Clinical UM Guideline
Subject: Gene Mutation Testing for Cancer Susceptibility and Management
Guideline #: CG-GENE-14 Publish Date: 06/29/2022
Status: Revised Last Review Date: 02/17/2022
Description

This document addresses gene mutation testing:

  1. To determine whether an individual is at risk for the development of malignant tumors (including but not limited to breast, colon, lung, pancreatic and ovarian cancers); and
  2. To guide targeted cancer therapy in individuals with malignant conditions.

This document also addresses the use of circulating tumor testing to assess solid malignant tumor gene mutations.

Note(s):

Clinical Indications

Medically Necessary:

  1. Gene Mutation Testing for Cancer Susceptibility (See Table A below)
    Gene mutation testing for cancer susceptibility is considered medically necessary when all of the following criteria are met:
    1. The genetic disorder is associated with a potentially significant cancer; and
    2. The risk of the significant cancer associated with the genetic disorder cannot be identified through biochemical or other testing; and
    3. A specific mutation, or set of mutations, has been established in the scientific literature to be reliably associated with the risk of developing malignancy; and
    4. The results of the genetic test may impact the medical management (for example, surveillance; life-style) of the individual; and
    5. Genetic counseling, which encompasses all of the following components, has been performed:
      1. Interpretation of family and medical histories to assess the probability of disease occurrence or recurrence; and
      2. Education about inheritance, genetic testing, disease management, prevention and resources; and
      3. Counseling to promote informed choices and adaptation to the risk or presence of a genetic condition; and
      4. Counseling for the psychological aspects of genetic testing.
  2. Gene Mutation Testing to Guide Targeted Cancer Therapy (See Table B below)
    Gene mutation testing to identify individuals who may benefit from the use of a targeted cancer therapy (associated therapeutic product [ATP]) is considered medically necessary when all of the following criteria are met:
    1. The individual is a candidate for targeted therapy using an ATP (for example, pharmaceutical or biologic treatment) and the mutation status of a specific gene is required prior to initiating treatment with the ATP; and
    2. A specific mutation, or set of mutations, has been established in the scientific literature to identify those most likely to respond to a targeted therapy or ATP.
  3. Circulating Tumor DNA (Liquid Biopsy) (See Table C below)
    Use of a circulating tumor DNA (ctDNA) test is considered medically necessary to guide targeted cancer therapies in individuals with solid tumors when the mutation(s) meets criteria “B” above and when formalin-fixed paraffin-embedded tumor tissue (FFPET) is inadequate in quality or quantity or is unavailable for testing.

Note: For information on circulating tumor DNA panel testing (defined by five or more genes or gene variants tested on the same day on the same member by the same rendering provider), see GENE.00052 Whole Genome Sequencing, Whole Exome Sequencing, Gene Panels, and Molecular Profiling or GENE.00049 Circulating Tumor DNA Panel Testing for Cancer (Liquid Biopsy).

Not Medically Necessary:

  1. Gene Mutation Testing for Cancer Susceptibility
    Gene mutation testing for cancer susceptibility is considered not medically necessary in individuals not meeting all of the Section A criteria above.
  2. Gene Mutation Testing to Guide Targeted Cancer Therapy
    Gene mutation testing to identify individuals who may benefit from the use of a targeted cancer therapy is considered not medically necessary when the medically necessary criteria in Section B above are not met.
  3. Circulating Tumor DNA (Liquid Biopsy)
    Use of a circulating tumor DNA (ctDNA) test is considered not medically necessary when the medically necessary criteria in Section C above is not met, including to detect the recurrence of a solid tumor, including colorectal cancer, and to test for solid tumor cancer susceptibility.
Coding

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

When services may be Medically Necessary when criteria are met:

CPT

 

81120

IDH1 (isocitrate dehydrogenase 1 [NADP+], soluble) (eg glioma), common variants (eg, R132H, R132C)

81121

IDH2 (isocitrate dehydrogenase 2 [NADP+], mitochondrial) (eg glioma), common variants (eg, R140W, R172M)

<81175

ASXL1 (additional sex combs like 1, transcriptional regulator) (eg, myelodysplastic syndrome, myeloproliferative neoplasms, chronic myelomonocytic leukemia), gene analysis; full gene sequence

81176

ASXL1 (additional sex combs like 1, transcriptional regulator) (eg, myelodysplastic syndrome, myeloproliferative neoplasms, chronic myelomonocytic leukemia), gene analysis; targeted sequence analysis (eg, exon 12)

81191

NTRK1 (neurotrophic receptor tyrosine kinase 1) (eg, solid tumors) translocation analysis

81192

NTRK2 (neurotrophic receptor tyrosine kinase 2) (eg, solid tumors) translocation analysis

81193

NTRK3 (neurotrophic receptor tyrosine kinase 3) (eg, solid tumors) translocation analysis

81194

NTRK (neurotrophic-tropomyosin receptor tyrosine kinase 1, 2, and 3) (eg, solid tumors) translocation analysis

81206

BCR/ABL1 (t(9;22)) (eg, chronic myelogenous leukemia) translocation analysis; major breakpoint, qualitative or quantitative

81207

BCR/ABL1 (t(9;22)) (eg, chronic myelogenous leukemia) translocation analysis; minor breakpoint, qualitative or quantitative

81208

BCR/ABL1 (t(9;22)) (eg, chronic myelogenous leukemia) translocation analysis; other breakpoint, qualitative or quantitative

81210

BRAF (B-Raf proto-oncogene, serine/threonine kinase) (eg, colon cancer, melanoma), gene analysis, V600 variant(s)

81218

CEBPA (CCAAT/enhancer binding protein [C/EBP], alpha) (eg, acute myeloid leukemia), full gene sequence

81219

CALR (calreticulin) (eg, myeloproliferative disorders), gene analysis, common variants in exon 9

81233

BTK (Bruton's tyrosine kinase) (eg, chronic lymphocytic leukemia) gene analysis, common variants (eg, C481S, C481R, C481F)

81235

EGFR (epidermal growth factor receptor) (eg, non-small cell lung cancer) gene analysis, common variants (eg, exon 19 LREA deletion, L858R, T790M, G719A, G719S, L861Q) [including but not limited to cobas® Mutation Test v2, OncoBEAM Lung1: EGFR, therascreen EGFR]

81236

EZH2 (enhancer of zeste 2 polycomb repressive complex 2 subunit) (eg, myelodysplastic syndrome, myeloproliferative neoplasms) gene analysis, full gene sequence

81237

EZH2 (enhancer of zeste 2 polycomb repressive complex 2 subunit) (eg, diffuse large B-cell lymphoma) gene analysis, common variant(s) (eg, codon 646)

81245

FLT3 (fms-related tyrosine kinase 3) (eg, acute myeloid leukemia), gene analysis; internal tandem duplication (ITD) variants (ie, exons 14, 15)

81246

FLT3 (fms-related tyrosine kinase 3) (eg, acute myeloid leukemia), gene analysis; tyrosine kinase domain (TKD) variants (eg, D835, I836)

81270

JAK2 (Janus kinase 2) (eg, myeloproliferative disorder) gene analysis, p.Val617Phe (V617F) variant

81272

KIT (v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog) (eg, gastrointestinal stromal tumor [GIST], acute myeloid leukemia, melanoma), gene analysis, targeted sequence analysis (eg, exons 8, 11, 13, 17, 18)

81273

KIT (v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog) (eg, mastocytosis), gene analysis, D816 variant(s)

81275

KRAS (Kirsten rat sarcoma viral oncogene homolog) (eg, carcinoma) gene analysis; variants in exon 2 (eg, codons 12 and 13)

81276

KRAS (Kirsten rat sarcoma viral oncogene homolog) (eg, carcinoma) gene analysis; additional variant(s) (eg, codon 61, codon 146)

81279

JAK2 (Janus kinase 2) (eg, myeloproliferative disorder) targeted sequence analysis (eg, exons 12 and 13)

81307

PALB2 (partner and localizer of BRCA2) (eg, breast and pancreatic cancer) gene analysis; full gene sequence

81308

PALB2 (partner and localizer of BRCA2) (eg, breast and pancreatic cancer) gene analysis; known familial variant

81309

PIK3CA (phosphatidylinositol-4, 5-biphosphate 3-kinase, catalytic subunit alpha) (eg, colorectal and breast cancer) gene analysis, targeted sequence analysis (eg, exons 7, 9, 20)

81310

NPM1 (nucleophosmin) (eg, acute myeloid leukemia) gene analysis, exon 12 variants

81311

NRAS (neuroblastoma RAS viral [v-ras] oncogene homolog) (eg, colorectal carcinoma), gene analysis, variants in exon 2 (eg, codons 12 and 13) and exon 3 (eg, codon 61)

81314

PDGFRA (platelet-derived growth factor receptor, alpha polypeptide) (eg, gastrointestinal stromal tumor [GIST]), gene analysis, targeted sequence analysis (eg, exons 12, 18)

81315

PML/RARalpha, (t(15;17)), (promyelocytic leukemia/retinoic acid receptor alpha) (eg, promyelocytic leukemia) translocation analysis; common breakpoints (eg, intron 3 and intron 6), qualitative or quantitative

81316

PML/RARalpha, (t(15;17)), (promyelocytic leukemia/retinoic acid receptor alpha) (eg, promyelocytic leukemia) translocation analysis; single breakpoint (eg, intron 3, intron 6 or exon 6), qualitative or quantitative

81320

PLCG2 (phospholipase C gamma 2) (eg, chronic lymphocytic leukemia) gene analysis, common variants (eg, R665W, S707F, L845F)

81321

PTEN (phosphatase and tensin homolog) (eg, Cowden syndrome, PTEN hamartoma tumor syndrome) gene analysis; full sequence analysis

81322

PTEN (phosphatase and tensin homolog) (eg, Cowden syndrome, PTEN hamartoma tumor syndrome) gene analysis; known familial variant

81323

PTEN (phosphatase and tensin homolog) (eg, Cowden syndrome, PTEN hamartoma tumor syndrome) gene analysis; duplication/deletion variant

81334

RUNX1 (runt related transcription factor 1) (eg, acute myeloid leukemia, familial platelet disorder with associated myeloid malignancy), gene analysis, targeted sequence analysis (eg, exons 3-8)

81338

MPL (MPL proto-oncogene, thrombopoietin receptor) (eg, myeloproliferative disorder) gene analysis; common variants (eg, W515A, W515K, W515L, W515R)

81339

MPL (MPL proto-oncogene, thrombopoietin receptor) (eg, myeloproliferative disorder) gene analysis; sequence analysis, exon 10

81347

SF3B1 (splicing factor [3b] subunit B1) (eg, myelodysplastic syndrome/acute myeloid leukemia) gene analysis, common variants (eg, A672T, E622D, L833F, R625C, R625L)

81348

SRSF2 (serine and arginine-rich splicing factor 2) (eg, myelodysplastic syndrome, acute myeloid leukemia) gene analysis, common variants (eg, P95H, P95L)

81357

U2AF1 (U2 small nuclear RNA auxiliary factor 1) (eg, myelodysplastic syndrome, acute myeloid leukemia) gene analysis, common variants (eg, S34F, S34Y, Q157R, Q157P)

81360

ZRSR2 (zinc finger CCCH-type, RNA binding motif and serine/arginine-rich 2) (eg, myelodysplastic syndrome, acute myeloid leukemia) gene analysis, common variant(s) (eg, E65fs, E122fs, R448fs)

81401

Molecular pathology procedure, Level 2 (eg, 2-10 SNPs, 1 methylated variant, or 1 somatic variant [typically using nonsequencing target variant analysis], or detection of a dynamic mutation disorder/triplet repeat) [when specified as the following]:

  • CBFB/MYH11 (inv(16)) (eg, acute myeloid leukemia), qualitative, and quantitative, if performed
  • EML4/ALK (inv(2)) (eg, non-small cell lung cancer), translocation or inversion analysis
  • ETV6/RUNX1 (t(12;21)) (eg, acute lymphocytic leukemia), translocation analysis, qualitative, and quantitative, if performed
  • MLL/MLLT3 (t(9;11)) (eg, acute myeloid leukemia), translocation analysis, qualitative, and quantitative, if performed
  • RUNX1/RUNX1T1 (t(8;21)) (eg, acute myeloid leukemia) translocation analysis, qualitative, and quantitative, if performed

81403

Molecular pathology procedure, Level 4 (eg, analysis of single exon by DNA sequence analysis, analysis of >10 amplicons using multiplex PCR in 2 or more independent reactions, mutation scanning or duplication/deletion variants of 2-5 exons) [when specified as the following]:

  • DNMT3A (DNA [cytosine-5-]-methyltransferase 3 alpha) (eg, acute myeloid leukemia), targeted sequence analysis (eg, exon 23)
  • GNAQ (guanine nucleotide-binding protein G[q] subunit alpha) (eg, uveal melanoma), common variants (eg, R183, Q209)
  • VHL (von Hippel-Lindau tumor suppressor) (eg, von Hippel-Lindau familial cancer syndrome), deletion/duplication analysis

81404

Molecular pathology procedure, Level 5 (eg, analysis of 2-5 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 6-10 exons, or characterization of a dynamic mutation disorder/triplet repeat by Southern blot analysis) [when specified as the following]:

  • FGFR2 (fibroblast growth factor receptor 2) (eg, craniosynostosis, Apert syndrome, Crouzon syndrome), targeted sequence analysis (eg, exons 8, 10)
  • FGFR3 (fibroblast growth factor receptor 3) (eg, achondroplasia, hypochondroplasia), targeted sequence analysis (eg, exons 8, 11, 12, 13)
  • MEN1 (multiple endocrine neoplasia 1) (eg, multiple endocrine neoplasia type 1, Wermer syndrome), duplication/deletion analysis
  • SDHC (succinate dehydrogenase complex, subunit C, integral membrane protein, 15kDa) (eg, hereditary paraganglioma-pheochromocytoma syndrome), duplication/deletion analysis
  • SDHD (succinate dehydrogenase complex, subunit D, integral membrane protein) (eg, hereditary paraganglioma), full gene sequence
  • STK11 (serine/threonine kinase 11) (eg, Peutz-Jeghers syndrome), duplication/deletion analysis
  • VHL (von Hippel-Lindau tumor suppressor) (eg, von Hippel-Lindau familial cancer syndrome), full gene sequence

81405

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

  • MEN1 (multiple endocrine neoplasia 1) (eg, multiple endocrine neoplasia type 1, Wermer syndrome ), full gene sequence
  • SMAD4 (SMAD family member 4) (eg, hemorrhagic telangiectasia syndrome, juvenile polyposis), duplication/deletion analysis
  • SDHB (succinate dehydrogenase complex, subunit B, iron sulfur) (eg, hereditary paraganglioma), full gene sequence
  • SDHC (succinate dehydrogenase complex, subunit C, integral membrane protein, 15kDa) (eg, hereditary paraganglioma-pheochromocytoma syndrome), full gene sequence
  • STK11 (serine/threonine kinase 11) (eg, Peutz-Jeghers syndrome), full gene sequence
  • WT1 (Wilms tumor 1) (eg, Denys-Drash syndrome, familial Wilms tumor), full gene sequence

81406

Molecular pathology procedure, Level 7 (eg, analysis of 11-25 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 26-50 exons, cytogenomic array analysis for neoplasia) [when specified as the following]:

  • CDH1 (cadherin 1, type 1, E-cadherin [epithelial]) (eg, hereditary diffuse gastric cancer), full gene sequence
  • SMAD4 (SMAD family member 4) (eg, hemorrhagic telangiectasia syndrome, juvenile polyposis), full gene sequence

81408

Molecular pathology procedure, Level 9 (eg, analysis of >50 exons in a single gene by DNA sequence analysis) [when specified as the following]:

  • ATM (ataxia telangiectasia mutated) (eg, ataxia telangiectasia), full gene sequence
  • NF1 (neurofibromin 1) (eg, neurofibromatosis, type 1), full gene sequence [considered medically necessary for breast cancer]

81479

Unlisted molecular pathology procedure [when specified as testing for the following genes: ABL2, BCOR, BMPR1A, BRIP1, CALT, CBF, CBF2, CBL, CHEK2, CRLF2, CSF1R, DDX41, EPOR, GATA2, IGHV, IL7R, JAK1, JAK3, KMT2A, MECOM (EVI1), MET, MYC, MYH11, NBN, PDGFRG, PHF6, PPM1D, RAD51C, RAD51D, RB1, ROS1, SDHAF2, SETBP1, SH2B3, STAG2, STAT3, TET2]

0016U

Oncology (hematolymphoid neoplasia), RNA, BCR/ABL1 major and minor breakpoint fusion transcripts, quantitative PCR amplification, blood or bone marrow, report of fusion not detected or detected with quantitation

BCR-ABL1 major and minor breakpoint fusion transcripts, University of Iowa, Department of Pathology, Asuragen

0017U

Oncology (hematolymphoid neoplasia), JAK2 mutation, DNA, PCR amplification of exons 12-14 and sequence analysis, blood or bone marrow, report of JAK2 mutation not detected or detected
JAK2 Mutation, University of Iowa, Department of Pathology

0023U

Oncology (acute myelogenous leukemia), DNA, genotyping of internal tandem duplication, p.D835, p.I836, using mononuclear cells, reported as detection or nondetection of FLT3 mutation and indication for or against the use of midostaurin
LeukoStrat® CDx FLT3 Mutation Assay, LabPMM LLC, an Invivoscribe Technologies, Inc company, Invivoscribe Technologies, Inc

0027U

JAK2 (Janus kinase 2) (eg, myeloproliferative disorder) gene analysis, targeted sequence analysis exons 12-15
JAK2 Exons 12 to 15 Sequencing, Mayo Clinic, Mayo Clinic

0040U

BCR/ABL1 (t(9;22)) (eg, chronic myelogenous leukemia) translocation analysis, major breakpoint, quantitative
MRDx BCR-ABL Test; MolecularMD

0046U

FLT3 (fms-related tyrosine kinase 3) (eg, acute myeloid leukemia) internal tandem duplication (ITD) variants, quantitative
FLT3 ITD MRD by NGS; LabPMM LLC, an Invivoscribe Technologies, Inc. Company

0049U

NPM1 (nucleophosmin) (eg, acute myeloid leukemia) gene analysis, quantitative
NPM1 MRD by NGS; LabPMM LLC, an Invivoscribe Technologies, Inc. Company

0111U

Oncology (colon cancer), targeted KRAS (codons 12, 13, and 61) and NRAS (codons 12, 13, and 61) gene analysis utilizing formalin-fixed paraffin-embedded tissue
PraxisExtended RAS Panel, Illumina, Illumina

0154U

Oncology (urothelial cancer), RNA, analysis by real-time RT-PCR of the FGFR3 (fibroblast growth factor receptor 3) gene analysis (ie, p.R248C [c.742C>T], p.S249C [c.746C>G], p.G370C [c.1108G>T], p.Y373C [c.1118A>G], FGFR3-TACC3v1, and FGFR3-TACC3v3), utilizing formalin-fixed paraffin-embedded urothelial cancer tumor tissue, reported as FGFR gene alteration status
therascreen® FGFR RGQ RT-PCR Kit, QIAGEN, QIAGEN GmbH

0155U

Oncology (breast cancer), DNA, PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha) (eg, breast cancer) gene analysis (ie, p.C420R, p.E542K, p.E545A, p.E545D [g.1635G>T only], p.E545G, p.E545K, p.Q546E, p.Q546R, p.H1047L, p.H1047R, p.H1047Y), utilizing formalin-fixed paraffin-embedded breast tumor tissue, reported as PIK3CA gene mutation status
therascreen® PIK3CA RGQ PCR Kit, QIAGEN, QIAGEN GmbH

0177U

Oncology (breast cancer), DNA, PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) gene analysis of 11 gene variants utilizing plasma, reported as PIK3CA gene mutation status
therascreen® PIK3CA RGQ PCR Kit, QIAGEN, QIAGEN GmbH

0235U

PTEN (phosphatase and tensin homolog) (eg, Cowden syndrome, PTEN hamartoma tumor syndrome), full gene analysis, including small sequence changes in exonic and intronic regions, deletions, duplications, mobile element insertions, and variants in non-uniquely mappable regions
Genomic Unity® PTEN Analysis, Variantyx Inc, Variantyx Inc

 

 

HCPCS

 

S3841

Genetic testing for retinoblastoma

S3842

Genetic testing for von Hippel-Lindau disease

 

 

ICD-10 Diagnosis

 

 

All malignancy-related diagnoses, including but not limited to

C00.0-C96.9

Malignant neoplasms

D45

Polycythemia vera

D47.01-D47.09

Mast cell neoplasms of uncertain behavior

D47.1

Chronic myeloproliferative disease [primary myelofibrosis]

D47.3

Essential (hemorrhagic) thrombocythemia

D47.4

Osteomyelofibrosis

E71.440

Ruvalcaba-Myhre-Smith syndrome

E88.89

Metabolic disorder, unspecified [Erdheim-Chester Disease]

Q85.8-Q85.9

Other/unspecified phakomatoses, not elsewhere classified [Peutz-Jeghers, von Hippel-Lindau syndromes, PTEN hamartoma syndrome]

Z15.01-Z15.09

Genetic susceptibility to malignant neoplasm

Z80.0-Z80.9

Family history of primary malignant neoplasm

Z85.00-Z85.9

Personal history of malignant neoplasm

When services are Not Medically Necessary:
For the procedure and diagnosis codes listed above when criteria are not met.

