Pharmacogenomic profiling appears promising - Health Net

Pharmacogenetic Testing May 15 1

National Medical Policy Subject: Pharmacogenetic Testing

Policy Number: NMP348

Effective Date*: June 2007

Updated: May 2015

This National Medical Policy is subject to the terms in the

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X National Coverage Determination (NCD)

Pharmacogenomic Testing for Warfarin

Response (90.1):

http://www.cms.gov/medicare-coverage-

database/search/advanced-search.aspx

National Coverage Manual Citation

Local Coverage Determination (LCD)*

Article (Local)*

X Other MLN Matters Number: MM6715. January 8, 2010.

Revised November 20, 2012. Pharmacogenomic

Testing for Warfarin Response:

http://www.cms.gov/Outreach-and-

Education/Medicare-Learning-Network-

MLN/MLNMattersArticles/downloads/MM6715.pdf

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Current Policy Statement Please refer to the HN NMP on Molecular Tumor Markers for Non-Small Cell

Lung Cancer (NSCLC)

I. Health Net, Inc. considers screening for HLA-B*5701 allele prior to initiation of abacavir

(Ziagen; ABC) therapy medically necessary to reduce the risk of hypersensitivity

reaction.

II. Health Net, Inc. considers genotyping for HLA-B* 1502 medically necessary for persons

of Asian ancestry before commencing treatment with carbamazepine (Tegretol).

III. Health Net, Inc. considers genotyping for CYP2C19 polymorphisms, a variant of

Cytochrome P450 medically necessary, one time, in individuals being considered for

treatment with clopidogrel or currently receiving clopidogrel (Plavix).

IV. Health Net, Inc. considers an FDA-approved test for **BRAF V600E mutation (e.g., the

Cobas 4800 BRAF mutation test) medically necessary for individuals who are considering

vemurafenib*** (Zelboraf) for the treatment of unresectable or metastatic melanoma.

Mutational status should be tested by an FDA-approved/CLIA approved facility.

**NOTE: The Cobas 4800 BRAF V600 mutation test, a companion diagnostic test

to determine the tumor mutational status, received FDA approval along with he

agent. The NCCN panel (2013) added vemurafenib to the list of available

systemic treatments of patients with a documented V600 E or K mutation of the

BRAF gene.

***NOTE: Vemurafenib has the potential for significant dermatologic

complications including cutaneous squamous cell carcinoma and extreme

photosensitivity. Regular dermatologic evaluation with referral to a dermatologist

is recommended. Patients should also be carefully monitored for the development

of other adverse reactions such as joint pain and swelling.

V. Health Net, Inc. considers an FDA-approved test for BRAF V600E and/or V600K

mutations (e.g., the THxID BRAF test) medically necessary for individuals with

unresectable or metastatic melanoma who are being considered for treatment with

either dabrafenib* (Tafinlar) or trametinib** (Mekinist). Mutational status should be

tested by an FDA-approved/CLIA approved facility.

*NOTE: Dabrafenib (Tafinlar) administration can be associated with significant

episodic and recurrent fevers that should be managed by discontinuation of

dabrafenib (Tafinlar) and anti-pyretics. Dabrafenib (Tafinlar) is associated with

keratoacanthoma/low grade squamous carcinoma and little if any significant

photosensitivity. Regular dermatologic evaluation is recommended. Patients


should also be educated to report the development of other adverse reactions

such as joint pain and swelling.

**NOTE: Single-agent trametinib (Mekinist)is not indicated for the treatment of

patients who have experienced progression of disease on prior BRAF inhibitor

therapy. Single-agent trametinib (Mekinist)can be used for the treatment of

BRAF-mutated melanoma in patients who are intolerant to single-agent BRAF

inhibitors.

The NCCN panel (2014) added the single agents of Dabrafenib (Tafinlar) and

Trametinib (Mekinist)as Category 1 recommendations for the systemic therapy

options for the treatment of BRAF V600E or V600K mutation-positive

unresectable or metastatic melanoma.

VI. Health Net, Inc. considers the *MGMT (0-6-methylguanine-DNA methyltransferase) gene

methylation assay medically necessary for predicting response to the chemotherapeutic

agent temozolomide (i.e., Temodar) in individuals with glioblastoma, aged 70 years or

younger, with a good PS.

*NOTE: The NCCN Panel (Version2.2013, CNS Cancers). See Scientific Rationale

update March 2014.

VII. Health Net, Inc. considers anaplastic lymphoma kinase (ALK) gene

rearrangement testing* with an FDA approved test medically necessary for metastatic

Non-Small Cell Lung Cancer (NSCLC) for prediction of response to crizotinib and

ceritinib therapy in ALK-positive NSCLC patients.

*NOTE: NCCN (Version 6.2015, 2A recommendation on NSCLC)

Health Net, Inc. considers any of the following pharmacogenetic testing (pharmacogenomic

profiling) investigational, because although there are ongoing studies, the efficacy and

clinical value have not been established:

As an approach to drug surveillance in the post FDA-approval period in an

effort to reduce adverse drug reaction (ADRs);

Genotyping for other cytochrome P450 polymorphism (including genetic testing panels that include multiple CYP450 mutations) other than the one

noted above (e.g., CYP2C9, CPY450, CYP3A4, CYP2D6, and VKORC1) to

determine reduced/enhanced effect or severe side effects of drugs

metabolized by the cytochrome P450 system such as opoid analgeics,

warfarin, tamoxifen, proton pump inhibitors, antipsychotic medications, and

selective serotonin reuptake inhibitors;

SureGene Test for Antipsychotic and Antidepressant Response (STA2R);

GeneSightRx or PHARMAchip assay genotyping of CYP1A2, CYP2C9, CYP2C19,

CYP2D6, HTR2A, and SCL6A4 to help guide administration of antidepressants

and antipsychotics;

Invader UGT1A1 molecular assay to determine the proper dosage of irinotecan

for persons with cancer (e.g., colorectal,);


Genotyping for apolipoprotein E (Apo E) to determine therapeutic response to

lipid-lowering medications;

Genotyping for methylenetetrahydrofolate reductase (MTHFR) to determine

therapeutic response to antifolate chemotherapy;

For Interleukin 28B (IL28B) single nucleotide polymorphism (SNP) testing in

patients with chronic hepatitis C virus (HCV) genotype 1 being considered for

treatment with triple therapy (i.e., pegylated interferon alpha (PegIFN),

ribavirin (RBV), and a protease inhibitor);

For Interleukin 28B (IL28B) single nucleotide polymorphism (SNP) testing in

patients with chronic hepatitis C virus (HCV) genotype 2 or 3 being considered

for treatment with pegylated interferon alpha (PegIFN), ribavirin (RBV), with

or without a protease inhibitor;

For the use of HLA-B*1502 genotyping in patients of other ethnicities (non-

Asian) for whom treatment with carbamazepine (Tegretol), or with phenytoin

(Dilantin) is being considered;

For the use of HLA-B*1502 genotyping in patients for whom treatment with

lamotrigine (Lamictal) is being considered;

For the use of genotyping for HLA-B variants other than HLA-B*1502 in

patients for whom treatment with carbamazepine (Tegretol), phenytoin

(Dilantin), or lamotrigine (Lamictal) is being considered.

The Comprehensive Personalized Medicine Panel

For the Genecept Assay which tests for polymorphisms in a number of genes,

including several CYP genes (CYP2D6, CYP2C19, and CYP3A4), and attempts

to integrate this information with clinical and pharmacologic information to

make treatment recommendations for patients with neuropsychiatric

disorders.

Health Net, Inc. considers Cytochrome P450 (CYP450) genotyping to predict response to

antidepressant and antipsychotic medications investigational since the evidence supporting

the clinical validity of this testing for response to medications varies significantly and is

limited significantly by the variability in study design. Additional peer-reviewed studies are

necessary. The following are therefore all considered investigational:

1. For CYP1A2 genotyping in patients with psychiatric disorders who are being considered

for treatment with antipsychotics.

2. For CYP2C9 genotyping in patients with a mental illness who are being considered for

treatment with antidepressants or antipsychotics.

3. For CYP2C19 genotyping in patients with depression who are being considered for

treatment with antidepressants.

4. For CYP2C19 genotyping in patients with psychiatric disorders who are being considered


5. For CYP2D6 genotyping in patients with a mental illness who are being considered for



6. For CYP3A4 genotyping in patients with a mental illness who are being considered for


7. For CYP3A5 genotyping in patients with depression who are being considered for

treatment with antidepressants.

8. For CYP3A5 genotyping in patients with psychiatric disorders who are being considered


9. For CYP450 genotyping panels (e.g., GeneSight Psychotropic, PsychiaGene, YouScript

Psychotropic, Mental Health DNA Insight, STA2R SureGene) in patients with a mental

illness who are being considered for treatment with antidepressants or antipsychotics.

10. For CYP450 genotyping in patients who are being treated with antidepressants or

antipsychotics and exhibiting a poor response (e.g., inadequate remission of symptoms)

or adverse side effect

Abbreviations ABC Abacavir

ABC HSR Abacavir hypersensitivity reaction

ADR Adverse drug reaction

HIV Human immunodeficiency virus

IC Immunologically confirmed

PT-INR Prothrombin time international normalized ratio

CYP2C9 Cytochrome P450, subfamily IIC, polypeptide 9

VKORC1 Vitamin K epoxide reductase subunit protein 1

Apo E Apolipoprotein E

MTHFR Antifolate chemotherapy

ACMG American College of Medical Genetics

SNPs Single nucleotide polymorphisms

PCI Percutaneous coronary intervention

ACS Acute coronary syndrome

PPI Protein pump inhibitor

MACE Major adverse cardiovascular events

Cytochrome P450 Refers to a family of 60 different enzymes involved in drug and toxin

metabolism.

Genotype Testing Determining the DNA sequence in genes

MAPK Mitogen-activated protein kinases

MEK Mitogen-activated protein kinase

SCAR / cADR Severe cutaneous adverse reaction

SJS Steven-Johnson Syndrome

TEN Toxic epidermal necrolysis

MPE Maculopapular eruption

DIHS Drug-induced hypersensitivity syndrome

IL28B Interleukin 28B

PegIFN Pegylated interferon alpha

Codes Related To This Policy (may not be all inclusive)

NOTE:

The codes listed in this policy are for reference purposes only. Listing of a code in this policy

does not imply that the service described by this code is a covered or non-covered health

service. Coverage is determined by the benefit documents and medical necessity criteria.

This list of codes may not be all inclusive.

On October 1, 2015, the ICD-9 code sets used to report medical diagnoses and inpatient

procedures will be replaced by ICD-10 code sets. Health Net National Medical Policies will


now include the preliminary ICD-10 codes in preparation for this transition. Please note

that these may not be the final versions of the codes and that will not be accepted for billing

or payment purposes until the October 1, 2015 implementation date.

ICD-9 Codes 042 Human immunodeficiency virus (HIV) disease

140.0 - 208.91,

230.0 - 234.9

Malignant neoplasms

V58.61 Long-term (current) use of anticoagulants

V08 Asymptomatic human immunodeficiency virus (HIV) infection

status

V58.61 - V58.69 Long-term (current) drug use

ICD-10 Codes B2Ø Human immunodeficiency virus [HIV] disease

C17-C17.9 Malignant neoplasm of colon

C22-C22.9 Malignant neoplasm of liver and intrahepatic bile ducts

C34-C34.92 Malignant neoplasm of bronchus and lung

Z21 Asymptomatic human immunodeficiency virus [HIV] infection status

Z79.Ø1 Long term (current) use of anticoagulants

Z79-Z79.890 Long term current drug therapy

Z79.891 Long term (current) use of opiate analgesic

Z79.899 Other long term (current) drug therapy

CPT Codes 81225 CYP2C19 (cytochrome P450, family 2, subfamily C, polypeptide 19)

(eg. Drug metabolism), gene analysis common variants (eg. *2,*3,

*4, *8, *17)

81226 CYP2D6 (cytochrome P450, family 2, subfamily D, polypeptide 6) (eg,

drug metabolism), gene analysis, common variants (eg, *2, *3, *4,

*5, *6, *9, *10, *17, *19, *29, *35, *41, *1XN, *2XN, *4XN)

81227 CYP2C9 (cytochrome P450, family 2, subfamily C, polypeptide 9) (eg,

drug metabolism), gene analysis, common variants (eg, *2, *3, *5,

*6)

81200-81383 Tier 1 Molecular Pathology

81245 FLT3 (fms-related tyrosine kinase 3) (eg, acute myeloid leukemia),

gene analysis; internal tandem duplication (ITD) variants (ie, exons

14, 15) (Revised in 2015)

81371 HLA-A, -B, and DRB1 (eg, verification typing) (Revised 2014)

81376 HLA Class 11 typing, low resolution. One locus (eg, HLA-DRB1, -

DRB3/4/5, -DQB1, -DQA1, -DPB1, OR DPA1), each (Revised 2014)

81400 Molecular pathology procedure, Level 1 (eg., identification of single

germline variant [eg, SNP] by techniques such as restriction enzyme

digestion or melt curve analysis) (Revised 2014) (Codes 81400-

81479 Tier 2 Molecular Pathology Codes)

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) (Revised 2014)

81402 Molecular pathology procedure, Level 3 (eg., >10 SNPs, 2-10

methylated variants, or 2-10 somatic variants, [typically using non-


sequencing target variant analysis], immunoglobulin and T-cell

receptor gene rearrangements, duplication/deletion variants of 1

exon, loss of heterozygosity (LOH), uniparental disomy (UPD]).

(Revised 2015)

81403 Molecular pathology procedure, Level 4 (eg., analysis of single exon

by DNA sequence analysis, analysis of >10amplicons using multiplex

PCR in 2 or more independent reactions, mutation scanning or

duplication/deletion variants of 2-5 exons) (Revised 2015)

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) (Revised 2015)



variants of 11-25 exons), regionally targeted cytogenomic array

analysis (Revised 2015)



variants of 26-50 exons, cytogenomic array analysis for neoplasia)

((Revised 2015)



variants of >50 exons, sequence analysis of multiple genes on one

platform)

81408 Molecular pathology procedure, Level 9 (eg., analysis of >50 exons in

a single gene by DNA sequence analysis (Revised 2015)

87999 Unlisted microbiology procedure

88384-88386 Array-based evaluation of multiple molecular probes [when

specified as genotype testing for polymorphisms of Human

Leukocyte Antigen B*1502 (HLAB*1502) for carbamazepine

metabolism, or P450 2C19 for clopidogrel metabolism; (Codes

88384-88386 deleted in 2015. To report see 81161, 81200-81479)

2014 New CPT Codes 81287 MGMT (0-6-mrthylguanine-DNA methyltransferase (eg. Glioblastoma

multiforme), methylation analysis

2015 New CPT Codes 81246 Tyrosine kinase domain (TKD) variants (eg, D835, I836)

81288 MLH1 (mutL homolog 1, colon cancer, Nonpolyposis type 2) (eg,

hereditary non-polyposis colorectal cancer, Lynch syndrome) gene

analysis: full sequence analysis

81313 PCA3/KLK3 (prostate cancer antigen 3[non-protein coding]/kallilrein-

related peptidase 3 [prostate specific antigen]) ratio (eg, prostate

cancer)

HCPCS Codes G9143 Warfarin responsiveness testing by genetic technique using

any method, any number of specimen(s)


Scientific Rationale – Update May 2015 Per NCCN Guidelines Version 6.2015 on Non-Small Cell Lung Cancer, “Anaplastic lymphoma

kinase (ALK) gene rearrangements represent the fusion between ALK and various partner

genes, including echinoderm microtubule-associated protein-like 4 (EML4). ALK fusions have

been identified in a subset of patients with NSCLC and represent a unique subset of NSCLC

patients for whom ALK inhibitors may represent a very effective therapeutic strategy.

Crizotinib and ceritinib are oral ALK inhibitors that are approved by the FDA for patients with

metastatic NSCLC who have the ALK gene rearrangement (i.e., ALK positive)”. The

International panel and NCCN recommend that all patients with adenocarcinoma be tested

for EGFR mutations; the NCCN Panel also recommends that these patients be tested for

anaplastic lymphoma kinase (ALK) gene rearrangements.

Per the FDA, the Vysis ALK Break Apart FISH Probe Kit is a qualitative test that received FDA

Premarket Approval (P110012) on August 26, 2011. It is indicated for detection of

rearrangements involving the ALK gene using FISH methodology on formalin-fixed paraffin-

embedded (FFPE) NSCLC tissue specimens, to identify patients eligible for crizotinib therapy.

Crizotinib is indicated for the treatment of patients with locally advanced or metastatic

NSCLC that is ALK-positive, detected using an FDA-approved test.

The Genecept Assay tests for polymorphisms in a proprietary panel of ten genes, including

several CYP genes (CYP2D6, CYP2C19, and CYP3A4), and attempts to integrate this

information with clinical and pharmacologic information to make treatment

recommendations for patients with neuropsychiatric conditions. The panel is unique for its

dual approach since it includes both pharmacokinetic and pharmacodynamics genes. No

published peer-reviewed studies of the use of the Genecept Assay in particular or of the

combination of genes included in the Genecept Assay were identified. Therefore, at this time

there is a paucity of peer-reviewed published evidence to assess the impact of using this

test in the care of patients with neuropsychiatric disorders.

Scientific Rationale – Update April 2015 The Comprehensive Personalized Medicine Panel is a pharmacogenetic test that assays

variants in 19 genes, including CYP1A2 and CYP2D6, as well as CYP3A4, CYP3A5, and

others, and uses this information to predict patient response to medications. Although there

are many studies investigating the impact of variants in individual genes on response to

individual drugs, there are no published studies evaluating the use of variant information for

the set of genes included in the Comprehensive Personalized Medicine Panel to predict

patient response to drugs. Therefore, it is currently not possible to assess the impact of

using this test in patient care.

