary coverage criteria.
For members with contracts without primary coverage criteria, genetic cancer susceptibility panels (with or without next generation sequencing) for any situation not described above are considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Next-generation sequencing for the assessment of measurable residual disease (MRD) in any situation not described above, including but not limited to the assessment of MRD in individuals with diffuse large B-cell lymphoma or mantle cell lymphoma, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
For members with contracts without primary coverage criteria, next-generation sequencing for the assessment of measurable residual disease (MRD) in any situation not described above, including but not limited to the assessment of MRD in individuals with diffuse large B-cell lymphoma or mantle cell lymphoma, is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective Prior to January 2023
In general, genetic cancer susceptibility panels are not covered, however, when coverage criteria of this policy or other policies are met (see policies 1998051, 2004038, 2014013, 2015004, 2015002, 2013010), limited genetic cancer susceptibility panels, including only the gene variants for which a given member qualifies, meets primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Next-generation sequencing (eg clonoSEQ) to detect measurable residual disease (MRD) at a threshold of 10-4 (10 to the power of -4) as an alternative test in patients with acute lymphoblastic leukemia meets member benefit certificate primary coverge criteria that there be scientific evidence of effectiveness.
Next-generation sequencing (eg clonoSEQ) to detect MRD at a threshold of 10-4 (10 to the power of -4) as an alternative test in patients with chronic lymphocytic leukemia meets member benefit certificate primary coverge criteria that there be scientific evidence of effectiveness.
Next-generation sequencing (eg clonoSEQ) to detect MRD at a threshold of 10-5 (10 to the power of -5) as an alternative test in patients with multiple myeloma meets member benefit certificate primary coverge criteria that there be scientific evidence of effectiveness.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Next-generation sequencing (eg clonoSEQ) to detect measurable residual disease (MRD) at a threshold of less than 10-4 (10 to the power of -4) in patients with acute lymphoblastic leukemia does not meet member benefit certificate primary coverage criteria.
For members with contracts without primary coverage criteria, next-generation sequencing (eg clonoSEQ) to detect measurable residual disease (MRD) at a threshold of less than 10-4 (10 to the power of -4) in patients with acute lymphoblastic leukemia is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Next-generation sequencing (eg clonoSEQ) to detect measurable residual disease (MRD) at a threshold of less than 10-4 (10 to the power of -4) in patients with chronic lymphocytic leukemia does not meet member benefit certificate primary coverage criteria.
For members with contracts without primary coverage criteria, next-generation sequencing (eg clonoSEQ) to detect measurable residual disease (MRD) at a threshold of less than 10-4 (10 to the power of -4) in patients with chronic lymphocytic leukemia is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Next-generation sequencing (eg clonoSEQ) to detect measurable residual disease at a threshold of less than 10-5 (10 to the power of -5) in patients with multiple myeloma does not meet member benefit certificate primary coverage criteria.
For members with contracts without primary coverage criteria, next-generation sequencing (eg clonoSEQ) to detect measurable residual disease at a threshold of less than 10-5 (10 to the power of -5) in patients with multiple myeloma is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
General genetic cancer susceptibility panels (with or without next generation sequencing) for any situation not described above does not meet member benefit certificate primary coverage criteria.
For members with contracts without primary coverage criteria, genetic cancer susceptibility panels (with or without next generation sequencing) for any situation not described above are considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Next-generation sequencing for the assessment of measurable residual disease in any situation not described above does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
For members with contracts without primary coverage criteria, next-generation sequencing for the assessment of measurable residual disease in any situation not described above is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective Prior to January 2021
In general, genetic cancer susceptibility panels are not covered, however, when coverage criteria of other policies are met (see policies 1998051, 2004038, 2014013, 2015004, 2015002, 2013010), limited genetic cancer susceptibility panels, including only the gene variants for which a given member qualifies, meets primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
General genetic cancer susceptibility panels (with or without next generation sequencing) do not meet member benefit certificate primary coverage criteria.
For members with contracts without primary coverage criteria, genetic cancer susceptibility panels (with or without next generation sequencing) are considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Next-generation sequencing for the assessment of measurable residual disease does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
For members with contracts without primary coverage criteria, Next-generation sequencing for the assessment of measurable residual disease is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective Prior to Novermber 2020
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Genetic cancer susceptibility panels (with or without next generation sequencing) do not meet member benefit certificate primary coverage criteria.
For members with contracts without primary coverage criteria, genetic cancer susceptibility panels (with or without next generation sequencing) are considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Next-generation sequencing for the assessment of measurable residual disease does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
For members with contracts without primary coverage criteria, Next-generation sequencing for the assessment of measurable residual disease is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective November 2018
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Genetic cancer susceptibility panels using next generation sequencing do not meet member benefit certificate primary coverage criteria.
For members with contracts without primary coverage criteria, genetic cancer susceptibility panels using next generation sequencing are considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Next-generation sequencing for the assessment of measurable residual disease does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
For members with contracts without primary coverage criteria, Next-generation sequencing for the assessment of measurable residual disease is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective Prior to November 2018
Genetic cancer susceptibility panels using next generation sequencing do not meet member benefit certificate primary coverage criteria.
For members with contracts without primary coverage criteria, genetic cancer susceptibility panels using next generation sequencing are considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
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| Rationale: |
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 (GeneDx, 2014).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) (Walsh, 2010). 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)
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?
· Is the impact of ancillary information provided by panel testing well-defined?
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 (Cragun, 2014). 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 (Mauer, 2013). 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 (ambrygen.com, 2015).