When services are also Not Medically Necessary:
For the following procedure codes; or when the code describes a procedure designated in the Clinical Indications section as not medically necessary.

CPT

 

81242

FANCC (Fanconi anemia, complementation group C) (eg, Fanconi anemia, type C) gene analysis, common variant (eg, IVS4+4A>T)

81403

Molecular pathology procedure, Level 4 (eg, analysis of single exon by DNA sequence analysis, analysis of >10 amplicons using multiplex PCR in 2 or more independent reactions, mutation scanning or duplication/deletion variants of 2-5 exons) [when specified as the following]:

  • HRAS (v-Ha-ras Harvey rat sarcoma viral oncogene homolog) (eg, Costello syndrome), exon 2 sequence

81404

Molecular pathology procedure, Level 5 (eg, analysis of 2-5 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 6-10 exons, or characterization of a dynamic mutation disorder/triplet repeat by Southern blot analysis) [when specified as the following]:

  • HRAS (v-Ha-ras Harvey rat sarcoma viral oncogene homolog) (eg, Costello syndrome), full gene sequence

81406

Molecular pathology procedure, Level 7 (eg, analysis of 11-25 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 26-50 exons, cytogenomic array analysis for neoplasia) [when specified as the following]:

  • BRAF (B-Raf proto-oncogene, serine/threonine kinase) (eg, Noonan syndrome), full gene sequence

81479

Unlisted molecular pathology procedure [when specified as testing for the following genes]:

  • MRE11A
  • RAD50
  • RECQL4
  • RINT1
  • SLX4
  • SMARCA4
  • XRCC2

0229U

BCAT1 (Branched chain amino acid transaminase 1) and IKZF1 (IKAROS family zinc finger 1) (eg, colorectal cancer) promoter methylation analysis
Colvera®, Clinical Genomics Pathology Inc

 

 

ICD-10 Diagnosis

 

 

All malignancy-related diagnoses, including but not limited to

C00.0-C96.9

Malignant neoplasms

Z15.01-Z15.09

Genetic susceptibility to malignant neoplasm

Z80.0-Z80.9

Family history of primary malignant neoplasm

Z85.00-Z85.9

Personal history of malignant neoplasm

Discussion/General Information

A. Gene Mutation Testing for Cancer Susceptibility in Individuals with Cancer (See Table A below)

Genetic testing for cancer susceptibility is used to predict an individual’s risk of cancer development in the future and to identify carriers (individuals who do not have the cancer but have a copy of a genetic variant which has been associated with the development of cancer). It has been estimated that approximately 5-10% of all cancers are considered to be hereditary (the result of inherited genetic susceptibility).

Genetic testing for cancer susceptibility (a form of predictive genetic testing) is generally carried out in asymptomatic individuals who are considered to be at high risk for developing cancer due to a strong family medical history of the disease, or other factors. Predictive genetic testing can be further divided into two categories: presymptomatic and predispositional. Presymptomatic predictive genetic testing confirms or denies the development of the disease in those at risk as the condition's genetic variant is highly penetrant and there is little or no variable expression. Predispositional predictive genetic tests provide information about an individual's risk of developing a specific disorder in the future. Predispositional predictive genetic testing is generally carried out for incompletely penetrant conditions and the results are not indicative of the inevitable occurrence of a condition or disease, nor are they a guarantee that a disease will not develop in the future.

One of the limitations of predictive genetic testing is the challenge in interpreting positive test results. Some individuals who test positive for a disease-associated variant may never develop the disease. In order to be useful in the clinical setting, the results of predictive genetic testing should have a high positive predictive value (PPV) and evidence should demonstrate that such results improve either disease prevention or management, as compared with care without genetic testing. Please refer to CG-GENE-13 Genetic Testing for Inherited Diseases for more information on the specific types of genetic tests, including but not limited to predictive genetic testing.

A position statement published by the American Society of Clinical Oncology (ASCO) indicates that genetic testing for cancer susceptibility is appropriate when the:

1) Individual has personal or family history features suggestive of a genetic cancer susceptibility condition, 2) the genetic test can be adequately interpreted, and 3) the test results will aid in diagnosis or influence the medical or surgical management of the patient or family members at hereditary risk of cancer (ASCO, 2003).

ASCO also recommends that genetic testing only be provided in the setting of pre- and post-test counseling, which should include a discussion of the risks and benefits of cancer early detection and prevention modalities (ASCO, 2003).

In assessing the value of a specific genetic test for susceptibility to a particular malignant condition, consideration should be given to the peer-reviewed, published literature addressing the analytical validity, clinical validity, and clinical utility of the test. Each genetic test must be carefully evaluated to determine whether or not the identified variant reliably identifies a specific type of cancer, and that the results of the genetic test, whether affirmative or negative, will impact the clinical management of the individual (for example, guide treatment decisions, surveillance recommendations or preventive strategies). The results of genetic testing are also expected to improve net health outcomes, (that is, the anticipated health benefits of the interventions outweigh any harmful effects [medical or psychological] of the intervention).

The National Comprehensive Cancer Networks (NCCN) guidelines do not contain recommendations for the general strategy of testing a tumor for a wide range of biomarkers. However, the guidelines do contain recommendations for specific genetic testing for individual cancers, when there is a known drug-biomarker combination that has demonstrated benefits for that particular type of tumor, such as non-small cell lung cancer (NCCN NSCLC).

PTEN Hamartoma Tumor Syndrome

Germline mutations in PTEN have been identified in a variety of rare syndromic manifestations that are collectively known as PTEN hamartoma tumor syndrome (PHTS). The defining clinical feature of PHTS is the presence of hamartomatous tumors, benign tumors resulting from an overgrowth of normal tissue. The phenotypic spectrum of PHTS includes Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome (BRRS), and adult Lhermitte-Dulcos disease (ALDD). Notably, germline mutations in PTEN are also associated with adult Lhermitte-Dulcos disease, autism spectrum disorders with macrocephaly, and possibly intellectual disability/developmental delay with macrocephaly. The estimated penetrance of PTEN mutation is approximately 80%, although risk estimates vary.

CS is characterized by multiple hamartomas and/or an increased risk of developing cancerous lesions in various tissues and organs, including the skin, mucous membranes, breast, thyroid, endometrium and brain. Other cancers associated with CS include colorectal cancer, kidney cancer, and possibly melanoma. Additional conditions associated with CS include macrocephaly and Lhermitte-Duclos disease. A small percentage of affected individuals have delayed development or intellectual disability. The features of CS overlap with those of BRRS.

The BRRS variant of Cowden syndrome/PHTS is characterized by the presence of macrocephaly, gastrointestinal hamartomatous polyps, multiple lipomas, hemangiomas, developmental delay, and in males, pigmented macules of the glans penis. The signs of BRRS that may be present at birth include macrocephaly and macrosomia. Developmental delays may present in early childhood. Other signs associated with BRRS include pectus excavatum, hypotonia, hyperextensibility of joints, thyroid disorders, seizures and scoliosis.

Adult Lhermitte-Dulcos disease (ALDD, also known as dysplastic gangliocytoma of the cerebellum) is characterized by the development of slow-growing, benign hamartomatous outgrowths of the cerebellum. The lesions typically arise in the cerebellar hemispheres, most frequently in the left hemisphere. This condition is most frequently seen in adults, with the average age at diagnosis of 34 years. Developmental abnormalities including macrocephaly and intellectual developmental disorder are common. A presumptive diagnosis of PHTS may be made based on clinical findings; however, a definitive diagnosis of PHTS is made when genetic testing identifies a germline mutation.

The diagnostic criteria for CS are multifaceted. The NCCN guidelines include testing criteria and clinical diagnostic criteria for CS. According to the NCCN guidelines, the CS/PHTS testing algorithm was established to assist in determining which individuals are candidates for testing for PTEN pathogenic or likely pathogenic variants and can be used to evaluate the need for further risk assessment and genetic testing. The revised clinical diagnostic criteria can be used to identify clinical features associated with CS/PHTS. Individuals who meet the revised clinical diagnostic criteria for CS/PHTS are candidates for testing for PTEN pathogenic or likely pathogenic variants (NCCN Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic, 2022).

According to the NCCN guidelines, the testing criteria for CS/PHTS are divided into three categories (see criteria below). An individual is considered for testing for PTEN pathogenic or likely pathogenic variants based on whether he or she meets specific criteria or combinations of criteria from these three categories.

  1. The first category includes any individual with a personal history of BRRS, adult LDD, autism spectrum disorder with macrocephaly, or two or more biopsy-proven trichilemmomas. Additionally, individuals with a family history positive for the presence of a known PTEN pathogenic or likely pathogenic variant.
  2. The next category represents “major” features which have been associated with CS/PHTS. An individual exhibiting at least two of the major criteria where one of these is macrocephaly meets the threshold for genetic testing. Similarly, an individual exhibiting three or more of the major criteria without macrocephaly or an individual who meets one of the major criteria and three or more of the minor criteria, would also meet the genetic testing threshold. If an individual has two or more major criteria but does not have macrocephaly, then one of the major criteria may be included as one of the three minor criteria in order to meet the testing threshold. Lastly, an individual with a first-degree relative diagnosed with CS/PHTS or BRRS for whom testing has not been performed would also fulfill the threshold for PTEN testing if the individual meets at least one major criterion and two or more minor criteria. With respect to the presence of mucocutaneous lesions, the panel did not consider the published evidence sufficient to specify an exact number or extent of these lesions required for the condition to be defined as a major criterion for Cowden syndrome. The NCCN panel also felt that evidence from the literature was not sufficient to include fibrocystic breast disease, uterine fibroids or fibromas as part of the testing criteria.
  3. The final category of criteria includes features with a “minor” association with CS/PHTS. In order to fulfill the genetic testing criteria in this category, an individual would need to meet at least four or more of the minor criteria or three or more minor criteria and one of the major criteria.  

It is also worth noting that an individual with a first-degree relative diagnosed with CS or BRRS for whom testing has not been completed would also meet the PTEN gene mutation testing criteria provided the individual meets at least one of the major criteria and two or more of the minor criteria (NCCN Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic, 2022).

The testing criteria below provides a summary of NCCN’s testing criteria for CS/PHTS as well as the major and minor criteria.

  • Individual has a family history of a known PTEN pathogenic or likely pathogenic variant: OR
  • Individual meets the clinical diagnostic criteria for CS/PHTS as evidenced by Any of the following:
    • Personal history of Bannayan-Riley-Ruvalcaba syndrome (BRRS); or
    • Personal history of Adult Lhermitte-Duclos disease; or
    • Personal history of autism spectrum disorder AND macrocephaly; or
    • Personal history of two or more biopsy-proven trichilemmomas:
      OR
  • Individual has ANY of the following combinations of the “Major*” criteria (features) associated with CS/PHTS:
    • Personal history of two or more major criteria (one of which is macrocephaly); or
    • Personal history of three or more major criteria without macrocephaly; or
    • Personal history of one major criterion and three or more minor criteria; or
    • If an individual has two or more major criteria but does not have macrocephaly, then one of the major criteria can be included as one of the three minor criteria to fulfill the testing threshold.
      OR
  • Individual has ANY of the following combinations of the “Minor+” criteria (features) associated with CS/PHTS:
    • Personal history of four or more minor criteria: or
    • As mentioned above, individual has a personal history of three or more minor criteria and one of the major criteria.
      OR
  • Individual has a first-degree relative who has a clinical diagnosis of CS, PHTS or BRRS for who testing to confirm the diagnosis of CS/PHTS has not been performed, provided the individual meets at least one of the major criteria or two or more of the minor criteria.

 

*Major Criteria (Features)

+Minor Criteria (Features)

  • Breast cancer
  • Endometrial cancer
  • Follicular thyroid cancer
  • Multiple GI hamartomas or ganglioneuromas
  • Macrocephaly (megalocephaly) (that is, ≥ 97%, 58 cm in adult female, 60 cm in adult male)
  • Macular pigmentation of glans penis
  • Mucocutaneous lesions
    • One biopsy-proven trichilemmoma
    • Multiple palmoplantar keratoses
    • Multifocal or extensive oral mucosal papillomatosis
    • Multiple cutaneous facial papules (often verrucous)
  • Autism spectrum disorder
  • Colon cancer
  • ≥ 3 esophageal glycogenic acanthoses
  • Lipomas
  • Intellectual disability (that is, IQ < 75)
  • Papillary or follicular variant of papillary thyroid cancer
  • Thyroid structural lesions (that is, adenoma, nodule[s], goiter)
  • Renal cell carcinoma
  • Single GI hamartomas or ganglioneuroma
  • Testicular lipomatosis
  • Vascular anomalies (including multiple intracranial developmental venous anomalies)

TABLE A: Testing for conditions listed in the table below without a “Yes” in the column for “Clinical Utility of Gene Mutation Testing for Cancer Susceptibility Demonstrated” have not been shown to be useful in making determinations regarding cancer susceptibility. In many cases, this is because knowledge of the genetic status does not change management. The following table lists commonly requested gene testing targets along with an assessment of whether or not they have been shown to be useful in determining if an individual is at increased risk for the development of a specific type of malignancy or in guiding clinical management in an at-risk individual (for example, increased cancer surveillance).

TABLE A Gene Mutation Testing for Cancer Susceptibility
(Return to Clinical Indications)(Return to Discussion/General Information)

Gene

Condition

Clinical Utility of Gene Mutation Testing for Cancer Susceptibility Demonstrated

APC

Colorectal cancer

CG-GENE-15 Genetic Testing for Lynch Syndrome, Familial Adenomatous Polyposis (FAP), Attenuated FAP and MYH-associated Polyposis

ATM

Breast cancer

CG-GENE-16 BRCA Genetic Testing
GENE.00052 Whole Genome Sequencing, Whole Exome Sequencing, Gene Panels, and Molecular Profiling

RAD.00036 MRI of the Breast

BARD1

Breast cancer

CG-GENE-16  BRCA Genetic Testing
GENE.00052 Whole Genome Sequencing, Whole Exome Sequencing, Gene Panels, and Molecular Profiling

Ovarian cancer

No

BMPR1A

Familial Juvenile Polyposis

Yes

BRCA1

Breast cancer

CG-GENE-16 BRCA Genetic Testing

GENE.00052 Whole Genome Sequencing, Whole Exome Sequencing, Gene Panels, and Molecular Profiling

BRCA2

Breast cancer

CG-GENE-16 BRCA Genetic Testing

GENE.00052 Whole Genome Sequencing, Whole Exome Sequencing, Gene Panels, and Molecular Profiling

BRIP1

Ovarian cancer

Yes

CDH1

Breast cancer

RAD.00036 MRI of the Breast

Hereditary diffuse gastric cancer

RAD.00036 MRI of the Breast

Ovarian cancer

No

CHEK2

Breast cancer

CG-GENE-16 BRCA Genetic Testing
GENE.00052 Whole Genome Sequencing, Whole Exome Sequencing, Gene Panels, and Molecular Profiling

RAD.00036 MRI of the Breast

EPCAM

 

Lynch-related tumors (cancers) including: colorectal, gastric, small bowel, endometrial, ovarian, pancreas, ureter, renal pelvis, biliary tract, brain, sebaceous gland adenomas and keratocanthomas

CG-GENE-15 Genetic Testing for Lynch Syndrome, Familial Adenomatous Polyposis (FAP), Attenuated FAP and MYH-associated 

FANCC

Breast cancer

No

Ovarian cancer

No

MEN1

Multiple endocrine neoplasia type 1 (MEN1)

Yes

MET

Non-small cell lung cancer

Yes

MLH1

 

Lynch-related tumors (cancers) including: colorectal, gastric, small bowel, endometrial, ovarian, pancreas, ureter, renal pelvis, biliary tract, brain, sebaceous gland adenomas and keratocanthomas

CG-GENE-15 Genetic Testing for Lynch Syndrome, Familial Adenomatous Polyposis (FAP), Attenuated FAP and MYH-associated Polyposis

 

MRE11A

Breast cancer

No

Ovarian cancer

No

MSH2

 

Lynch-related tumors (cancers) including: colorectal, gastric, small bowel, endometrial, ovarian, pancreas, ureter, renal pelvis, biliary tract, brain, sebaceous gland adenomas and keratocanthomas

CG-GENE-15 Genetic Testing for Lynch Syndrome, Familial Adenomatous Polyposis (FAP), Attenuated FAP and MYH-associated Polyposis

MSH6

 

Lynch-related tumors (cancers) including: colorectal, gastric, small bowel, endometrial, ovarian, pancreas, ureter, renal pelvis, biliary tract, brain, sebaceous gland adenomas and keratocanthomas

CG-GENE-15 Genetic Testing for Lynch Syndrome, Familial Adenomatous Polyposis (FAP), Attenuated FAP and MYH-associated Polyposis

MUTYH (MYH)

Colorectal cancer

CG-GENE-15 Genetic Testing for Lynch Syndrome, Familial Adenomatous Polyposis (FAP), Attenuated FAP and MYH-associated Polyposis

NBN

Breast cancer

Yes

NF1

Breast Cancer

Yes

PALB2

Breast cancer

CG-GENE-16 BRCA Genetic Testing
GENE.00052

RAD.00036 MRI of the Breast

Gastric cancer

No

PMS2

 

Lynch-related tumors (cancers) including: colorectal, gastric, small bowel, endometrial, ovarian, pancreas, ureter, renal pelvis, biliary tract, brain, sebaceous gland adenomas and keratocanthomas

CG-GENE-15 Genetic Testing for Lynch Syndrome, Familial Adenomatous Polyposis (FAP), Attenuated FAP and MYH-associated Polyposis

PTEN

 

Ovarian cancer

No

PTEN hamartoma tumor syndrome, Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome (BRRS) and Adult Lhermitte-Duclos disease (ALDD)

Yes;
see Discussion section

 

RAD50

Breast cancer

No

Ovarian cancer

No

RAD51C

 

Breast cancer

CG-GENE-16 BRCA Genetic Testing

GENE.00052 Whole Genome Sequencing, Whole Exome Sequencing, Gene Panels, and Molecular Profiling 

Ovarian cancer

Yes

RAD51D

Breast cancer

CG-GENE-16 BRCA Genetic Testing

GENE.00052 Whole Genome Sequencing, Whole Exome Sequencing, Gene Panels, and Molecular Profiling 

Ovarian cancer

Yes

RB1

Retinoblastoma

Yes

RECQL4

Breast cancer

No

Ovarian cancer

No

RET

Multiple endocrine neoplasia type 2 (MEN2)

CG-GENE-17 RET Proto-oncogene Testing for Endocrine Gland Cancer Susceptibility

RINT1

Breast cancer

No

Ovarian cancer

No

SDHAF2

Hereditary paraganglioma-pheochromocytoma syndrome

Yes

SDHB

Hereditary paraganglioma-pheochromocytoma syndrome

Yes

SDHC

Hereditary paraganglioma-pheochromocytoma syndrome

Yes

SDHD

Hereditary paraganglioma-pheochromocytoma syndrome

Yes

SLX4

Breast cancer

No

Ovarian cancer

No

SMAD4

Colorectal cancer

Yes

Juvenile polyposis syndrome

Yes

SMARCA4

Breast cancer

No

Ovarian cancer

No

STK11

Breast cancer

RAD.00036 MRI of the Breast

Colorectal cancer

Yes

Peutz-Jegher syndrome

Yes

TP53

Breast cancer

CG-GENE-18 Genetic Testing for TP53 Mutations

Li-Fraumeni syndrome

CG-GENE-18 Genetic Testing for TP53 Mutations

VHL

Von Hippel-Lindau Syndrome

Yes

WT1

Wilms tumor

Yes

XRCC2

Breast cancer

No

Ovarian cancer

No

B.  Gene Mutation Testing to Guide Targeted Therapy in Individuals with a Malignant Condition (See Table B below)

Increased understanding of the human genome has made it possible to identify genomic variation in both normal and malignant tissues. Newer therapies may be targeted to specific variants ("targeted biologic therapy") and may not have been evaluated in individuals without the specific variant or be considered unlikely to benefit individuals without the specific variant.