Scientific Rationale – Update February 2015 The STA2R SureGene Test is a pharmacogenetic test that assays variants in 7 genes,

including CYP1A2, CYP2C19, and CYP2D6, as well as the serotonin receptor (SLC6A4) gene,

the sulfotransferase 4A1 (SULT4A1) gene, CYP3A4, and CYP3A5, and uses this information

to predict patient response to a large number of antidepressant and antipsychotic drugs

(click here). Although there are many studies investigating the impact of variants in

individual genes on response to individual drugs, there is a paucity of peer-reviewed studies

evaluating the use of variant information for the 7 genes included in the STA2R SureGene

Test to predict patient response to a wide range of antidepressant and antipsychotic drugs.

Therefore, the impact of using this test in the care of patients being prescribed

antidepressant or antipsychotic drugs cannot be determined at this time.


Scientific Rationale – Update May 2014 Anticonvulsant hypersensitivity syndrome is a term used to describe the adverse drug

reactions (ADRs) that may occur in patients taking antiepileptic drugs (i.e., AEDs). These

adverse reactions are estimated to occur in 1/1,000 to 1/10,000 AED exposures, and are

commonly from the use of aromatic anticonvulsants, named because of the process in which

these medications are metabolized. This includes carbamazepine (CBZ; also known by the

brand name Tegretol), phenytoin (PHT; also known as fosphenytoin or by the brand name

Dilantin), oxcarbazepine (OXC; also known by the brand name Trileptal), lamotrigine (LTG;

also known by the brand name Lamictal), phenobarbital, and zonisamide (also known by the

brand name Zonegran).

Carbamazepine or CBZ, is the most commonly prescribed first-line treatment for seizure

disorders or epilepsy, and is also known to be effective in the treatment of bipolar disorder,

trigeminal neuralgia, neuropathic pain, and tinnitus. However, up to 10% of patients who

are treated with CBZ may experience a severe cutaneous adverse reaction (i.e., cADR, or

SCAR). Because of the chance of developing a severe reaction to CBZ and related

medications, research has focused on identifying genetic variants that may be used to help

assess the likelihood of an adverse drug reaction (ADR) prior to treatment initiation.

It was discovered that some reactions to aromatic antiepileptic drugs (AEDs) are associated

with specific variants in the human leukocyte antigen (HLA) genes. The HLA genes encode

cell surface proteins that function in immune response. The most common HLA allele, or

version of an HLA gene, linked to the development of ADRs in patients taking aromatic

AEDs, is the HLA-B*1502 allele. The HLA-B*1502 allele is most common among individuals

from Southeast Asia. It is significantly less common among Japanese and Korean

individuals, and is essentially absent in those of European, African, and Hispanic descent.

Per the U.S. FDA site, “The risk of Stevens Johnson syndrome (SJS)/toxic epidermal

necrolysis (TEN) from carbamazepine and other aromatic anticonvulsants (eg, phenytoin,

phenobarbital) is significantly increased in patients positive for the HLA-B*1502 allele. This

allele is found almost exclusively in patients with ancestry across broad areas of Asia,

including South Asian Indians. Due to wide variability in rates of HLA-B*1502 even within

ethnic groups, the difficulty in ascertaining ethnic ancestry, and the likelihood of mixed

ancestry, screening for HLA-B*1502 should be performed for most patients of Asian

ancestry”.

Primary treatment for TEN consists of removal of the offending agent along with transfer to

an intensive care, burn unit, or other specialty unit, and supportive therapy. Minimizing the

time between the onset of cutaneous symptoms and the arrival at the specialty unit is

crucial for improving the potential for survival. Identification of the offending agent can be

difficult in patients in whom a number of new medications have recently been started.

Although in vitro lymphocyte transformation testing (LTT) had initially shown promising

results in determining the causative agent in TEN when testing is performed within 1 week

of disease onset, a subsequent study evaluating LTT in patients with SJS/TEN secondary to

lamotrigine has shown a low rate of positive LTT during both the acute and recovery phase,

rendering the use of LTT in clinical setting unconvincing.[88] The frequently negative LTT

results may be related to the poor proliferative properties of CD8+ T cells.

Therefore, patients a history of TEN/SJS must avoid the offending agent and any cross-

reacting medications. Carbamazepine, phenytoin, and phenobarbital may cross react with

one another. Patients with a history of TEN/SJS induced by an aromatic anticonvulsant


should avoid this class of medications. However, there is no evidence of cross-reactivity

between aromatic anticonvulsants and lamotrigine.

The cellular mechanism of the action of lamotrigine (LTG) is not completely understood, and

it may have multiple effects. LTG is approved by the FDA for the adjunctive treatment of

focal seizures in adults and children as young as two years old, as well as for adjunctive

therapy for primary generalized tonic-clonic seizures and Lennox-Gastaut syndrome.

Guidelines published by the American Academy of Neurology (AAN) support use of LTG as

initial therapy in patients with newly diagnosed focal epilepsy and idiopathic generalized

epilepsy, as well as mixed seizure disorders. LTG may also be used for the treatment of

newly diagnosed absence seizures in children.

Tangamornsuksan et al. (2013) completed a comprehensive review in which the inclusion

criteria were studies that investigated the relationship between HLA-B*1502 and

carbamazepine-induced Stevens Johnson syndrome (SJS) and toxic epidermal necrolysis

(TEN) and that reported sufficient data for calculating the frequency of HLA-B*1502 carriers

among cases and controls. The search yielded 525 articles, of which 16 met the inclusion

criteria. The studies included 227 SJS or TEN cases, 602 matched control subjects, and 2949

population control subjects. Two reviewers independently extracted the following data:

study design, eligibility criteria, diagnostic criteria, patient demographics, genotype

distribution, HLA-B genotyping technique, selection of cases and controls, dosage of

carbamazepine and duration of use, and results of Hardy-Weinberg equilibrium in the control

group. The Newcastle-Ottawa Scale was used to assess the quality of studies. The overall

odds ratios (ORs) with corresponding 95% CIs were calculated using a random-effects

model. The primary analysis was based on matched control studies. Subgroup analyses by

race/ethnicity were also performed. The primary outcome was carbamazepine-induced SJS

and TEN. The outcome measure is given as an overall odds ratio (OR). The summary OR for

the relationship between HLA-B*1502 and carbamazepine-induced SJS and TEN was 79.84

(95% CI, 28.45-224.06). Racial/ethnic subgroup analyses yielded similar findings for Han-

Chinese (115.32; 18.17-732.13), Thais (54.43; 16.28-181.96), and Malaysians (221.00;

3.85-12; 694.65). Among individuals of white or Japanese race/ethnicity, no patients with

SJS or TEN were carriers of the HLA-B*1502 allele. We found a strong relationship between

the HLA-B*1502 allele and carbamazepine-induced SJS and TEN in Han-Chinese, Thai, and

Malaysian populations. HLA-B*1502 screening in patients requiring carbamazepine therapy

is warranted in this population.

Tang et al. (2012) Prior use of 'lymphocyte transformation test' (LTT) in Stevens-Johnson

syndrome (SJS) and toxic epidermal necrolysis (TEN) provided conflicting results, possibly

dependent on sampling dates (acute vs. late). Evaluation of LTT in patients with SJS or TEN

who reacted to lamotrigine (LTG). In a small subgroup we explored the possible role of

regulatory T cells (T-reg). Acute phase samples (9) and post-recovery samples (14) from

cases of SJS or TEN to LTG were provided by the RegiSCAR-study group. Controls were

persons never exposed to LTG (12), patients exposed without reaction (6), and patients who

developed a mild eruption to LTG (6). LTT was performed by measuring (3) H-thymidine

incorporation after 3 days of incubation with phytohemmaglutinin, LTG or medium. In 16

cases LTT was redone after depletion of T-reg by fluorescence activated cell sorting.

Positive LTT was observed in 3/6 cases of mild eruptions, 1/9 SJS/TEN-cases tested during

the acute phase and 3/14 SJS/TEN-cases tested after recovery. We noted a very mild and

nonsignificant trend for an increased response after depletion of T-reg in late samples from

SJS or TEN patients. With the largest number of LTT performed in patients with SJS or TEN

to a single drug, the authors confirmed that reactive cells are rarely detected in these

reactions. Poor reactivity did not seem related to T-reg. Other in vitro assays than those


testing proliferation should be evaluated, before raising the hypothesis that specific cells

disappeared by undergoing apoptosis during the reaction.

HLA-B is a human gene that plays a critical role in the immune system, and is part of a

family of genes called the human leukocyte antigen (HLA) complex. The HLA complex helps

the immune system distinguish the body's own proteins from proteins made by viruses or

bacteria. The HLA-B gene has many different normal variations, allowing each person's

immune system to react to a wide range of foreign invaders. Hundreds of versions, or alleles

of HLA-B are known, each of which is given a particular number (i.e., HLA-B 1502).

Scientific Rationale – Update March 2014 Trametinib (Mekinist) and Dabrafenib (Tafinlar) were previously approved by the U.S. FDA in

May 2013 as single agents for the treatment of BRAF V600E or V600K mutation-positive

unresectable or metastatic melanoma. Trametinib (Mekinist)and dabrafenib (Tafinlar) target

two different tyrosine kinases in the RAS/RAF/MEK/ERK pathway.

Dabrafenib (Tafinlar) is an inhibitor of BRAF, the protein encoded by the BRAF gene. BRAF is

a key component of the mitogen-activated protein kinases (MAPK) signaling pathway.

Increased activation of the MAPK pathway is a driving force in many cancers, including

melanoma-harboring BRAF gene variants. Dabrafenib (Tafinlar) is specifically not indicated

for the treatment of patients with wild-type BRAF melanoma.

Trametinib (Mekinist) is an inhibitor of mitogen-activated protein kinase (MEK) enzymes,

key components in the mitogen-activated protein kinases (MAPK) signaling pathway.

Increased activation of this pathway is a driving force in many cancers, including melanoma-

harboring BRAF gene variants. Trametinib (Mekinist)is specifically not indicated for the

treatment of patients previously treated with BRAF inhibitor therapy.

Hauschild et al. (2012) completed a randomized controlled trial on dabrafenib (Tafinlar) for

melanoma. The main objective of this RCT was to study the efficacy of dabrafenib (Tafinlar)

vs. standard dacarbazine treatment in patients selected to have BRAF V600E mutated

metastatic melanoma. Two-hundred-fifty patients were randomized 3:1 to receive oral

dabrafenib (Tafinlar) 150 mg twice daily versus intravenous dacarbazine 1,000 mg/m2 every

3 weeks. The primary outcome was progression-free survival and secondary outcomes were

overall survival, objective response rates, and adverse events. Median progression-free

survival for the dabrafenib (Tafinlar) and dacarbazine groups was 5.1 months and 2.7

months, respectively. Overall survival did not differ significantly between groups; 11% of

patients in the dabrafenib (Tafinlar) group died compared with 14% in the dacarbazine

group (hazard ratio [HR]: 0.61,·30; 95% CI: 0.25-1.48). However, 28 patients (44%) in the

dacarbazine arm crossed over at disease progression to receive dabrafenib (Tafinlar). The

objective response rate, defined as complete plus partial responses was higher 7 - GT41 in

the dabrafenib (Tafinlar) group (50%, 95% CI: 42.4-57.1%) compared with the dacarbazine

group (6%, 95% CI: 1.8-15.5%). Treatment-related adverse events grade 2 or higher

occurred in 53% of patients who received dabrafenib (Tafinlar) and in 44% of patients who

received dacarbazine. Grade 3-4 adverse events were uncommon in both groups. The most

common serious adverse events were cutaneous squamous cell carcinoma (7% vs. none in

controls); serious non-infectious, febrile drug reactions (3% grade 3 pyrexia vs. none in

controls); and severe hyperglycemia (>250-500 mg/dL), requiring the dacarbazine group

(6%, 95% CI: 1.8-15.5%). Treatment-related adverse events grade 2 or higher occurred in

53% of patients who received dabrafenib (Tafinlar) and in 44% of patients who received

dacarbazine. Grade 3-4 adverse events were uncommon in both groups. The most common

serious adverse events were cutaneous squamous cell carcinoma (7% vs. none in controls);


serious non-infectious, febrile drug reactions (3% grade 3 pyrexia vs. none in controls); and

severe hyperglycemia (>250-500 mg/dL), requiring medical management in non-diabetic or

change in management of diabetic patients (6% vs. none in controls). The results

demonstrate that targeting dabrafenib (Tafinlar) against BRAF V600E mutated melanoma

results in a benefit in progression-free survival. Patients were allowed to cross over at the

time of progression, and the effect of dabrafenib (Tafinlar) on overall survival was favorable

but not statistically significant. All tissue specimens from patients screened for enrollment in

the clinical trial were analyzed centrally by a clinical trial assay. [24] Outcomes were linked

retrospectively to BRAF testing by the THxID BRAF kit. Of 250 patients enrolled in the trial,

specimens from 237 patients (177 [95%] in the dabrafenib (Tafinlar) arm and 55 [87%] in

the dacarbazine arm) were retested with the THxID BRAF kit. Reanalysis of the primary end

point, PFS, in patients who were V600E positive by the THxID BRAF kit showed a treatment

effect that was nearly identical to the overall result by central assay. Additional analysis for

discordant results assumed a worst case scenario, i.e., a hazard ratio of 1 for patients

V600E-mutation-positive by the THxID BRAF test but mutation negative by central assay.

The hazard ratio was 0.34 (95% CI: 0.23–0.50).

Flaherty et al. (2012) the clinical efficacy and safety of trametinib (Mekinist)was assessed in

the Phase III, open-label METRIC trial. Patients with stage IV or unresectable stage IIIC

cutaneous melanoma were randomized 2:1 to receive trametinib (Mekinist)2 mg orally once

daily (n=214) or chemotherapy (n=108), either dacarbazine 1,000 mg/m2 IV every 3 weeks

or paclitaxel 175 mg/m2 IV every 3 weeks at investigator discretion. Most patients (67%)

were previously untreated. The primary efficacy endpoint was PFS; secondary endpoints

included overall survival, overall response rate, and safety. Tumor assessments were

performed at baseline and at weeks 6, 12, 21, and 30 and then every 12 weeks. Median PFS

was 4.8 months (95% CI: 4.3–4.9) in the trametinib (Mekinist)arm and 1.5 months (95%

CI: 1.4-2.7) in the chemotherapy arm, a statistically significant difference. Although median

overall survival had not been reached at the time of the report publication, 6-month survival

was statistically longer in the trametinib (Mekinist)group than in the chemotherapy group

(p=0.01); 51 of 108 patients (47%) in the chemotherapy group crossed over at disease

progression to receive trametinib. In the trametinib (Mekinist)and chemotherapy groups,

adverse events led to dose interruption in 35% and 22% of patients, respectively, and to

dose reduction in 27% and 10% of patients, respectively. Decreased ejection fraction or

ventricular dysfunction was observed in 14 patients (7%) in the trametinib (Mekinist)group;

2 patients had grade 3 cardiac events that led to permanent drug discontinuation. Twelve

percent of the trametinib (Mekinist)group and 3% of the chemotherapy grouped experienced

grade 3 hypertension. Nine percent of patients in the trametinib (Mekinist)group

experienced ocular events (mostly grade 1 or 2), most commonly blurred vision (4%). The

most common adverse events in the trametinib (Mekinist)group were rash, diarrhea,

peripheral edema, and fatigue; rash was grade 3 or 4 in 16 patients (8%). Cutaneous

squamous cell carcinoma was not observed during treatment. Tumor tissue was evaluated

for BRAF mutations at a central site using a clinical trial assay. Retrospective THxID BRAF

analysis was conducted on tumor samples from 289 patients (196 [92%] in the trametinib

(Mekinist)arm and 93 [86%] in the chemotherapy arm). Reanalysis of PFS in patients who

were 8 - GT41 V600E or V600K-positive by the THxID BRAF kit showed a treatment effect

that was almost identical to the overall result by central assay. Additional analysis for

discordant results assuming a worst case scenario as above yielded a hazard ratio of 0.48

(95% CI: 0.35–0.63).

In January 2014, the U.S. FDA granted accelerated approval to trametinib (Mekinist)

tablets), and dabrafenib (Tafinlar) for use in combination in the treatment of patients with


unresectable or metastatic melanoma with a BRAF V600E or V600K mutation as detected by

an FDA-approved test.

Common BRAF variants include p.Val600Glu (i.e., V600E) and p.Val600Lys (i.e., V600K).

In order to be treated with trametinib (Mekinist)or dabrafenib (Tafinlar) either as single

agents or in combination, melanoma patients’ tumor tissue must be tested for BRAF variants

using an FDA-approved test. In addition to the cobas 4800 BRAF V600 Mutation Test

manufactured by Roche Molecular Systems, approved by the U.S. FDA in August 17, 2011,

which detects BRAF p.Val600Glu variants (i.e. V600E), the THxID-BRAF test (bioMérieux SA)

has been approved by the FDA on May 29, 2013, to detect BRAF p.Val600Glu (i.e., V600E)

or p.Val600Lys (i.e., V600K) variants. THxID-BRAF is a real-time polymerase chain reaction

(PCR) test for use with formalin-fixed, paraffin-embedded melanoma tumor tissue. THxID-

BRAF was developed in collaboration with GlaxoSmithKline, the manufacturer of trametinib

(Mekinist)and dabrafenib (Tafinlar). Two clinical laboratories in the United States, Clarient

Diagnostic Services Inc. and Hematogenix Laboratory Services LLC are listed on the

bioMérieux website as providers of the THxID-BRAF test.