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.
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 (Robson, 2010). 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) (NCCN, 2014) 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.” Updated 2014 NCCN guidelines on genetic/familial high-risk assessment for break and
ovarian cancer (v2.2014)(NCCN, 2014) include a new multigene testing section which reviews benefits and limitations to multigene panel testing for cancer risk assessment. The guidelines state that “In some cases, multi-gene testing may be a preferable way to begin testing over the single-gene testing process.”
Recommendations for consideration for multi-gene testing are included for the following clinical situations:
· In patients in whom hereditary breast and ovarian cancer (HBOC) testing criteria are met and who have no known familial BRCA1/BRCA2 mutation, or who have no mutation found or variant of uncertain significance found on comprehensive BRCA1/BRCA2 testing.
· In patients in whom Li-Fraumeni testing criteria are met and who have no known familial TP53 mutation, or who have no mutation found or variant of uncertain significance found on comprehensive TP53 testing.
· In patients in whom Cowden syndrome/PTEN hamartoma syndrome testing criteria are met and who have no known familial PTEN mutation, or who have no mutation found or variant of uncertain significance found on comprehensive PTEN testing.
The most recent NCCN guidelines on genetic/familial high risk assessment for colorectal cancer (v1.2014) does not address next generation sequencing gene panels (NCCN, 2014).
2016 Update
A literature search conducted through November 2016 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
Analytic Validity
In 2015, Lincoln and colleagues reported on a comparison of traditional and multigene panel testing for hereditary and ovarian cancer genes (Lincoln, 2015). They tested over a 1000 individuals using a 29-gene NGS panel. The population consisted of patients referred for hereditary breast and ovarian cancer counseling and/or testing (n=735), patients referred for known familial mutations (n=118) and patients referred for high-risk personal and family features (n=209). Of the total patients, 92% had previously undergone traditional BRCA1 and/or BRCA2 testing, and a small subset (4%) had undergone testing for other genetic mutations. Analytic concordance was 100% when the 29-gene panel results were compared with previous traditional and reference data. In 4.5% of cases considered previously to be BRCA-negative, panel testing identified pathogenic variants in other genes considered to be clinically relevant. Forty-one percent of cases had at least 1 variant of unknown significance (VOUS) among the 29 genes, with 11.4% having 2 or more VOUS.
Also in 2015, Judkins and colleagues reported on the development and analytic validity of a 25-gene NGS panel to assess genes associated with hereditary cancer syndromes (Judkins, 2015). The panel of genes were selected for their association with hereditary cancer syndromes, some of which are associated with clinical management changes; genes included were BRCA1, BRCA, MLH1, MSH2, MSH6, PMS2, EPCAM (for large rearrangements of the last 2 exons only), APC, MUTYH, CDKN2A, PALB2, ATM, STK11, PTEN, TP53, CDH1, BMPR1A, SMAD4, BARD1, CHEK2, CDK4, NBN, RAD51C, BRIP1, and RAD51D. The test’s analytic characteristics were compared with Sanger sequencing for BRCA1 and BRCA2, using 1864 anonymized samples, with an estimated analytical sensitivity for NGS greater than 99.96% (lower limit of the 95% confidence interval) and an estimated analytical specificity greater than 99.99% (lower limit 95% confidence interval). The panel was validated against Sanger sequencing in 100 anonymized samples, with 100% concordance for variants. The estimated analytical sensitivity of the NGS assay was greater than 99.92% (lower limit of 95% confidence interval) and the estimated analytical specificity was greater than 99.99% (lower limit of 95% confidence interval), with good reproducibility.
Chong and colleageus reported the design and validation of BRCAplus, a panel that detects mutations in the 6 high-risk breast cancer susceptibility genes (BRCA1, BRCA2, CDH1, PTEN, TP53, STK11) using NGS and aCGH (Chong, 2014). NGS analysis was confirmed by Sanger sequencing and aCGH analysis (for duplications and deletions) was confirmed by multiplex ligation-dependent probe amplification analysis. The analyses were conducted on 250 previously characterized, archived genomic DNA samples, which harbored a total of 3025 previously defined germline variants in the 6 targeted genes. The BRCAplus test correctly identified all variants, resulting in 100% sensitivity. There were 30 false positives from 5,788,250 base pairs interrogated, resulting in an analytic specificity for NGS of 99.99%
In 2014, Kurian and colleagues evaluated the information from a NGS panel of 42 cancer associated genes in women who had been previously referred for clinical BRCA1 and BRCA2 testing after clinical evaluation of hereditary breast and ovarian cancer from 2002 to 2012 (Kurian, 2014). The authors aimed to assess concordance of the results of the panel with prior clinical sequencing, the prevalence of potentially clinically actionable results, and the downstream effects on cancer screening and risk reduction. Potentially actionable results were defined as pathogenic variants that cause recognized hereditary caner syndromes or have a published association with a 2-fold or greater relative risk of breast cancer compared with average-risk women. In total, 198 women participated in the study. Of these, 174 had breast cancer and 57 carried 59 germline BRCA1 and BRCA2 mutations. Testing with the panel confirmed 57 of 59 of the pathogenic BRCA1 and BRCA2 mutations; of the 2 others, 1 was detected but reclassified as a VOUS, and the other was a large insertion that would not be picked up by NGS panel testing. Of the women who tested negative for BRCA1 and BRCA2 mutations (n=141), 16 had pathogenic mutations in other genes (11.4%). The affected genes were ATM (n=2), BLM (n=1), CDH1 (n=1), CDKN2A (n=1), MLH1 (n=1), MUTYH (n=5), NBN (n=2), PRSS1 (n=1), and SLX4 (n=2). Eleven of these variants had been previously reported in the literature and 5 were novel. Eighty percent of the women with pathogenic mutations in the non-BRCA1 and -BRCA2 genes had a personal history of breast cancer. Overall, a total of 428 VOUS were identified in 39 genes, among 175 patients. Six women with mutations in ATM, BLM, CDH1, NBN, and SLX4 were advised to consider annual breast magnetic resonance imaging because of an estimated doubling of breast cancer risk, and 6 with mutations in CDH1, MLH1, and MUTYH were advised to consider frequent colonoscopy and/or endoscopic gastroduodenoscopy (once every 1-2 years) due to estimated increases in gastrointestinal cancer risk. One patient with a MLH1 mutation consistent with Lynch syndrome underwent risk-reducing salpingo-oophorectomy and early colonoscopy, which identified a tubular adenoma that was excised (she had previously undergone hysterectomy for endometrial carcinoma).