Examples of targeted therapies include those that:

The Food and Drug Administration (FDA) has approved numerous companion diagnostic devices to detect variants in specific genes for the targeted treatment of cancer. Methodologies include, but are not necessarily limited to: immunohistochemistry (IHC), real-time or multiplex polymerase chain reaction (PCR), fluorescence in situ hybridization (FISH), and next generation sequencing (NGS). As an example of a targeted cancer therapy, in 2017, the FDA approved IDHIFA® (enasidenib) for the treatment of relapsed or refractory acute myeloid leukemia (AML). However, the FDA drug label also stipulated that IDHIFA should only be used in individuals with an isocitrate dehydrogenase-2 (IDH2) mutation as detected by an FDA approved test.

In some cases, genetic testing, also called molecular characterization, is recommended for risk stratification and treatment planning, which affects choice of chemotherapeutic regimen, surveillance considerations, and minimal (measurable) disease detection.

Targeted Therapy and Treatment Planning for Leukemias

Leukemia, which is sometimes referred to as a blood cancer, begins early blood-forming cells. Frequently, leukemia starts the white blood cells, but some leukemias start in other blood cell types. There are various forms of leukemia, which are generally categorized based on whether the leukemia is acute (fast growing) or chronic (slower growing), and whether it starts in myeloid cells or lymphoid cells. Targeted therapy may be used for the treatment of various types of leukemias.

Acute Lymphoblastic Leukemia

Acute lymphoblastic leukemia (also known lymphoblastic lymphoma [ALL/LBL] and acute lymphocytic leukemia) refers to blood malignancies of lymphoid precursor cells. These entities are described as ALL/LBL because in this setting, leukemia and lymphoma display overlapping clinical presentations of the same disease; the systems for classification and diagnosis do not distinguish between leukemia and lymphoma. Broadly, ALL/LBL is divided into tumors of B cell and T cell descent; tumors of natural killer (NK) cell lineage are also recognized but occur less frequently. Because the various subtypes are morphologically indistinguishable, immunophenotyping is required to determine the lineage.

Most cases of ALL/LBL have molecular and/or cytogenetic abnormalities that are associated with unique phenotypes, prognostic features, and/or influence the choice of treatment. The World Health Organization (WHO) classification system uses immunophenotype and cytogenetic/molecular features to delineate specific categories of ALL/LBL.

With regards to gene mutation testing in individuals suspected of having ALL/LBL, the NCCN recommends:

The Ph-like phenotype is associated with recurrent gene fusions and mutations that activate tyrosine kinase pathways and includes gene fusions involving ABL1, ABL2, CRLF2, CSFIR, EPOR, JAK2, and PDGFRD and mutations involving FLT3, IL7R, SH2B3, JAK1, JAK3, and JAK2 (in combination with CRLF2 gene fusions). Testing for these abnormalities at diagnosis may aid in risk stratification. The safety and efficacy of targeted agents in this population is an area of active research… In cases of hypodiploid ALL where germline TP53 mutations are common, testing should be considered (NCCN ALL, 2021). 

For information on ALL mutation analysis, please refer to CG-GENE-07 BCR-ABL Mutation Analysis.

Acute Myeloid Leukemia

Acute myeloid leukemia (AML) refers to a group of leukemias that arise from a myeloid precursor in the bone marrow. Although AML is fairly rare overall, accounting for only about 1% of all cancers it is still one of the most common types of leukemia in adults. Cytogenetically normal AML is the largest defined subclass of AML and accounts for approximately 45% of all AML cases. In spite of the lack of cytogenetic abnormalities, these cases frequently have genetic variants that influence outcomes. The incidence of AML increases with age, with a median age at diagnosis of 68 years. Clinical signs and symptoms include but are not limited to, anemia, neutropenia, and thrombocytopenia. AML is also known as acute myelocytic leukemia, acute myelogenous leukemia, acute granulocytic leukemia, acute non-lymphocytic leukemia) (ACS, 2022).

Management of individuals with AML relies on the results of genetic testing to inform diagnosis, prognosis, and predict response to therapy. Abnormalities in specific genes, such as mutations in ASXL1, BCR-ABL, c-KIT, FLT3-ITD, FLT3-TKD, NPM1, CEBPA (biallelic), IDH1, IDH2, PML-RARA, RUNX1, and TP53 confer prognostic significance in adults with AML. In addition to prognostic implications, some gene may impact medical decision making or have therapeutic significance in AML (NCCN AML 2022).

The revised 2008 World Health Organization (WHO) AML classification scheme emphasizes the importance of genetic testing in AML Similarly, NCCN recommends that all individuals suspected of having AML be tested for specific gene mutations. Because numerous mutations are associated with AML, testing using multiplex gene panels and comprehensive next-generation sequencing (NGS) analysis may be used for the ongoing management of AML and various phases of treatment (NCCN AML 2022; Swerdlow, 2008). For information on gene panel testing in MDS, please refer GENE.00052 Whole Genome Sequencing, Whole Exome Sequencing, Gene Panels, and Molecular Profiling.

Acute Promyelocytic Leukemia

Acute promyelocytic leukemia (APL) is a biologically and clinically distinct variation of AML. In particular, individuals with APL typically present with symptoms related to complications of anemia, neutropenia, and thrombocytopenia. Other signs and symptoms include combinations of weakness and easy fatigability, infections of variable severity, and/or hemorrhagic findings such as gingival bleeding, ecchymoses, menorrhagia or epistaxis. Unique to APL is a presentation with bleeding caused by disseminated intravascular coagulation. Frequently, by the time that individual seeks medical care, the situation has become a life-threatening emergency because of the risk of catastrophic bleeding. Often, at diagnosis, the marrow is nearly 100 percent replaced by malignant promyelocytes, which results in severe anemia, thrombocytopenia, and neutropenia.

APL represents a medical emergency with a high rate of mortality due to hemorrhage. Treatment of the bleeding disorder is usually initiated as soon as the diagnosis is suspected based on cytologic criteria, and even before definitive cytogenetic or molecular confirmation of the diagnosis has been made. Gene mutation testing is not required to diagnose or treat APL. Diagnosis of APL may be made based on an evaluation of the clinical presentation, cell morphology, immunophenotyping, identification of PML/RARα rearrangements using karyotyping, real-time polymerase chain reaction (RT-PCR), or fluorescence in situ hybridization (FISH), and immunofluorescence with anti-PML monoclonal antibodies.

Chronic Lymphocytic Leukemia

Chronic lymphocytic leukemia (CLL) is one of the chronic lymphoid neoplasms (lymphoproliferative disorders) that is characterized by a progressive accumulation of functionally incompetent lymphocytes, which are usually of monoclonal origin. CLL is considered identical (that is, one disease with different manifestations) to small lymphocytic lymphoma (SLL). The term CLL is used when the disease manifests predominately in the blood, whereas the term SLL is used when involvement is predominately nodal.

The evaluation of suspected cases of CLL varies according to the presentation. The diagnosis of CLL is generally suspected in asymptomatic individuals when a routine blood count reveals an absolute lymphocytosis. Evaluation of such individuals would usually include a complete blood count with differential and peripheral blood immunophenotyping using flow cytometry. Tests to identify genetic changes that occur in CLL might include but are not necessarily limited to FISH and PCR to identify chromosomal deletions, 13 [del(13q)], and trisomy 12.

The NCCN guidelines on Chronic Lymphocytic Leukemia indicate that TP53 mutation status is associated with low response rates to chemoimmunotherapy and recommends that TP53 mutation testing be done to inform prognosis and/or therapy determination.

Del(17p), which reflects the loss of the TP53 gene and is frequently associated with mutations in the remaining TP53 allele, is associated with short treatment-free interval, short median survival (32 months), and poor response to chemotherapy. TP53 abnormalities can occur in the absence of del(17p) and TP53 mutations have been identified as predictors of resistance to fludarabine-based or bedamustine-based regimens and poor survival, independent of 17p chromosome status (NCCN Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, 2022).

Additionally, the NCCN also recommends that IGHV mutation status be determined prior to initiating treatment for CLL:

The choice of first-line treatment for CLL/SLL should be based on the disease stage, presence or absence of del(17p) or TP53 mutation, IGHV mutation status (if considering chemoimmunotherapy), patient’s age, performance status, comorbid conditions, and the agent’s toxicity profile. (NCCN Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, 2022).

The mutation status of at least two other genes have been identified as playing an important role in the selection of targeted therapies for the treatment of CLL. In individuals with CLL/SLL who do not have del(17p)/TP53 mutation, the NCCN states “testing for BTK and PLCG2 mutations may be useful in patients with disease progression or no response while on BTK inhibitor therapy. BTK and PLCG2 mutation status alone is not an indication to change treatment” (NCCN Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, 2022).

CLL is an extremely diverse disease with certain subsets of individuals having survival rates without treatment that are similar to the normal population. With the possible exception of allogeneic hematopoietic cell transplantation (HCT), there currently is no treatment option that can cure CLL. According to the NCCN: “Long-term results from several prospective studies have shown that allogeneic hematopoietic cell transplant (HCT) can provide long-term disease control and also overcome the poor prognosis associated with del(17p) and TP53 mutations” (NCCN Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, 2022).

Chronic Myeloid Leukemia

Chronic myeloid leukemia (CML), also known as chronic myelogenous, chronic myelocytic or chronic granulocytic leukemia) is a myeloproliferative neoplasm characterized by the poorly regulated production and uncontrolled proliferation of mature and maturing granulocytes with fairly normal differentiation. CML is associated with the BCR-ABL mutation that is formed by the combining of two genes: BCR (on chromosome 22) and ABL1 (on chromosome 9), resulting in the BCR-ABL1 fusion gene (also known as the Philadelphia chromosome). The presence of the BCR-ABL1 fusion gene confirms the diagnosis of CML. Testing for the BCR-ABL abnormality can be done using cytogenetics (chromosome analysis or karyotyping), FISH and RT-PCR (to detect and measure the BCR-ABL1 RNA transcripts in leukemic cell). DNA sequencing methods may be used to identify secondary mutations within BCR-ABL1 that are known to cause resistance to therapy.

Point mutations in the BCR-ABL1 kinase domain are a frequent mechanism of secondary resistance to tyrosine kinase inhibitor (TKI) therapy and are associated with poor prognosis and higher risk of disease progression.

The NCCN recommends that in individuals who present with advanced phase CML, the selection of TKI should be based on prior therapy and/or BCR-ABL1 mutation profile.

Additionally, according to the NCCN, “NGS allows for the detection of low-level BCR-ABL11 kinase domain mutations as well as resistance mutations in genes other than BCR-ABL1 that may confer resistance to TKIs or portend disease progression” and “NGS with myeloid mutation panel should be considered for patients with no identifiable BCR-ABL1 mutations” (NCCN Chronic Myeloid Leukemia, 2022). For information on BCR-ABL mutation analysis, please refer to CG-GENE-07 BCR-ABL Mutation Analysis.

The NCCN also recommends gene mutational analysis when allogeneic hematopoietic cell transplantation is being considered for patients with advanced phase CML

Hairy Cell Leukemia

Hairy cell leukemia (HCL) is a relatively uncommon chronic B cell lymphoproliferative disorder (lymphoid neoplasm) characterized by the build-up of small mature B cell lymphoid cells with abundant cytoplasm and "hairy" projections inside the peripheral blood, bone marrow, and splenic red pulp. This typically causes splenomegaly and a variable decline in the production of normal red blood cells, platelets, mature granulocytes, and monocytes. The amplified production of malignant cells, along with a decrease in these mature elements, results in a variety of systemic consequences, including, but not limited to, anemia, splenomegaly, bleeding, and an increased risk of infection.

The etiology of HCL is not completely understood. Most cases of HCL are believed to arise from a late, activated memory B cell somatic BRAF V600E gene mutation. The resultant abnormal activation of the RAF-MEK-ERK signaling pathway leads to a distinct phenotype and prolonged cell survival.

Exposures to environmental hazards such as ionizing radiation and pesticides have been mentioned as possible causes. Exposure to cigarette smoke, alcohol consumption, solvents and obesity do not appear to be risk factors for the development of HCL.

The diagnosis of HCL is generally made based on the results of bone marrow biopsy and aspirate in conjunction with immunophenotyping by flow cytometry. The aberrant (“hairy”) cells exhibit expression of pan-B cell antigens (for example, CD19, CD20, CD22) along with CD103, CD11c, and CD25. Gene mutation testing is typically not required to make the diagnosis of HCL.

Because this malignancy progresses very slowly and sometimes doesn't progress at all, it is not always necessary to begin treatment for HCL immediately after the diagnosis is confirmed.

Systemic Mastocytosis

Systemic mastocytosis is a rare disorder characterized by the expansion and focal accumulation of neoplastic mast cells (MC) in various organs, including the skin, spleen, liver, bone marrow and gastrointestinal tract. The World Health Organization (WHO) categorizes mastocytosis into cutaneous mastocytosis (CM), systemic mastocytosis (SM) and mast cell sarcoma (MCS). WHO also further delineates SM into additional categories based on disease-specific features:

  1. Indolent SM (ISM)
  2. Smoldering SM (SSM)
  3. Aggressive SM (ASM)
  4. SM with an associated hematopoietic neoplasm (SM-AHN) and
  5. MC leukemia (MCL).

MCS is a rare, localized, aggressive MC tumor that typically progresses to MCL within a short time. Advanced SM (ASM, SM-AHN, MCL) and MCS have unfavorable prognoses. Without successful therapy, the estimated median survival time in these individuals is less than 3 years. Once the diagnosis of SM has been made, the subtype (variant) of disease must be identified, as treatment and prognosis differ for each disorder\ (Valent, 2021).

Systemic mastocytosis is frequently diagnosed after affected individuals seek medical care for symptoms caused by the disorder. Symptoms of systemic mastocytosis may include cutaneous lesions, flushing, itching, hives, abdominal pain, diarrhea, nausea or vomiting, bone or muscle pain, anemia, bleeding disorders, splenomegaly, lymphadenopathy, depression, mood changes and problems concentrating.

A somatic mutation in the KIT gene is the most common genetic alteration found in systemic mastocytosis. The KIT gene encodes a protein that helps regulate cell growth and division. When the KIT gene is mutated, it can cause uncontrolled production of MCs which then accumulate in various organs of the body.

With regards to gene mutation testing for individuals suspected of having systemic mastocytosis, the NCCN recommends that:

If a diagnosis of SM is suspected, molecular testing for KIT D816V using an assay with high sensitivity (eg, ASO-qPCR or digital droplet PCT) can first be undertaken on the peripheral blood, in combination with measurement of the serum tryptase level and evaluation of clinical signs and/or symptoms suggestive of SM-related organ involvement.

Following a positive test of peripheral blood, KIT mutational analysis may also be performed on the bone marrow aspirate. Fresh bone marrow is aspirate is preferable but formalin-fixed paraffin-embedded tissue can also be used. Decalcified tissue typically interferes with DNA/RNA assays, and thus, decalcified BM should not be used for mutational analysis. If initial screening of the peripheral blood fails to detect the KIT D816V mutation in a patient with suspected SM, testing of the bone marrow should be undertaken with a highly sensitive assay (eg, ASO-qPCR or digital droplet PCR).

Additionally, the NCCN recommends:

Myeloid mutation panel testing should be performed on the bone marrow, but can be performed on the peripheral blood in the presence of an AHN and/or circulating mast cells. Myeloid mutation panels alone are not recommended for the detection of KIT D816V. Next-generation sequencing (NGS) assays can exhibit low sensitivity and higher-sensitivity assays should always be performed (NCCN Systemic Mastocytosis, 2021).

Currently, there is no treatment of systemic mastocytosis. Treatment is targeted at relieving the effects of MC overgrowth and avoiding environmental and dietary triggers.

Targeted Therapy and Treatment Planning for Myelodysplastic Syndromes

The myelodysplastic syndromes (MDS) consist of a group of blood malignancies characterized by clonal hematopoiesis, one or more cytopenias (ie, anemia, neutropenia, and/or thrombocytopenia), and atypical cellular maturation. MDS shares some pathologic and clinical features with AML, but MDS has a lower percentage of blasts in bone marrow and peripheral blood (by definition, < 20 percent). Individuals with MDS are at risk for symptomatic anemia, infection, bleeding, and transformation to AML. Because the clinical presentation of MDS in individuals varies significantly, diagnosis and disease stratification are based on multiple factors including clinical data, morphology of peripheral blood and bone marrow, cytogenetics, fluorescence in situ hybridization (FISH), flow cytometry and next-generational sequencing myeloid mutations studies. The primary clinical challenge in these disorders are morbidities caused by cytopenias and the potential for MDS to evolve into acute myeloid leukemia (AML). Additionally, there are complications that may arise as a result of chronic transfusions, treatment toxicity and in some cases systemic inflammatory conditions (NCCN Myelodysplastic Syndromes, 2022).

Genetic frequently somatically mutated in MDS include: ASXL1, BCOR, CALR, CBL, DDX41, DNMT3A, ETV6, EZH2, FLT3, GATA2, IDH1, IDH2, JAK2, MPL, NF1, NPM1, NRAS, PHF6, PPM1D, RUNX1, SETBP1, SF3B1, SRSF2, STAG2, STAT3, TET2, TP53, U2AF1, WT1, ZRSR2. However, it is important to note that several MDS-associated genes, (including but not limited to DNMT3A, EZH2, NRAS, SF3B1, TP53 and TET2) can occur in non-disease states and no single gene mutation is diagnostic of MDS. Additionally, mutations in several genes can occur in neoplasms other than MDS including malignancies of lymphoid origin such as acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia (CLL). Therefore, mutations should not be considered presumptive evidence of MDS when the diagnostic criteria for MDS have not been met. Instead, gene mutation testing may be used to inform the diagnosis of MDS (NCCN Myelodysplastic Syndromes, 2022). For information on gene panel testing in MDS, please refer GENE.00052 Whole Genome Sequencing, Whole Exome Sequencing, Gene Panels, and Molecular Profiling.