Approval of the combination therapy was based on the demonstration of durable objective

responses in a multicenter, open-label, randomized (1:1:1), active-controlled, dose-ranging

trial enrolling 162 patients with histologically confirmed Stage IIIC or IV melanoma

determined to be BRAF V600E or V600K. No more than one prior chemotherapy regimen

and/or interleukin-2 were permitted. Patients with prior exposure to BRAF inhibitors or MEK

inhibitors were ineligible. Patients were randomized to receive trametinib (Mekinist)2 mg

orally once daily in combination with dabrafenib (Tafinlar) 150 mg orally twice daily (n=54),

trametinib (Mekinist)1 mg orally once daily in combination with dabrafenib (Tafinlar) 150 mg

orally twice daily (n=54), or single-agent dabrafenib (Tafinlar) 150 mg orally twice daily

(n=54). Of the 162 patients enrolled, 57% were male, the median age was 53 years, all had

baseline ECOG PS of 0 or 1, 67% had M1c disease, and 81% had not received prior

anticancer therapy for unresectable or metastatic disease. All patients had tumor tissue with

mutations in BRAF V600E (85%) or V600K (15%) on local or centralized testing. The

investigator-assessed objective response rates and response duration were 76% (95% CI:

62, 87) and 10.5 months (95% CI: 7, 15), respectively, in the trametinib (Mekinist)2 mg

plus dabrafenib (Tafinlar) combination arm and 54% (95% CI: 40, 67) and 5.6 months

(95% CI: 5, 7), respectively, in the single-agent dabrafenib (Tafinlar) arm. Objective

response rates were similar in subgroups defined by BRAF V600 mutation subtype, V600E

and V600K. Analyses of objective response rates based on blinded independent central

review were consistent with the investigator results. The incidence of cutaneous squamous

cell carcinoma (including squamous cell carcinomas of the skin and keratoacanthomas), the

trial’s primary safety endpoint, was 7% (95% CI: 2, 18) in the trametinib (Mekinist)2 mg

plus dabrafenib (Tafinlar) combination arm compared to 19% (95% CI: 9, 32) in the single-

agent dabrafenib (Tafinlar) arm. The most frequent (greater than or equal to 20%

incidence) adverse reactions from trametinib (Mekinist)in combination with dabrafenib

(Tafinlar) were pyrexia, chills, fatigue, rash, nausea, vomiting, diarrhea, abdominal pain,

peripheral edema, cough, headache, arthralgia, night sweats, decreased appetite,

constipation, and myalgia. The most frequent grades 3 and 4 adverse events (greater than

or equal to 5% incidence) were acute renal failure, pyrexia, hemorrhage, and back pain.

Serious adverse drug reactions occurring in patients taking trametinib (Mekinist)in

combination with dabrafenib (Tafinlar) were hemorrhage, venous thromboembolism, new

primary malignancy, serious febrile reactions, cardiomyopathy, serious skin toxicity, and eye

disorders such as retinal pigmented epithelial detachments.


Granting of this accelerated approval is contingent upon the successful completion of the

ongoing MEK115306 trial, (i.e., ClinicalTrials.gov Identifier:NCT01584648), to verify the

clinical benefit of trametinib (Mekinist)for use in combination with dabrafenib (Tafinlar).

MEK115306 is an international, multicenter, randomized (1:1), double-blind, placebo-

controlled trial comparing the combination of dabrafenib (Tafinlar) and trametinib

(Mekinist)to dabrafenib (Tafinlar) and placebo as first-line therapy in approximately 340

patients with unresectable (Stage IIIC) or metastatic (Stage IV) BRAF V600E or V600K

mutation-positive cutaneous melanoma. The primary endpoint is progression-free survival.

Overall survival is a key secondary endpoint. Estimated study completion is January 2015.

Menzies et al. (2014) MAPK inhibitors (MAPKi) are active in BRAF-mutant metastatic

melanoma patients, but the extent of response and progression-free survival (PFS) is

variable, and complete responses are rare. The authors sought to examine the patterns of

response and progression in patients treated with targeted therapy. MAPKi-naïve patients

treated with combined dabrafenib (Tafinlar) and trametinib (Mekinist)had all metastases ≥5

mm (lymph nodes ≥15 mm in short axis) visible on computed tomography measured at

baseline and throughout treatment. 24 patients had 135 measured metastases (median

4.5/patient, median diameter 16 mm). Time to best response (median 5.5 mo, range 1.7–

20.1 mo), and the degree of best response (median −70%, range +9 to −100%) varied

amongst patients. 17% of patients achieved complete response (CR), whereas 53% of

metastases underwent CR, including 42% ≥10 mm. Metastases that underwent CR were

smaller than non-CR metastases (median 11 vs 20 mm, P<0.001). PFS was variable among

patients (median 8.2 mo, range 2.6–18.3 mo), and 50% of patients had disease progression

in new metastases only. Only 1% (1/71) of CR-metastases subsequently progressed.

Twelve-month overall survival was poorer in those with a more heterogeneous initial

response to therapy than less heterogeneous (67% vs 93%, P = 0.009. Melanoma response

and progression with MAPKi displays marked inter- and intra-patient heterogeneity. Most

metastases undergo complete response, yet only a small proportion of patients achieve an

overall complete response. Similarly, disease progression often occurs only in a subset of

the tumor burden, and often in new metastases alone. Clinical heterogeneity, likely

reflecting molecular heterogeneity, remains a barrier to the effective treatment of melanoma

patients.

Flaherty et al. (2012) noted an ongoing, phase II, Clinical Trial with the purpose to

investigate the safety, pharmacokinetics, pharmacodynamics and clinical activity of the

BRAF Inhibitor GSK2118436 (i.e. dabrafenib (Tafinlar)/Tafinlar) and the MEK inhibitor

GSK1120212 (i.e., Trametinib/Mekinist), in combination, given to patients with BRAF Mutant

Metastatic Melanoma. This study is designed in four parts. In Part A, the effect of repeat

doses of GSK1120212 on the pharmacokinetics of single dose GSK2118436, will be

investigated prior to evaluating combination regimens. In Part B, the range of tolerated dose

combinations will be identified using a dose-escalation procedure. In Part C, different dose

combinations of GSK2118436 and GSK1120212 will be evaluated, based on results from the

dose escalation cohorts. In Part D, the pharmacokinetics and safety of GSK2118436

administered as HPMC capsules alone and in combination with GSK1120212 will be

evaluated involving 247 patients with metastatic melanoma and BRAF V600 mutations. The

authors evaluated the pharmacokinetic activity and safety of oral dabrafenib (Tafinlar) (75

or 150 mg twice daily) and trametinib (Mekinist)(1, 1.5, or 2 mg daily) in 85 patients and

then randomly assigned 162 patients to receive combination therapy with dabrafenib

(Tafinlar) (150 mg) plus trametinib (Mekinist)(1 or 2 mg) or dabrafenib (Tafinlar)

monotherapy. The primary end points were the incidence of cutaneous squamous-cell

carcinoma, survival free of melanoma progression, and response. Secondary end points

were overall survival and pharmacokinetic activity. Dose-limiting toxic effects were


infrequently observed in patients receiving combination therapy with 150 mg of dabrafenib

(Tafinlar) and 2 mg of trametinib (Mekinist)(combination 150/2). Cutaneous squamous-cell

carcinoma was seen in 7% of patients receiving combination 150/2 and in 19% receiving

monotherapy (P = 0.09), whereas pyrexia was more common in the combination 150/2

group than in the monotherapy group (71% vs. 26%). Median progression-free survival in

the combination 150/2 group was 9.4 months, as compared with 5.8 months in the

monotherapy group (hazard ratio for progression or death, 0.39; 95% confidence interval,

0.25 to 0.62; P<0.001). The rate of complete or partial response with combination 150/2

therapy was 76%, as compared with 54% with monotherapy (P = 0.03). Dabrafenib

(Tafinlar) and trametinib (Mekinist)were safely combined at full monotherapy doses. The

rate of pyrexia was increased with combination therapy, whereas the rate of proliferative

skin lesions was nonsignificantly reduced. Progression-free survival was significantly

improved. The authors believe that the combination of dabrafenib (Tafinlar) and trametinib

(Mekinist)warrants further evaluation as a potential treatment for metastatic melanoma with

BRAF V600 mutations and other cancers with these mutations. This study was last updated

September 19, 2013 and the estimated study completion date is May 2016. (Funded by

GlaxoSmithKline; ClinicalTrials.gov number, NCT01072175.)

The NCCN Guidelines on Melanoma (Version 3.2014) include the following systemic therapy

options for advanced or metastatic melanoma:

The preferred regimens note the addition of the single agents of Dabrafenib (Tafinlar)

and Trametinib (Mekinist)as Category 1 recommendations;

A revisions which notes Vemurafenib, dabrafenib (Tafinlar) and trametinib (Mekinist)are

recommended only for patients with V600 mutation of the BRAF gene documented by an

FDA-approved or Clinical Laboratory Improvement Amendment (CLIA)-approved facility;

Dabrafenib (Tafinlar) administration can be associated with significant episodic and

recurrent fevers that should be managed by discontinuation of dabrafenib (Tafinlar) and

institution of anti-pyretics such as acetaminophen and/r NSAIDs. Dabrafenib (Tafinlar) is

associated with keratoacanthoma/low grade squamous carcinomas and little if any

significant photosensitivity. Regular dermatologic evaluation and referral to a

dermatologist is recommended. Patients should also be educated to report the

development of other adverse reactions such as joint pain and swelling;

The combination of dabrafenib (Tafinlar) with trametinib (Mekinist)was associated with

improved progression-free survival (PFS) compared to dabrafenib (Tafinlar)

monotherapy in a phase I/II Trial. However, improvement in overall survival has not

been demonstrated. Combination therapy may be associated with less cutaneous

toxicity than monotherapy.

Single-agent trametinib (Mekinist)is not indicated for the treatment of patients who

have experienced progression of disease on prior BRAF inhibitor therapy. Single-agent

trametinib (Mekinist)can be used for the treatment of BRAF-mutated melanoma in

patients who are intolerant to single-agent BRAF inhibitors.

The combination of dabrafenib (Tafinlar) and trametinib (Mekinist)appears to have a

superior response rate and progression free survival than dabrafenib (Tafinlar) alone with

less skin toxicity, however, formal comparison of safety and efficacy of the combination and

relative to dabrafenib (Tafinlar) alone awaits the completion of ongoing phase III trials. For

patients who are ineligible for clinical trials and who are candidates for targeted therapy, the

authors suggest starting patients with the combination of dabrafenib (Tafinlar) and

trametinib (Mekinist)rather than a single agent (UpToDate, Grade 2B*).


*NOTE: A Grade 2 recommendation is a weak recommendation. It means "this is our

suggestion, but you may want to think about it." It is unlikely that you should follow the

suggested approach in all your patients, and you might reasonably choose an alternative

approach. For Grade 2 recommendations, benefits and risks may be finely balanced, or the

benefits and risks may be uncertain. In deciding whether to follow a Grade 2

recommendation in an individual patient, you may want to think about your patient's values

and preferences or about your patient's risk aversion. Grade B means that the best

estimates of the critical benefits and risks come from randomized, controlled trials with

important limitations (eg, inconsistent results, methodologic flaws, imprecise results,

extrapolation from a different population or setting) or very strong evidence of some other

form. Further research (if performed) is likely to have an impact on our confidence in the

estimates of benefit and risk, and may change the estimates.

Clinical trials investigating the potential for improvement in survival based upon combination

treatment with dabrafenib (Tafinlar) and trametinib (Mekinist)for individuals with V600E or

V600K mutation of the BRAF gene, who have advanced or metastatic melanoma, are

ongoing.

The NCCN Guidelines (Version 3.2014) for Colon Cancer note” Irinotecan should be used

with caution and with decreased doses in patients with Gilbert’s disease or elevated serum

bilirubin. There is a commercially available test for UGT1A1, however guidelines for use in

clinical practice have not been established. UGT1A1 testing on patients who experience

irinotecan toxicity is not recommended, because they will require a dose reduction

regardless of the UGT1A1 test result”.

The NCCN Guidelines (Version 2.2013) on Thyroid Cancer notes: “ Molecular diagnostics to

detect individual mutations (eg, BRAF, RET/PTC, RAS, PAX8/PPAR), or pattern recognition

approaches using molecular classifiers may be useful in the evaluation of FNA samples that

are indeterminate. For the 2013 update, the NCCN Panel added recommendations to

consider molecular diagnostics for evaluating fine needle aspiration (FNA) results that are

suspicious for follicular or Hurthle cell neoplasms; or follicular lesion of undetermined

significance. Rather than proceeding to immediate surgical resection to obtain a definitive

diagnosis in these categories, patients can be followed with observation if the application of

a specific molecular diagnostic test results in a predicted risk of malignancy that is

comparable to the rate seen in cytologically benign malignancy that is comparable to the

rate seen in cytologically benign thyroid FNAs (approximately <5%). It is important to note

that the predictive value of molecular diagnostics may be significantly influenced by the pre-

test probability of disease associated with the various FNA cytology categories. In the

cytologically indeterminate groups, the risk for malignancy for FNA can vary widely between

institutions. Because the published studies have focused primary on adult thyroid nodules,

the diagnostic utility of molecular diagnostics in pediatric patients remains to be defined.

Therefore, proper implementation of molecular diagnostics into clinical care requires an

understanding of both the performance characteristics of the specific molecular test and its

clinical meaning across a range of pre-test disease possibilities. Some tumor features have a

profound influence on prognosis. The most important features are tumor histology, primary

tumor size, local invasion, necrosis, vascular invasion, BRAF mutation status, and

metastases. For example vascular invasion (even within the thyroid gland) is associated with

more aggressive disease and with a higher incidence of recurrence.” There is no specific

information on this site about the BRAF V600E mutation.

The NCCN Guidelines (Version 2.2013) on Central Nervous System Cancers notes the

following: “ MGMT (0-6-methylguanine-DNA methyltransferase) is a DNA repair enzyme that


can cause resistance to DNA-alkylating drugs. Oligodendrogliomas frequently exhibit MGMT

hypermethylation and low expression levels, which may explain its enhanced

chemosensitivity. Chemotherapy for glioblastoma (i.e., temozolomide if methylguanine

methyl-transferase [MGMT] promoter is methylation positive) was added as an adjuvant

treatment option for age >70years.” NCCN also notes: “ If glioblastoma is diagnosed, the

adjuvant options mainly depend on the patients’ PS. Patients with good PS (KPS>70) are

further stratified by age. Fractionated RT plus concurrent and adjuvant temozolomide is a

Category 1 recommendation for patients aged 70 years or younger. The panel noted that

although data are focused on 96 cycles of post-RT temozolomide, 12 cycles are increasingly

common, especially in recent clinical trial designs. Options for those > 70 years include

fractionated radiation plus concurrent and adjuvant temozolomide (Category 2A for this

group), hypofractionated RT (Category 1), or chemotherapy with deferred RT. Patients

opting for chemotherapy should receive temozolomide if they had MGMT methylation.

MGMT methylation is associated with an improved response to treatment with DNA-

damaging chemotherapeutics, such as temozolomide.

Scientific Rationale – Update March 2013 Although the FDA has officially approved a few tests, the major contribution of the agency in

the field of pharmacogenetics has been in the updating of drug labels to contain information

on pharmacogenomic issues that are applicable to a given therapeutic agent. Warfarin holds

a unique place in the current recommendations, as it is the only therapeutic agent for which

testing for two independent genetic variants (in the CYP2C9 and VKORC1 genes) are

recommended. CYP2C9 is the primary enzyme involved in the metabolism of warfarin, while

polymorphisms within the VKORC1 gene appear to modulate the mean daily dose of warfarin

required to acquire target anticoagulation intensity. Thus, the warfarin recommendations

incorporate testing of variants involved in both the pharmacokinetics and

pharmacodynamics of warfarin. (UpToDate, January 2013)

Crews et al. (2012) Codeine is bioactivated to morphine, a strong opioid agonist, by the

hepatic cytochrome P450 2D6 (CYP2D6); hence, the efficacy and safety of codeine as an

analgesic are governed by CYP2D6 polymorphisms. Codeine has little therapeutic effect in

patients who are CYP2D6 poor metabolizers, whereas the risk of morphine toxicity is higher

in ultrarapid metabolizers. The purpose of this guideline (periodically updated at

http://www.pharmgkb.org) is to provide information relating to the interpretation of CYP2D6

genotype test results to guide the dosing of codeine.

Martin et al. (2012) Human leukocyte antigen B (HLA-B) is responsible for presenting

peptides to immune cells and plays a critical role in normal immune recognition of

pathogens. A variant allele, HLA-B*57:01, is associated with increased risk of a

hypersensitivity reaction to the anti-HIV drug abacavir. In the absence of genetic

prescreening, hypersensitivity affects ~6% of patients and can be life-threatening with

repeated dosing. The authors provide recommendations (updated periodically at

http://www.pharmkgb.org) for the use of abacavir based on HLA-B genotype.

In March 2010, a new black box warning from the US Food and Drug Administration for the

antiplatelet agent clopidogrel was issued to alert clinicians that genetic testing (using the

Roche AmpliChip Cytochrome P450 Genotyping test) is available to identify individuals with

poor metabolizer variants of CYP2C19 who may not receive the full benefits of the drug.

However, two separate meta-analyses have come to opposite conclusions regarding the

influence of CYP2C19 genotype on adverse cardiovascular events in patients treated with

clopidogrel. It remains to be seen whether genetic testing will be implemented in clinical

practice. These data have not led to a change in the FDA recommendation. Although


guidelines for CYPC19 genotype-directed antiplatelet therapy are available from the Clinical

Pharmacogenetics implementation Consortium, many experts do not recommend routine

testing of patients for "clopidogrel resistance" by genetic testing for CYP2C19 poor

metabolizers.

Genetic testing for detecting variants of the VKORC1 genes is available to help clinicians

assess whether a patient may be especially sensitive to warfarin, and require a lower

starting dose; they also test for genetic variants in CYP2C9 that influence warfarin

metabolism. However, routine genotyping of patients prior to starting warfarin is not widely

accepted or recommended in guidelines from the American College of Chest Physicians

because of the limited evidence from prospective randomized trials that pharmacogenetic-

based individualized dosing improves clinical outcomes.