2018 Update
A literature search was conducted through October 2018. There was no new information identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
Colorectal Cancer
Hansen et al published a retrospective analysis using multigene panel testing to identify genetic causes for increased CRC risk (Hansen, 2017). A custom gene panel targeting 112 genes, including both well-known and candidate CRC susceptibility genes was designed and variants were validated by Sanger sequencing. DNA samples from 274 familial CRC patients who fulfilled the Amsterdam I/II and/or the Revised Bethesda guidelines were included. All had previously been screened for variants in 1 or more of the MMR genes (MLH1, MSH2, MSH6, PMS2) without any pathogenic findings. In well-known cancer susceptibility genes, 17 pathogenic variants and 19 VUS were identified. Thirty-seven potentially pathogenic variants in candidate CRC susceptibility genes were also identified. Clinical correlations were not available.
Rosenthal et al published an industry-sponsored study evaluating the clinical utility of a 25-gene pan-cancer panel (Rosenthal, 2017). The analysis included 252,223 consecutive individuals, most of whom (92.8%) met testing criteria for hereditary breast and ovarian cancer and/or Lynch syndrome. Pathogenic variants (n=17,340) were identified in 17,000 (6.7%) patients; the most common pathogenic variants were BRCA1 and BRCA2 (42.2%), other breast cancer genes (32.9%), Lynch syndrome genes (13.2%), and ovarian cancer genes (6.8%). Among individuals who met only hereditary breast and ovarian cancer or Lynch syndrome testing criteria, half of the pathogenic variants found were genes other than BRCA1 and BRCA2 or Lynch syndrome genes, respectively. The study was limited by reliance on providers for personal and family cancer histories and by uncertainty regarding the exact cancer risk spectrum for each gene included on the panel.
December 2018 Update
NEXT-GENERATION SEQUENCING TO DETECT MEASURABLE RESIDUAL DISEASE
Evidence reviews assess whether a medical test is clinically useful. A useful test provides information to make a clinical management decision that improves the net health outcome. That is, the balance of benefits and harms is better when the test is used to manage the condition than when another test or no test is used to manage the condition.
The first step in assessing a medical test is to formulate the clinical context and purpose of the test. The test must be technically reliable, clinically valid, and clinically useful for that purpose. Evidence reviews assess the evidence on whether a test is clinically valid and clinically useful. Technical reliability is outside the scope of these reviews, and credible information on technical reliability is available from other sources.
Clinical Context and Test Purpose
The purpose of next-generation sequencing (NGS) to detect measurable residual disease (MRD) in patients who have been treated for hematologic cancers and achieved a complete response after induction therapy is to inform a decision regarding subsequent treatment.
The question addressed in this evidence review is: Does the use of NGS testing for MRD improve the net health outcome in patients with hematologic cancers?
The following PICOTS were used to select literature to inform this review.
Patients
The relevant population of interest is patients who have been treated for hematologic cancers and exhibit complete morphologic remission.
Interventions
The test being considered is NGS (eg, clonoSEQ). This test is proposed as an adjunct to existing methods of assessing MRD with complete blood count and cell morphology, and as an alternative to flow cytometry or polymerase chain reaction (PCR).
Comparators
The following tests are currently being used to detect MRD: flow cytometry and PCR. The reference standard is clinical (hematologic) relapse.
Outcomes
The general outcomes of interest are remission and relapse in the short term and survival at longer follow-up.
Beneficial outcomes of a true-positive test result would be intensification or continuation of an effective treatment leading to a reduction in relapse and improvement in overall survival (OS). The beneficial outcome of a true-negative test is the avoidance of unnecessary treatment and reduction of adverse events.
Harmful outcomes of a false-positive test include an increase or continuation of unnecessary treatment resulting in treatment-related harms. Harmful outcomes of a false-negative test include a reduction in necessary treatment that would delay treatment, with a potential impact in progression-free survival (PFS) and OS.
Direct harms of the test are repeated bone marrow biopsy, although this test can also be performed in blood and would, therefore, reduce direct harms of the invasive test.
Timing
Relapse of acute hematologic malignancies may be measured in months and chronic hematologic malignancies measured in years. Changes in survival from acute hematologic malignancies would be observable at 2 years, while chronic hematologic malignancies would typically be observable by 10 years.
Setting
Evaluation of MRD would be in an outpatient care setting by a hematologic oncologist.