Mutations in several genes have prognostic value. As an example, mutations of ASXL1, ETV6, EZH2, RUNX1 and TP53 have been associated with decreased overall survival, while only mutations in SF3B1 have been associated with a more favorable prognosis in several, but not all studies NCCN Myelodysplastic Syndromes, 2022). 

Therapeutic options for individuals with MDS include supportive care, low-intensity therapy, high-intensity therapy (including allogeneic HCT) and participation in clinical trials.

Targeted Therapy and Treatment Planning for Myeloproliferative Neoplasms (MPNs)/Myeloproliferative Disorders (MPDs)

The MPDs/MPNs are a large group of relatively rare pathogenetically related diseases arising in the bone marrow and characterized by the proliferation of one or more myeloid cell lines in the bone marrow resulting in increased numbers of relatively mature neoplastic cells in the peripheral blood. According to the World Health Organization (WHO) Classification of Tumours of Haematopoietic and Lymphoid Tissue, MPNs include chronic myelogenous leukemia (BCR-ABL1 positive [CML]), PV, PMF and ET. However, CML is unique in that it is the only one of these conditions that is positive for the BCR-ABL1 translocation. The others, PV, MF and ET are considered part of the operational sub-category of BCR-ABL1 negative conditions (Swerdlow, 2017).

MPNs are characterized by a complex collection of symptoms. The symptoms vary within and between each MPN subtype, but typically include constitutional symptoms such as fatigue, weight loss, pruritus, symptoms associated with splenomegaly, and a variety of laboratory abnormalities, including leukocytosis, thrombocytosis and erythrocytosis. And while there are a number of shared clinical features across the conditions, each of the three BCR-ABL–negative MPNs is considered a distinct clinical entity. ET is characterized by elevation in platelet count and megakaryocyte proliferation in the bone marrow. PV is distinguished by an increase in red blood cell production, with resulting increases in RBC mass and hemoglobin and hematocrit levels. Frequently, platelet and white blood cell count are also elevated. PMF is characterized by anemia, progressive splenomegaly and bone marrow fibrosis, and multi-organ extramedullary hematopoiesis. Most of these features, however, are not diagnostically specific, and secondary causes of erythrocytosis, thrombocytosis and bone marrow fibrosis must be excluded.

The BCR-ABL1–negative MPNs are genetically characterized by the overlapping presence of mutations in three driver genes—JAK2, CALR, and MPL. Mutations in either of these driver genes results in increased activity in the JAK/STAT signal transduction pathway.

The diagnosis and monitoring of individuals with BCR-ABL–negative MPN can be challenging because several of the clinical and laboratory features of the classic forms of these diseases-PV, ET, or PMF-can be mimicked by other conditions such as myeloid fibrosis. Additionally, these diseases cannot always be identified with certainty on morphologic bone marrow exam, and diagnosis can be complicated by altering disease patterns. As an example, PV and ET can undergo a leukemic transformation or evolve into PMF.

The 2017 WHO guidelines on the Classification of Tumours of Haematopoietic and Lymphoid Tissue were revised in 2017 to reflect the recent discovery of genetic abnormalities involved in the pathogenesis of BCR-ABL1 negative MPN. The WHO diagnostic criteria include a combination of clinical, laboratory cytogenetic, and molecular testing. The diagnosis of PMF requires the individual to meet 3 major and 2 minor criteria. The diagnosis of PV requires meeting both major criteria and one minor criterion or the presence of the first major criterion together with two minor criteria, whereas the diagnosis of ET requires meeting all 4 criteria The 2017 WHO criteria recommends that JAK2V617F and other clonal markers be tested in individuals suspected of having ET and PMF. WHO also recommends that testing for JAK2V617F and JAK2 exon 12 variants be conducted in individuals suspected of having PV. These guidelines also provide the following information regarding JAK2 mutation testing:

JAK2 mutations are not specific for any single clinical or morphologic MPN phenotype, and are also reported in some cases of myelodysplastic syndromes (MDS), myelodysplastic/myeloproliferative neoplasms (MDS/MPN) and acute myeloid leukaemia (AML). Thus, an integrated, multidisciplinary approach is necessary for the classification of myeloid neoplasms (Swerdlow, 2017).

The National Comprehensive Cancer Network (NCCN) guidelines on Myeloproliferative Neoplasms recommends that molecular testing for JAK2V617F mutations be performed in all individuals suspected of having ET, MF or PV. For individuals suspected of having PV, when JAK2V617F mutation testing is negative, molecular testing for the JAK2 exon 12 mutation should also be conducted. These NCCN guidelines include MPL mutation testing in the initial workup of all individuals suspected of having an MPN. The NCCN recommends that when JAK2 V617F mutation testing is negative, molecular testing for MPL and CALR mutations should be performed for individuals with MF and ET (NCCN, 2021).

Table B below contains a list of targeted cancer therapies, the associated cancer and the genetic variant that may be tested in order to direct targeted cancer therapy, including to guide recommended treatment planning. This information may be used to determine the appropriateness of a requested genetic test when considering the medical necessity criteria in the section above labeled: Gene Mutation Testing to Guide Targeted Cancer Therapy. Table B is current as of the publish date of this document. FDA approvals after the publish date (for example new drugs or new indications for existing drugs), will not be reflected in Table B until the next publish date. Reviewers should not rely solely on the absence of a drug/gene combination in Table B when determining whether a particular gene test meets the medical necessity criteria. For additional information and periodic updates on drug and companion diagnostic device approvals/clearances, visit the FDA websites at: https://labels.fda.gov/ and https://www.fda.gov/medical-devices/vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-vitro-and-imaging-tools.

TABLE B Gene Mutation Testing to Guide Targeted Cancer Therapy
(Return to Clinical Indications)(Return to Discussion/General Information)

Gene Mutation Status Tested

Condition

Cancer Treatment Considerations

Related Anthem Document

ABL1

Acute lymphoblastic leukemia (ALL)

Treatment planning (NCCN)

GENE.00052 Whole Genome Sequencing, Whole Exome Sequencing, Gene Panels, and Molecular Profiling

ABL2

Acute lymphoblastic leukemia (ALL)

Treatment planning (NCCN)

GENE.00052

ALK

 

Non-small cell lung cancer (NSCLC)

 

 

Alecensa (alectinib)

GENE.00052

Alunbrig (brigatinib)

Keytruda (pembrolizumab)

Gene mutation testing required to exclude individuals with EGFR or ALK genomic tumor abberations

Lorbrena (lorlatinib)

Opdivo (nivolumab)

Tecentriq (atezolizumab)

Xalkori (crizotinib)

Yervoy (ipilimumab)

Zykadia (ceritinib)

ASXL1

 

Acute myeloid leukemia (AML)

Treatment planning (NCCN)

GENE.00052

Myelodysplastic syndrome (MDS)

Treatment planning (NCCN)

GENE.00052

Myeloproliferative neoplasm (MPN)

Treatment planning (NCCN)

GENE.00052

BCOR

Myelodysplastic syndrome (MDS)

Treatment planning (NCCN)

GENE.00052

BCR-ABL

Acute myeloid leukemia (AML)

Treatment planning (NCCN)

GENE.00052

CG-GENE-07 BCR-ABL Mutation Analysis

BRAF

 

Central nervous system tumor(s)

FDA-approved BRAF inhibitor

 

 

Hairy cell leukemia

 

Hepatobiliary cancer

Tafinlar (dabrafenib)

 

Non-small cell lung cancer (NSCLC)

 

Opdivo (nivolumab)

GENE.00052

Yervoy (ipilimumab)

BRAF fusion

Pilocytic astrocytoma

Koselugo (selumetinib)

 

BRAF V600

 

Erdheim-Chester Disease

Zelboraf (vemurafenib)

 

Melanoma

 

Braftovi (encorafenib)

 

Cotellic (cobimetinib)

 

Mekinist (trametinib)

 

MEKTOVI (binimetinib)

 

Tafinlar (dabrafenib)

 

BRAF V600E

 

Anaplastic thyroid cancer

 

Mekinist (trametinib)

 

Tafinlar (dabrafenib)

 

Colorectal cancer

 

Braftovi (encorafenib

 

Erbitux (cetuximab)

 

Vectibix (panitumumab)

 

Hepatobiliary cancer

Mekinist (trametinib)

 

Melanoma

 

Braftovi (encorafenib

 

Cotellic (cobimetinib)

 

Mekinist (trametinib)

 

MEKTOVI (binimetinib)

 

Tafinlar (dabrafenib)

 

Zelboraf (vemurafenib)

 

Non-small cell lung cancer (NSCLC)

 

Erbitux (cetuximab)

GENE.00052

 

Mekinist (trametinib)

Tafinlar (dabrafenib)

Pilocytic astrocytoma

Koselugo (selumetinib)

 

BRAF V600K

 

Melanoma

 

Braftovi (encorafenib

 

Cotellic (cobimetinib)

 

Mekinist (trametinib)

 

MEKTOVI (binimetinib)

 

Tafinlar (dabrafenib)

 

BRCA

 

Breast cancer

 

Lynparza (olaparib)

GENE.00052

CG-GENE-16 BRCA Testing for Breast and/or Ovarian Cancer Syndrome

 

 

Talzenna (talazoparib)

Zejula (niraparib)

Ovarian cancer

Lynparza (olaparib)

Ovarian cancer (epithelial ovarian, fallopian tube, or primary peritoneal cancer)

Rubraca (rucaparib)

Pancreatic cancer

Lynparza (olaparib)

BTK

Chronic lymphocytic leukemia/Small lymphocytic lymphoma

Treatment planning (NCCN)

 

c-KIT

Acute myeloid leukemia (AML)

Treatment planning (NCCN)

GENE.00052

CALR

 

Myelodysplastic syndrome (MDS)

Treatment planning (NCCN)

GENE.00052

Myeloproliferative neoplasm (MPN)

Treatment planning (NCCN)

GENE.00052

CALT Type 1/

Type 1-like

Myeloproliferative neoplasm (MPN)

Treatment planning (NCCN)

 

CBF

Acute myeloid leukemia (AML)

Treatment planning (NCCN)

GENE.00052

CBF-MYH11

Acute myeloid leukemia (AML)

Treatment planning (NCCN)

GENE.00052

CBF2

Acute myeloid leukemia (AML)

Treatment planning (NCCN)

GENE.00052

CBL

Myelodysplastic syndrome (MDS)

Treatment planning (NCCN)

GENE.00052

CEBPA

Acute myeloid leukemia (AML)

Treatment planning (NCCN)

GENE.00052

CRLF2

Acute lymphocytic leukemia/lymphoblastic lymphoma (ALL/LBL)

Treatment planning (NCCN)

GENE.00052

CSFIR

Acute lymphocytic leukemia/lymphoblastic lymphoma (ALL/LBL)

Treatment planning (NCCN)

GENE.00052

DDX41

Myelodysplastic syndrome (MDS)

Treatment planning (NCCN)

GENE.00052

DNMT3A

Myelodysplastic syndrome (MDS)

Treatment planning (NCCN)

GENE.00052

EGFR

 

Non-small cell lung cancer (NSCLC)

 

Gilotrif (afatinib)

GENE.00052

Keytruda (pembrolizumab)

Gene mutation testing required to exclude individuals with EGFR or ALK genomic tumor abberations

GENE.00052

 

Opdivo (nivolumab)

Tecentriq (atezolizumab)

Yervoy (ipilimumab)

EGFR exon 19 deletions

 

Non-small cell lung cancer (NSCLC)

 

Iressa (gefitinib)

GENE.00052

 

Tagrisso (osimertinib)

Tarceva (erlotinib)

Vizimpro (dacomitinib)

EGFR exon 20

Non-small cell lung cancer (NSCLC)

Rybrevant (amivantamab)

GENE.00052

EGFR exon 20f

Non-small cell lung cancer (NSCLC)

Exkivity (mobocertinib)

GENE.00052

EGFR exon 21 (L858R) mutation

Non-small cell lung cancer (NSCLC)

Tagrisso (osimertinib)

GENE.00052

EGFR exon 21 (L858R) substitution

 

Non-small cell lung cancer (NSCLC)

 

Iressa (gefitinib)

GENE.00052

 

Tarceva (erlotinib)

EGFR T790M mutation

Non-small cell lung cancer (NSCLC)

Tagrisso (osimertinib)

GENE.00052

EPOR

Acute lymphocytic leukemia/lymphoblastic lymphoma (ALL/LBL)

Treatment planning (NCCN)

GENE.00052

ETV6

Myelodysplastic syndrome (MDS)

Treatment planning (NCCN)

GENE.00052

EZH2

 

Myelodysplastic syndrome (MDS)

Treatment planning (NCCN)

GENE.00052

Myeloproliferative neoplasm (MPN)

Treatment planning (NCCN)

 

FGFR2

Urothelial cancer

Balversa (erdafitinib)

 

FGFR2 fusion or non-fusion rearrangement

Cholangiocarcinoma

Truseltiq (infigratinib)

 

FGFR3

Urothelial cancer

Balversa (erdafitinib)

 

FLT3

 

Acute lymphocytic leukemia/lymphoblastic lymphoma (ALL/LBL)

Treatment planning (NCCN)

GENE.00052

Acute myeloid leukemia (AML)

 

Rydapt (midostaurin)

GENE.00052

Xospata (gilterinib)

Myelodysplastic syndrome (MDS)

Treatment planning (NCCN)

GENE.00052

FLT3-ITD

Acute myeloid leukemia (AML)

Treatment planning (NCCN)

GENE.00052

FLT3-TKD

Acute myeloid leukemia (AML)

Treatment planning (NCCN)

GENE.00052

GATA2

 

Acute myeloid leukemia (AML)

Treatment planning (NCCN)

GENE.00052

Myelodysplastic syndrome (MDS)

Treatment planning (NCCN)

GENE.00052

Homologous recombination repair (HRR) gene alterations (for example: ATM, BARD1, BRIP1, BRCA1, BRCA2, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D,  RAD54L).

Prostate cancer

Poly(ADP-ribose) polymerase (PARP) inhibitor

GENE.00052

IDH1

Acute myeloid leukemia (AML)

Tibsovo (ivosidenib)

GENE.00052

Cholangiosarcoma

Tibsovo (ivosidenib)

 

Chondrosarcoma

Tibsovo (ivosidenib)

 

Myelodysplastic syndrome (MDS)

Treatment planning (NCCN)

GENE.00052

IDH2

 

Acute myeloid leukemia (AML)

 

Idhifa (enasidenib)

 

GENE.00052

 

Myelodysplastic syndrome (MDS)

Treatment planning (NCCN)

GENE.00052

IGHV

Chronic lymphocytic leukemia/Small lymphocytic lymphoma (CLL/SLL)

Treatment planning (NCCN)

GENE.00052

IL7R

Acute lymphocytic leukemia/lymphoblastic lymphoma (ALL/LBL)

Treatment planning (NCCN)

GENE.00052

ITD

Acute myeloid leukemia (AML)

Treatment planning (NCCN)

GENE.00052

JAK1

Acute lymphocytic leukemia/lymphoblastic lymphoma (ALL/LBL)

Treatment planning (NCCN)

GENE.00052

JAK2

 

Acute lymphocytic leukemia/lymphoblastic lymphoma (ALL/LBL)

Treatment planning (NCCN)

GENE.00052

Myelodysplastic syndrome (MDS)

Treatment planning (NCCN)

GENE.00052

Myeloproliferative neoplasm (MPN)

Treatment planning (NCCN)

GENE.00052

JAK3

Acute lymphocytic leukemia/lymphoblastic lymphoma (ALL/LBL)

Treatment planning (NCCN)

GENE.00052

KIT

Gastrointestinal stromal tumor

Gleevec (imatinib mesylate)

 

KIT D816V

Systemic mastocytosis

Treatment planning (NCCN)

 

KMT2A

Acute myeloid leukemia (AML)

Treatment planning (NCCN)

GENE.00052

KRAS

 

Colorectal cancer

 

Erbitux (cetuximab)

 

Vectibix (panitumumab)

 

KRAS G12C

Non-small cell lung cancer (NSCLC)

Lumakras (sotorasib

GENE.00052

MECOM (EVI1)

Acute myeloid leukemia (AML)

Treatment planning (NCCN)

GENE.00052

MET

 

Non-small cell lung cancer (NSCLC)

 

Tabrecta (capmatinib)

GENE.00052

 

Tepmetko (tepotinib)

Xalkori (crizotinib)

MLLT3

Acute myeloid leukemia (AML)

Treatment planning (NCCN)

GENE.00052

MPL

 

Myelodysplastic syndrome (MDS)

Treatment planning (NCCN)

GENE.00052

Myeloproliferative neoplasm (MPN) (MPL and MPL W515l/K)

Treatment planning (NCCN)

 

Acute myeloid leukemia (ALL) (MPL-RARA)

Treatment planning (NCCN)

 

MYC and BCL2 and/or BCL6

High grade B-cell lymphomas translocations

Levoleucovorin (levoleucovorin)

 

MYH11

Acute myeloid leukemia (AML)

Treatment planning (NCCN)

GENE.00052

NF1

Myelodysplastic syndrome (MDS)

Treatment planning (NCCN)

GENE.00052

NPM1

 

Acute myeloid leukemia (AML)

Treatment planning (NCCN)

GENE.00052

Myelodysplastic syndrome (MDS)

Treatment planning (NCCN)

GENE.00052

NRAS

 

Colorectal cancer

 

Erbitux (cetuximab)

 

Vectibix (panitumumab)

 

Myelodysplastic syndrome (MDS)

Treatment planning (NCCN)

GENE.00052

NTRK

Unresectable or metastatic solid tumors

Vitrakvi (larotrectinib)

 

PDGFRA

 

Gastrointestinal stromal tumor (PDGFRA D842V)

Gleevec (imatinib mesylate)

 

Unresectable or metastatic gastrointestinal stromal tumor (GIST) (PDGFRA D842V)

Ayvakit (avapritinib)

 

Unresectable or metastatic gastrointestinal stromal tumor (GIST) (PDGFRA exon 18)

Ayvakit (avapritinib)

 

PDGFRD

Acute lymphocytic leukemia/lymphoblastic lymphoma   GENE.00052
PHF6 Myelodysplastic syndrome (MDS) Treatment planning (NCCN) GENE.00052

Philadelphia chromosome (BCR-ABL)

Acute lymphoblastic leukemia (ALL)

_____________________

Chronic myeloid leukemia (CML)

Gleevec (imatinib mesylate)

_____________________

Tasigna (nilotinib)

CG-GENE-07 BCR-ABL Mutation Analysis
PIK3CA Breast cancer Piqray (alpelisib)  
PLCG2 Chronic lymphocytic leukemia/Small lymphocytic lymphoma Treatment planning (NCCN)  
PML-RARA Acute myeloid leukemia Treatment planning (NCCN) GENE.00052
PPM1D Myelodysplastic syndrome (MDS) Treatment planning (NCCN) GENE.00052
RAS

Myelodysplastic syndrome (MDS)

_____________________

Myeloproliferative neoplasm (MPN)

Treatment planning (NCCN)

____________________

Treatment planning (NCCN)

 
ROS1 Non-small cell lung cancer (NSCLC)

Opdivo (nivolumab)

____________________

Xalkori (crizotinib

____________________

Yervoy (ipilimumab)

 

GENE.00052
RUNX1

Acute myeloid leukemia (AML)

_____________________

Myelodysplastic syndromes (MDS)

Treatment planning (NCCN)

____________________

Treatment planning (NCCN)

GENE.00052

____________________

GENE.00052

RUNX1T1 Acute myeloid leukemia (AML) Treatment planning (NCCN)  
SETBP1 Myelodysplastic syndrome (MDS) Treatment planning (NCCN) GENE.00052
SF3B1 Myelodysplastic syndrome (MDS) Treatment planning (NCCN) GENE.00052

C.  Circulating Tumor DNA (Liquid Biopsy)

Cancer develops from genetic alterations in DNA that affect the way cells grow and divide. A tissue biopsy is the gold standard for detecting DNA alterations that can be used to identify cancer, determine treatment options, or evaluate responsiveness to treatment. Tissue biopsies have several disadvantages: the biopsy procedure may be painful, such as the insertion of a long needle or a surgical procedure; the retrieved tissue may be too small for analysis; or an individual may not be able to physically tolerate the procedure. In addition, because tissue biopsies only represent cellular samples from parts of a tumor, important diagnostic data could be missed.