The role of apolipoprotein E (APOE) phenotypes in cerebrovascular disease and ischemic

stroke is unsettled. This apolipoprotein is a ligand for hepatic chylomicron and VLDL remnant

receptors, leading to clearance of these lipoproteins from the circulation, and for LDL

receptors. The APOE e4 allele has been reported to be a stroke risk factor in some studies

(eg. Mccarron 1999, Schneider 2005) but not other studies (eg. Basun 1996, Zhu 2000,

Frikke-Schmidt 2001, Casas 2004, Sturgeon 2005).

In 2005, the FDA recommended modification of the irinotecan drug labeling to specify that

individuals who are homozygous for the UGT1A1 *28 allele are at increased risk for

neutropenia following treatment with irinotecan. Genetic testing for the presence of the

UGT1A1*28 allele is available, and the FDA-approved label recommends testing. The

manufacturer also recommends reducing the initial irinotecan dose in those who are

homozygous for UGT 1A1*28 to reduce the likelihood of dose-limiting neutropenia. However,

routine use of this assay in all patients who are to receive irinotecan for treatment of

metastatic disease has not been widely accepted for several reasons:

As noted above, the clinical relevance of identifying homozygotes is unclear. Only

about 1 in 10 patients will be identified as being homozygous, and the excess risk of

severe neutropenia that is attributable to the inheritance of this polymorphism seems

to be small, particularly at doses <150 mg/m2 per week. As an example, the risk of

severe neutropenia with the first course of irinotecan in one study was 14 versus 2

percent in those with the UGT1A1*28 and wild-type allele, respectively.

However, others report a much higher rate of grade 3 or 4 hematologic toxicity over

an entire course of treatment in patients receiving irinotecan doses <150 mg/m2

weekly who inherit the 7/7 variant as compared to carriers of the 6/7 or 6/6 allele (48

versus 10 and 8 percent, respectively), a higher rate of hospitalization during therapy,

and greater short-term death rate as well. Whether outcomes would have been

altered by upfront identification of 7/7 carriers and initial dose modification is unclear.

Whether initial dose reduction is needed for UGT1A1*28 homozygotes, and how much

to reduce the dose remain unresolved issues. Some have recommended an initial 20

percent dose reduction [80], but there is no consensus on this point. Others have

suggested that patients without the *28/*28 genotype can tolerate much higher doses

of irinotecan than are contained in standard regimens such as FOLFIRI. However,

whether the risk to benefit ratio can be improved by selecting the irinotecan dose

based on genotype will require prospective genotype-driven trials.


Inheritance of UGT1A1*28 polymorphisms seems to account for only a fraction of the

observed variability in irinotecan toxicity. It is likely that both inherited (eg,

alternative UGT1A haplotypes or polymorphisms in other genes involved in irinotecan

disposition and nongenetic factors (eg, pretreatment bilirubin levels, gender, smoking,

co-medications) contribute to a patient's risk of irinotecan-related toxicity.

For all of these reasons, the clinical utility of pretreatment testing for the UGT1A1 *28 allele

remains uncertain.

Rare causes of folate deficiency include a number of congenital enzyme deficiencies

involving the metabolism of folate. These include methylenetetrahydrofolate reductase

deficiency, glutamate formiminotransferase deficiency, and functional methionine synthase

deficiency.

The 2013 NCCN Guidelines on Colon Cancer note that there are insufficient data to guide the

use of anti-EGFR therapy in the first line setting with active chemotherapy based on BRAF V

600 mutation status. 2013 NCCN Guidelines on Melanoma notes that Vemurafenib is

recommended for patients with V600 mutation of the BRAF gene documented by an FDA-

approved or Clinical Laboratory Improvement Amendments CLIA approved facility

Sosman et al. (2012) designed a multicenter phase 2 trial of vemurafenib in patients with

previously treated BRAF V600-mutant metastatic melanoma to investigate the efficacy of

vemurafenib with respect to overall response rate (percentage of treated patients with a

tumor response), duration of response, and overall survival. The primary end point was the

overall response rate as ascertained by the independent review committee; overall survival

was a secondary end point. A total of 132 patients had a median follow-up of 12.9 months

(range, 0.6 to 20.1). The confirmed overall response rate was 53% (95% confidence interval

[CI], 44 to 62; 6% with a complete response and 47% with a partial response), the median

duration of response was 6.7 months (95% CI, 5.6 to 8.6), and the median progression-free

survival was 6.8 months (95% CI, 5.6 to 8.1). Primary progression was observed in only

14% of patients. Some patients had a response after receiving vemurafenib for more than 6

months. The median overall survival was 15.9 months (95% CI, 11.6 to 18.3). The most

common adverse events were grade 1 or 2 arthralgia, rash, photosensitivity, fatigue, and

alopecia. Cutaneous squamous-cell carcinomas (the majority, keratoacanthoma type) were

diagnosed in 26% of patients. Vemurafenib induces clinical responses in more than half of

patients with previously treated BRAF V600-mutant metastatic melanoma. In this study with

a long follow-up, the median overall survival was approximately 16 months. (Funded by

Hoffmann-La Roche; ClinicalTrials.gov number, NCT00949702).

Chapman et al. (2011) conducted a phase 3 randomized clinical trial comparing

vemurafenib with dacarbazine in 675 patients with previously untreated, metastatic

melanoma with the BRAF V600E mutation. Patients were randomly assigned to receive

either vemurafenib (960 mg orally twice daily) or dacarbazine (1000 mg per square meter

of body-surface area intravenously every 3 weeks). Coprimary end points were rates of

overall and progression-free survival. Secondary end points included the response rate,

response duration, and safety. A final analysis was planned after 196 deaths and an interim

analysis after 98 deaths. At 6 months, overall survival was 84% (95% confidence interval

[CI], 78 to 89) in the vemurafenib group and 64% (95% CI, 56 to 73) in the dacarbazine

group. In the interim analysis for overall survival and final analysis for progression-free

survival, vemurafenib was associated with a relative reduction of 63% in the risk of death

and of 74% in the risk of either death or disease progression, as compared with dacarbazine

(P<0.001 for both comparisons). After review of the interim analysis by an independent


data and safety monitoring board, crossover from dacarbazine to vemurafenib was

recommended. Response rates were 48% for vemurafenib and 5% for dacarbazine.

Common adverse events associated with vemurafenib were arthralgia, rash, fatigue,

alopecia, keratoacanthoma or squamous-cell carcinoma, photosensitivity, nausea, and

diarrhea; 38% of patients required dose modification because of toxic effects. Vemurafenib

produced improved rates of overall and progression-free survival in patients with previously

untreated melanoma with the BRAF V600E mutation. (Funded by Hoffmann-La Roche;

BRIM-3 ClinicalTrials.gov number, NCT01006980).

The 2013 NCCN Thyroid Cancer Guidelines notes in their text that molecular diagnostics to

detect individual mutations in BRAF, RET, or RAS or pattern recognition approaches using

molecular classifiers may be useful in the evaluation of FNA samples that are indeterminate

(eg. Follicular thyroid lesion of undetermined significance). However, there are no specific

recommendations on BRAF testing for thyroid cancer noted.

Kalydeco (ivacaftor), a CFTR potentiator, is the first treatment to the underlying cause of CF

in patients with the G551D mutation (approximately 4% of CF patients in U.S. Cystic

Fibrosis Foundation Registry). Ivacaftor facilitates increased chloride transport by

potentiating the channel-open probability (or gating) of the G551D-CFTR protein. It

improves lung function, reduces pulmonary exacerbations, decreases the length of time

needed to treat a pulmonary exacerbation with intravenous antibiotics, and improves weight

gain. In clinical trials in patients with the G551D mutation, Kalydeco led to statistically

significant reductions in sweat chloride concentration. Additional studies are under way to

further evaluate PTC124's efficacy. Several molecules have been identified that allow for

proper processing of class 2 mutations; clinical trials are planned to evaluate a number of

these substances. Significant progress has been made on a group of small molecules

referred to as ‘potentiators,’ including VX-770 (Vertex Pharmaceuticals, Cambridge, MA),

that activate CFTR mutants (G551D-CFTR) that traffic to the plasma membrane but do not

appropriately activate.

Ramsey et al. (2011) conducted a randomized, double-blind, placebo-controlled trial to

evaluate ivacaftor (VX-770), a CFTR potentiator, in subjects 12 years of age or older with

cystic fibrosis and at least one G551D-CFTR mutation. Subjects were randomly assigned to

receive 150 mg of ivacaftor every 12 hours (84 subjects, of whom 83 received at least one

dose) or placebo (83, of whom 78 received at least one dose) for 48 weeks. The primary

end point was the estimated mean change from baseline through week 24 in the percent of

predicted forced expiratory volume in 1 second (FEV(1)). The change from baseline through

week 24 in the percent of predicted FEV(1) was greater by 10.6 percentage points in the

ivacaftor group than in the placebo group (P<0.001). Effects on pulmonary function were

noted by 2 weeks, and a significant treatment effect was maintained through week 48.

Subjects receiving ivacaftor were 55% less likely to have a pulmonary exacerbation than

were patients receiving placebo, through week 48 (P<0.001). In addition, through week 48,

subjects in the ivacaftor group scored 8.6 points higher than did subjects in the placebo

group on the respiratory-symptoms domain of the Cystic Fibrosis Questionnaire-revised

instrument (a 100-point scale, with higher numbers indicating a lower effect of symptoms on

the patient's quality of life) (P<0.001). By 48 weeks, patients treated with ivacaftor had

gained, on average, 2.7 kg more weight than had patients receiving placebo (P<0.001). The

change from baseline through week 48 in the concentration of sweat chloride, a measure of

CFTR activity, with ivacaftor as compared with placebo was -48.1 mmol per liter (P<0.001).

The incidence of adverse events was similar with ivacaftor and placebo, with a lower

proportion of serious adverse events with ivacaftor than with placebo (24% vs. 42%).

Ivacaftor was associated with improvements in lung function at 2 weeks that were sustained


through 48 weeks. Substantial improvements were also observed in the risk of pulmonary

exacerbations, patient-reported respiratory symptoms, weight, and concentration of sweat

chloride. (Funded by Vertex Pharmaceuticals and others; VX08-770-102 ClinicalTrials.gov

number, NCT00909532.). Limitations of the study, such as early termination, have lead to

small numbers of participants analyzed and technical problems with measurement, leading

to unreliable or uninterpretable data.

Scientific Rationale – Update March 2012 Drug Surveillance in the Post FDA-Approval Period in an Effort to Reduce Adverse

Drug Reaction (ADRs)

Pharmacogenomics is the study of the role of inherited and acquired genetic variation in

drug response. Clinically relevant pharmacogenetic examples, mainly involving drug

metabolism, have been known for decades, but recently, the field of pharmacogenetics has

evolved into “pharmacogenomics,” involving a shift from a focus on individual candidate

genes to genomewide association studies. Such studies are based on a rapid scan of

markers across the genome of persons affected by a particular disorder or drug-response

phenotype and persons who are not affected, with tests for association that compare genetic

variation in a case–control setting.

The FDA-mandated incorporation of pharmacogenomic information in drug labeling will

remain an important step in the acceptance of pharmacogenomics in clinical practice.

Perhaps equally important will be the willingness of physicians to reexamine suboptimal

pharmacologic management programs.

Meckley et al. (2010) In 2007, the US FDA added information about pharmacogenomics to

the warfarin label based on the influence of the CYP2C9 and VKORC1 genes on

anticoagulation-related outcomes. Payers will be facing increasing demand for coverage

decisions regarding this technology, but the potential clinical and economic impacts of

testing are not clear. The objective was to develop a policy model to evaluate the potential

outcomes of warfarin pharmacogenomic testing based on the most recently available data.

A decision-analytic Markov model was developed to assess the addition of genetic testing to

anticoagulation clinic standard care for a hypothetical cohort of warfarin patients. The model

was based on anticoagulation status (international normalized ratio), a common outcome

measure in clinical trials that captures both the benefits and risks of warfarin therapy. Initial

estimates of testing effects were derived from a recently completed randomized controlled

trial (n = 200). The perspective was that of a US third-party payer. Probabilistic and one-

way sensitivity analyses were performed to explore the range of plausible results. The policy

model included thromboembolic events (TEs) and bleeding events and was populated by

data from the COUMAGEN trial. The rate of bleeding calculated for standard care

approximated bleeding rates found in an independent cohort of warfarin patients. According

to our model, pharmacogenomic testing provided an absolute reduction in the incidence of

bleeds of 0.17%, but an absolute increase in the incidence of TEs of 0.03%. The

improvement in QALYs was small, 0.003, with an increase in total cost of $US162 (year

2007 values). The authors’ model, based on initial clinical studies to date, suggests that

warfarin pharmacogenomic testing may provide a small clinical benefit with significant

uncertainty in economic value. Given the uncertainty in the analysis, further updates will be

important as additional clinical data become available.


Genotyping for Other Cytochrome P450 Polymorphism (i.e. CYP2C9 and VKORC1)

to Determine Reduced/Enhanced Effect or Severe Side Effects of Drugs

Metabolized by the Cytochrome P450 System

Knieppeiss et al. (2011) tacrolimus and everolimus are immunosuppressive drugs

metabolized by enzymes of the CYP3A subfamily. A common variant of the CYP3A5 gene,

CYP3A5*3, results in strongly decreased CYP3A5 activity and has been shown to influence

Tacrolimus blood concentrations, but its role for the pharmacogenetics of Everolimus

remains unclear. Aim of the study was to examine the role of CYP3A5*3 variant in

tacrolimus and everolimus dose and drug levels after heart transplantation. The present

study comprised 15 patients with Tacrolimus and 30 patients with Everolimus-based

maintenance therapy after heart transplantation. CYP3A5 genotypes were determined and

correlated with clinical data. RESULTS In the Tacrolimus group, 13 subjects were CYP3A5

non-expressors (*3/*3 genotype) and two were heterozygous expressors (*1/*3 genotype).

Average Tacrolimus dose was significantly higher in subjects expressing CYP3A5 compared

to non-expressors. Tacrolimus levels were not significantly different at any point of time. In

the Everolimus group, 27 subjects were CYP3A5 non-expressors (*3/*3 genotype) and three

were heterozygous expressors (*1/*3). Neither Everolimus dose nor levels were significantly

different between CYP3A5 expressors and non-expressors at any point of time. Additional

peer-reviewed studies are necessary.

Invader UGT1A1 Molecular Assay to Determine the Proper Dosage of Irinotecan for

Cancer

Irinotecan is one of the first widely used chemotherapy agents that is dosed according to the

recipient's genotype. Genetic polymorphism of the UGT1A1 gene is related to severe toxicity

caused by the drug, such as leukopenia and diarrhea. In order to identify the group of

patients with aberration of the UGT1A1 gene who will need a reduced dose of irinotecan, a

pharmacodiagnostic test was developed (Invader UGT1A1 Molecular Assay).

National Cancer Comprehensive Network (NCCN) Guidelines Version 3.2012 for Colon

Cancer state the following:

Irinotecan should be used with caution and with decreased doses in patients with

Gilbert’s disease or elevated serum bilirubin. There is a commercially available test

for UGT1A1. Guidelines for the use has not been clinically established.

Peer-reviewed studies regarding the use of UGT1A1 molecular assay to determine the proper

dosage of irinotecan for individuals with colon cancer, are ongoing. However, efficacy and

long-term outcomes have not been determined. Additional studies are necessary.

Palomaki et al. (2009) This evidence-based review addresses the question of whether

testing for UGT1A1 mutations in patients with metastatic colorectal cancer treated with

irinotecan leads to improvement in outcomes (e.g., irinotecan toxicity, response to

treatment, morbidity, and mortality), when compared with no testing. No studies were

identified that addressed this question directly. The quality of evidence on the analytic

validity of current UGT1A1 genetic testing methods is adequate (scale: convincing,

adequate, inadequate), with available data indicating that both analytic sensitivity and

specificity for the common genotypes are high. For clinical validity, the quality of evidence is

adequate for studies reporting concentration of the active form of irinotecan (SN-38),

presence of severe diarrhea, and presence of severe neutropenia stratified by UGT1A1

common genotypes. The strongest association for a clinical endpoint is for severe

neutropenia. Patients homozygous for the *28 allele are 3.5 times more likely to develop


severe neutropenia compared with individuals with the wild genotype (risk ratio 3.51; 95%

confidence interval 2.03–6.07). The proposed clinical utility of UGT1A1 genotyping would be

derived from a reduction in drug-related adverse reactions (benefits) while at the same time

avoiding declines in tumor response rate and increases in morbidity/mortality (harms). At

least three treatment options for reducing this increased risk have been suggested:

modification of the irinotecan regime (e.g., reduce initial dose), use of other drugs, and/or

pretreatment with colony-stimulating factors. However, we found no prospective studies that

examined these options, particularly whether a reduced dose of irinotecan results in a

reduced rate of adverse drug events. This is a major gap in knowledge. Although the quality

of evidence on clinical utility is inadequate, two of three reviewed studies (and one published

since our initial selection of studies for review) found that individuals homozygous for the

*28 allele had improved survival. Three reviewed studies found statistically significant higher

tumor response rates among individuals homozygous for the *28 allele. We found little or no

direct evidence to assess the benefits and harms of modifying irinotecan regimens for

patients with colorectal cancer based on their UGT1A1 genotype; however, results of our

preliminary modeling of prevalence, acceptance, and effectiveness indicate that reducing the

dose would need to be highly effective to have benefits outweigh harms. An alternative is to

increase irinotecan dose among wild-type individuals to improve tumor response with

minimal increases in adverse drug events. Given the large number of colorectal cancer cases

diagnosed each year, a randomized controlled trial of the effects of irinotecan dose

modifications in patients with colorectal cancer based on their UGT1A1 genotype is feasible

and could clarify the tradeoffs between possible reductions in severe neutropenia and

improved tumor response and/or survival in patients with various UGT1A1 genotypes.

There is no information in the 2012 NCCN guidelines on Non-Small Cell Lung Cancer

regarding UGT1A1.