Study Selection Criteria
For the evaluation of clinical validity of the clonoSEQ test, studies that met the following eligibility criteria were considered:
Studies were excluded from the evaluation of the clinical validity of the test because they did not use the marketed or earlier version of the test, did not include information needed to calculate performance characteristics, did not use an appropriate reference standard or reference standard was unclear, did not adequately describe the patient characteristics, or did not adequately describe patient selection criteria.
Technically Reliable
Assessment of technical reliability focuses on specific tests and operators and requires review of unpublished and often proprietary information. Review of specific tests, operators, and unpublished data are outside the scope of this evidence review and alternative sources exist. This evidence review focuses on the clinical validity and clinical utility.
Clinically Valid
A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).
Diagnostic Accuracy for Hematologic or Clinical Relapse
Kurtz et al reported a sensitivity of 31% and specificity of 100% to predict clinical relapse, with an MRD threshold of 10-6 (Kurtz, 2015). A malignant clonal sequence was identified in 83% of patients.
Section Summary: Clinically Valid
The performance characteristics of NGS at 10-6 to detect relapse are not well defined. One prospective study was identified and it evaluated the diagnostic accuracy of NGS. In this study, a clonal sequence could be identified in only 83% of the samples, which can be compared with the 100% identification of clonal cells by flow cytometry. At a detection limit of 10-6, NGS had 31% sensitivity and 100% specificity to detect clinical relapse. Several prognostic studies have reported on the association between MRD at various sensitivities and relapse prediction. The percentage of cases in which a clonal sequence could be identified ranged from 91% to 95.4%. The timing of the test and the outcome measures of these studies were variable, which complicates analysis, but overall, higher levels of MRD were associated with worse prognosis. One study, however, found that the maximal hazard ratio was obtained at a sensitivity of 10-4, the same as flow cytometry and that higher levels of sensitivity were associated with a decrease in specificity. Thus, the clinical validity of NGS to detect MRD is uncertain.
Clinically Useful
A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.
Direct Evidence
Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from randomized controlled trials (RCTs).
No RCTs assessing the clinical utility of NGS to detect malignant clonal sequences were identified.
Chain of Evidence
Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.
The evidence is insufficient to demonstrate clinical validity, and it is not known whether management changes based on the increase in sensitivity with NGS to detect malignant clonal sequences would improve health outcomes.
Section Summary: Clinically Useful
The evidence is insufficient to determine the test performance of NGS for detecting MRD, and no chain of evidence can be constructed to establish clinical utility in hematologic malignancies. Direct evidence from RCTs are needed to evaluate whether patient outcomes are improved by changes in postinduction care (eg, continuing therapy, escalating to hematopoietic cell transplantation, avoiding unnecessary adverse events) following NGS detection of MRD at 10-6 compared with the established methods of flow cytometry or PCR at 10-5.
NGS TO INFORM TREATMENT OF B-CELL ACUTE LYMPHOBLASTIC LEUKEMIA
Evidence reviews assess the clinical evidence to determine whether the use of a technology improves the net health outcome. Broadly defined, health outcomes are length of life, quality of life, and ability to function-- including benefits and harms. Every clinical condition has specific outcomes that are important to patients and to managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.
To assess whether the evidence is sufficient to draw conclusions about the net health outcome of a technology, 2 domains are examined: the relevance and the quality and credibility. To be relevant, studies must represent one or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. Randomized controlled trials are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.
Clinical Context and Test Purpose
The purpose NGS to detect MRD in patients who are in remission for B-cell acute lymphoblastic leukemia (B-ALL) is to provide a treatment option that is an alternative to or an improvement on existing therapies.
In 2018, blinatumomab received approval from the Food and Drug Administration for the treatment of MRD positive B-cell precursor ALL in first or second complete remission with MRD positivity of 0.1% or greater (10-3 or 1 in 1000 cells) (FDA, 2018).
The question addressed in this evidence review is: Does the use of NGS testing for MRD improve the net health outcome in patients with B-ALL who are being considered for treatment with blinatumomab?
The following PICOTS were used to select literature to inform this review.
Patients
The relevant population of interest is patients who have been treated for B-ALL and exhibit complete morphologic remission.
Interventions
The test being considered is NGS (eg, liter). This test is proposed as an adjunct to existing methods of assessing MRD with complete blood count and cell morphology, and as an alternative to flow cytometry or PCR.
Comparators
The following tests are currently being used to inform treatment decisions for those with B-ALL in remission: flow cytometry and PCR. The reference standard is clinical (hematologic) relapse.
Outcomes
The general outcomes of interest are remission and relapse in the short term and survival at longer follow-up.
Beneficial outcomes of a true-positive test result would be the administration of an effective treatment leading to a reduction in relapse and improvement in OS. The beneficial outcome of a true-negative test is the avoidance of unnecessary treatment and reduction of adverse events.
Harmful outcomes of a false-positive test are unnecessary treatment resulting in treatment-related harms. Harmful outcomes of a false-negative test are a reduction in necessary treatment that would delay treatment, with a potential impact in PFS and OS.
Direct harms of the test are repeated bone marrow biopsy, although this test can also be performed in blood and would, therefore, reduce direct harms of the invasive test.
Timing
Relapse of B-ALL may be measured in months. Changes in survival from B-ALL would be observable at 2 years.
Setting
Evaluation of MRD would be in an outpatient care setting by a hematologic oncologist.
Study Selection Criteria
Methodologically credible studies were selected using the following principles:
Clinical Studies
No studies were identified that assessed the clinical validity or clinical utility of using NGS to inform a decision to treat B-ALL patients in remission with blinatumomab.
