Pharmacogenomic profiling appears promising - Health Net
Transcript of 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
IMPORTANT NOTICE
At the end of this document
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coverage guidelines prior to applying Health Net Medical Policies
The Centers for Medicare & Medicaid Services (CMS)
For Medicare Advantage members please refer to the following for coverage guidelines first:
Use Source Reference/Website Link
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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instructions. Enter the topic and your specific state to find the coverage determinations
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Administration Contractors (MACs) located outside their service area when those MACs have exclusive coverage of an item or service. (CMS Manual Chapter 4 Section 90.2)
If more than one source is checked, you need to access all sources as, on occasion, an
LCD or article contains additional coverage information than contained in the NCD or
National Coverage Manual.
If there is no NCD, National Coverage Manual or region specific LCD/Article, follow the
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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
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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,);
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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
for treatment with antipsychotics.
5. For CYP2D6 genotyping in patients with a mental illness who are being considered for
treatment with antidepressants or antipsychotics.
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6. For CYP3A4 genotyping in patients with a mental illness who are being considered for
treatment with antidepressants or antipsychotics.
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
for treatment with antipsychotics.
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
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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-
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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)
81405 Molecular pathology procedure, Level 6 (eg., analysis of 6-10 exons
by DNA sequence analysis, mutation scanning or duplication/deletion
variants of 11-25 exons), regionally targeted cytogenomic array
analysis (Revised 2015)
81406 Molecular pathology procedure, Level 7 (eg., analysis of 11-25 exons
by DNA sequence analysis, mutation scanning or duplication/deletion
variants of 26-50 exons, cytogenomic array analysis for neoplasia)
((Revised 2015)
81407 Molecular pathology procedure, Level 8 (eg., analysis of 26-50 exons
by DNA sequence analysis, mutation scanning or duplication/deletion
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)
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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.
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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
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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
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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);
Pharmacogenetic Testing May 15 12
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
Pharmacogenetic Testing May 15 13
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.
Pharmacogenetic Testing May 15 14
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
Pharmacogenetic Testing May 15 15
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*).
Pharmacogenetic Testing May 15 16
*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
Pharmacogenetic Testing May 15 17
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
Pharmacogenetic Testing May 15 18
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.
Pharmacogenetic Testing May 15 19
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
Pharmacogenetic Testing May 15 20
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
Pharmacogenetic Testing May 15 21
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.
Pharmacogenetic Testing May 15 22
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
Pharmacogenetic Testing May 15 23
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
Pharmacogenetic Testing May 15 24
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
Pharmacogenetic Testing May 15 25
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
Pharmacogenetic Testing May 15 26
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
Pharmacogenetic Testing May 15 27
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
Pharmacogenetic Testing May 15 28
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.
Pharmacogenetic Testing May 15 29
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
Pharmacogenetic Testing May 15 30
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
Pharmacogenetic Testing May 15 31
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
Pharmacogenetic Testing May 15 32
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
Pharmacogenetic Testing May 15 33
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
Pharmacogenetic Testing May 15 34
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
Pharmacogenetic Testing May 15 35
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
Pharmacogenetic Testing May 15 36
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.
Pharmacogenetic Testing May 15 37
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
Pharmacogenetic Testing May 15 38
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.
Pharmacogenetic Testing May 15 39
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.
Pharmacogenetic Testing May 15 40
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.
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3. Innocenti F, Schilsky RL, Ramírez J, et al. Dose-finding and pharmacokinetic study to
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26.
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5. He XJ, Jian LY, He XL, et al. Association between the HLA-B*15:02 allele and
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11. Lin YT, Chang YC, Hui RC, et al. A patch testing and cross-sensitivity study of
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14. Nirken MH, High WA, Roujeau JC, et al. Stevens-Johnson syndrome and toxic epidermal
necrolysis: Pathogenesis, clinical manifestations, and diagnosis. UpToDate. April 15,
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18. Tangamornsuksan W, Chaiyakunapruk N, Somkrua R, et al. Relationship between the
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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
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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
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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
Pharmacogenetic Testing May 15 46
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
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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)
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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.
2010; 376(9749):1320-1328.
References – Update February 2010 1. CMS. Centers for Medicare & Medicaid. NCD for Pharmacogenomic TESTING for Warfarin
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irinotecan? Genet Med. 2009; 11(1):15-20.
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