Circulating tumor DNA (ctDNA), also known as liquid biopsy, is proposed as a less-invasive method for cancer identification, surveillance, and treatment guidance. The National Cancer Institute (NCI) defines liquid biopsy as “A test done on a sample of blood to look for cancer cells from a tumor that are circulating in the blood or for pieces of DNA from tumor cells that are in the blood.” Tests of ctDNA detect small fragments of mutated DNA that are released from tumors into blood, presumably by apoptosis and/or necrosis. These tests are being explored as a less-invasive diagnostic alternative to tissue biopsies to improve the selection of targeted therapeutic agents for late-stage cancers and for post-cancer monitoring.

There are several limitations of liquid biopsies. Regarding cancer management, many cancers do not have specific DNA variants that can be identified and, when present, can be different in individuals with the same cancer. The DNA found in the fluid sample may not fully represent the tumor and mislead treatment decisions. The genetic variants found may not be “driver” variants and may not provide useful information about the cancer. Regarding cancer detection, liquid biopsies can test positive for cancer when no cancer is present (false-positive) or test negative when cancer is present (false-negative). Because cancer cells release more mutated DNA fragments in later cancer stages, the test may not identify early cancer. Likewise, a liquid biopsy can detect cancerous cells that may never actually cause harm, leading to overtreatment (NCI, 2018). While liquid biopsies are promising, a great deal of research is still needed to determine when these tests improve outcomes for individuals with cancer. Nonetheless, in circumstances when tumor tissue is inadequate in quality or quantity or is unavailable for testing, and the presence or absence of a variant is likely to guide drug treatment, it is reasonable to test for ctDNA given that no alternative exists.

Liquid biopsies are regulated by the Clinical Laboratory Improvement Amendments (CLIA) program, which oversees and certifies the laboratories conducting FDA-approved and non-FDA approved tests. The FDA approval or clearance does not necessarily imply that the test improves clinical outcomes or should be used for clinical management. Testing for ctDNA performed in CLIA-certified laboratories also do not require evidence of clinical utility; only analytical and clinical validity of the test must be demonstrated prior to clinical use.

This document does not address ctDNA panel testing (defined by five or more genes or gene variants tested on the same day on the same member by the same rendering provider). For information on ctDNA panel testing, see GENE.00049 Circulating Tumor DNA Panel Testing for Cancer (Liquid Biopsy).

EGFR Mutation Testing to Select Targeted Therapy in Individuals with Non-small Cell Lung Cancer

Liquid biopsy tests for ctDNA are targeted for specific gene variants. For example, in the instance of NSCLC, a targeted liquid biopsy may be used to identify the presence of the epidermal growth factor receptor (EGFR) variant and determine if individuals may benefit from kinase inhibitor medication.

The College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology released a joint guideline for the selection of lung cancer patients for treatment with targeted tyrosine kinase inhibitors (TKI) (Lindeman, 2018). This document has a strong recommendation stating, “In lung adenocarcinoma patients who harbor sensitizing EGFR mutations and have progressed after treatment with an EGFR-targeted TKI, physicians must use EGFR T790M mutational testing when selecting patients for third-generation EGFR-targeted therapy.” Regarding circulating tumor cell testing (also referred to as circulating plasma cfDNA, plasma cfDNA and cfDNA), they state the following:

The NCCN has the following category 2A recommendation regarding ctDNA testing to identify the EGFR variant in individuals with NSCLC: “If there is insufficient tissue to allow testing for all of EGFR, ALK, ROS1 and BRAF, repeat biopsy and/or plasma testing should be done.” (NCCN NSCLC V2.2021).

The FDA has approved at least two tests for detecting the EGFR variant in individuals with NSCLC. For example:

In addition to the FDA-approved companion diagnostic tests, some commercially available tests (performed at a CLIA certified laboratories) are available which detect EGFR variants in individuals with non-small cell lung cancer are also available. As an example, OncoBEAM (Sysmex Inostics, Mundelein, IL) has developed the Lung1 EGFR ctDNA test which may be used to identify individuals with non-small cell lung cancer who may benefit from treatment with an EGFR-targeted tyrosine kinase inhibitor.

PIK3CA Mutation Testing to Select Targeted Therapy in Individuals with Breast Cancer

Mutations in the phosphatidylinositol-4, 5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) gene have been implicated in the pathogenesis of several cancers, including but not limited to colon, gastric, breast, endometrial, and lung cancer. Researchers are exploring the role of PIK3CA mutations in the initiation, progression and management of various cancers.

Mutations in the PIK3CA gene can also lead to the development of a group of rare, non-malignant disorders collectively known as PIK3CA-related overgrowth spectrum (PROS). PROS disorders include fibroadipose hyperplasia, CLOVES syndrome, megalencephaly-capillary malformation (MCAP) syndrome, hemihyperplasia‐multiple lipomatosis (HHML) syndrome, hemimegalencephaly and facial infiltrating lipomatosis. This document does not address PROS.

Other names for PIK3CA include but are not limited to:

The FDA approved the companion diagnostic test therascreen PIK3CA RGQ PCR Kit (QIAGEN Germantown, MD) to detect the PIK3CA variants in both, a breast tumor tissue specimen and a plasma specimen (ctDNA). According to the FDA, individuals who are negative by the therascreen test using the ctDNA should undergo tumor biopsy for PIK3CA variant testing. Use of the ctDNA test has not been evaluated in a prospective clinical study; approval was based on a retrospective secondary analysis of participants enrolled in the SOLAR-1 clinical trial. The SOLAR-1 trial evaluated alpelisib on the basis of tumor-tissue PIK3CA mutation status.

The May 24, 2019 FDA Summary and Effectiveness Data (SSED) includes a discussion of the concordance of the PIK3CA variant results of the therascreen PIK3CA RGQ PCR Kit (P190004) which uses plasma samples and the therascreen PIK3CA RGQ PCR Kit, which uses tissue samples (P190001). Of the 328 PIK3CA tissue positive subjects, only 179 were plasma PIK3CA positive. Of the 215 PIK3CA tissue negative subjects, 209 were plasma PIK3CA negative. The negative percent agreement (NPA) was 97.2% while the positive percent agreement (PPA) was only 54.6%. It was noted that five PIK3CA variants (H1047Y, Q546R, Q546E, E545D and E545A) were not identified by the therascreen PIK3CA RGQ PCR Kit using plasma clinical samples. FDA approval of the PIK3CA RGQ PCR Kit is contingent upon additional post market accuracy studies of those variants. Because of the high false negative rate (the plasma test failed to discover approximately 46% of the variants identified in the tumor tissue test), reflex testing of plasma mutation negative samples using tissue specimens is required.

The NCCN Clinical Practice Guidelines on Breast Cancer (V2.2022) recommends that in individuals with HR-positive/HER2-negative breast cancer, PIK3CA mutation testing using tumor tissue or ctDNA in peripheral blood (liquid biopsy) be conducted in order to identify candidates for alpelisib plus fulvestrant, (category 1 rating). If liquid biopsy results are negative, tumor tissue testing is recommended.

With regard to treatment regimens for men with breast cancer, the NCCN indicates the following:

Management of advanced breast cancer in males is similar to that in females; however, it is preferred that when an aromatase inhibitor is used, a GnRH analog should be given concurrently. Available data suggest single-agent fulvestrant has similar efficacy in males as in females. Newer agents such as CDK4/6 inhibitors in combination with an aromatase inhibitor or fulvestrant, mTOR inhibitors, and PIK3CA inhibitors have not been systematically evaluated in clinical trials in males with breast cancer. However available real-world data suggest comparable efficacy and safety profiles and it is reasonable to recommend these agents to males based on extrapolation of data from studies comprised largely of female participants with advanced breast cancer.

Testing to Detect the Recurrence of Colorectal Cancer

Colvera™ (Clinical Genomics Pathology, Bridgewater, NJ) has been explored as a liquid biopsy test to detect the recurrence of colorectal cancer (CRC). In 2017, Murray and colleagues investigated the analytical and clinical validity of the Colvera plasma test for the detection of methylated BCAT1 and IKZF1 in individuals with CRC. The researchers randomized 264 plasma samples and 120 buffer samples, divided the samples into 8 batches of 48, and processed the samples over 8 days using 2 equipment lines. Clinical validity was analyzed by using Colvera on 222 archived plasma samples (n=26 with known CRC) from individuals who were scheduled for colonoscopy as part of a previous trial (Pedersen, 2015). The researchers found that the limit of detection (LOD) was 12.6 pg/ml (95% confidence interval [CI], 8.6 to 23.9), the equivalent of 2 diploid genomes/ml of plasma. Colvera tested positive for 19/26 known cancer cases for an agreement of 73% (95% CI, 52% to 88%). For the 196 nonneoplastic subjects, Colvera had an agreement of 89% (95% CI, 84% to 93%). Total agreement was 87% (194/222; 95% CI, 82% to 91%). Limitations of the study included a small sample size.

In 2020, Musher and colleagues published a cross-sectional study evaluating the diagnostic accuracy of the Colvera test compared with carcinoembryonic antigen (CEA) for identifying recurrence of CRC. The study enrolled 537 adults who were undergoing surveillance after treatment for stage II or III CRC. Blood samples were collected at a single time point, within 6 months of surveillance radiological imaging, and evaluated using the Colvera test and CEA. A total of 322 (60%) individuals were included in the final analysis; 20 (3.7%) were excluded because they did not meet eligibility criteria and 195 (36.3%) were excluded for insufficient information. Among the evaluable participants, CRC recurrence occurred in 27 (8.4%) of individuals. The sensitivity of the Colvera test for detecting CRC recurrence (63%) was significantly higher than CEA testing (48.1%), p=0.046. However, the specificity of CEA testing (96.3%) was significantly higher than Colvera testing (91.5%), p=0.012. While the Colvera test appears to be a promising diagnostic tool to predict the recurrence of CRC, the study has several limitations which prevent drawing conclusions regarding its diagnostic accuracy. For example, as discussed above, a substantial proportion (40%) of study participants were excluded from the analysis. Additionally, the authors acknowledge that although this study demonstrated that the specificity of CEA in the 295 subjects without cancer recurrence was higher than that of Colvera, the significance of a false positive result in this study is uncertain due to the relatively short follow-up period. Because the Colvera and CEA results were correlated with only one imaging test, it is possible that some individuals thought to be without recurrence might later prove to have recurrent disease after further imaging. Additional well-designed prospective, randomized controlled trials with longer follow-up are needed to determine whether, Colvera, when compared to CEA facilitates earlier diagnosis of CRC recurrence and, in turn, improves cancer-related outcomes.

TABLE C Circulating Tumor DNA Testing to Guide Targeted Cancer Therapy in Individuals with Solid Tumor(s) (when Criteria B in the Clinical Indications section are met). (Return to Clinical Indications)

 

Drug Being Considered for Targeted Cancer Therapy

 

 

Gene Mutation Status Tested

 

Condition

 

 

Related Anthem Document

Gilotrif (Afatinib)

EGFR

Non-small cell lung cancer

 

Iressa (Gefitinib)

EGFR exon 19 deletions
or EGFR exon 21 (L858R) substitution

Non-small cell lung cancer

 

PIQRAY (alpelisib)

PIK3CA

Breast cancer

 

Tarceva (Erlotinib)

 

EGFR exon 19 deletions or
EGFR exon 21 (L858R) substitution

Non-small cell lung cancer

 

Tagrisso (Osimertinib)

EGFR) exon 19 deletions or
EGFR exon 21 (L858R) mutations or
EGFR T790M mutation

Non-small cell lung cancer

 

Vizimpro (Dacomitinib)

 

EGFR exon 19 deletions or

EGFR exon 21 L858R substitution

Non-small cell lung cancer

 

Note: This document does not address ctDNA panel testing (defined by five or more genes or gene variants tested on the same day on the same member by the same rendering provider. For information on ctDNA panel testing for indications other than selecting targeted therapy agents in individuals with cancer, see:

Definitions

Associated Therapeutic Product (ATP): The therapeutic, preventive, and prophylactic drugs and biological products approved in association with an IVD (FDA, 2016).

Biallelic Mutation: A mutation in both copies of a particular gene that affects the function of both copies.

Bone marrow: The inner, soft part of certain bones, where new blood cells are made.

Circulating tumor DNA (ctDNA): Also known as a liquid biopsy, this test detects small fragments of mutated DNA that are released from tumors into blood, presumably by apoptosis and/or necrosis.

Cytogenetics: The branch of genetics that examines the structure of DNA within the cell nucleus, (the number and morphology of chromosomes).

Epidermal growth factor receptor (EGFR): A cell receptor that is associated with regulation of cell growth.

Genome: The total genetic composition of an organism.

In Vitro Companion Diagnostic Devices (IVD): An in vitro device or an imaging tool that provides information essential for the safe and effective use of a corresponding therapeutic product. The use of an IVD companion diagnostic device with a particular therapeutic product is stipulated in the instructions for use in the FDA labeling of both the diagnostic device and the corresponding therapeutic product, as well as in the FDA labeling of any generic equivalents and biosimilar equivalents of the therapeutic product (FDA, 2016).

Lymphoid cells: Cells derived from the lymphatic system, including lymphocytes, lymphoblasts, and plasma cells.

Lymphoid tissue: Relating to the tissue responsible for producing antibodies and lymphocytes. Examples of lymphoid tissue includes but is not limited to the lymph nodes, thymus, tonsils, and spleen.

Mast cells: Immune cells of the myeloid lineage that are present in connective tissues. Mast cells are also known as mastocytes.

Mast cell sarcoma: A particularly aggressive form of sarcoma.

Myeloid cells: A subgroup of lymphocytes (white blood cells) derived from the bone marrow, and which play a major role in innate immunity. Myeloid cells include granulocytes, monocytes, macrophages, and dendritic cells.

Next-generation sequencing (NGS): Any of the technologies that allow rapid sequencing of large numbers of segments of DNA, up to and including entire genomes.

Point mutation: A change within a gene that results in one base pair in the DNA sequence being altered

Sarcoma: A tumor that is mad of connective tissue cell.

Targeted cancer therapy: Targeted cancer therapies are drugs or other substances that block the growth and spread of cancer by interfering with specific molecules ("molecular targets") that are involved in the growth, progression, and spread of cancer. They recognize a specific feature of the cancer cell, attach to it, and destroy it. Targeted cancer therapies are sometimes called "molecularly targeted drugs," "molecularly targeted therapies," "precision medicines," or similar names (NCI, 2014).