Section Summary: NGS to Inform Treatment of B-Cell Acute Lymphoblastic Leukemia
The evidence is insufficient to determine the utility of using NGS to inform a decision to treat B-ALL patients in remission with blinatumomab. Direct evidence from RCTs is needed to evaluate whether patient outcomes are improved by directing treatment with blinatumomab following NGS detection of MRD at 10-6 compared with the Food and Drug Administration directed threshold of 10-3 or more.
SUMMARY OF EVIDENCE
For individuals who have achieved a complete response and are being evaluated for MRD who receive NGS for MRD, the evidence includes studies on diagnostic accuracy and prognosis. Relevant outcomes are overall survival, disease-specific survival, test validity, change in disease status, quality of life, and treatment-related morbidity. The evidence is insufficient to determine the clinical validity of NGS for assessing MRD, and no chain of evidence can be constructed to establish clinical utility in hematologic malignancies. NGS can identify more blast cells with an identified clonal sequence by a factor of 10. However, the clinical utility of this increase in the detection of clonal sequences is uncertain. Direct evidence from randomized controlled trials is needed to evaluate whether patient outcomes are improved by changes in postinduction care (eg, continuing therapy, escalating to hematopoietic cell transplant, avoiding unnecessary therapy) following NGS detection of MRD at 10-6 compared with the established methods of flow cytometry or polymerase chain reaction (at 10-5). The evidence is insufficient to determine the effects of the technology on health outcomes.
For individuals with B-ALL who are in remission who are being considered for treatment with blinatumomab who receive NGS for MRD, the evidence is lacking. Relevant outcomes are overall survival, disease-specific survival, test validity, change in disease status, quality of life, and treatment related morbidity. Direct evidence from RCTs is needed to evaluate whether patient outcomes are improved by directing treatment with blinatumomab based on NGS assessment of MRD at 10-6 compared with the threshold of 10-3 approved by the Food and Drug Administration. The evidence is insufficient to determine the effects of the technology on health outcomes.
2019 Update
Annual policy review completed with a literature search using the MEDLINE database through October 2019. No new literature was identified that would prompt a change in the coverage statement.
2020 Update
Annual policy review completed with a literature search using the MEDLINE database through October 2020. No new literature was identified that would prompt a change in the coverage statement.
Kurian et al evaluated the association between gene variants on the Myriad 25-gene panel in 95,561 women and documented risk of breast or ovarian cancer from provider-completed test requisition forms (Kurian, 2017). Pathogenic variants were detected in 6,775 (7%) of the women. Multivariate regression models and case-control analysis estimated that 8 genes were associated with breast cancer with odds ratio (OR) from 2-fold (ATM) to 6-fold (BRCA1). Eleven genes were associated with ovarian cancer, with OR ranging from 2-fold (ATM) to 40 fold (STK11), but statistical significance was achieved for only 3 genes (BRCA1, BRCA2, RAD51C). The clinical significance of the increase in cancer risk for the other genes is uncertain. Out of the 25 genes tested on the panel, there was overlap of 3 genes (ATM, BRCA1, BRCA2) for the association of both breast or ovarian cancer, and not all genes on the panel were associated with risk for either cancer.
Idos et al conducted a prospective study that enrolled 2000 patients who had been referred for genetic testing at 1 of 3 academic medical centers (Idos, 2018). Patients underwent differential diagnosis by a genetic clinician prior to cancer panel testing for 25 or 28 genes associated with breast or ovarian cancer, Lynch syndrome, and genes associated with gastric, colon, or pancreatic cancer. Twelve percent of the patients were found to have a pathogenic variant, of which 66% was anticipated by the genetic clinician and 34% which were not anticipated. Most of the unanticipated results were in moderate to low penetrance genes. Thirty-four percent of the patients had a VUS and 53% of patients had benign results. Prophylactic surgery was performed more frequently in patients with a pathogenic variant (16%) compared to patients with a benign (2.4%) or unknown (2.3%) variant. Information on the actions associated with low to moderate penetrance genes were not reported. One concern with large panels is the increase in VUS. Having a VUS did not increase distress or uncertainty or diminish a positive experience of the testing in this study, and there was no increase in prophylactic surgery in patients with a VUS. However, all patients had received genetic counseling at an academic medical center regarding the outcomes of testing and this study may not be representative of community practice. In addition, a threshold for testing of 2.5% on a risk prediction model is a lower threshold than what is typically recommended. Patients with a positive result were more likely to encourage relatives to undergo testing. Longer-term follow-up for clinical outcomes is ongoing. A limitation of the study was data completeness. Surveys were completed by 69% of the patients at 3 months and 57% of the patients at 12 months.
In 2020, the American Society of Clinical Oncology (ASCO) published a guideline on germline and somatic tumor testing in epithelial ovarian cancer (Konstantinopoulos, 2020). Based on a systematic review of evidence and expert panel input, ASCO recommended that women with epithelial ovarian cancer should be offered germline testing for BRCA1/2 and other specified ovarian susceptibility genes with a multigene panel. ASCO considered it more practical to evaluate a minimum of the 10 genes that have been associated with inherited risk of ovarian cancer in a panel in comparison to testing BRCA1 and BRCA2 alone.
In 2020, the Collaborative Group of the Americas on Inherited Gastrointestinal Cancer published a position statement on multigene panel testing for patients with colorectal cancer (Heald, 2020). Recommendations were based on the evidence, professional society recommendations endorsing testing of a given gene, and opinion of the expert panel. The group noted the variability in genes included in commercially available panels, and recommended that multigene panels include a minimum of 11 specific genes associated with defective mismatch repair (Lynch syndrome) and polyposis syndromes. Additional genes to be considered had low to moderately increased risk, had limited data of colorectal cancer risk, or causation for colorectal cancer was not proven.