Genotyping for Apolipoprotein E (Apo E) to Determine Therapeutic Response to

Lipid-Lowering Medications

The Agency for Healthcare Research and Quality (AHRQ, 2008) technology assessment on

pharmacogenetic testing reviewed available evidence of Apo E genotype (e2, e3, and e4)

and statin treatment and found that genotyping for Apo E has not been shown to help

specific individuals:

"No studies addressed the effects of therapeutic choice: there were no data on the

benefits, harms, or adverse effects on patients from subsequent therapeutic

management after pharmacogenetic testing for the three Apo E genotypes."

The AHRQ assessment found that the pooled reduction in total and LDL cholesterol

from baseline values was lower for all 3 genotypes but did not differ significantly

among them.

The AHRQ also found significant between-study heterogeneity. "Although few studies

included certain subgroups, factors that may affect the associations between all three

Apo E genotypes and response to statin therapy were ethnicity, sex, familial

hyperlipidemia, the type of statin used, and possibly the presence of diabetes."

In addition, there are no prospective data showing improved clinical management of

hypercholesterolemia patients as a result of genotyping for Apo E.

Genotyping for methylenetetrahydrofolate reductase (MTHFR) to determine

therapeutic response to antifolate chemotherapy


D’Angelo et al. (2012) Folate-metabolizing single-nucleotide polymorphisms (SNPs) are

emerging as important pharmacogenetic prognostic determinants of the response to

chemotherapy. With high doses of methotrexate (MTX) in the consolidation phase,

methylenetetrahydrofolate reductase (MTHFR) polymorphisms could be potential modulators

of the therapeutic response to antifolate chemotherapeutics in identifying a possible

correlation with the outcome. This study aims to analyse the potential role of the MTHFR

C677T and A1298C genetic variants in modulating the clinical toxicity and efficacy of high

doses of MTX in a cohort of paediatric ALL patients (n = 151) treated with AIEOP protocols.

This work includes DNA extraction by slides and RFLP-PCR. The first observation relative to

early toxicities (haematological and non-haematological), after the first doses of MTX in all

protocols, was an association between the 677T and 1298C carriers and global toxicity. We

found that in the 2 g/m(2) MTX group, patients harbouring 677TT homozygously exhibited a

substantial 12-fold risk of developing toxicity. In this study, we demonstrate that the MTHFR

677TT variant is associated with an increased risk of relapse when compared to other

genotypes. The Kaplan-Meier analysis showed that the 677TT variant had a lower 7-year

DFS(disease-free survival) probability compared to the 677C carrier genotype (log-rank test

P = 0.003) and OS (overall survival) and also confirms the lower probability of survival for

patients with the 677TT variant (log-rank test, P = 0.006). This authors’ study provides

further evidence of the critical role played by folate pathway enzymes in the outcome of ALL,

possibly through the interference of MTX. However, further peer-reviewed studies or clinical

trials are necessary to determine the efficacy of this treatment.

Scientific Rationale – Update March 2011 Dual antiplatelet therapy with aspirin and a thienopyridine is recommended both in patients

after acute MI and in patients undergoing percutaneous coronary intervention (PCI) with

stenting. Clopidogrel (Plavix; Sanofi-Aventis Inc.) has been the main thienopyridine

prescribed for antiplatelet therapy. Another recently approved option is prasugrel (Effient;

Eli Lilly & Co). Clopidogrel with aspirin is effective at reducing recurrent coronary events and

mortality; however, patients have a variable response to clopidogrel, with up to 30% of

patients not experiencing complete platelet inhibition. One source of the variable response

to clopidogrel is its pharmacokinetics, as clopidogrel is a prodrug that must be converted to

an active metabolite before having any effect. The main enzyme that is responsible for this

conversion to the active metabolite is the cytochrome P450 (CYP) enzyme CYP2C19. There

are 3 major CYP2C19 genetic polymorphisms. CYP2C19*1 corresponds to normal function.

CYP2C19*2 and CYP2C19*3 are loss-of-function alleles and explain most of the reduced

function in those who are “poor metabolizers.” CYP2C19*2 and *3 account for 85% and

99% of the nonfunctional alleles in whites and Asians, respectively.

On March 12, 2010, the FDA approved a new label for clopidogrel with a “boxed warning”

about the diminished effectiveness of the drug in patients with impaired ability to convert

the drug into its active form. The boxed warning is based on the concern that the

antiplatelet effect of clopidogrel depends primarily on its activation by the cytochrome P450

(CYP) system. Patients with decreased CYP2C19 function because of genetic polymorphisms

metabolize clopidogrel poorly and have higher rates of cardiovascular events after acute

coronary syndrome (ACS) and percutaneous coronary interventions (PCIs) than patients

with normal CYP2C19 function. The warning notes that tests are available to identify

patients with genetic polymorphisms, and that alternative treatment strategies should be

considered in poor metabolizers of the drug.

The dosage and administration section of the prescribing information was also updated by

the FDA noting that CYP2C19 poor metabolizer status is associated with diminished


antiplatelet response to clopidogrel. Although a higher dose regimen in poor metabolizers

increases platelet response, an appropriate dose regimen for this patient population has not

been established. It was also noted that Omeprazole, a moderate CYP2C19 inhibitor,

reduces the pharmacological activity of Plavix. It was recommended to avoid using

omeprazole concomitantly or 12 hours apart with Plavix or to consider using another acid-

reducing agent with less CYP2C19 inhibitor activity. A higher dose regimen of clopidogrel

concomitantly administered with omeprazole increases antiplatelet response; an appropriate

dose regimen has not been established.

The FDA reported on a single study of 40 healthy individuals (10 each with different degrees

of CYP2C19 function—poor, intermediate, extensive, and ultrarapid) in a crossover design.

Each group was randomized to a 300-mg loading dose (LD) followed by a 75-mg per day

maintenance dose (MD), or a 600-mg LD followed by 150-mg per day MD, each for a total of

5 days. After a washout period, subjects were crossed over to the alternate

treatment. The chief findings were decreased active metabolite exposure and increased

platelet aggregation in the poor metabolizers compared with the other groups. When poor

metabolizers received the 600-mg LD followed by 150 mg daily MD, active metabolite

exposure and antiplatelet response were greater than with the 300-mg LD and 75 mg

per day MD regimen, but remained quantitatively less than the response in the extensive

metabolizers when they received the 300 mg and 75 mg regimen. Two different assays for

platelet function were used—platelet aggregation stimulated by 5 micromolar adenosine

diphosphate (ADP) and the vasodilator-stimulated phosphoprotein phopsphorylation

assay. Improvement in platelet inhibitory responses with higher-dose clopidogrel in poor

metabolizers was apparent only with the former assay. There was no comment about

statistical significance in the labeling material. Analysis of the final as yet unpublished data

set of this study, which played a prominent role in the boxed warning, will be essential to a

more complete understanding of the issues.

A clinical alert regarding the FDA box warning on Clopidogrel was issued by the American

College of Cardiology Foundation (ACCF)/American Heart Association (AHA) in June 2010.

Per the alert, “CYP2C19 polymorphism accounts for only approximately 12% of variability in

clopidogrel platelet response, and the positive predictive value of CYP2C19 loss-of function

genetic polymorphisms is estimated to be between 12% and 20% in patients with ACS

undergoing PCI. In addition, there is no prospective randomized evidence to support

genotyping, a direct effect of genetic polymorphisms cannot be excluded, and there is a

larger body of evidence to support platelet function testing as a risk stratifier for adverse

events. These issues must be considered in the context that there are multiple unknown

factors including, most importantly, the fact that the specific role of an individual genetic

polymorphism in influencing outcome for the individual patient remains unknown.” The alert

notes, “In the most recent labeling for clopidogrel, the FDA only informs physicians and

patients that genetic testing is available; it neither mandates, requires, nor recommends

genetic testing, thereby allowing for flexibility in clinical decisions.” “Genetic testing to

determine if a patient is predisposed to poor clopidogrel metabolism (“poor metabolizers”)

may be considered before starting clopidogrel therapy in patients believed to

be at moderate or high risk for poor outcomes. This might include, among others, patients

undergoing elective high-risk PCI procedures (e.g., treatment of extensive and/or very

complex disease). If such testing identifies a potential poor metabolizer, other therapies,

should be considered.”

The clinical validity of CYP2C19 genotyping in the dose management of clopidogrel has been

investigated in both comparative and noncomparative studies that examined clinical

endpoints. In two placebo-controlled studies [Clopidogrel in Unstable Angina to Prevent


Recurrent Events (CURE) and Atrial Fibrillation Clopidogrel Trial with Irbesartan for

Prevention of Vascular Events (ACTIVE A)] of patients with ACS, there was no significant

difference in the composite clinical endpoints between patients with and without CYP2C19

loss-of-function alleles who received clopidogrel. In the CURE study, the rate of

cardiovascular events was significantly lower in patients with CYP2C19 gain-of-function

alleles who received clopidogrel compared to patients who did not carry these alleles.

Simon et al (2011) compared treatment outcomes for patients in the French Registry of

Acute ST-Elevation and Non-ST-Elevation Myocardial Infarction (FAST-MI) who did or did not

receive clopidogrel and/or protein pump inhibitor (PPIs). The FAST-MI registry included

3670 patients (2744 clopidogrel- and PPI-naïve patients) presenting with definite MI.

Patients were categorized according to use of clopidogrel and/or PPI within 48 hours after

hospital admission. PPI use was not associated with an increased risk for any of the main in-

hospital events (in-hospital survival, reinfarction, stroke, bleeding, and transfusion).

Likewise, PPI treatment was not an independent predictor of 1-year survival or 1-year MI,

stroke, or death. No differences were seen when the type of PPI or CYP2C19 genotype was

taken into account. In the propensity-matched cohorts, the odds ratios for major in-hospital

events in PPI versus no PPI were 0.29 and 1.70 for patients with 1 and 2 variant alleles,

respectively. Similarly, the hazard ratio for 1-year events in hospital survivors was 0.68 and

0.55, respectively. The investigators concluded PPI use was not associated with an increased

risk of cardiovascular events or mortality in patients administered clopidogrel for recent MI,

whatever the CYP2C19 genotype, although harm could not be formally excluded in patients

with 2 loss-of-function alleles.

Pare et al (2010) genotyped patients from these two large, randomized trials that showed

that clopidogrel, as compared with placebo, reduced the rate of cardiovascular events (the

primary efficacy outcome) among patients with ACS and among patients with atrial

fibrillation. Patients were genotyped for three single-nucleotide polymorphisms (*2, *3, *17)

that define the major CYP2C19 alleles. Among 5059 genotyped patients with ACS,

clopidogrel as compared with placebo significantly reduced the rate of the primary efficacy

outcome, irrespective of the genetically determined metabolizer phenotype. The effect of

clopidogrel in reducing the rate of the primary efficacy outcome was similar in patients who

were heterozygous or homozygous for loss-of-function alleles and in those who were not

carriers of the alleles (rate among carriers, 8.0% with clopidogrel vs. 11.6% with placebo;

hazard ratio with clopidogrel, 0.69; 95% confidence interval [CI], 0.49 to 0.98; rate among

noncarriers, 9.5% vs. 13.0%; hazard ratio, 0.72; 95% CI, 0.59 to 0.87). In contrast, gain-

of-function carriers derived more benefit from clopidogrel treatment as compared with

placebo than did noncarriers (rate of primary outcome among carriers, 7.7% vs. 13.0%;

hazard ratio, 0.55; 95% CI, 0.42 to 0.73; rate among noncarriers, 10.0% vs. 12.2%;

hazard ratio, 0.85; 95% CI, 0.68 to 1.05; P=0.02 for interaction). The effect of clopidogrel

on bleeding did not vary according to genotypic subgroups. Among 1156 genotyped patients

with atrial fibrillation, there was no evidence of an interaction with respect to either efficacy

or bleeding between the study treatment and the metabolizer phenotype, loss-of-function

carrier status, or gain-of-function carrier status. The investigators concluded among

patients with acute coronary syndromes or atrial fibrillation, the effect of clopidogrel as

compared with placebo is consistent, irrespective of CYP2C19 loss-of-function carrier status.

Malek et al (2010) sought to determine whether the 681 G>A (*2) polymorphism of

cytochrome P450 (CYP2C19) is related to suboptimal reperfusion and mortality in patients

with acute myocardial infarction (AMI) pretreated with clopidogrel in a study of 276

consecutive patients with AMI in whom percutaneous coronary intervention (PCI) with

stenting was attempted. Four-year follow-up for all-cause mortality was obtained. There


were 15 failed procedures (5.4%). In the remaining 261 patients, suboptimal reperfusion

(post-PCI TIMI flow <3) was observed in 12.6% of the cases. There were 56 carriers (50

heterozygous and 6 homozygous) of CYP2C19*2. The prevalence of carriers in patients with

suboptimal flow was 39.4% in comparison to 18.9% in the other patients. Independent

predictors of suboptimal reperfusion were initial TIMI flow ≤1 and CYP2C19*2. Thirty

patients died during follow-up (11.5%). Four-year mortality tended to be higher in carriers

of CYP2C19*2 (17.9%) versus non-carriers (9.8%), but the only independent predictors of

death were age and suboptimal reperfusion. The investigators concluded the CYP2C19*2

allele is an independent predictor of suboptimal reperfusion in patients with AMI undergoing

PCI with stenting after pretreatment with clopidogrel and may increase the risk of all-cause

mortality.

Mega et al (2009) investigated the association between CYP variants and cardiovascular

outcomes among 1477 patients treated with clopidogrel for ACS. Patients were participants

in the Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in

MI (TRITON-TIMI) 38 trial. Genotyping for CYP2C19 alleles was performed using the

Affymetrix Targeted Human DMET 1.0 assay or PCR with restriction fragment length

polymorphism (RFLP) analysis. Patients with ACS who were carriers of at least one loss-of-

function allele of CYP2C19 were 1.53 times more likely to experience fatal cardiovascular

events, MI, or stroke, compared to individuals with normal genotype (95% CI, 1.97 to 2.19;

P=0.01). Furthermore, the risk of stent thrombosis was 3.09 times greater for patients with

CYP2C19 loss-of-function alleles compared to those with a normal genotype (95% CI, 1.19

to 8.00; P=0.02)

Sorich et al (2010) performed a secondary analysis of the TRITON-TIMI 38 trial to estimate

the clinical benefit of prasugrel over clopidogrel in subgroups defined by CYP2C19 genotype,

by integrating the published results of the genetic substudy and the overall TRITON-TIMI 38

trial. Individuals with a CYP2C19 reduced-metabolizer genotype were estimated to have a

substantial reduction in the risk of the composite primary outcome (cardiovascular death,

myocardial infarction, or stroke) with prasugrel as compared with clopidogrel. For CYP2C19

extensive metabolizers (70% of the population), however, the composite outcome risks with

prasugrel and clopidogrel were not substantially different. The authors concluded

integration of the TRITON-TIMI 38 data suggests that the CYP2C19 genotype can

discriminate between individuals who receive extensive benefit from using prasugrel instead

of clopidogrel, and individuals with comparable clinical outcomes with prasugrel and

clopidorel. Thus, CYP2C19 genotyping has the potential to guide the choice of antiplatelet

therapy, and further research is warranted to validate this estimate.

Hulot et al (2010) assessed the association between the loss-of-function cytochrome P450

2C19 (CYP2C19)*2 variant (10 studies, 11,959 patients) or the use of proton pump

inhibitors (PPIs) (13 studies, 48,674 patients) and ischemic outcomes (major adverse

cardiovascular events [MACE]) in patients treated with clopidogrel. The meta-analysis was

performed on 23 studies using the odds ratio (OR) as the parameter of efficacy, with a

fixed-effect model. The end points were MACE, mortality, or stent thrombosis. Of the

11,959 patients, carriers of the loss-of-function CYP2C19*2 allele (28% [n = 3,418])

displayed a 30% increase in the risk for MACE compared with noncarriers (9.7% vs. 7.8%.)

This single gene variant (CYP2C19*2) was also associated with an excess of mortality (1.8%

vs. 1.0% n = 6,225) and of stent thrombosis (2.9% vs. 0.9%; n = 4,905). This increased

risk was apparent in both heterozygotes and homozygotes and was independent of the

baseline cardiovascular risk. PPI users (42% [n = 19,614]) displayed increased risk for

MACE (21.8% vs. 16.7%) and mortality (12.7% vs. 7.4%; n = 23,977) compared with

nonusers. The impact of PPI use was, however, significantly influenced by baseline


cardiovascular risk, being significant only in high-risk patients. The authors concluded in

this global meta-analysis, reduced CYP2C19 function appears to expose clopidogrel-treated

patients to excess cardiovascular risk and mortality. Conflicting results among studies may

be explained by differences in types and/or levels of risk of patients

Mega et al (2010) sought to define the risk of major adverse cardiovascular outcomes

among carriers of 1 (≈ 26% prevalence in whites) and carriers of 2 (≈ 2% prevalence in

whites) reduced-function CYP2C19 genetic variants in patients treated with clopidogrel. A

literature search was conducted. Genetic studies were included in which clopidogrel was

initiated in predominantly invasively managed patients in a manner consistent with the

current guideline recommendations and in which clinical outcomes were ascertained.

Investigators from 9 studies evaluating CYP2C19 genotype and clinical outcomes in patients

treated with clopidogrel contributed the relevant hazard ratios (HRs) and 95% confidence

intervals (CIs) for specific cardiovascular outcomes by genotype. Among 9685 patients

(91.3% who underwent percutaneous coronary intervention and 54.5% who had an acute

coronary syndrome), 863 experienced the composite end point of cardiovascular death,

myocardial infarction, or stroke; and 84 patients had stent thrombosis among the 5894

evaluated for such. Overall, 71.5% were noncarriers, 26.3% had 1 reduced-function

CYP2C19 allele, and 2.2% had 2 reduced-function CYP2C19 alleles. A significantly increased

risk of the composite end point was evident in both carriers of 1 and 2 reduced-function

CYP2C19 alleles, as compared with noncarriers. Similarly, there was a significantly increased

risk of stent thrombosis in both carriers of 1 and 2 reduced-function alleles, as compared

with noncarriers. The authors concluded among patients treated with clopidogrel for

percutaneous coronary intervention, carriage of even 1 reduced-function CYP2C19 allele

appears to be associated with a significantly increased risk of major adverse cardiovascular

events, particularly stent thrombosis.