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Circulating Tumor DNA

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EGFR Mutation Analysis

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  21. Hirsch FR, Varella-Garcia M, Cappuzzo F, et al. Combination of EGFR gene copy number and protein expression predicts outcome for advanced non-small-cell lung cancer patients treated with gefitinib. Ann Oncol. 2007; 18(4):752-760.
  22. Hirsch FR, Varella-Garcia M, McCoy J, et al. Increased epidermal growth factor receptor gene copy number detected by fluorescence in situ hybridization associates with increased sensitivity to gefitinib in patients with bronchioloalveolar carcinoma subtypes: A Southwest Oncology Group Study. J Clin Oncol. 2005; 23(28):6838-6845.
  23. Huang SF, Liu HP, Li LH, et al. High frequency of epidermal growth factor receptor mutations with complex patterns in non-small cell lung cancers related to gefitinib responsiveness in Taiwan. Clin Cancer Res. 2004; 10(24):8195-8203.
  24. Inoue A, Suzuki T, Fukuhara T, et al. Prospective phase II study of gefitinib for chemotherapy-naive patients with advanced non-small-cell lung cancer with epidermal growth factor receptor gene mutations. J Clin Oncol. 2006; 24(21):3340-3346.
  25. Janne PA, Yang JC, Kim DW, et al. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N Engl J Med. 2015; 372(18):1689-1699.
  26. Jenkins S, Yang JC, Ramalingam SS, et al. Plasma ctDNA analysis for detection of the EGFR T790M mutation in patients with advanced non-small cell lung cancer. J Thorac Oncol. 2017; 12(7):1061-1070.
  27. John T, Akamatsu H, Delmonte A, et al. EGFR mutation analysis for prospective patient selection in AURA3 phase III trial of osimertinib versus platinum-pemetrexed in patients with EGFR T790M-positive advanced non-small-cell lung cancer. Lung Cancer. 2018; 126:133-138.
  28. Karlovich C, Goldman JW, Sun JM, et al. Assessment of EGFR mutation status in matched plasma and tumor tissue of NSCLC patients from a phase I study of rociletinib (CO-1686). Clin Cancer Res. 2016; 22(10):2386-2395.
  29. Katakami N, Atagi S, Goto K, et al. LUX-Lung 4: a phase II trial of afatinib in patients with advanced non–small-cell lung cancer who progressed during prior treatment with erlotinib, gefitinib, or both. J Clin Oncol. 2013; 31(27):3335-3341.
  30. Krug AK, Enderle D, Karlovich C, et al. Improved EGFR mutation detection using combined exosomal RNA and circulating tumor DNA in NSCLC patient plasma. Ann Oncol. 2018; 29(3):700-706.
  31. Laurent-Puig P, Cayre A, Manceau G, et al. Analysis of PTEN, BRAF, and EGFR status in determining benefit from cetuximab therapy in wild-type KRAS metastatic colon cancer. J Clin Oncol. 2009; 27(35):5924-5930.
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  33. Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004; 350(21):2129-2139.
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  37. Mitsudomi T, Morita S, Yatabe Y, et al. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol. 2010; 11(2):121–128.
  38. Mok TS, Wu Y-L, Ahn M-J, et al.; AURA3 Investigators. Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N Engl J Med. 2017; 376(7):629-640.
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  45. Park K, Haura EB, Leighl NB, et al. Amivantamab in EGFR exon 20 insertion-mutated non-small-cell lung cancer progressing on platinum chemotherapy: Initial results from the chrysalis phase I study. J Clin Oncol. 2021; 39(30):3391-3402.
  46. Parra HS, Cavina R, Latteri F, et al. Analysis of epidermal growth factor receptor expression as a predictive factor for response to gefitinib ('Iressa', ZD1839) in non-small-cell lung cancer. Br J Cancer. 2004; 91(2):208-212.
  47. Passiglia F, Rizzo S, Di Maio M et al. The diagnostic accuracy of circulating tumor DNA for the detection of EGFR-T790M mutation in NSCLC: a systematic review and meta-analysis. Sci Rep. 2018; 8(1):13379.
  48. Pirker R, Pereira JR, von Pawel J, et al. EGFR expression as a predictor of survival for first-line chemotherapy plus cetuximab in patients with advanced non-small-cell lung cancer: analysis of data from the phase 3 FLEX study. Lancet Oncol. 2012; 13(1):33-42.
  49. Ramalingam SS, O'Byrne K, Boyer M, et al. Dacomitinib versus erlotinib in patients with EGFR-mutated advanced nonsmall-cell lung cancer (NSCLC): pooled subset analyses from two randomized trials. Ann Oncol. 2016; 27(3):423-429.
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  54. Sequist LV, Joshi VA, Jänne PA, et al. Response to treatment and survival of patients with non-small cell lung cancer undergoing somatic EGFR mutation testing. Oncologist. 2007; 12(1):90-98.
  55. Sequist LV, Yang JC, Yamamoto N, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013; 31(27):3327-3334.
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  58. Takano T, Ohe Y, Sakamoto H, et al. Epidermal growth factor receptor gene mutations and increased copy numbers predict gefitinib sensitivity in patients with recurrent non-small-cell lung cancer. J Clin Oncol. 2005; 23(28):6829-6837.
  59. Tan EH, Ramlau R, Pluzanska A, et al. A multicentre phase II gene expression profiling study of putative relationships between tumour biomarkers and clinical response with erlotinib in non-small-cell lung cancer. Ann Oncol. 2010; 21(2):217-222.
  60. Tanaka T, Matsuoka M, Sutani A, et al. Frequency of and variables associated with the EGFR mutation and its subtypes. Int J Cancer. 2010; 126(3):651-655.
  61. Tsao MS, Sakurada A, Cutz JC, et al. Erlotinib in lung cancer - molecular and clinical predictors of outcome. N Engl J Med. 2005; 353(2):133-144.
  62. Usui K, Yokoyama T, Naka G, et al. Plasma ctDNA monitoring during epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor treatment in patients with EGFR-mutant non-small cell lung cancer (JP-CLEAR trial). Jpn J Clin Oncol. 2019; 49(6):554-558.
  63. Van Damme N, Deron P, Van Roy N, et al. Epidermal growth factor receptor and K-RAS status in two cohorts of squamous cell carcinomas. BMC Cancer. 2010; 10:189.
  64. van Zandwijk N, Mathy A, Boerrigter L, et al. EGFR and KRAS mutations as criteria for treatment with tyrosine kinase inhibitors: retro- and prospective observations in non-small-cell lung cancer. Ann Oncol. 2007; 18(1):99-103.
  65. Wang Z, Cheng Y, An T, et al. Detection of EGFR mutations in plasma circulating tumour DNA as a selection criterion for first-line gefitinib treatment in patients with advanced lung adenocarcinoma (BENEFIT): a phase 2, single-arm, multicentre clinical trial. Lancet Respir Med. 2018; 6(9):681-690.
  66. Weber B, Meldgaard P, Hager H, et al. Detection of EGFR mutations in plasma and biopsies from non-small cell lung cancer patients by allele-specific PCR assays. BMC Cancer. 2014; 14:294.
  67. Wu YL, Cheng Y, Zhou X, et al. Dacomitinib versus gefitinib as first-line treatment for patients with EGFR-mutation-positive non-small-cell lung cancer (ARCHER 1050): a randomised, open-label, phase 3 trial. Lancet Oncol. 2017; 18(11):1454-1466.
  68. Wu YL, Zhong WZ, Li LY, et al. Epidermal growth factor receptor mutations and their correlation with gefitinib therapy in patients with non-small cell lung cancer: a meta-analysis based on updated individual patient data from six medical centers in mainland China. J Thorac Oncol. 2007; 2(5):430-439.
  69. Yang JC, Hirsh V, Schuler M, et al. Symptom control and quality of life in LUX-Lung 3: a phase III study of afatinib or cisplatin/pemetrexed in patients with advanced lung adenocarcinoma with EGFR mutations J Clin Oncol. 2013; 31(27):3342-3350.
  70. Yang JC, Sequist LV, Geater SL, et al. Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations: a combined post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6. Lancet Oncol. 2015; 16(7):830-838.
  71. Yang JC, Shih JY, Su WC, et al. Afatinib for patients with lung adenocarcinoma and epidermal growth factor receptor mutations (LUX-Lung 2): a phase 2 trial. Lancet Oncol. 2012; 13(5):539-548.
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  74. Zhou C, Wu YL, Chen G, et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 2011; 12(8):735-742.
  75. Zhu CQ, da Cunha Santos G, Ding K, et al.; National Cancer Institute of Canada Clinical Trials Group Study BR.21. Role of KRAS and EGFR as biomarkers of response to erlotinib in National Cancer Institute of Canada Clinical Trials Group Study BR.21. J Clin Oncol. 2008; 26(26):4268-4275.

Myeloproliferative Neoplasms/Myeloproliferative Disorders

  1. Baxter EJ, Scott LM, Campbell PJ, et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet. 2005; 365(9464):1054-1061.
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  4. De Klein A, van Kessel AG, Grosveld G, et al. A cellular oncogene is translocated to the Philadelphia chromosome in chronic myelocytic leukemia. Nature. 1982; 300(5894):765-767.
  5. Guglielmelli P, Pancrazzi A, Bergamaschi G, et al. Anaemia characterises patients with myelofibrosis harbouring Mpl mutation. Br J Haematol. 2007; 137(3):244-247.
  6. Guglielmelli P, Rotunno G, Fanelli T, et al. Validation of the differential prognostic impact of type 1/type 1-like versus type 2/type 2-like CALR mutations in myelofibrosis. Blood Cancer J. 2015; 5:e360.
  7. James c, et al, Detection of JAK2V617F as first intention diagnostic test for erythrocytosis. Leukemia. 2006; 20(2):350-353.
  8. Kralovics R, Passamonti F, Buser AS, et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med. 2005; 352(17):1779-1790.
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  10. McLornan D, Percy M, McMullin M. JAK2V617F: a single mutation in the myeloproliferative group of disorders. Ulster Med J. 2006; 75(2):112-119.
  11. Mejía-Ochoa M, Acevedo Toro PA, Cardona-Arias JA. Systematization of analytical studies of polycythemia vera, essential thrombocythemia and primary myelofibrosis, and a meta-analysis of the frequency of JAK2, CALR and MPL mutations: 2000-2018. BMC Cancer. 2019; 19(1):590.
  12. Michiels JJ, Bernema Z, Van Bockstaele D, et al. Current diagnostic criteria for the chronic myeloproliferative disorders (MPD) essential thrombocythemia (ET), polycythemia vera (PV) and chronic idiopathic myelofibrosis (CIMF). Pathol Biol. 2007; 55(2):92-104.
  13. Michiels JJ, De Raeve H, Hebeda K, et al. WHO bone marrow features and European clinical, molecular, and pathological (ECMP) criteria for the diagnosis of myeloproliferative disorders. Leuk Res. 2007; 31(8):1031-1038.
  14. Milosevic Feenstra JD, Nivarthi H, Gisslinger H, et al. Whole-exome sequencing identifies novel MPL and JAK2 mutations in triple-negative myeloproliferative neoplasms. Blood. 2016; 127(3):325-332.
  15. Nelson ME, Steensma DP. JAK2V617F in myeloid disorders: what do we know now, and where are we headed? Leuk Lymphoma. 2006; 47(2):177-194. 
  16. Nussenzveig RH, Swierczek SI, Jelinek J, et al. Polycythemia vera is not initiated by JAK2V617F mutation. Exp Hematol. 2007; 35(1):32-38.
  17. Pardanani A, Lasho TL, Finke C, et al. Prevalence and clinicopathologic correlates of JAK2 exon 12 mutations in JAK2V617F-negative polycythemia vera. Leukemia. 2007; 21(9):1960-1963.
  18. Passamonti F, Elena C, Schnittger S, et al. Molecular and clinical features of the myeloproliferative neoplasm associated with JAK2 exon 12 mutations. Blood. 2011; 117(10):2813-2816.
  19. Rumi E, Pietra D, Pascutto C, et al. Clinical effect of driver mutations of JAK2, CALR, or MPL in primary myelofibrosis. Blood. 2014; 124(7):1062-1069.
  20. Scott LM. The JAK2 exon 12 mutations: a comprehensive review. Am J Hematol. 2011; 86(8):668-676.
  21. Scott LM, Tong W, Levine RL, et al. JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis. N Engl J Med. 2007; 356(5):459-468.
  22. Siemiatkowska A, Bieniaszewska M, Hellmann A, Limon J. JAK2 and MPL gene mutations in V617F-negative myeloproliferative neoplasms. Leuk Res. 2010; 34(3):387-389.
  23. Sokol K, Tremblay D, Bhalla S, et al. Implications of mutation profiling in myeloid malignancies-part 2: myeloproliferative neoplasms and other myeloid malignancies. Oncology (Williston Park). 2018; 32(5):e45-e51.
  24. Speletas M, Katodritou E, Daiou C, et al. Correlations of JAK2V617F mutation with clinical and laboratory findings in patients with myeloproliferative disorders. Leuk Res. 2007; 31(8):1053-1062.
  25. Spivak JL, Barosi G, Tognoni G, et al. Chronic myeloproliferative disorders. Hematology Am Soc Hematol Educ Program. 2003; 200-224.
  26. Tefferi A. Classification, diagnosis and management of myeloproliferative disorders in the JAK2V617F era. Hematology Am Soc Hematol Educ Program. 2006; 240-245.
  27. Tefferi A, Gilliland DG. Oncogenes in myeloproliferative disorders. Cell Cycle. 2007; 6(5):550-556.
  28. Tefferi A, Gilliland DG, Villeval JL, et al. The JAK2V617F tyrosine kinase mutation in myeloproliferative disorders: status report and immediate implications for disease classification and diagnosis. Mayo Clin Proc. 2005; 80(7):947-958.
  29. Tefferi A, Lasho TL, Finke CM, et al. CALR vs JAK2 vs MPL-mutated or triple-negative myelofibrosis: clinical, cytogenetic and molecular comparisons. Leukemia. 2014; 28(7):1472-14777.
  30. Vannucchi AM, Antonioli E, Guglielmelli P, et al. Clinical profile of homozygous JAK2V617F mutation in patients with polycythemia vera or essential thrombocythemia. Blood. 2007; 110(3):840-846.
  31. Villeval JL, James C, Pisani DF, et al. New insights into the pathogenesis of JAK2V617F positive myeloproliferative disorders and consequences for the management of patients. Semin Thromb Hemost. 2006; 32(4):341-351.
  32. Walz C, Cross NC, Van Etten RA, Reiter A. Comparison of mutated ABL1 and JAK2 as oncogenes and drug targets in myeloproliferative disorders. Leukemia. 2008; 22(7):1320-1334.
  33. Wolanskyj AP, Lasho TL, Schwager SM, et al. JAK2 mutation in essential thrombocythemia: clinical associations and long-term prognostic relevance. Br J Haematol. 2005; 131(2):208-213.

Non-small Cell Lung Cancer

  1. Gerber DE, Minna JD. ALK inhibition for non-small cell lung cancer: from discovery to therapy in record time. Cancer Cell. 2010; 18(6):548-551.
  2. Li Y, Ye X, Liu J, et al. Evaluation of EML4-ALK fusion proteins in non-small cell lung cancer using small molecule inhibitors. Neoplasia. 2011; 13(1):1-11.

PIK3CA Mutation Analysis

  1. André F, Ciruelos E, Rubovszky G, et al. Alpelisib for PIK3CA-Mutated, Hormone Receptor-Positive Advanced Breast Cancer. N Engl J Med. 2019; 380(20):1929-1940.
  2. Arsenic R, Treue D, Lehmann A, et al. Comparison of targeted next-generation sequencing and Sanger sequencing for the detection of PIK3CA mutations in breast cancer. BMC Clin Pathol. 2015; 15:20.
  3. Baselga J, Im SA, Iwata H, et al. Buparlisib plus fulvestrant versus placebo plus fulvestrant in postmenopausal, hormone receptor-positive, HER2-negative, advanced breast cancer (BELLE-2): a randomised, double-blind, placebo-controlled, phase 3 trial. The Lancet Oncology. 2017; 18(7):904-916.
  4. Cappuzzo F, Varella-Garcia M, Finocchiaro G, et al. Primary resistance to cetuximab therapy in EGFR FISH-positive colorectal cancer patients. Br J Cancer. 2008; 99(1):83-89.
  5. Chae YK, Davis AA, Jain S, et al. Concordance of genomic alterations by next-generation sequencing in tumor tissue versus circulating tumor DNA in breast cancer. Molecular cancer therapeutics. 2017; 16(7):1412-1420.
  6. Dearden S, Stevens J, Wu YL, Blowers D. Mutation incidence and coincidence in non small-cell lung cancer: meta-analyses by ethnicity and histology (mutMap). Ann Oncol. 2013; 24(9):2371-2376.
  7. De Roock W, Claes B, Bernasconi D, et al. Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis. Lancet Oncol. 2010; 11(8):753-762.
  8. De Stefano A, Carlomagno C. Beyond KRAS: Predictive factors of the efficacy of anti-EGFR monoclonal antibodies in the treatment of metastatic colorectal cancer. World J Gastroenterol. 2014; 20(29):9732-9743.
  9. Ellis MJ, Lin L, Crowder R, et al. Phosphatidyl-inositol-3-kinase alpha catalytic subunit mutation and response to neoadjuvant endocrine therapy for estrogen receptor positive breast cancer. Breast Cancer Res Treat. 2010; 119(2):379-390.
  10. Fiala O, Pesek M, Finek J, et al. Gene mutations in squamous cell NSCLC: insignificance of EGFR, KRAS and PIK3CA mutations in prediction of EGFR-TKI treatment efficacy. Anticancer Res. 2013; 33(4):1705-1711.
  11. Hahn AW, Gill DM, Maughan B, et al. Correlation of genomic alterations assessed by next-generation sequencing (NGS) of tumor tissue DNA and circulating tumor DNA (ctDNA) in metastatic renal cell carcinoma (mRCC): potential clinical implications. Oncotarget. 201; 8(20):33614-33620.
  12. Henry NL, Schott AF, Hayes DF. Assessment of PIK3CA mutations in human epidermal growth factor receptor 2–positive breast cancer: clinical validity but not utility. J Clin Oncol. 2014; 32(29):3207-3209.
  13. Higgins MJ, Jelovac D, Barnathan E, et al. Detection of tumor PIK3CA status in metastatic breast cancer using peripheral blood. Clinical cancer research. 2012; 18(12):3462-3469.
  14. Hynes NE, Lane HA. ERBB receptors and cancer: the complexity of targeted inhibitors. Nat Rev Cancer. 2005; 5(5):341-354.
  15. Kalinsky K, Jacks LM, Heguy A, et al. PIK3CA mutation associates with improved outcome in breast cancer. Clin Cancer Res. 2009; 15(16):5049-5059.
  16. Karapetis CS, et al. PIK3CA, BRAF, and PTEN status and benefit from cetuximab in the treatment of advanced colorectal cancer- results from NCIC CTG/AGITG CO. 17. Clin Cancer Res. 2014; 20(3):744-53.
  17. Kawano O, Sasaki H, Endo K, et al. PIK3CA mutation status in Japanese lung cancer patients. Lung Cancer. 2006; 54(2):209-215.
  18. Kidess E., Heirich K., Wiggin M., et al. Mutation profiling of tumor DNA from plasma and tumor tissue of colorectal cancer patients with a novel, high-sensitivity multiplexed mutation detection platform. Oncotarget, 6(4), p.2549-2561.
  19. Kodahl AR, Ehmsen S, Pallisgaard N, et al. Correlation between circulating cell‐free PIK 3 CA tumor DNA levels and treatment response in patients with PIK 3 CA‐mutated metastatic breast cancer. Molecular oncology. 2018; 12(6):925-935.
  20. Krasinskas AM. EGFR Signaling in Colorectal Carcinoma. Patholog Res Int. Pathology Research International, vol. 2011, Article ID 932932, 6 pages, 2011.
  21. Lin JS, Webber EM, Senger CA, et al. Systematic review of pharmacogenetic testing for predicting clinical benefit to anti-EGFR therapy in metastatic colorectal cancer. Am J Cancer Res. 2011; 1(5):650-662.
  22. Loi S, Michiels S, Lambrechts D, et al. Somatic mutation profiling and associations with prognosis and trastuzumab benefit in early breast cancer. J Natl Cancer Inst. 2013, 105(13):960-967.
  23. Mao C, Yang ZY, Hu XF, et al. PIK3CA exon 20 mutations as a potential biomarker for resistance to anti-EGFR monoclonal antibodies in KRAS wild-type metastatic colorectal cancer: a systematic review and meta-analysis. Ann Oncol. 2012; 23(6):1518-1525.
  24. Normanno N, Rachiglio AM, Lambiase M, ET AL. Heterogeneity of KRAS, NRAS, BRAF and PIK3CA mutations in metastatic colorectal cancer and potential effects on therapy in the CAPRI GOIM trial. Ann Oncol. 2015; 26(8):1710-1714.
  25. Ogino S, Liao X, Imamura Y, et al. Predictive and prognostic analysis of PIK3CA mutation in stage III colon cancer intergroup trial. J Natl Cancer Inst. 2013; 105(23):1789-1798.
  26. Ogino S, Nosho K, Kirkner GJ, et al. PIK3CA mutation is associated with poor prognosis among patients with curatively resected colon cancer. J Clin Oncol. 2009; 27(9):1477-1484.
  27. Papaxoinis G, Kotoula V, Alexopoulou Z, ET AL. Significance of PIK3CA Mutations in Patients with Early Breast Cancer Treated with Adjuvant Chemotherapy: A Hellenic Cooperative Oncology Group (HeCOG) Study. PLoS One. 2015; 10(10):e0140293.
  28. Prenen H, De Schutter J, Jacobs B, et al. PIK3CA mutations are not a major determinant of resistance to the epidermal growth factor receptor inhibitor cetuximab in metastatic colorectal cancer. Clin Cancer Res. 2009; 15(9):3184-3188.
  29. Razis E, Bobos M, Kotoula V, et al. Evaluation of the association of PIK3CA mutations and PTEN loss with efficacy of trastuzumab therapy in metastatic breast cancer. Breast Cancer Res Treat. 2011, 128(2):447-456.
  30. Rothe F, Laes JF, Lambrechts D, et al. Plasma circulating tumor DNA as an alternative to metastatic biopsies for mutational analysis in breast cancer. Ann Oncol. 2014; 25(10):1959-1965.
  31. Sartore-Bianchi A, Martini M, Molinari F, et al. PIK3CA mutations in colorectal cancer are associated with clinical resistance to EGFR-targeted monoclonal antibodies. Cancer Res. 2009; 69(5):1851-1857.
  32. Tol J, Dijkstra JR, Klomp M, et al. Markers for EGFR pathway activation as predictor of outcome in metastatic colorectal cancer patients treated with or without cetuximab. Eur J Cancer. 2010; 46(11):1997-2009.