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through December 2020. The key identified literature is summarized below.
Treatment is indicated for patients with disease-related complications, termed "active disease" by the International Workshop on Chronic Lymphocytic Leukemia (Hallek, 2018). Criteria for active disease include 1 or more of the following: progressive marrow failure, splenomegaly, lymphadenopathy, progressive lympocytosis, autoimmune anemia and/or thrombocytopenia, extranodal involvement (eg, skin, kidney, lung, spine), and constitutional symptoms such as weight loss, fatigue, fever, and night sweats. The goal of therapy is to ameliorate symptoms and improve progression-free and overall survival. The choice of therapy is based on patient and tumor characteristics and goals of therapy. Most patients will have an initial complete or partial response to treatment, but will eventually relapse. Relapse may be asymptomatic but is monitored closely for progression to active disease.
Material submitted for U.S. Food and Drug Administration (FDA) approval included data analyzed from 2 studies that assessed MRD with clonoSeq using available blood samples from 2 clinical trials (NCT02242942 and NCT00759798) (clonoSEQ, 2020). The primary endpoint of the first study was to evaluate whether MRD at a threshold of 10-5 at 3 mo after treatment could predict PFS. Secondary objectives were to assess different cutoff values and repeated measurements. Patients with MRD > 10-5 had a 6.64-fold higher event risk compared to MRD negative patients (95% CI: 3.65-12.1). The primary distinction was at a cutoff of 10-4, where only 16.5% of patients with MRD in blood >10-4 were progression free at 4 yr follow-up, compared to 44%, 49%, and 47% with MRD < 10-6, 10-5, and 10-4, respectively.
The second study was published by Thompson et al, who analyzed MRD with NGS in stored samples of bone marrow (n=57), blood (n=29) and plasma (n=32) from 62 patients who had previously tested negative for MRD by FC (N=63) in a phase 2 clinical trial (Thompson, 2019). MRD rates by NGS varied according to sample type with fewer patients with undetectable MRD in bone marrow (25%) than blood (55%) or plasma (75%). MRD at the end of treatment was predictive of PFS. Patients with undetectable MRD did not progress by the end of the study (mean 82 mo, range 28 to 112) compared with PFS of 67 months (bone marrow) or 74 months (blood). The percent of patients who were progression free with MRD < 10-6, 10-5, and 10-4 was 85%, 75%, and 67.5%, respectively. The authors note that "At this time, no additional treatment is offered to eradicate low-level MRD (<10-4) after first-line treatment of CLL, given the generally favorable prognosis for such patients."
Martinez-Lopez et al reported a retrospective analysis of patients (N=234) treated at their center for newly diagnosed or relapsed MM who had been evaluated for MRD by NGS (Martinez-Lopez, 2020). MRD assessment by clonoSEQ was performed after a CR, but there was no consistent time after treatment; most were performed within 1 year. Successful identification of at least 1 trackable sequence in the pretreatment sample was obtained in 234 out of 251 (93%) patients. Sensitivity was assessed at 10-4, 10-5, and 10-6. Out of all patients, 91 (39%) had MRD < 10-6 and 129 (55%) had MRD <10-5. For both newly diagnosed MM and relapsed MM patients, MRD <10-5 or <10-6 was associated with prolonged survival. In patients who had repeat testing, rising MRD levels preceded clinical relapse by a median of 13 months (range 1 to 28 months). Patients who reached a molecular response at 10-5 had similar outcomes to those who achieved MRD negativity at 10-6.
Kriegsmann et al found moderate concordance between NGS and NGF in a study of 113 patients with MM (Kriegsmann, 2020). Concordance between methods was obtained in 68% of patients while discordant results were found in 28 patients (11.2% in each direction). Cohen’s kappa coefficient for interrater agreement between the MRD status of the 2 methods was 0.536 (n = 113, p < 0.001). A threshold of 10-5 was chosen as the best-fit MRD cut-off for evaluation as it met the international guidelines and resulted in a tolerable proportion of nonassessable cases in both methods (1.6%, n = 2 in NGS and 8.0%, n = 10 in NGF).
The 2018 guidelines from the International Workshop on Chronic Lymphocytic Leukemia have the following recommendations regarding the assessment of MRD (Hallek, 2018):
"The complete eradication of the leukemia is a desired end point. Use of sensitive multicolor flow cytometry, PCR, or next generation sequencing can detect MRD in many patients who achieved a complete clinical response. Prospective clinical trials have provided substantial evidence that therapies that are able to eradicate MRD usually result in an improved clinical outcome. The techniques for assessing MRD have undergone a critical evaluation and have become well standardized. Six-color flow cytometry (MRD flow), allele-specific oligonucleotide PCR, or high-throughput sequencing using the ClonoSEQ assay are reliably sensitive down to a level of 1 CLL cell in 10 000 leukocytes. Refinement and harmonization of these technologies has established that a typical flow cytometry–based assay comprises a core panel of 6 markers (ie, CD19, CD20, CD5, CD43, CD79b, and CD81).As such, patients will be defined as having undetectable MRD (MRD-neg) remission if they have blood or marrow with ,1 CLL cell per 10,000 leukocytes."