Scientific Rationale – Update February 2010 The goal of pharmacogenetic testing is to predict the right drug at the right dose for each

individual by incorporating the patient's genetic profile in drug and dose selection decisions.

However, challenges continue to exist in incorporating genotyping as standard of care.

Apolipoprotein E (Apo E), a member of the apolipoprotein gene family, is essential in the

formation of very low-density lipoprotein (VLDL) and chylomicrons. Among the variants of

this gene, alleles e2, e3, and e4 are the common polymorphism found in most populations.

However, the available evidence in peer-reviewed studies of Apo E genotype (e2, e3, and

e4) and statin treatment has not determined that genotyping for Apo E has shown

improvements in clinical management of hypercholesterolemia patients. Additional data in

randomized controlled studies on the benefits, potential adverse effects, and efficacy on

patients from subsequent therapeutic management after pharmacogenetic testing for the

three Apo E genotypes, is necessary.

Cytochrome P450, subfamily IIC, polypeptide 9 (CYP2C9) and Vitamin K epoxide reductase

subunit protein 1 (VKORC1) are two genes that together with environmental factors could

partly explain the inter-individual variation in warfarin dose requirements. Three single

nucleotide polymorphisms (SNPs), two in the CYP2C9 gene and one in the VKORC1 gene,

have been found to play key roles in determining the effect of warfarin therapy on

coagulation. Although studies have shown that genetic polymorphisms in CYP2C9 and

VKORC1 may affect warfarin dosing, additional randomized controlled trials are necessary to

link the use of pharmacogenomic testing to improvements in clinical outcomes.


There have been recent discussions regarding the dosing for warfarin, with the hope of

decreasing the incidence and severity of adverse events, particularly bleeding episodes. By

using knowledge of the metabolic and the signaling pathways and gene variants affecting

warfarin metabolism, a mathematical model to predict initial or maintenance dose maybe a

possibility. However, whether the laboratory should give dosing recommendations is

controversial. To do so, laboratories need to collect more information than typically is

provided, such as height, weight, clinical status (eg, diagnosis and liver function), and

concomitant medications. In providing these recommendations, laboratories may be

involved in the practice of medicine to a greater extent than they have been in the past,

without having a direct relationship with the patient. In the future, as dosing algorithms are

refined, laboratories may be able to guide physicians in treatment. Despite the FDA-required

warfarin label update, adoption of sensitivity genotyping by physicians has been limited.

Establishing the utility of warfarin sensitivity genotyping is promising in realizing its potential

in preventing bleeding episodes. Questions remain as to its use in establishing starting or

maintenance doses, and how to incorporate genotyping into patient management.

Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme regulating intracellular folate

levels, which in turn affects DNA synthesis and methylation. Two MTHFR gene

polymorphisms, C677T and A1298C, influence the metabolism of folates and could modify

the pharmacodynamics of antifolates and many other drugs whose metabolism, biochemical

effects, or target structures require methylation reactions. Several studies have shown

these two polymorphisms may reduce cancer susceptibility and increase drug-related

toxicity when folate antagonists (e.g., methotrexate, fluorouracil) are utilized, but data are

inconsistent and contradictory. According to the National Cancer Institute, 5 of 6 patients

who experienced grade-4 toxicity in their first cycle of adjuvant chemotherapy with

cyclophosphamide, methotrexate and fluorouracil (5-FU) for early breast cancer had the

variant C677T MTHFR genotype. Studies have shown that MTHFR polymorphisms may affect

the sensitivity to antifolate chemotherapy however, there is insufficient evidence of its

clinical effectiveness.

The Agency for Healthcare Research Quality (AHRQ) published a final report on November

12, 2008 in which the following four 4 pharmacogenetic tests were assessed:

1. Cytochrome P450, subfamily IIC, polypeptide 9 (CYP2C9),

2. Vitamin K epoxide reductase subunit protein 1 (VKORC1),

3. Apolipoprotein E (Apo E), and

4. Methylenetetrahydrofolate reductase (MTHFR) for their associations with patient’s

response to therapy with warfarin (CYP2C9 and VKORC1), statins (Apo E), or antifolate

chemotherapy (MTHFR).

The published studies were identified through an electronic search up to October 2007, and

relevant bibliographies were reviewed. Focused searches for specific topics were conducted

through April 2008 to identify published randomized controlled trials, systematic reviews,

and ongoing clinical trials. The report included studies of any design that evaluated adults

and abstracted data on all relevant clinical and laboratory outcomes. When sufficient data

were available from studies making the same comparisons, the data were summarized in a

meta-analysis. Additional subgroup, sensitivity, and meta-regression analyses were

conducted as appropriate.

Reports on the 103 completed studies noted the following: Twenty-nine tested the

association of CYP2C9 and the response to warfarin. Of the 29 studies of CYP2C9 gene

polymorphisms, 26 evaluated their association with responses to maintenance does of


warfarin. The remaining three studies were randomized controlled trials that evaluated

response to therapy based on dosage-based algorithms among patients with

pharmacogenetic test results. Carriers of the CYP2C9 gene variant alleles *2 or *3 had lower

mean maintenance warfarin dose requirements than did non-carriers.

Nineteen tested the association of VKORC1 and the response to warfarin. Few studies

investigated the relationship between genetic variations in CYP2C9 or VKORC1 and warfarin

dose requirements in the induction phase. CYP2C9 variants were associated with an

increased rate of bleeding complications during the induction phase of warfarin therapy, but

the studies did not report whether affected patients had normal or supratherapeutic INR

ranges. As with the CYP2C9 variants, carriers of the three common VKORC1 variants (alleles

T, G, and C) required lower mean maintenance doses of warfarin than did non-carriers.

Studies of CYP2C9 and VKORC1 had significant between-study heterogeneity. Few studies

evaluated the relationship between pharmacogenetic test results and patient and disease

related factors or response to therapy. No study addressed how therapeutic choices affected

the benefits, harms, or adverse effects of patients from subsequent therapeutic

management after pharmacogenetic testing for CYP2C9 and VKORC1.

Forty-four tested the association of Apo E and the response to statins. In studies of the Apo

E genotype (e2 carriers, e3 homozygotes, and e4 carriers) and statin treatment, the pooled

reduction in total and LDL cholesterol from baseline values was lower for all three genotypes

but did not differ significantly among them. These studies also had significant between-study

heterogeneity. Although few studies included certain subgroups, factors that may affect the

associations between all three Apo E genotypes and response to statin therapy were

ethnicity, sex, familial hyperlipidemia, the type of statin used, and possibly the presence of

diabetes. No studies addressed the effects of therapeutic choice: there were no data on the

benefits, harms, or adverse effects on patients from subsequent therapeutic management

after pharmacogenetic testing for the three Apo E genotypes.

Eleven tested the association of MTHFR with the response to antifolate chemotherapy.

Limited data preclude making meaningful inferences about the relationship between

common variants in MTHFR and chemotherapy of the folate metabolic pathway.

Per the AHRQ review, certain CYP2C9 and VKORC1 variants are associated with lower

warfarin maintenance doses, and CYP2C9 variants are associated with increased bleeding

rates among patients who use warfarin. Total and LDL cholesterol levels among patients on

statin therapy were lower than baseline values among patients with the three ApoE

genotypes. Response to chemotherapy based on the folate metabolic pathway in solid organ

cancers was not associated with genetic variations in MTHFR. Overall, studies evaluating

associations between the pharmacogenetic test results and the patient’s response to therapy

for non-cancer and cancer conditions showed considerable variation in study designs, study

populations, medication dosages, and the type of medications. This variation warrants

caution when interpreting our results. Data on the relationships among pharmacogenetic

test results and patient- and disease-related factors and on the patient’s response to

therapy are limited. We found no data on the benefits, harms, or adverse effects from

subsequent therapeutic management after pharmacogenetic testing. Detailed patient-level

analyses are needed to adjust estimates for the effects of modifiers, such as age or tumor

stage.

This systematic review also found that the majority of studies evaluated the associations of

pharmacogenetic test results with intermediate, not clinical, outcomes, such as the

effectiveness of drug dose, and adverse clinical outcomes, such as bleeding events. Only a


few studies evaluated the effects of patient and disease related characteristics on the

association between test results and intermediate or clinical outcomes. Across all four topics,

no studies investigated the influence of gene testing on the impact of therapeutic choices

and on the benefits and harms or adverse effects for patients from their subsequent

therapeutic management after pharmacogenetic testing. Another major limitation of the

analyses is that it included studies with significant diversity in terms of clinical diagnosis, co-

morbidities, polypharmacy, and outcome definitions. Future analyses with more studies of

homogeneous groups, with strict inclusion criteria and definitions of phenotypes and

responses to therapy, may alter the current findings. Moreover, if researchers can make

their data on individual patients readily available, adjusted estimates for the effects of

modifiers (such as age or tumor stage) can also be analyzed.

(2008) The American College of Medical Genetics (ACMG) position statement notes that in

the context of variable warfarin sensitivity, there is limited evidence at this time to support

routine testing of the CYP2C9 and VKORC1 genes for functional polymorphisms that affect

warfarin dosing. Although the analytic testing is currently being performed in a number of

laboratories, there is less linkage of the genotype data produced with phenotypic warfarin

dosing than is optimal for the development of recommendations for clinical practice.

Flockhart et al. (2008) The ACMG policy statement includes the following recommendations:

There is no prospective data to recommend for or against routine CYP2C9 and VKORC1

testing in warfarin-naïve patients since there are no substantive prospective study that

has yet shown this intervention to be effective in reducing the incidence of high INR

values, the time to stable INR, or the occurrence of serious bleeding events, while

maintaining the ability of the drug to prevent thromboembolic events.

CYP2C9 and VKORC1 genotypes can potentially be used as part of diagnostic efforts to

determine the cause of an unusually low maintenance dose of warfarin or an unusually

high INR during standard dosing.

CYP2C9 testing beyond *2 and *3 alleles involves rare alleles for which there is much

more limited data available to support their inclusions.

Per Eckman et al. (2009) [Annals of Internal Medicine], Only a few published studies using

pharmacogenetic information in warfarin dosing describe the effect of genotype-guided

dosing on major bleeding events, and although these studies show a trend toward decreased

bleeding, the results are not statistically significant.

Per Bon Homme et al. (2008) To date, most attempts to prospectively apply CYP2C9 and

VKORC1 genotyping to better manage warfarin therapy have limited the application of these

test results in the context of associative multivariate equations. These equations take

genetic and clinical factors into account to calculate an estimate of the eventual

maintenance dose for a given patient. Although the application of such equations has yielded

some improvement in patient outcomes in a limited number of studies, they fail to provide

clear and ongoing guidance for use of the information during the various stages of warfarin

therapy.

Technology Evaluation Center (TEC) [2007] completed a report on ‘Cardiovascular

Pharmacogenomics’. A MEDLINE search (via PubMed) for relevant review articles was

completed for the period up to June 2007. The study of pharmacogenetic interactions for

cardiovascular diseases is at an early stage of development, and there are no tests that

appear close to clinical utility. The literature is characterized by many exploratory findings

that have not been replicated or have been contradicted. Strong and consistent associations


between particular genotypes and drug response will be required for pharmacogenomics

findings to be translated into clinical practice. Clinical trials may be necessary to determine

whether patient outcomes are actually improved by treatment directed by genetic

information.

In summary, the Agency for Healthcare Research and Quality (AHRQ, 2008) technology

assessment on pharmacogenetic testing reviewed the available evidence of Apo E genotype

(e2, e3, and e4) and statin treatment and found that genotyping for Apo E did not note

improvements in clinical management of hypercholesterolemia patients. In addition,

although studies have shown that genetic polymorphisms in CYP2C9 and VKORC1 affect

warfarin dosing, additional randomized controlled trials are necessary that link the initiation

of pharmacogenomic testing to improvements in clinical outcomes in safety and efficacy with

warfarin therapy. Additional prospective clinical studies are currently ongoing both in the

United States and Europe. It has also been noted that response to chemotherapy based on

the folate metabolic pathway in solid organ cancers was not associated with genetic

variations in MTHFR. AHRQ found limited data on MTHFR gene testing and therapeutic

choice, which preclude making meaningful inferences about the relationship between

common variants in MTHFR and chemotherapy of the folate metabolic pathway. AHRQ also

found considerable variation in study designs, study populations, medication dosages, and

the type of medications. Studies have also shown that MTHFR polymorphisms may affect the

sensitivity to antifolate chemotherapy however, there is insufficient evidence of its clinical

effectiveness.

A major limitation in the use of pharmacogenetic testing in the clinical setting is the lack of

prospective clinical trials demonstrating that such testing can improve the benefit and/or

risk ratio of drug therapy.

Medicare National Coverage Determination (NCD) (90.1)

Per a Medicare National Coverage Determination (NCD) for ‘Pharmacogenomic Testing for

Warfarin Response’ (90.1), effective August 3, 2009, the Centers for Medicare & Medicaid

Services (CMS) believes that the available evidence does not demonstrate that

pharmacogenomic testing of CYP2C9 or VKORC1 alleles to predict warfarin responsiveness

improves health outcomes in Medicare beneficiaries outside the context of CED, and is

therefore not reasonable and necessary under §1862(a)(1)(A) of the Act. This NCD does not

determine coverage to identify CYP2C9 or VKORC1 alleles for other purposes, nor does it

determine national coverage to identify other alleles to predict warfarin responsiveness.

Effective August 3, 2009, the Centers for Medicare & Medicaid Services (CMS) believes that

the available evidence supports that coverage with evidence development (CED) under

§1862(a)(1)(E) of the Social Security Act (the Act) is appropriate for pharmacogenomic

TESTING of CYP2C9 or VKORC1 alleles to predict warfarin responsiveness by any method,

and is therefore covered only when provided to Medicare beneficiaries who are candidates

for anticoagulation therapy with warfarin who meet specific criteria noted in the NCD.

Scientific Rationale – Update August 2008 The abacavir hypersensitivity reaction (ABC HSR) that occurs in 3-8% of treated individuals,

is typically seen within the initial 6 weeks of abacavir treatment. Symptoms include fever

and malaise, often with nausea, vomiting, diarrhea, myalgia, arthralgia, respiratory

symptoms (cough, sore throat, or shortness of breath), and rash, although rash may be

absent. Laboratory abnormalities may include acute lymphopenia, elevated liver function

tests, and elevated creatine phosphokinase levels. Symptoms usually resolve within 1 to 2


days after discontinuation of abacavir, whereas subsequent rechallenge can cause a rapid,

severe, and even life-threatening recurrence.

In a double-blind, prospective, randomized study (The PREDICT-1 study) reported by Mallal

et al (2008), 1956 patients infected with HIV-1 who had not previously received abacavir

were randomized to undergo prospective HLA-B*5701 screening, with exclusion of HLA-

B*5701-positive patients from abacavir treatment (prospective-screening group), or to

undergo a standard-of-care approach of abacavir use without prospective HLA-B*5701

screening (control group). All patients who started abacavir were observed for 6 weeks.

Epicutaneous patch testing with the use of abacavir was perfomed to immunologically

confirm, and enhance the specificity of, the clinical diagnosis of hypersensitivity reaction to

abacavir. The author reported that the HLA-B*5701 prevalence in this predominately white

population was 5.6% (109 of 1956 patients). In this cohort, screening eliminated

immunologically confirmed hypersensitivity reaction (0% in the prospective-screening group

vs. 2.7% in the control group), with a negative predictive value of 100% and a positive

predictive value of 47.9%. Hypersensitivity reaction was clinically diagnosed in 93 patients,

with a significantly lower incidence in the prospective-screening group (3.4%) than in the

control group (7.8%).

The SHAPE study evaluated the sensitivity of detection of the HLA-B*5701 allele as a marker

of ABC HSRs in both white and black patients, using skin patch testing to supplement clinical

diagnosis. White and black patients were classified as ABC HSR based on clinical findings

only (a clinically suspected ABC HSR) or based on clinical findings and a positive skin patch

test result (an immunologically confirmed [IC] ABC HSR). Control subjects were racially

matched subjects who tolerated ABC for >/=12 weeks without experiencing an ABC HSR.

Patients and control subjects were tested for the presence of HLA-B*5701. The investigator

reported that forty-two (32.3%) of 130 white patients and 5 (7.2%) of 69 black patients

met the criteria for clinically suspected HSRs and had immunologically confirmed (IC) HSRs.

All 42 white patients with IC HSRs were HLA-B*5701 positive (sensitivity, 100%). Among all

white patients with clinically suspected HSRs, sensitivity was 44% (57 of 130 patients tested

positive for HLA-B*5701); specificity among white control subjects was 96%. Five of 5 black

patients with IC HSRs were HLA-B*5701 positive (sensitivity, 100%). Among black patients

with clinically suspected HSRs, the sensitivity was 14% (10 of 69 tested positive for HLA-

B*5701); specificity among black control subjects was 99%. The investigator concluded that

although IC ABC HSRs are uncommon in black persons, the 100% sensitivity of HLA-B*5701

as a marker for IC ABC HSRs in both US white and black patients suggests similar

implications of the association between HLA-B*5701 positivity and risk of ABC HSRs in both

races.

Based on the results of these two studies, the Department of Health and Human Services

Panel on Antiretroviral Guidelines for Adults and Adolescents (2008) recommends screening

for HLA-B*5701 before starting patients on an abacavir-containing regimen and HLA-

B*5701–positive patients not be prescribed abacavir. Per the recommendations, HLA-

B*5701 testing should only be performed once in a lifetime, and results should be recorded

in the patients records. The panel noted that the specificity of the HLA-B*5701 test is lower

than the sensitivity (i.e., 33%–50% of HLA-B*5701 positive patients would likely not

develop confirmed ABC HSR if exposed to ABC). The panel notes that HLA-B*5701 should

not be used as a substitute for clinical judgment or pharmacovigilance, as a negative HLA-

B*5701 result does not absolutely rule out the possibility of some form of abacavir

hypersensitivity reaction. When HLA-B*5701 screening is not readily available, it remains

reasonable to initiate abacavir with appropriate clinical counseling and monitoring for any


signs of ABC HSR. Testing for presence of HLA-B*5701 should not be used to supersede

clinical judgment, but rather to guide therapy for treatment-naïve subjects.