RAS Mutation Analysis

  1. Al-Jehani RM, Jeyarajah AR, Hagen B, et al. Model for the molecular genetic diagnosis of endometrial cancer using K-ras mutation analysis. J Natl Cancer Inst. 1998; 90(7):540-542.
  2. Amado RG, Wolf M, Peeters M et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol 2008; 26(10):1626-1634.
  3. Bokemeyer C, Bondarenko I, Hartmann JT, et al. KRAS status and efficacy of first-line treatment of patients with metastatic colorectal cancer (mCRC) with FOLFOX with or without cetuximab: The OPUS experience. J Clin Oncol 26: 2008 (May 20 suppl; abstr 4000).
  4. Bokemeyer C, Cutsem EV, Rougier P, et al. Addition of cetuximab to chemotherapy as first-line treatment for KRAS wild-type metastatic colorectal cancer: pooled analysis of the CRYSTAL and OPUS randomised clinical trials. Eur J Cancer 2012; 48(10):1466-1475.
  5. Caduff RF, Johnston CM, Frank TS. Mutations of the Ki-ras oncogene in carcinoma of the endometrium. Am J Pathol 1995; 146(1):182-188.
  6. Cervantes A, Macarulla T, Martinelli E, et al. Correlation of KRAS status (wild type [wt] vs. mutant [mt]) with efficacy to first-line cetuximab in a study of cetuximab single agent followed by cetuximab + FOLFIRI in patients (pts) with metastatic colorectal cancer (mCRC). J Clin Oncol 26: 2008 (May 20 suppl; abstr 4129).
  7. Cuatrecasas M, Villanueva A, Matias-Guiu X, Prat J. K-ras mutations in mucinous ovarian tumors: a clinicopathologic and molecular study of 95 cases. Cancer. 1997; 79(8):1581-1586.
  8. De Roock W, Piessevaux H, De Schutter J, et al. KRAS wild-type state predicts survival and is associated to early radiological response in metastatic colorectal cancer treated with cetuximab. Ann Oncol. 2008; 19(3):508-515.
  9. Douillard JY, Shepherd FA, Hirsh V, et al. Molecular predictors of outcome with gefitinib and docetaxel in previously treated non-small-cell lung cancer: data from the randomized phase III INTEREST trial. J Clin Oncol. 2010; 28(5):744-752.
  10. Duggan BD, Felix JC, Muderspach LI, et al. Early mutational activation of the c-Ki-ras oncogene in endometrial carcinoma. Cancer Res. 1994; 54(6):1604-1607.
  11. Eberhard DA, Johnson BE, Amler LC et al. Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non-small-cell lung cancer treated with chemotherapy alone and in combination with erlotinib. J Clin Oncol 2005; 23(25):5900-5909.
  12. Esteller M, García A, Martínez-Palones JM, et al. The clinicopathological significance of K-RAS point mutation and gene amplification in endometrial cancer. Eur J Cancer. 1997; 33(10):1572-1577.
  13. Fujimoto I, Shimizu Y, Hirai Y, et al. Studies on ras oncogene activation in endometrial carcinoma. Gynecol Oncol. 1993; 48(2):196-202.
  14. Hogdall EV, Hogdall CK, Blaakaer J, et al. K-ras alterations in Danish ovarian tumour patients. From the Danish "Malova" Ovarian Cancer study. Gynecol Oncol. 2003; 89(1):31-36.
  15. Hunt JD, Mera R, Strimas A, et al. KRAS mutations are not predictive for progression of preneoplastic gastric lesions. Cancer Epidemiol Biomarkers Prev. 2001; 10(1):79-80.
  16. Karapetis CS, Khambata-Ford S, Jonker DJ, et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med. 2008; 359(17):1757-1765.
  17. Khalid A, McGrath KM, Zahid M, et al. The role of pancreatic cyst fluid molecular analysis in predicting cyst pathology. Clin Gastroenterol Hepatol. 2005; 3(10):967-973.
  18. Khalid A, Zahid M, Finkelstein SD et al. Pancreatic cyst fluid DNA analysis in evaluating pancreatic cysts: a report of the PANDA study. Gastrointest Endosc. 2009; 69(6):1095-1102.
  19. Khambata-Ford S, Harbison CT, Hart LL, et al. Analysis of potential predictive markers of cetuximab benefit in BMS099, a phase III study of cetuximab and first-line taxane/carboplatin in advanced non-small-cell lung cancer. J Clin Oncol. 2010; 28(6):918-927.
  20. Mao C, Qiu LX, Liao RY, et al. KRAS mutations and resistance to EGFR-TKIs treatment in patients with non-small cell lung cancer: a meta-analysis of 22 studies. Lung Cancer 2010; 69(3):272-278.
  21. Messersmith WA, Ahnen DJ. Targeting EGFR in colorectal cancer. N Engl J Med. 2008; 359(17):1834-1836.
  22. Olsen C, Schefter T, Chen, et al. Results of a phase I trial of 12 patients with locally advanced pancreatic carcinoma combining gefitinib, paclitaxel, and 3-dimensional conformal radiation: report of toxicity and evaluation of circulating K-ras as a potential biomarker of response to therapy. Am J Clin Oncol. 2009; 32(2):115-121.
  23. Peeters M, Douillard JY, Van Cutsem E, et al. Mutant KRAS codon 12 and 13 alleles in patients with metastatic colorectal cancer: assessment as prognostic and predictive biomarkers of response to panitumumab. J Clin Oncol. 2013; 31(6):759-765.
  24. Rockacy MJ, Zahid M, McGrath KM, et al. Association between KRAS mutation, detected in pancreatic cyst fluid, and long-term outcomes of patients. Clin Gastroenterol Hepatol. 2013; 11(4):425-429.
  25. Schneider CP, Heigener D, Schott-von-Romer K et al. Epidermal growth factor receptor-related tumor markers and clinical outcomes with erlotinib in non-small cell lung cancer. J Thorac Oncol. 2008; 3(12):1446-1453.
  26. Semczuk A, Postawski K, Przadka D et al. K-ras gene point mutations and p21ras immunostaining in human ovarian tumors. Eur J Gynaecol Oncol. 2004; 25(4):484-488.
  27. Sorich MJ, Wiese MD, Rowland A, et al. Extended RAS mutations and anti-EGFR monoclonal antibody survival benefit in metastatic colorectal cancer: a meta-analysis of randomized, controlled trials. Ann Oncol. 2015; 26(1):13-21.
  28. Van Cutsem E, Lang I, D'haens G, et al. KRAS status and efficacy in the first-line treatment of patients with metastatic colorectal cancer (mCRC) treated with FOLFIRI with or without cetuximab: The CRYSTAL experience. Clin Oncol 26: 2008 (May 20 suppl; abstr 2).
  29. Varras MN, Sourvinos G, Diakomanolis E, et al. Detection and clinical correlations of ras gene mutations in human ovarian tumors. Oncology. 1999; 56(2):89-96.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. American Board of Genetic Counselors. Genetic Counselors' Scope of Practice. Available at: https://www.nsgc.org/p/cm/ld/fid=18#scope. Accessed on February 2, 2021.
  2. American Society of Clinical Oncology. American Society of Clinical Oncology policy statement update: genetic testing for cancer susceptibility. J Clin Oncol. 2003; 21(12):2397-2406.
  3. Canadian Retinoblastoma Society. National Retinoblastoma Strategy Canadian Guidelines for Care. Can J Ophthalmol. 2009; 44 Suppl 2: S1-88. Available at: https://www.canadianjournalofophthalmology.ca/article/S0008-4182(09)80179-8/pdf. Accessed on February 2, 2021.
  4. Casali PG, Abecassis N, Bauer S, et al. Gastrointestinal stromal tumours: ESMO-EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2018; 29 Suppl 4: iv68-iv78.
  5. Decker J, Neuhaus C, Macdonald F, et al. Clinical utility gene card for: von Hippel-Lindau (VHL). Eur J Hum Genet. 2014; 22(4).
  6. Else T, Greenberg S, Fishbein L. Hereditary Paraganglioma-Pheochromocytoma Syndromes. 2008 May 21 [Updated 2018 Oct 4]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020.
  7. Green RC, Berg JS, Grody WW, et al. ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genet Med. 2013; 15(7):565-574.
  8. Hampel H, Bennett RL, Buchanan A, et al. A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. Genet Med. 2015; 17(1):70-87.
  9. Kalia SS, Adelman K, Bale SJ, et al. Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics. Genet Med. 2017; 19(2):249-255.
  10. Lohmann DR, Gallie BL. Retinoblastoma. 2000 Jul 18 [Updated 2018 Nov 21]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. Available at: https://www.ncbi.nlm.nih.gov/books/NBK1452/. Accessed on February 2, 2021.
  11. NCCN Clinical Practice Guidelines in Oncology®. © 2022 National Comprehensive Cancer Network, Inc. For additional information visit the NCCN website: visit the NCCN website: http://www.nccn.org/index.asp. Accessed on February 7, 2022.
  1. Nielsen SM, Rhodes L, Blanco I, et al. von Hippel-Lindau Disease: genetics and role of genetic counseling in a multiple neoplasia syndrome. J Clin Oncol. 2016; (34)18: 2172-2181.
  2. No authors listed. Corrigendum: Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics. Genet Med. 2017; 19(4):484.
  3. Raman G, Avendano EE, Chen M. Update on emerging genetic tests currently available for clinical use in common cancers. Evidence Report/Technology Assessment. No. (Prepared by the Tufts Evidence-based Practice Center under contract No. 290-2007-10055-I.). Rockville, MD: Agency for Healthcare Research and Quality (AHRQ). July 2013. Available at: https://www.ncbi.nlm.nih.gov/books/NBK285327/ . Accessed on February 2, 2021.
  4. Smith RA, Cokkinides V, Brawley OW. Cancer screening in the United States, 2009: a review of current American Cancer Society guidelines and issues in cancer screening. CA Cancer J Clin. 2009; 59(1):27-41.
  5. Sun F, Bruening W, Erinoff E, Schoelles KM. Addressing Challenges in Genetic Test Evaluation: Evaluation Frameworks and Assessment of Analytic Validity [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2011 Report No.: 11-EHC048-EF. AHRQ Methods for Effective Health Care. Available at: https://www.ncbi.nlm.nih.gov/books/NBK56750/. Accessed on February 2, 2021.
  6. U.S. Food and Drug Administration (FDA).
  7. van Leeuwaarde RS, Ahmad S, Links TP, et al. Von Hippel-Lindau Syndrome. 2000 May 17 [Updated 2018 Sep 6]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020.

Acute Lymphoblastic Leukemia

  1. Hoelzer D, Bassan R, Dombret H, et al. ESMO Guidelines Committee. Acute lymphoblastic leukaemia in adult patients: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2016; 27(suppl 5):v69-v82.
  2. NCCN Clinical Practice Guidelines in Oncology®. © 2022 National Comprehensive Cancer Network, Inc. For additional information visit the NCCN website: visit the NCCN website: http://www.nccn.org/index.asp. Accessed on January 12, 2022.

Acute Myeloid Leukemia

  1. Heuser M, Freeman SD, Ossenkoppele GJ, et al. 2021 Update on MRD in acute myeloid leukemia: a consensus document from the European LeukemiaNet MRD Working Party. Blood. 2021 Dec 30;138(26):2753-2767.
  2. NCCN Clinical Practice Guidelines in Oncology®. © 2022 National Comprehensive Cancer Network, Inc. For additional information visit the NCCN website: visit the NCCN website: http://www.nccn.org/index.asp. Accessed on January 12, 2022.
  3. Schuurhuis GJ, Heuser M, Freeman S, et al. Minimal/measurable residual disease in AML: a consensus document from the European LeukemiaNet MRD Working Party. Blood. 2018; 131(12):1275-1291

Acute Promyelocytic Leukemia

  1. NCCN Clinical Practice Guidelines in Oncology®. © 2022 National Comprehensive Cancer Network, Inc. For additional information visit the NCCN website: visit the NCCN website: http://www.nccn.org/index.asp. Accessed on January 12, 2022.
  2. Pagnano KB, Rego EM, Rohr Set al. Guidelines on the diagnosis and treatment for acute promyelocytic leukemia: Associação Brasileira de Hematologia, Hemoterapia e Terapia Celular Guidelines Project: Associação Médica Brasileira - 2013. Rev Bras Hematol Hemoter. 2014;36(1):71-92.

BRAF Mutation Analysis

  1. Bonis PA, Trikalinos TA, Chung M, et al. Hereditary Nonpolyposis Colorectal Cancer: Diagnostic Strategies and Their Implications. Evidence Report/Technology Assessment No. 150 (Prepared by Tufts-New England Medical Center Evidence-based Practice Center under Contract No. 290-02-0022). AHRQ Publication No. 07-E008. Rockville, MD: Agency for Healthcare Research and Quality. May 2007.
  2. Diamond EL, Subbiah V, Lockhart AC, et al. FDA approval summary: Vemurafenib for the treatment of patients with Erdheim-Chester Disease with the BRAFV600 mutation. Oncologist. 2018; 23(12):1520-1524.
  3. Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group. Recommendations from the EGAPP Working Group: can testing of tumor tissue for mutations in EGFR pathway downstream effector genes in patients with metastatic colorectal cancer improve health outcomes by guiding decisions regarding anti-EGFR therapy? Genet Med. 2013; 15(7):517-527.
  4. Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group. Recommendations from the EGAPP Working Group: genetic testing strategies in newly diagnosed individuals with colorectal cancer aimed at reducing morbidity and mortality from Lynch syndrome in relatives. Genet Med. 2009; 11(1):35-41.
  5. Garbe C, Peris K, Hauschild A, et al. Diagnosis and treatment of melanoma. European consensus-based interdisciplinary guideline--Update 2012. Eur J Cancer. 2012; 48(15):2375-2390.
  6. Giardiello FM, Allen JI, Axilbund JE, et al. Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement by the U.S. Multi-Society Task Force on Colorectal Cancer. Gastrointest Endosc. 2014; 80(2):197-220.
  7. Hedge M, Ferber M, Mao R, et al. ACMG technical standards and guidelines for genetic testing for inherited colorectal cancer (Lynch syndrome, familial adenomatous polyposis, and MYH-associated polyposis). Genet Med. 2014; 16(1):101-116.
  8. National Comprehensive Cancer Network®. NCCN Drugs & Biologics Compendium(electronic version). For additional information, visit the NCCN website: http://wwe.nccn.org. Accessed on July 17, 2020.
  9. NCCN Clinical Practice Guidelines in Oncology. © 2021 National Comprehensive Cancer Network, Inc. For additional information visit NCCN website: http://www.nccn.org/index.asp. Accessed on December 16, 2020.
  10. Odogwu L, Mathieu L, Blumenthal G, et al. FDA approval Summary: Dabrafenib and Trametinib for the treatment of metastatic non-small cell lung cancers harboring BRAF V600E mutations. Oncologist. 2018; 23(6):740-745.
  11. Palomaki GE, McClain MR, Melillo S, et al. EGAPP supplementary evidence review: DNA testing strategies aimed at reducing morbidity and mortality from Lynch syndrome. Genet Med. 2009; 11(1):42-65.
  12. Planchard D, Mazieres J, Riely GJ, et al. Interim results of phase II study BRF113928 of dabrafenib in BRAF V600E mutation–positive non-small cell lung cancer (NSCLC) patients. J Clin Oncol 31, 2013 (suppl; abstr 8009).
  13. U.S. Food and Drug Administration. Label and approval information: Mekinist (trametinib). Updated June 2020. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/204114s016lbl.pdf. Accessed on January 12, 2022.
  14. U.S. Food and Drug Administration. Label and approval information: Tafinlar (dabrafenib). Updated April 2020. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/202806s015lbl.pdf. Accessed on January 12, 2022.
  15. U.S. Food and Drug Administration. Label and approval information: Welireg (belzutifan). Updated August 2021. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/215383s000lbl.pdf. Accessed on January 12, 2022.
  16. U.S. Food and Drug Administration. Label and approval information: Zelboraf (vemurafenib) Tablet, 240mg. Updated May 2020. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/202429s019lbl.pdf. Accessed on January 12, 2022.
  17. U.S. Food and Drug Administration. List of cleared or approved companion diagnostic devices (in vitro and imaging tools). Updated 11/16/2020. Available at: https://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/InVitroDiagnostics/ucm301431.htm. Accessed on January 12, 2022.
  18. United States Food and Drug Administration (FDA). Premarket Approval Letter (PMA). cobas® 4800 BRAF V600 Mutation Test, PMA # P110020. Available at: http://www.accessdata.fda.gov/cdrh_docs/pdf11/P110020a.pdf. Accessed on January 12, 2022.
  19. U.S. Food and Drug Administration. Premarket Notification Database. THxID BRAF Kit for use on the ABI 7500 Fast Dx Real-Time PCR Instrument Summary of Safety and Effectiveness. Available at: http://www.accessdata.fda.gov/cdrh_docs/pdf12/P120014b.pdf. Accessed on January 12, 2022.
  20. U.S. Food and Drug Administration. Summary of Safety and Effectiveness Data (SEED). THxID BRAF Kit for use on the ABI 7500 Fast Dx Real-Time PCR Instrument. Available at: http://www.accessdata.fda.gov/cdrh_docs/pdf12/P120014b.pdf. Accessed on January 12, 2022.

Chronic Lymphocytic Leukemia

  1. Eichhorst B, Robak T, Montserrat E, et al. ESMO Guidelines Committee. Chronic lymphocytic leukaemia. ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2021; 32(1):23-33.
  2. Hallek M, Cheson BD, Catovsky D, et al. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. Blood. 2018; 131(25):2745-2760.
  3. Ladetto M, Buske C, Hutchings M, et al. ESMO Lymphoma Consensus Conference Panel Members. ESMO consensus conference on malignant lymphoma: general perspectives and recommendations for prognostic tools in mature B-cell lymphomas and chronic lymphocytic leukaemia. Ann Oncol. 2016; 27(12):2149-2160.
  4. NCCN Clinical Practice Guidelines in Oncology®. © 2022 National Comprehensive Cancer Network, Inc. For additional information visit the NCCN website: visit the NCCN website: http://www.nccn.org/index.asp. Accessed on January 12, 2022.

Chronic Myeloid Leukemia

  1. NCCN Clinical Practice Guidelines in Oncology®. © 2022 National Comprehensive Cancer Network, Inc. For additional information visit the NCCN website: visit the NCCN website: http://www.nccn.org/index.asp. Accessed on February 7, 2022.

Circulating Tumor DNA

  1. Merker JD, Oxnard GR, Compton C, et al. Circulating tumor DNA analysis in patients with cancer: American Society of Clinical Oncology and College of American Pathologists joint review. J Clin Oncol. 2018; 36(16):1631-1641.
  2. National Cancer Institute. Definition of liquid biopsy - NCI Dictionary of Cancer Terms. National Cancer Institute. Available at: https://www.cancer.gov/publications/dictionaries/cancer-terms/def/liquid-biopsy. Accessed on January 22, 2022.