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through December 2021. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
Pearlman et al reported on the prevalence of germline pathogenic variants among patients with CRC in the Ohio Colorectal Cancer Prevention Initiative (Pearlman, 2021). All 3,310 patients enrolled in the study underwent testing for mismatch repair deficiency, and patients meeting at least 1 clinical criterion (mismatch repair deficiency, CRC diagnosis at less than 50 years of age, multiple primary tumors [CRC or endometrial cancer], or first degree relative with CRC or endometrial cancer) underwent subsequent multigene panel testing. The specific multigene panel test used depended on the results of mismatch repair deficiency testing; patients with mismatch repair deficiency not explained by MLH1 hypermethylation (n=224) underwent testing with ColoSeq or BROCA panels, while patients with MLH1 hypermethylated tumors (n=99) and patients without mismatch repair deficiency (n=1,139) underwent testing with a myRisk panel. Panels tested for 25 to 66 cancer genes. Among the 1,462 patients who underwent multigene panel testing, 248 pathogenic or likely pathogenic variants were detected in 234 patients (16% of patients who underwent multigene panel testing, and 7.1% of the entire study population). One hundred forty two pathogenic variants were in mismatch repair deficiency genes, while 101 were in non-mismatch repair deficiency genes. If mismatch repair deficiency testing had been the only method used to screen for hereditary cancer syndromes, 38.6% (91 of 236) of patients with a pathogenic variant in a cancer susceptibility gene or constitutional hypermethylation would have been missed, including 6.3% (9 of 144) of those with Lynch syndrome. One hundred seventy-five patients (5.3% of the entire study population) had pathogenic variants in genes with therapeutic targets. Variants of uncertain significance were found in 422 patients who underwent multigene panel testing (28.9%).
The U.S. Preventive Services Task Force has recommended that primary care providers screen women with a personal or family history of breast, ovarian, tubal, or peritoneal cancer or who have an ancestry associated with BRCA1/2 gene mutations with an appropriate brief familial risk assessment tool (USPSTF, 2021). Women with positive screening results should receive genetic counseling and if indicated after counseling, BRCA testing (grade B recommendation). The use of genetic cancer susceptibility panels was not specifically mentioned.
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through December 2022. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
In an analysis of samples from 2 multicenter studies, Pulsipher et al compared FC at a threshold of 10-4 with NGS at thresholds of 10-4, 10-5, 10-6, and any detectable level (approximately 10-7) in pediatric and young adult patients with B-ALL who received tisagenlecleucel (Pulsipher, 2022). In 95 patients with both NGS and FC results, 18% of samples were MRD-positive with FC compared with 22%, 29%, 33%, and 41% with NGS at cutoff values of 10-4, 10-5, 10-6, and any detectable level, respectively. No samples were positive by FC and negative by NGS.
Cavo et al analyzed pooled data from 4 phase 3 studies in patients with relapsed or refractory MM who were ineligible for transplant (Cavo, 2022). MRD was assessed at a sensitivity of 10-5. Patients who achieved a complete response or better and were MRD negative had improved PFS and an 80% reduction in the risk of disease progression or death compared with those who failed to reach CR or were MRD positive (HR, 0.20; p<.0001).
Lymphoma refers to any cancer that starts in the lymph system and includes 2 broad categories of disease, Hodgkin lymphoma and non-Hodgkin lymphoma (CDC, 2018). There are multiple forms of non-Hodgkin lymphoma with B-cell malignancies comprising 85% of cases (ACS, 2019). Of the B-cell lymphomas, diffuse large B-cell lymphoma (DLBCL) accounts for approximately one-third of cases. DLBCL occurs most commonly in older patients with the mean age of diagnosis of approximately 60 years of age. Although aggressive, DLBCL generally responds well to treatment, and 75% of patients have no signs of disease after initial treatment. Historically, PET and CT imaging have been used to assess lymphoma tumor burden and disease response; however, techniques such as flow cytometry, PCR-based methods, and NGS-based techniques are being increasingly used (Herrera, 2017).
A small percentage of B-cell lymphomas (about 5%) are categorized as mantle cell lymphoma (MCL) (ACS, 2019). Similar to DLBCL, it occurs most commonly in patients over 60 years of age and tends to be an aggressive lymphoma; however, the response to treatment has traditionally been poor. Most patients present with advanced stage disease, and treatment is dependent on stage and eligibility for HSCT. Historically, PET and CT imaging have been used to assess lymphoma tumor burden and disease response; however, techniques such as flow cytometry, PCR-based methods, and NGS-based techniques are being increasingly used (Herrera, 2017).
There are 2 studies assessing the prognostic value of NGS for MRD specifically in patients with DLBCL. One prospective, single-center, observational study by Chase et al attempted to correlate MRD with prognosis in patients with newly diagnosed DLBCL receiving conventional treatment; however, attrition limited outcome assessment (Chase, 2021). Only 3 patients had early clinical relapse, and no conclusions can be drawn.
In a phase 2, single-center, prospective trial in patients with DLBCL undergoing HSCT, Kambhampati et al assessed 15 patients for MRD with NGS (Kambhampati, 2021). Of the 14 patients with available MRD samples after salvage therapy, 11 were MRD negative and 3 were MRD positive. MRD tests were predictive of survival in these patients.
Smith et. al. conducted a retrospective review of samples from patients enrolled in the ECOG1411 trial which evaluated MCL patients treated with bendamustine-rituximab induction followed by rituximab (with or without lenalidomide) consolidation and evaluated MRD by both FC and NGS (Smith, 2019). Concordance between tests was high both after cycle 3 and end of induction. MRD status correlated with PFS. For patients who were MRD negative after cycle 3 by either method, PFS was 58.9 months. For those who were MRD positive by NGS, PFS was 26.9 months and PFS was 29.9 months for those who were positive by FC. The authors concluded both NGS and FC were feasible to assess MRD.