Carbamazepine is FDA-approved for treatment of epilepsy, bipolar disorder, and neuropathic

pain. It is sold under the brand names Carbatrol, Equetro and Tegretol. The prescribing

information for these drugs already includes a warning that for all patients, Stevens Johnson

syndrome (SJS) and toxic epidermal necrolysis (TEN), rare but severe and sometimes life-

threatening skin reactions can result from carbamazepine therapy, regardless of ethnicity.

These reactions are characterized by multiple skin lesions, blisters, fever, itching and other

symptoms. The risk of these reactions is estimated to be about 1 to 6 per 10,000 new users

of the drug in countries with mainly white populations. However, the risk is estimated to be

about 10 times higher in some Asian countries. Studies have found a strong association

between these serious skin reactions and an inherited variant of a gene, human leukocyte

antigen (HLA) allele, HLA-B* 1502, which is found almost exclusively in people with Asian

ancestry.

According to an FDA alert, released in December 2007, patients with ancestry from areas in

which HLA-B*1502 is present should be screened for the HLA-B*1502 allele prior to starting

treatment with carbamazepine. The FDA recommends that Carbamazepine should not be

started in those individuals that test positive unless the expected benefit clearly outweighs

the increased risk of serious skin reactions. They note that patients who have taken

carbamazepine for more than a few months and not experienced any skin reactions are

unlikely to ever experience these reactions, regardless of ancestry or genetic test results

Cytochrome P450 enzymes are essential for the metabolism of many medications with more

than 50 enzymes in this class. These enzymes are most predominant in the liver but can

also be found in the intestines, lungs and other organs. These cytochrome P450 enzymes

are designated by the letters "CYP" followed by an Arabic numeral, a letter and another

Arabic numeral. Cytochrome P450 enzymes can be inhibited or induced by drugs, resulting

in clinically significant drug-drug interactions that can cause unanticipated adverse reactions

or therapeutic failures. Interactions with beta blockers, warfarin, antidepressants,

antiepileptic drugs, and statins often involve the cytochrome P450 enzymes.

Diagnostic genotyping tests for some CYP450 enzymes are now available. One such test is

the Verigene Warfarin Metabolism Nucleic Acid Test (Nanosphere Inc.), FDA approved in

September 2007, for warfarin sensitivity. The Verigene test detects variants of 2 genes

(CYP2C9 and VKORC1) that predict individual differences in warfarin pharmacokinetics.

Warfarin (Coumadin) is an established and widely used anticoagulant indicated for the

prevention or treatment of venous thrombosis, pulmonary embolism, and thromboembolic

complications, as well as for the reduction of the risk of thromboembolic events (eg, stroke).

According to the FDA approval, the test is intended to be used in conjunction with other

clinical tools such as the prothrombin time international normalized ratio (PT-INR) to

determine appropriate warfarin dosing. Polymorphisms in genes responsible for production

of CYP2C9 enzymes (a subfamily of cytochrome P450) and VKORC1 significantly affect

individual responses to warfarin. Patients with either of 2 specific variants of the gene for

CYP2C9 (CYP2C9*2 or CYP2C9*3) metabolize warfarin slowly and need relatively low doses

when treatment is initiated. Genetic variations in VKORC1 are associated with higher or

lower sensitivity to warfarin.

Schwartz et al (2008) assessed CYP2C9 genotypes (CYP2C9 *1, *2, and *3), VKORC1

haplotypes (designated A and non-A), clinical characteristics, response to therapy (as

determined by the international normalized ratio [INR]), and bleeding events in 297 patients


starting warfarin therapy. The investigator reported that compared with patients with the

non-A/non-A haplotype, patients with the A/A haplotype of VKORC1 had a decreased time to

the first INR within the therapeutic range and to the first INR of more than 4. In contrast,

the CYP2C9 genotype was not a significant predictor of the time to the first INR within the

therapeutic range but was a significant predictor of the time to the first INR of more than 4 .

Both the CYP2C9 genotype and VKORC1 haplotype had a significant influence on the

required warfarin dose after the first 2 weeks of therapy. The investigator concluded that

initial variability in the INR response to warfarin was more strongly associated with genetic

variability in the pharmacologic target of warfarin, VKORC1, than with CYP2C9.

According to the American Heart Association/American College of Cardiology Expert

Consensus Document on Warfarin Therapy, “ The relationship between the dose of warfarin

and the response is influenced by genetic and environmental factors, including common

mutations in the gene coding for cytochrome P450, the hepatic enzyme responsible for

oxidative metabolism of the warfarin S-isomer. Several genetic polymorphisms in this

enzyme have been described that are associated with lower dose requirements and higher

bleeding complication rates compared with the wild-type enzyme CYP2C9.” The AHA/ACC

document does not make any recommendations for or against testing for cytochrome P450

polymorphism.

A California Technology Assessment (March 2008) on the use of genetic testing to guide the

initiation of warfarin therapy concluded that genotype guided warfarin therapy (i.e., genetic

testing of CYP2C9 and VKORC1) does not meet its criteria for safety, effectiveness and

improvement in health outcomes.

The clinical impact of P450 polymorphisms on prediction of ADRs is limited due to small

retrospective studies. Large, prospective, randomized trials that evaluate the use of

genotyping are needed to determine effect on health outcomes and to direct patient

management before prospective P450 genotyping can be considered routine in clinical

practice.

Scientific Rationale Initial According to WHO, the definition of an adverse drug reaction (ADR) is "an appreciably

harmful or unpleasant reaction, resulting from an intervention related to the use of a

medicinal product, which predicts hazard from future administration and warrants

prevention or specific treatment, or alteration of the dosage regimen, or withdrawal of the

product." ADRs are responsible for many debilitating side effects and can range from the

relatively mild (e.g., drowsiness), the troublesome (e.g., chronic dry cough), the serious

(e.g., hemorrhage) and even death. It is now clear that a significant portion of these ADRs

as well as therapeutic failures are caused by genetic polymorphism and genetically-based

inter-individual differences in drug absorption, disposition, excretion or metabolism.

Pharmacogenetics is generally regarded as the study of genetic variation that gives rise to

differing response to drugs, while pharmacogenomics is the broader application of genomic

technologies to new drug discovery and further characterization of older drugs. Pharmaco-

genetics considers one or at most a few genes of interest, while pharmacogenomics

considers the entire genome. Much of current clinical interest is at the level of

pharmacogenetics, involving variation in genes involved in drug metabolism with a particular

emphasis on improving drug safety.

To date, drug therapy is targeted to the broadest patient population that is believed to have

the greatest advantage from it. Based on statistical analyses of population averages, patient

groups are assumed to be homogenous and are, therefore, treated regardless of potential


disparities in drug response according to empirical, if not arbitrary, guidelines. Inter-

individual variations of drug response, which are based on genetic variations between

different populations of common ancestry are, however, common and pose a substantial

clinical problem. A drug that is well tolerated and causes a good response in some patients

may be ineffective, toxic or cause adverse drug reactions in others. In fact, it has been

reported that 1 in 15 hospital admissions is due to adverse drug reactions and that adverse

drug side effects in hospitalized patients were identified to be the fifth leading cause of

death in the United States.

Even though it is practically impossible to determine the contribution of all factors that affect

drug response, pharmacogenetic studies on inter-individual polymorphisms (i.e. nucleotide

mutations, insertions, repeats and deletions) of genes that code for drug-metabolizing

enzymes and drug targets (e.g. cytochrome P450 mono-oxygenase and its subtypes, N-

acetyl transferase (NAT), genes creating 'slow' and 'fast' metabolizers, etc) have been able

to show that these account for a significant proportion of the heterogeneous response to

medicines that is observed across populations. Variability in drug response is, therefore, at

least in part inherited and is likely to be associated with patterns of multiple polymorphically

expressed traits, rather than with single causative polymorphisms. It is, therefore, to a

certain extent predictable through pharmacogenomics, which is the study that investigates

the inherited basis of such different responses to drugs. Drug response may, however, also

depend significantly on the cause, severity and course of the condition being treated and

may be influenced by concomitant medications and drug interactions, by patient age, sex

and organ function, lifestyle (e.g. smoking, alcohol consumption), education, socioeconomic

status, environmental factors and accompanying illnesses. Many of these factors are difficult

to control for and are likely to be affected, at least in some parts of the world, by a person's

ethnic background.

Abacavir use during primary HIV infection (PHI) may be associated with increased risk of

hypersensitivity. HLA-B 5701 has been shown to be associated with the abacavir

hypersensitivity reaction (HSR) in PHI. Although levels of CD8 T cells and HIV RNA may be

risk factors for hypersensitivity, the observed association may be due to correlation with

HLA-B 5701. Two studies have demonstrated an association between the HLA-B 5701

polymorphism and HSR due to abacavir. Sensitivity ranged from 72 to 78% in the

prospective study by Mallal et al and was 46% in the retrospective case-control study of

Hetherington et al. Both studies acknowledge the difficulties inherent in HLA testing with

rather limited sensitivity. Indeed, the clinical utility of genotyping for this HLA association

with abacavir-related HSR remains debatable. In order for pharmacogenomics to be used for

pharmacosurveillance, it is necessary to integrate information related to drug-metabolizing

enzymes, drug transporters and therapeutic targets, because these contribute to a drug’s

pharmacokinetics and pharmacodynamics. The interesting temporal association of

hypersensitivity with initiation of abacavir later in PHI merits future investigation.

An important scientific challenge arises from the statistical requirement of sufficient power

needed to associate a genotype definitively with a particular adverse event. At the present

time, association studies require a large number of patients in order to achieve adequate

statistical power. Generally, the purpose of surveillance during the post-approval period is to

determine ADRs from newly approved drugs that result in the withdrawal of the drug from

the market. However, a genotyping diagnostic test cannot meet the validation clinical

specificity and sensitivity standards without the sufficient sample size. This may entail

exposing a large number of patients to a given therapeutic agent and potentially to a serious

ADR.


Current pharmacogenomic studies are hampered by methodological and study design

constraints. In addition, a number of ethical and regulatory issues remain to be resolved. In

order for pharmacogenomics to be applied appropriately, there is a dire need to advance the

science of pharmacogenomics simultaneously on several fronts. To date, the advances in

pharmacogenomics have come primarily from studies of monogenic polymorphisms. More

attention to polygenic expressed traits is needed in order for this field to make a contribu-

tion that is consistent with the complexity of clinical reality. More emphasis needs to be

placed on refining association studies and developing new clinical trial design strategies as

well as technologies. Future studies should also include appropriate pharmacoepidemio-

logical criteria and methods to evaluate the utility of pharmacogenomic applications in

postmarketing surveillance, as well as during the phases of pre-approval clinical drug trials.

At the same time, the ethical and regulatory issues, especially those pertinent to the use of

databases, need to be resolved.

Review History


June 2007 Medical Advisory Council initial approval

August 2008 Added screening for HLA-B*5701 allele prior to initiation of abacavir (Ziagen; ABC) therapy as

medically necessary to reduce the risk of hypersensitivity reaction.

Added genotyping for HLA-B* 1502 as medically necessary for persons of

Asian ancestry before commencing treatment with carbamazepine

(Tegretol).

February 2010 Update. Added as not medically necessary, genotyping for Apo E for

determining therapeutic response to lipid-lowering medications, geno-

typing for CYP2C9 and VKORC1 to assist with induction dosing and

therapeutic response to warfarin therapy, and genotyping for MTHFR for

determining therapeutic response to antifolate chemotherapy. Codes

reviewed.

March 2010 Clarified 2nd Bullet, under III, in policy statement

March 2011 Updated policy to consider genotyping for CYP2C19 polymorphisms, a

variant of Cytochrome P450, medically necessary (one time), in

individuals for treatment with clopidogrel or currently receiving

clopidogrel.

March 2012 Update. No revisions.

March 2013 Update. Added BRAF V600E mutation (e.g., the Cobas 4800 BRAF

mutation test) as medically necessary for individuals who are considering

vemurafenib (Zelboraf) for the treatment of unresectable or metastatic

melanoma. (2013 NCCN recommendation). Codes updated.

March 2014 Update. Added FDA-approved test (e.g., the THxID BRAF test) as

medically necessary for detecting mutation of the BRAF gene (V600E or

V600K) in persons with unresectable or metastatic melanoma who are

being considered for treatment with either dabrafenib (Tafinlar) (Tafinlar)

or trametinib (Mekinist)(Mekinist). (NCCN Category 1 recommendation)

Added MGMT, gene methylation assay as medically necessary for

predicting response to the chemotherapeutic agent temozolomide for

glioblastoma, aged 70 years or younger, with a good PS (KPS>70).

(NCCN Category 1 recommendation). Codes updated.

May 2014 Added pharmacogenetic testing as investigational for the following:

HLA-B*1502 genotyping in patients of other ethnicities (non-Asian) for

whom treatment with carbamazepine (Tegretol), or with phenytoin

(Dilantin) is being considered; HLA-B*1502 genotyping in patients for

whom treatment with lamotrigIne (Lamictal) is being considered;

Genotyping for HLA-B variants other than HLA-B*1502 in patients for

whom treatment with carbamazepine (Tegretol), phenytoin (Dilantin),

or lamotrigine (Lamictal) is being considered. Codes updated.

February 2015 Added SureGene Test for Antipsychotic and Antidepressant Response

(STA2R), GeneSightRx and PHARMAChip as investigational. Codes

updated.

April 2015 Added Comprehensive personalized Medicine Panel as investigational

since there is a paucity of peer reviewed studies to evaluate the genes in

this panel and to predict patient responses to the drugs. Codes reviewed.


May 2015 Update – Added anaplastic lymphoma kinase (ALK) gene

rearrangement testing in NSCLC, for prediction of response to crizotinib

and ceritinib therapy in ALK-positive NSCLC patients, as medically

necessary. Added Genecept Assay as investigational to assist in making

treatment recommendations for patients with neuropsychiatric disorders,

since there is a paucity of peer reviewed literature. Codes updated.

June 2015 Added Cytochrome P450 (CYP450) genotyping to predict response to

antidepressant and antipsychotic medications as investigational since the

evidence supporting the clinical validity is limited. Additional peer

reviewed studies are necessary.

This policy is based on the following evidence-based guidelines: 1. No authors listed. Panel on Antiretroviral Guidelines for Adults and Adolescents.

Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents.

Department of Health and Human Services. January 29, 2008; 1-128. Accessed June

2008. Available at: http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf

2. Working Group on Antiretroviral Therapy and Medical Management of HIV-Infected

Children. NO authors listed. Guidelines for the use of antiretroviral agents in pediatric

HIV infection. U.S. Department of Health and Human Services; 2008 Feb 28. Accessed

June 2008. Available at: http://aidsinfo.nih.gov/contentfiles/PediatricGuidelines.pdf

3. Hirsh et al. AHA/ACC Expert Consensus Document on Warfarin Therapy. JACC 2003;

41:1633-52.

4. California Technology Assessment Forum. Use of Genetic Testing to Guide the Initiation

of Warfarin Therapy. March 2008.

5. Technology Evaluation Center (TEC) BC BS. Special Report: Cardiovascular

Pharmacogenomics. Assessment. Program Volume 22, No. 7, November 2007.

6. Raman G, Triclinic TA, Zintzaras E, et al. Reviews of selected pharmacogenetic tests for

non-cancer and cancer condtions. Technology Assessment Report. Prepared by the Tufts

Evidence-based Practice Center for the Agency for Healthcare Research and Quality

(AHRQ). Contract No. 290-02-0022. Rockville, MD: AHRQ; November 12, 2008.

Available at: http://www.cms.hhs.gov/determinationprocess/downloads/id61TA.pdf.

7. U.S. Food and Drug Administration. Prescribing and Label Information. Plavix. Hayes

Genetic Test Evaluation (GTE) Report. CYP2C19 Genotyping to Predict Response to

Clopidogrel. November 2010

8. Society for Cardiovascular Angiography and Interventions; Society of Thoracic

Surgeons; Writing Committee Members, Holmes DR Jr, Dehmer GJ, Kaul S, et al.

ACCF/AHA Clopidogrel clinical alert: approaches to the FDA “boxed warning”: a report of

the American College of Cardiology Foundation Task Force on Clinical Expert Consensus

Documents and the American Heart Association. Circulation.

2010; 122(5):537-557.

9. Hayes. Genetic Test Evaluation (GTE) Overview. Cytochrome P450 3A5 (CYP3A5)

Testing for Predict Response to Tacrolimus. November 16, 2011. Updated December 4,

2014.

10. National Comprehensive Cancer Network (NCCN). NCCN Guidelines Version 2.2012.

Non-Small Cell Lung Cancer. Updated Version 2.2013. Updated Version 3.2014. Updated

Version 6. 2015.

11. Hayes. Genetic Test Evaluation (GTE) Overview. BRAF p.Val600Glu (V600E) for

Assessment of Treatment Options in Metastatic Colorectal Cancer. February 19, 2013.

Updated February 4, 2014.

12. Hayes. GTE Synopsis. GTE Synopsis. BRAF Testing to Predict Response to Vemurafenib

in Malignant Melanoma. July 6, 2012. Updated April 23, 2013. Updated March 24, 2015.

http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf

http://aidsinfo.nih.gov/contentfiles/PediatricGuidelines.pdf

http://www.cms.hhs.gov/determinationprocess/downloads/id61TA.pdf


13. Hayes. Genetic Test Evaluation (GTE). BRAF p.Val600Glu Testing in Papillary Thyroid

Carcinoma for Papillary Thyroid Carcinoma. May 1, 2012. Updated March 13, 2013.