EGFR Mutation Analysis

  1. Hanna N, Johnson D, Temin S, Masters G. Systemic therapy for stage IV non-small-cell lung cancer: American Society of Clinical Oncology Clinical Practice Guideline update summary. J Oncol Pract. 2017; 13(12):832-837.
  2. Keedy VL, Temin S, Somerfield MR, et al. American Society of Clinical Oncology provisional clinical opinion: epidermal growth factor receptor (EGFR) mutation testing for patients with advanced non-small-cell lung cancer considering first-line EGFR tyrosine kinase inhibitor therapy. J Clin Oncol. 2011; 29(15):2121-2127.
  3. Lindeman NI, Cagle PT, Aisner DL, et al. Updated molecular testing guideline for the selection of lung cancer patients for treatment with targeted tyrosine kinase inhibitors: guideline from the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology. J Mol Diagn. 2018; 20(2):129-159.
  4. Masters GA, Temin S, Azzoli CG, et al.; American Society of Clinical Oncology Clinical Practice. Systemic therapy or stage IV non-small-cell lung Cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2015; 33(30):3488-515.
  5. Merker JD, Oxnard GR, Compton C, et al. Circulating tumor DNA analysis in patients with cancer: American Society of Clinical Oncology and College of American Pathologists joint review. J Clin Oncol. 2018; 36(16):1631-1641.
  6. National Comprehensive Cancer Network (NCCN). © 2021 National Comprehensive Cancer Network, Inc. For additional information visit the NCCN website at: http://www.nccn.org/index.asp. Accessed on January 12, 2022.
  7. Travis WD, Brambilla E, Nicholson AG, et al. On behalf of the WHO Panel. The 2015 World Health Organization classification of lung tumors. Impact of genetic, clinical, and radiologic advances since the 2004 classification. J Thorac Oncol. 2015; 10(9):1243-1260.
  8. U.S. Food and Drug Administration (FDA). Vizimpro package insert. FDA 2018(a). Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/211288s000lbl.pdf. Accessed on January 12, 2022.
  9. U.S. Food and Drug Administration (FDA). Gilotrif package insert. FDA 2018(b) Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/201292s014lbl.pdf. Accessed on January 12, 2022.
  10. U.S. Food and Drug Administration (FDA). Iressa package insert. FDA 2018(c). Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/206995s003lbl.pdf. Accessed on January 12, 2022.
  11. U.S. Food and Drug Administration (FDA). Tagrisso package insert. FDA 2018(d). Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/208065s008lbl.pdf. Accessed on January 12, 2022.
  12. U.S. Food and Drug Administration (FDA). Tarceva package insert. (FDA, 2016(a). Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/021743s025lbl.pdf. Accessed on January 12, 2022.
  13. U.S. Food and Drug Administration Premarket Approval Database. Cobas EGFR Mutation Test V2 Summary of Safety and Effectiveness. P150047. Rockville, MD: FDA 2016(b). June 1, 2016. Available at: https://www.accessdata.fda.gov/cdrh_docs/pdf15/P150047B.pdf. Accessed on January 12, 2022.
  14. U.S. Food and Drug Administration Premarket Approval Database. Cobas EGFR Mutation Test V2 Summary of Safety and Effectiveness. P150044. Rockville, MD: FDA (2016c). February 2, 2021. Available at: https://www.accessdata.fda.gov/cdrh_docs/pdf15/p150044b.pdf. Accessed on January 12, 2022.

Hairy Cell Leukemia

  1. Grever MR, Abdel-Wahab O, Andritsos LA, et al. Consensus guidelines for the diagnosis and management of patients with classic hairy cell leukemia. Blood. 2017;129(5):553-560.
  2. NCCN Clinical Practice Guidelines in Oncology®. © 2022 National Comprehensive Cancer Network, Inc. For additional information visit the NCCN website: visit the NCCN website: http://www.nccn.org/index.asp. Accessed on February 7, 2022.
  3. Parry-Jones N, Joshi A, Forconi F, et al. Guideline for diagnosis and management of hairy cell leukaemia (HCL) and hairy cell variant (HCL-V). Br J Haematol. 2020; 191(5):730-737.
  4. Robak T, Matutes E, Catovsky D, et al. ESMO Guidelines Committee. Hairy cell leukaemia: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2015; 26 Suppl 5:v100-v1007.
  5. Tiacci E, Pettirossi V, Schiavoni G, Falini B. Genomics of Hairy Cell Leukemia. J Clin Oncol. 2017; 35(9):1002-1010.

Multiple Myeloma

  1. Dimopoulos MA, Moreau P, Terpos Eet al. ESMO Guidelines Committee. Multiple myeloma: EHA-ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up†. Ann Oncol. 2021; 32(3):309-322.
  2. Moreau P, San Miguel J, Sonneveld P, et al. ESMO Guidelines Committee. Multiple myeloma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2017; 28(suppl_4):iv52-iv61.
  3. NCCN Clinical Practice Guidelines in Oncology®. © 2022 National Comprehensive Cancer Network, Inc. For additional information visit the NCCN website: visit the NCCN website: http://www.nccn.org/index.asp. Accessed on February 7, 2022.

Myelodysplastic Syndromes

  1. Killick SB, Ingram W, Culligan D, et al. British Society for Haematology guidelines for the management of adult myelodysplastic syndromes. Br J Haematol. 2021; 194(2):267-281.
  2. NCCN Clinical Practice Guidelines in Oncology®. © 2022 National Comprehensive Cancer Network, Inc. For additional information visit the NCCN website: visit the NCCN website: http://www.nccn.org/index.asp. Accessed on February 7, 2022.

Myeloproliferative Syndromes

  1. NCCN Clinical Practice Guidelines in Oncology®. © 2022 National Comprehensive Cancer Network, Inc. For additional information visit the NCCN website: visit the NCCN website: http://www.nccn.org/index.asp. Accessed on February 7, 2022.

Non-small Cell Lung Cancer

  1. NCCN Clinical Practice Guidelines in Oncology®. © 2022 National Comprehensive Cancer Network, Inc. For additional information visit the NCCN website: visit the NCCN website: http://www.nccn.org/index.asp. Accessed on February 7, 2022.

PIK3CA Mutation Analysis

  1. Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group. Recommendations from the EGAPP Working Group: can testing of tumor tissue for mutations in EGFR pathway downstream effector genes in patients with metastatic colorectal cancer improve health outcomes by guiding decisions regarding anti-EGFR therapy? Genet Med. 2013; 15(7):517-527.
  2. National Center for Biotechnology Information (NCBI). GTR: Genetic Testing Registry. PIK3CA Mutation by Sequencing. Last updated September 13, 2017. Available at: http://www.ncbi.nlm.nih.gov/gtr/tests/514565/performance-characteristics/. Accessed on February 2, 2021.
  3. National Comprehensive Cancer Network (NCCN).©  2021 National Comprehensive Cancer Network, Inc. For additional information visit the NCCN website at: http://www.nccn.org/index.asp. Accessed on December 16, 2020.
  4. U.S. Food and Drug Administration Premarket Approval Database. Therascreen PIK3CA RGQ PCR Kit. Summary of Safety and Effectiveness. P190001. Rockville, MD: FDA. 2019(a). Available at: https://www.accessdata.fda.gov/cdrh_docs/pdf19/P190001B.pdf. Accessed February 2, 2021.
  5. U.S. Food and Drug Administration Premarket Approval Database. Therascreen PIK3CA RGQ PCR Kit. Summary of Safety and Effectiveness. P19004B. Rockville, MD: FDA. 2019(b). Available at: https://www.accessdata.fda.gov/cdrh_docs/pdf19/P190004B.pdf. Accessed February 2, 2021.

RAS Mutation Analysis

  1. Allegra CJ, Rumble RB, Hamilton SR, et al. Extended RAS gene mutation testing in metastatic colorectal carcinoma to predict response to anti-epidermal growth factor receptor monoclonal antibody therapy: American Society of Clinical Oncology Provisional Clinical Opinion Update 2015. J Clin Oncol. 2016; 34(2):179-185.
  2. Cetuximab (systemic). In: DrugPoints® System (electronic version). Truven Health Analytics, Greenwood Village, CO. Updated December 6, 2019. Available at: http://www.micromedexsolutions.com. Accessed on April 13, 2020.
  3. Elta GH, Enestvedt BK, Sauer BG, Lennon AM. ACG Clinical Guideline: Diagnosis and Management of Pancreatic Cysts. Am J Gastroenterol. 2018; 113(4):464-479.
  4. Erbitux (cetuximab) [Product Information]. Branchburg, NJ. ImClone Systems Incorporated. Revised June 2018. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/125084s269lbl.pdf. Accessed on April 13, 2020.
  5. Kalemkerian GP, Narula N, Kennedy EB, et al. Molecular testing guideline for the selection of patients with lung cancer for treatment with targeted tyrosine kinase inhibitors: American Society of Clinical Oncology Endorsement of The College of American Pathologists/International Association for the Study of Lung Cancer/Association for Molecular Pathology Clinical Practice Guideline Update. J Clin Oncol. 2018; 36(9):911-919.
  6. Khalid, A, Brugge, W. ACG practice guidelines for the diagnosis and management of neoplastic pancreatic cysts. Am J Gastroenterol. 2007; 102(10):2339-2349.
  7. Lindeman NI, Cagle PT, Aisner DL, et al. Updated molecular testing guideline for the selection of lung cancer patients for treatment with targeted tyrosine kinase inhibitors: Guideline from the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology. Arch Pathol Lab Med. 2018; 142(3):321-346.
  8. Lorenzen S, Langer R, Rothling N, et al. Absence of mutations of the K-ras gene in squamous cell carcinoma of the esophagus: Analysis from the randomized oesotux phase II study (cetuximab and cisplatin/5-FU versus cisplatin/5-FU alone). ASCO. 2009; Suppl Abstract No.38
  9. NCCN Clinical Practice Guidelines in Oncology™. © 2020 National Comprehensive Cancer Network, Inc. For additional information visit the NCCN website: http://www.nccn.org/index.asp. Accessed April 13, 2020.
  10. Panitumumab (systemic). In: DrugPoints® System (electronic version). Truven Health Analytics, Greenwood Village, CO. Updated December 6, 2019. Available at: http://www.micromedexsolutions.com. Accessed on April 13, 2020.
  11. Sepulveda AR, Hamilton SR, Allegra CJ. Et al. Molecular biomarkers for the evaluation of colorectal cancer: Guideline from the American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology, and the American Society of Clinical Oncology. J Clin Oncol. 2017; 35(13):1453-1486.
  12. Tanaka M, Chari S, Adsay V, et al. International consensus guidelines for management of intraductal papillary mucinous neoplasms and mucinous cystic neoplasms of the pancreas. Pancreatology. 2006; 6(1-2):17-32.
  13. Van Cutsem E, Cervantes A, Adam R, et al. ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Ann Oncol. 2016; 27(8):1386-422.
  14. Van Cutsem E, Cervantes A, Nordlinger B, et al. Metastatic colorectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2014; 25 Suppl 3:iii1-9.
  15. Vectibix (Panitumumab) [Product Information], Thousand Oaks, CA. Amgen. Revised June 2017. Available at: https://pi.amgen.com/~/media/amgen/repositorysites/pi-amgen-com/vectibix/vectibix_pi.pdf. Accessed on February 2, 2021.

Systemic Mastocytosis

  1. NCCN Clinical Practice Guidelines in Oncology®. © 2022 National Comprehensive Cancer Network, Inc. For additional information visit the NCCN website: visit the NCCN website: http://www.nccn.org/index.asp. Accessed on February 7, 2022.
  2. Valent P, Akin C, Hartmann K, et al. Updated Diagnostic Criteria and Classification of Mast Cell Disorders: A Consensus Proposal. Hemasphere. 2021; 5(11):e646. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8659997/. Accessed on February 7, 2022.
Websites for Additional Information
  1. American Cancer Society. Key statistics for acute myeloid leukemia (AML). Last revised January 12, 2022. Available at: https://www.cancer.org/cancer/acute-myeloid-leukemia/about/key-statistics.html. Accessed on February 5, 2022.
  2. American Cancer Society. What Is Targeted Cancer Therapy? Last revised January 29, 2021. Available at: https://www.cancer.org/treatment/treatments-and-side-effects/treatment-types/targeted-therapy/what-is.html. Accessed on February 2, 2021.
  3. National Library of Medicine (NLM). Genetics Home Reference. Published August 31, 2020. Available at: http://ghr.nlm.nih.gov/. Accessed on February 2, 2021.
  4. National Society of Genetic Counselors' Definition Task Force, Resta R, Biesecker BB, et al. A new definition of Genetic Counseling: National Society of Genetic Counselors' Task Force report. J Genet Couns. 2006; 5(2):77-83.
  5. Robson ME, Storm CD, Weitzel J, et al. American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility. J Clin Oncol. 2010; 28(5):893-901.

BRAF Mutation Analysis

  1. Genetics Home Reference:
  2. National Institutes of Health. Genetic and Rare Diseases Information Center. Langerhans cell histiocytosis. Available at: https://rarediseases.info.nih.gov/diseases/6858/langerhans-cell-histiocytosis. Accessed on February 2, 2021.

Circulating Tumor DNA

  1. American Cancer Society. Liquid Biopsies: Past, Present, and Future. February 12, 2018. Available at: https://www.cancer.org/latest-news/liquid-biopsies-past-present-future.html. Accessed on September 30, 2020.
  2. National Cancer Institute. Liquid biopsy: using DNA in blood to detect, track, and treat cancer. November 8, 2017. Available at: https://www.cancer.gov/news-events/cancer-currents-blog/2017/liquid-biopsy-detects-treats-cancer. Accessed on September 30, 2020
  3. National Cancer Institute. What is circulating tumor DNA and how is it used to diagnose and manage cancer?. Published September 21, 2020. Available at: https://ghr.nlm.nih.gov/primer/testing/circulatingtumordna . Accessed on February 2, 2021.

Epidermal Growth Factor Receptor (EGFR) Mutation Analysis

  1. American Cancer Association. Lung Cancer - Non-Small Cell. Available at: http://www.cancer.org/Cancer/LungCancer-Non-SmallCell/DetailedGuide/index. Accessed on February 2, 2021.
  2. National Cancer Institute. Non-Small Cell Cancer Treatment (PDQ®). Available at: http://www.cancer.gov/cancertopics/pdq/treatment/non-small-cell-lung/HealthProfessional/page2. Accessed on February 2, 2021.
  3. National Library of Medicine. Medical Encyclopedia: Non-Small Cell Lung Cancer. Available at: http://www.nlm.nih.gov/medlineplus/ency/article/007194.htm. Accessed on February 2, 2021.

PIK3CA Mutation Analysis

  1. National Center for Biotechnology Information (NCBI). Genetic Testing Registry (GTR). Genetic tests for PIK3CA. Available at: https://www.ncbi.nlm.nih.gov/gtr/tests/514565.1/. Last updated: May 26, 2015. Accessed on February 2, 2021.

RAS Mutation Analysis

  1. National Library of Medicine. Genetics Home Reference. HRAS. Last updated: August 18, 2020. Available at: https://ghr.nlm.nih.gov/gene/HRAS. Accessed on February 2, 2021.
  2. National Library of Medicine. Genetics Home Reference. KRAS. Last updated August 18, 2020. Available at: http://ghr.nlm.nih.gov/gene/KRAS. Accessed on February 2, 2021.
  3. National Library of Medicine. Genetics Home Reference. NRAS. Last updated: August 18, 2020. Available at: https://ghr.nlm.nih.gov/gene/NRAS. Accessed on February 2, 2021.

Systemic Mastocytosis

  1. National Comprehensive Cancer Networks. NCCN guidelines for patients. Systemic Mastocytosis 2022. Available at: https://www.nccn.org/patients/guidelines/content/PDF/systemic-mastocytosis-patient-guideline.pdf. Accessed on February 7, 2022. 
Index

Acute lymphoblastic leukemia (ALL)
Acute myeloid leukemia (AML)
Acute promyelocytic leukemia (APL)
Afatinib
lpelisib (PIQRAY)
Anaplastic thyroid cancer
BRAF Mutation Analysis
Cancer susceptibility
Catalytic subunit alpha polypeptide gene (PIK3CA)
Central nervous system tumor
Chronic lymphocytic leukemia (CLL)
Chronic myeloid leukemia (CML)
Circulating tumor DNA
cobas Mutation Test V2
Cobas® 4800 BRAF V600 Mutation Test
Colorectal Cancer
Colvera test
Dacomitinib
EGFR
Epidermal Growth Factor Receptor
Erdheim-Chester Disease
Erlotinib
Gefitinib
Gilotrif
Hairy-cell leukemia
Iressa
KRAS
Langerhans cell histiocytosis
Liquid biopsy
Lynch Syndrome
Mekinist (trametinib)
Melanoma
Myelodysplastic syndrome (MDS)
Myeloproliferative neoplasm (MPN)
Non-small cell lung cancer
NRAS
OncoBEAMLung1: EGFR
PI3K
PI3K-alpha
PI3KCA
PI3-kinase p110 subunit alpha
PIK3CA
Systemic mastocytosis
Tafinlar (dabrafenib)
Tarceva
Targeted therapy
Therascreen EGFR
THxID BRAF assay
Tyrosine Kinase
Vizimpro
Zelboraf® (vemurafenib)

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

History

Status

Date

Action

  06/29/2022 Updated Coding section with 07/01/2022 CPT changes; revised descriptor for CPT 0229U.

Revised

02/17/2022

Medical Policy & Technology Assessment Committee (MPTAC) review. Expanded scope of document to address solid and non-solid tumors (removed “solid tumors” from title). Updated Table A and Table B. Folded content of CG-GENE-01 Janus Kinase 2, CALR and MPL Gene Mutation Assays and CG-GENE-08 Genetic Testing for PTEN Hamartoma Tumor Syndrome into this document. Updated Discussion and General Information, Definitions, References, and Index sections.  Updated Coding section; added 0017U, 0027U, 81219, 81270, 81279, 81338, 81339 previously addressed in CG-GENE-01; added 0235U, 81321, 81322, 81323 previously addressed in CG-GENE-08; added 81175, 81176, 81206, 81207, 81208, 81218, 81233, 81236, 81237, 81273, 81310, 81315, 81316, 81320, 81334, 81347, 81348, 81357, 81360, 0016U, 0040U, 0049U and genes to Tier 2 codes; expanded diagnosis codes to include non-solid tumors where applicable.

 

04/14/2021

Corrected Coding section to add HCPCS code S3841 missing from document.

Revised

02/11/2021

MPTAC review. Moved content on circulating tumor DNA to guide targeted cancer therapy in individuals with solid tumor(s) and to detect the recurrence of colorectal cancer (fewer than 5 genes or gene variants tested on the same day on the same member by the same rendering provider) from GENE.00049 to this document. Content formerly addressed in CG-GENE-02 Analysis of RAS Status, CG-GENE-03 BRAF Mutation Analysis, CG-GENE-12 PIK3CA Mutation Testing for Malignant Condition and CG-GENE-20 Epidermal Growth Factor Receptor [EGFR] Testing), folded into this document. Table B (formerly Appendix A) updated. Removed cross-references to CG-GENE-03, CG-GENE-12, CG-GENE-20. Document reformatted. Updated Description/Scope, Discussion/General Information, Definitions, References and Websites for Additional Information, and Index sections. Reformatted and updated Coding section.

 

11/12/2020

In Appendix A, updated the information on Lynparza (olaparib) to include BRCA mutation testing in individuals with pancreatic or prostate cancer and homologous recombination repair (HRR) genes alteration testing in individuals with prostate cancer. In the Description section, added cross-reference to GENE.00052 Whole Genome Sequencing, Whole Exome Sequencing, Gene Panels, and Molecular Profiling. Updated Coding section with 01/01/2021 CPT changes; added 81191, 81192, 81193, 81194 replacing Tier 2 code.

Reviewed

05/14/2020

MPTAC review. Updated the Clinical Utility table in the Discussion and General Information section. Also updated the References, Websites for Additional Information and Appendix A. Updated Coding section; added 81120, 81121, 81245, 81246, 81272, 81314, 0023U, 0046U, 0154U, S3842, 81401 and genes added to Tier 2 and unlisted CPT codes.

New

11/07/2019

MPTAC review. Initial document development. Moved content related to whole genome, whole exome and gene panel testing from GENE.00001 Genetic Testing for Cancer Susceptibility to GENE.00052 Whole Genome Sequencing, Whole Exome Sequencing, Gene Panels, and Molecular Profiling. Moved remaining content of GENE.00001 Genetic Testing for Cancer Susceptibility to new clinical utilization management guideline with new title (CG-GENE-14 Gene Mutation Testing for Solid Tumor Cancer Susceptibility and Management) which addresses gene mutation testing to determine cancer susceptibility and guide targeted cancer therapy in individuals with solid tumors. Updated the Coding section to add CPT codes 81242, 81307, 81308, 81403, 81408.

 

 

 


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