Lakhotia et. al conducted an exploratory review of circulating tumor DNA analyzed by NGS from a trial of bortezomib induction in 53 MCL patients found patients who had undetectable MRD after 2 induction cycles had longer PRS and OS than those with MRD (Lakhotia, 2022). As this was an exploratory analysis, key details are not included, and no firm conclusions can be drawn.
National Comprehensive Cancer Network Recommendation for B-cell lymphoma (Version 5.2022) states NGS may be used as additional diagnostic testing or to guide treatment selection in certain circumstances. MRD surveillance is not included in the current guidelines (NCCN, 2022).
2024 Update
Annual policy review completed with a literature search using the MEDLINE database through December 2023. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
Liang et al reported results of a study of the prognostic performance of the clonoSEQ assay in 111 adult participants with B-cell or T-cell ALL who underwent allogeneic HCT at Stanford University or Oregon Health & Science University between 2014 and 2021 (Liang, 2023). Participants were followed for leukemia relapse and/or death for up to 2 years after HCT. Relapse was defined as morphologic or clinical. The MRD samples came from either peripheral blood or bone marrow. The median age of the patients was 44 years (range, 19 to 70 years), 62 (56%) were male, and 95 (86%) had B-cell ALL. MRD before HCT was undetectable in 82 participants, low (<10) in 24 participants, high (>10–4 to ≤10–3) in 11 participants, and very high (10–3) in 5 participants.
Munir et al reported results of the prognostic performance of clonoSEQ in participants from the GLOW study (Munir, 2023). GLOW (NCT03462719; n=211) was a phase III trial comparing fixed-duration ibrutinib+venetoclax to chlorambucil+obinutuzumab in participants with previously untreated CLL who were older and/or had comorbidities. MRD was assessed by clonoSEQ from samples collected every 3-4 months from peripheral blood and at 9 and 18 months from bone marrow. Detectable MRD defined as having ≥1 CLL cell per 10,000 leukocytes. Median follow-up was 34 months. PFS at 12 months after the end of treatment with ibrutinib+venetoclax was high regardless of MRD status at the end of treatment: 96% versus 93% in patients with undetectable MRD versus detectable MRD.
Oliva et al reported results of analyses of MRD status from samples available from the FORTE trial (Oliva, 2023). The FORTE trial was a phase 2, multicenter RCT including participants with newly diagnosed, transplant-eligible multiple myeloma randomized between 2015 and 2021 to one of three induction-intensification-consolidation strategies. Multiparameter flow cytometry (MFC) status was assessed in patients with at least a very good partial response first at premaintenance and then every 6 months during maintenance treatment until progressive disease. The cut-off for MFC MRD positivity was set at ≥20 clonal plasma cells out of the total of nucleated cells, with a sensitivity of ≥10−5. NGS was performed in a subset of participants with at least a suspected complete response at pre-maintenance and monitored every 6 months during maintenance treatment until progressive disease using the clonoSEQ® assay with sensitivities at 10-5 and 10-6. 2020 samples were available for analysis of MFC MRD status and 728 samples were available for the analysis of the correlation between MFC and NGS in the “suspected complete response population”. Median follow-up was 62 months. The hazard ratios for PFS in MFC-MRD and NGS-MRD-negative vs -positive patients were 0.29 (95% CI, 0.20 to 0.40) and 0.27 (95% CI, 0.18 to 0.39), respectively.
Costa et al reported results of the MASTER multicenter (5 centers), single-arm, phase 2 study conducted in the US between 2018 and 2020 (Costa, 2023). MASTER was the first study to use prospective adaptation of treatment duration based on MRD status but MRD status was used to guide therapy in all participants with sufficient unique clonogenic sequences. There is no comparison to management without MRD status. Instead, MASTER demonstrates the feasibility of using MRD to guide therapy. MASTER included 123 adults with newly diagnosed multiple myeloma, life expectancy >12 months, Eastern Cooperative Oncology Group (ECOG) performance status of 0–2, and no previous treatment except up to one cycle of therapy containing bortezomib, cyclophosphamide, and dexamethasone. 70 (57%) of the participants were men; 94 (76%) of participants were non-Hispanic White, 25 (20%) were non-Hispanic Black. The median age was 61 years (IQR, 55 to 68). 53 (43%) had no high-risk chromosome abnormalities (HRCA), 46 (37%) had one HRCA, and 24 (20%) had two or more HRCAs. The median follow-up duration was 42 months (IQR, 35 to 46). MRD status was assessed by clonoSEQ using a detection threshold of 10-5 to adjudicate response-adapted therapy. 5 participants had an absence of sufficiently unique clonogenic sequences to enable tracking by the clonoSEQ assay. 84 participants who reached MRD negativity after or during two consecutive treatment phases stopped treatment and began observation with MRD surveillance. 20 participants who did not reach two consecutive MRD-negative results received maintenance lenalidomide. 10 participants discontinued treatment early: 3 died, 5 had disease progression, and 2 chose to discontinue. Of the 84 participants who transitioned to MRD surveillance, 36-month progression-free survival (PFS) was 88% (95% CI, 77 to 96) for those with no HRCAs, 85% (95% CI, 73 to 96) for those with one HRCA, and 60% (95% CI, 35 to 82) for those with two or more HRCAs. 23 of the 84 participants (27%) resumed therapy due to MRD resurgence or disease progression not preceded by MRD resurgence.
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