14. Hayes Prognosis. Zelboraf (Vemurafenib, PLX 4032). February 2012.

15. Agency for Healthcare Research and Quality (AHRQ). Testing of CYP2C19 variants and

platelet reactivity for guiding antiplatelet treatment. Draft Comparative Effectiveness

Review. Rockville, MD: AHRQ; 2012.

16. National Comprehensive Cancer Network (NCCN). NCCN Guidelines on Colon Cancer.

Version 3.2012. Updated Version 3.2013. Updated Version 3. 2014. Updated Version 5.

2015.

17. National Comprehensive Cancer Network (NCCN). NCCN Guidelines on Melanoma.

Version 2.2013. Updated Version 3. 2014. Updated Version 3.2015.

18. National Comprehensive Cancer Network (NCCN). NCCN Guidelines on Thyroid Cancer.

Version 1.2013. Updated Version 2.2013. Updated Version 2.2014.

19. National Comprehensive Cancer Network (NCCN). NCCN Guidelines on Central Nervous

System Cancers. Version 2. 2013. Updated Version 2.2014

20. Hayes. GTE Overview. BRAF p.Val600Glu (V600E) and p.Val600Lys (V600K) Testing for

Trametinib (Mekinist)and Dabrafenib (Tafinlar) Combination Therapy in Melanoma.

January 29, 2014. Updated February 12, 2015.

21. Hayes. GTE Overview. BRAF p.Val600Glu (V600E) Testing for Dabrafenib (Tafinlar)

Monotherapy in Melanoma. January 29, 2014. Updated January 15, 2015.

22. Hayes. GTE Overview. BRAF p.Val600Glu (V600E) and p.Val600Lys (V600K) Testing for

Trametinib (Mekinist). Monotherapy in Melanoma. January 29, 2014. Updated December

18, 2014.

23. Hayes. GTE Overview. HLA-B Testing for Guidance of Treatment with Anticonvulsant

Drugs. April 15, 2014.

24. Hayes. GTE Overview. STA2R SureGene Test for Antipsychotic and Antidepressant

Response. January 15, 2015.

25. Hayes. GTE Overview. Comprehensive Personalized Medicine Panel. March 12, 2015.

26. Hayes. GTE Overview. Anaplastic Lymphoma Kinase (ALK) Gene Rearrangement Testing

in Non-Small Cell Lung Cancer (NSCLC). June 18, 2014.

27. Blue Cross Blue Shield Technology Evaluation Center. CYP2D6 pharmacogenomics of

tamoxifen treatment. TEC Assessment Program. 2014 January. Volume 28, No. 8.

Available at: http://www.bcbs.com/blueresources/tec/vols/28/28_08.pdf

28. Hayes. GTE Synopsis. The Genecept Assay. December 2014.

29. Hayes. GTE Overview. Cytochrome P450 (CYP450) Genotyping to Predict Response to

Antidepressant and Antipsychotic Medications. May 14, 2015.

References – Update May 2015 1. AstraZenica Pharmaceutics, LP. Lynparza (olaparib) capsules, for oral use. Prescribing

Information. Reference ID: 3675412. Revised December 2014.

2. Crews KR, Gaedigk A, Dunnenberger HM, et al. Clinical Pharmacogenetics

Implementation Consortium Guidelines for Cytochrome P450 2D6 Genotype and Codeine

Therapy: 2014 Update. Clin Pharmacol Ther. 2014 Jan 23.

3. Innocenti F, Schilsky RL, Ramírez J, et al. Dose-finding and pharmacokinetic study to

optimize the dosing of irinotecan according to the UGT1A1 genotype of patients with

cancer. J Clin Oncol. 2014 Aug 1;32(22):2328-34. doi: 10.1200/JCO.2014.55.2307.

Epub 2014 Jun 23.

4. Laboratory Corporation of America Holdings and Lexi-Comp, Inc. Tamoxifen CYP2D6

genotype-a technical review. 2014.

5. Liu X, Cheng D, Kuang Q, et al. Association of UGT1A1*28 polymorphisms with

irinotecan-induced toxicities in colorectal cancer: a meta-analysis in Caucasians.

http://www.bcbs.com/blueresources/tec/vols/28/28_08.pdf


Pharmacogenomics J. 2014 Apr;14(2):120-9. doi: 10.1038/tpj.2013.10. Epub 2013 Mar

26.

6. Myriad Genetics. BRACAnalysis CDx. Technical Information Summary. Myriad Genetics;

2014.

7. Solomon B, Wilner KD, Shaw AT. Current status of targeted therapy for anaplastic

lymphoma kinase-rearranged non-small cell lung cancer. Clin Pharmacol Ther. 2014

Jan;95(1):15-23. doi: 10.1038/clpt.2013.200. Epub 2013 Oct 3.

8. U.S. Food and Drug Administration (FDA). Vysis ALK Break Apart FISH Probe Kit; Vysis

Paraffin Pretreatment IV and Post Hybridization Wash Buffer Kit; ProbeChek ALK

Negative Control Slides; and ProbeChek ALK Positive Control Slides - P110012. August

26, 2011.

9. U.S. Food and Drug Administration (FDA). BRACAnalysis CDx - P140020. Recently

Approved Medical Devices. FDA; updated December 30, 2014.

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HLA-B 15:02 as genetic markers for carbamazepine hypersensitivity in children. Clin

Pharmacol Ther. 2013;94 (1):142-149.

2. Cheung YK, Cheng SH, Chan EJ, Lo SV, Ng MH, Kwan P. HLA-B alleles associated with

severe cutaneous reactions to antiepileptic drugs in Han Chinese. Epilepsia.

2013;54(7):1307-1314.

3. Genin E, Chen DP, Hung SI, et al. HLA-A*31:01 and different types of carbamazepine-

induced severe cutaneous adverse reactions: an international study and meta-analysis.

Pharmacogenomics J. 2013. Epub ahead of print. December 10, 2013.

4. Grover S, Kukreti R. HLA alleles and hypersensitivity to carbamazepine: an updated

systematic review with meta-analysis. Pharmacogenet Genomics. 2014;24(2):94-112.

5. He XJ, Jian LY, He XL, et al. Association between the HLA-B*15:02 allele and

carbamazepine-induced Stevens-Johnson syndrome/toxic epidermal necrolysis in Han

individuals of northeastern China. Pharmacol Rep. 2013;65(5):1256-1262.

6. Hsiao YH, Hui RC, Wu T, et al. Genotype-phenotype association between HLA and

carbamazepine-induced hypersensitivity reactions: strength and clinical correlations. J

Dermatol Sci. 2014;73(2):101-109.

7. Kaniwa N, Saito Y. Pharmacogenomics of severe cutaneous adverse reactions and drug-

induced liver injury. J Hum Genet. 2013;58(6):317-326.

8. Leckband SG, Kelsoe JR, Dunnenberger HM, et al. Clinical Pharmacogenetics

Implementation Consortium guidelines for HLA-B genotype and carbamazepine dosing.

Clin Pharmacol Ther. 2013;94(3):324-328.

9. Lee HY, Chung WH. Toxic epidermal necrolysis: the year in review. Curr Opin Allergy

Clin Immunol. 2013;13(4):330-336.

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lamotrigine-induced maculopapular exanthema in Han Chinese. Epilepsy Res.

2013;106(1-2):296-300.

11. Lin YT, Chang YC, Hui RC, et al. A patch testing and cross-sensitivity study of

carbamazepine-induced severe cutaneous adverse drug reactions. J Eur Acad Dermatol

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12. Lv YD, Min FL, Liao WP, et al. The association between oxcarbazepine-induced

maculopapular eruption and HLA-B alleles in a northern Han Chinese population. BMC

Neurol. 2013;13:75.

13. Manuyakorn W, Siripool K, Kamchaisatian W, et al. Phenobarbital-induced severe

cutaneous adverse drug reactions are associated with CYP2C19*2 in Thai children.

Pediatr Allergy Immunol. 2013;24(3):299-303.


14. Nirken MH, High WA, Roujeau JC, et al. Stevens-Johnson syndrome and toxic epidermal

necrolysis: Pathogenesis, clinical manifestations, and diagnosis. UpToDate. April 15,

2014.

15. Rattanavipapong W, Koopitakkajorn T, Praditsitthikorn N, et al. Economic evaluation of

HLA-B*15:02 screening for carbamazepine-induced severe adverse drug reactions in

Thailand. Epilepsia. 2013;54(9):1628-1638.

16. Schwartz R, McDonough PH, Lee BW, et al. Toxic epidermal necrolysis. Journal of the

American Academy of Dermatology. Volume 69, Issue 2 (August 2013).

17. Tang YH. Poor relevance of a lymphocyte proliferation assay in lamotrigine-induced

Stevens-Johnson syndrome or toxic epidermal necrolysis. Clin Exp Allergy. 01-FEB-

2012; 42(2): 248-54.

18. Tangamornsuksan W, Chaiyakunapruk N, Somkrua R, et al. Relationship between the

HLA-B*1502 allele and carbamazepine-induced Stevens-Johnson syndrome and toxic

epidermal necrolysis: a systematic review and meta-analysis. JAMA Dermatol.

2013;149(9):1025-1032.

19. Then SM, Rani ZZM, Raymond AA, Jamal R. Pharmacogenomics screening of HLA-

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perspective. Asia Pac Allergy. 2013;3(4):215-223.

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22. Toh DS, Tan LL, Aw DC, et al. Building pharmacogenetics into a pharmacovigilance

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melanoma treated with immunotherapy prior to or after BRAF inhibitors. Cancer: 2013.

2. Azer MF, Menzies AM, Haydu LE, et al. Patterns of Response and Progression in Patients

with BRAF-mutant Melanoma Metastatic to the Brain treated with Dabrafenib (Tafinlar).

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Combination Therapy to Dabrafenib (Tafinlar) Monotherapy in Subjects With BRAF-

mutant Melanoma. Clinicaltrial.gov identifier: NCT01584648. August 22, 2013.

4. Flaherty KT, Infante JR, Daud A, et al. Combined BRAF and MEK inhibition in melanoma

with BRAF V600 mutations. N. Engl. J. Med. 2012;367(18):1694-1703.

5. Flaherty, KT, Robert, C, Hersey, P, et al. Improved survival with MEK inhibition in BRAF-

mutated melanoma. N Engl J Med. 2012 Jul 12;367(2):107-14.

6. Frederick DT, Piris A, Cogdill AP, et al. (2013) BRAF Inhibition Is Associated with

Enhanced Melanoma Antigen Expression and a More Favorable Tumor Microenvironment

in Patients with Metastatic Melanoma. Clinical Cancer Research 19: 1225–1231. doi:

10.1158/1078-0432.ccr-12-1630.

7. Hauschild A, Grob JJ, Demidov LV, et al. An update on BREAK-3, a phase III,

randomized trial: Dabrafenib (Tafinlar) versus dacarbazine in patients with BRAF V600E-


positive mutation metastatic melanoma. American Society of Clinical Oncology 2013

meeting.

8. Hauschild A, Grob JJ, Demidov LV, et al. Dabrafenib (Tafinlar) in BRAF-mutated

metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial.

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9. Liu X, Cheng D, Kuang Q, et al. Association of UGT1A1*28 polymorphisms with

irinotecan-induced toxicities in colorectal cancer: a meta-analysis in Caucasians.

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cancer. August 26, 2011. Available at:

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3. Crews KR, Gaedigk A, Dunnenberger HM, et al. Clinical Pharmacogenetics

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4. Gusti R. Bope & Kellerman: Conn's Current Therapy 2013, 1st ed. 2012 Saunders, An

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allopurinol dosing. Clin Pharmacol Ther 2013; 93:153.

6. Kim IS, Jeong YH, Park Y, et al. Interaction analysis between genetic polymorphisms

and pharmacodynamic effect in patients treated with adjunctive cilostazol to dual

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Triple Antiplatelet Therapy According to Gene Polymorphism) study. Br J Clin Pharmacol.

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patients treated with clopidogrel after myocardial infarction: a cohort study. Lancet.

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polymorphism to occurrence of drug-eluting coronary stent thrombosis. Am J Cardiol.

2009; 103(6):806-811.

3. Hochholzer W, Trenk D, Fromm MF, et al. Impact of cytochrome P450 2C19 loss-of-

function polymorphism and of major demographic characteristics on residual platelet

function after loading and maintenance treatment with clopidogrel in patients

undergoing elective coronary stent placement. J Am Coll Cardiol. 2010 Jun 1;

55(22):2427-34.

4. Hulot JS, Collet JP, Silvain J, et al. Cardiovascular risk in clopidogrel-treated patients

according to cytochrome P450 2C19*2 loss-of-function allele or proton pump inhibitor

coadministration: a systematic meta-analysis. J Am Coll Cardiol. 2010; 56(2):134-143.

5. Jeong YH, Kim IS, Park Y, et al. Carriage of cytochrome 2C19 polymorphism is

associated with risk of high post-treatment platelet reactivity on high maintenance-dose

clopidogrel of 150 mg/day: results of the ACCEL-DOUBLE (Accelerated Platelet Inhibition

by a Double Dose of Clopidogrel According to Gene Polymorphism) study. JACC

Cardiovasc Interv. 2010 Jul; 3(7):731-41.

6. Jin B, Ni HC, Shen W, et al. Cytochrome P450 2C19 polymorphism is associated with

poor clinical outcomes in coronary artery disease patients treated with clopidogrel. Mol

Biol Rep. 2011 Mar;38(3):1697-702

7. Małek LA, Przyłuski J, Spiewak M, et al. Cytochrome P450 2C19 polymorphism,

suboptimal reperfusion and all-cause mortality in patients with acute myocardial

infarction. Cardiology. 2010;117(2):81-7

8. Mega JL, Close SL, Wiviott SD, et al. Cytochrome p-450 polymorphisms and response to

clopidogrel. N Engl J Med. 2009; 360(4):354-362.

9. Mega JL, Close SL, Wiviott SD, et al. Genetic variants in ABCB1 and CYP2C19 and

cardiovascular outcomes after treatment with clopidogrel and prasugrel in the TRITON-

TIMI 38 trial: a pharmacogenetic analysis. Lancet. 2010;376(9749):1312-1319

10. Mega JL, Simon T, Collet JP, et al. Reduced-function CYP2C19 genotype and risk of

adverse clinical outcomes among patients treated with clopidogrel predominantly for

PCI: a meta-analysis. JAMA. 2010;304(16):1821-1830

11. Ned Mmsc PhD RM. Genetic testing for CYP450 polymorphisms to predict response to

clopidogrel: current evidence and test availability. Application: pharmacogenomics.

12. PLoS Curr. 2010 Sep 20; 2. Pii: RRN1180.

13. Paré G, Mehta SR, Yusuf S, et al. Effects of CYP2C19 genotype on outcomes of

clopidogrel treatment. N Engl J Med. 2010;363(18):1704-1714

14. Sawada T, Shinke T, Shite J, et al. Impact of cytochrome P450 2C19*2 polymorphism

on intra-stent thrombus after drug-eluting stent implantation in Japanese patients

receiving clopidogrel. Circ J. 2010 Dec 24;75(1):99-105

15. Shuldiner AR, O'Connell JR, Bliden KP, et al. Association of cytochrome P450 2C19

genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. JAMA.

2009; 302(8):849-857.

16. Sibbing D, Koch W, Gebhard D, et al. Cytochrome 2C19*17 allelic variant, platelet

aggregation, bleeding events, and stent thrombosis in clopidogrel-treated patients with

coronary stent placement. Circulation. 2010; 121(4):512-518.

17. Simon T, Steg PG, Gilard M, et al. Clinical Events as a Function of Proton Pump Inhibitor

Use, Clopidogrel Use, and Cytochrome P450 2C19 Genotype in a Large Nationwide


Cohort of Acute Myocardial Infarction: Results from the French Registry of Acute ST-

Elevation and Non-ST-Elevation Myocardial Infarction (FAST-MI) Registry.

18. Simon T, Verstuyft C, Mary-Krause M, et al.; French Registry of Acute ST-Elevation and

Non-ST-Elevation Myocardial Infarction (FAST-MI) Investigators. Genetic determinants

of response to clopidogrel and cardiovascular events. N Engl J Med. 2009;360(4):363-

375

19. Sofi F, Giusti B, Marcucci R, Gori AM, Abbate R, Gensini GF. Cytochrome P450 2C19 (*)

2 polymorphism and cardiovascular recurrences in patients taking clopidogrel: a meta-

analysis. Pharmacogenomics J. 2010

20. Sorich MJ, Vitry A, Ward MB, et al. Prasugrel versus clopidogrel for Cytochrome P450

2C19 genotyped subgroups: integration of the TRITON-TIMI 38 trial data. J Thromb

Haemost. 2010; 8(8):1678-1684.

21. Tiroch KA, Sibbing D, Koch W, et al. Protective effect of the CYP2C19 *17 polymorphism

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22. U.S. Food and Drug Administration. Amplichip CYP450 Test for CYP2C19 510(k)

Summary. Jan 2005. Available at:

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23. Wallentin L, Becker RC, Budaj A, et al; PLATO Investigators, Freij A, Thorsén M.

Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med.

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24. Wallentin L, James S, Storey RF, et al.; PLATO Investigators. Effect of CYP2C19 and

ABCB1 single nucleotide polymorphisms on outcomes of treatment with ticagrelor versus

clopidogrel for acute coronary syndromes: a genetic substudy of the PLATO trial. Lancet.

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References – Update February 2010 1. CMS. Centers for Medicare & Medicaid. NCD for Pharmacogenomic TESTING for Warfarin

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2. Derwinger K, Wettergren Y, Odin E, et al. A study of the MTHFR gene polymorphism

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4. Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group.

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irinotecan? Genet Med. 2009; 11(1):15-20.

5. Mega JL, Close SL, Wiviott SD, et al. Cytochrome p-450 polymorphisms and response to

clopidogrel. NEJM. 2009; 360(4):354-362.

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29. U.S. Food and Drug Administration. FDA alert. Carbamazepine. December 12, 2007.

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