Friday, February 22, 2019

CPT 11055, 11056, 11057, 11719, 11720, 11721 - Routine Foot Care Services

Coding   Code Description CPT

11055 Paring or cutting of benign hyperkeratotic lesion (eg, corn or callus); single lesion

11056 Paring or cutting of benign hyperkeratotic lesion (eg, corn or callus); 2 to 4 lesions

11057 Paring or cutting of benign hyperkeratotic lesion (eg, corn or callus); more than 4 lesions

11719 Trimming of nondystrophic nails, any number

11720 Debridement of nail(s) by any method(s); 1 to 5

11721 Debridement of nail(s) by any method(s); 6 or more


HCPCS

G0127 Trimming of dystrophic nails, any number

S0390 Routine foot care; removal and/or trimming of corns, calluses and/or nails and preventive maintenance in specific medical conditions (eg, diabetes), per visit






Introduction

Most adults are able to provide their own routine foot care, such as trimming nails or filing calluses. Therefore, this type of foot care is not covered under the medical benefits. However, for some individuals with certain medical conditions, it may be important to have professional help with routine foot care in order to prevent serious problems. Routine foot care includes services such as cutting corns and calluses or trimming, cutting, clipping, or removing part of the nail (debridement). This benefit coverage guideline discusses when routine foot care may be covered.

Note:   The Introduction section is for your general knowledge and is not to be taken as policy coverage criteria. The rest of the policy uses specific words and concepts familiar to medical professionals. It is intended for providers. A provider can be a person, such as a doctor, nurse, psychologist, or dentist. A provider also can be a place where medical care is given, like a hospital, clinic, or lab. This policy informs them about when a service may be covered. 
Coverage Guideline 

Indication Medical Necessity
Conditions associated with poor blood flow to the legs and feet
Routine foot care may be considered medically necessary for patients with conditions associated with poor blood flow to the legs and feet such as peripheral vascular disease and/or numbness (desensitization). 



Routine foot care Routine foot care, such as trimming nails or removing corns and calluses, does not typically require the skills of a qualified provider of foot care services and is therefore considered not medically necessary.



ICD-10 Diagnosis Codes - Covered

A52.16 Charcot's arthropathy (tabetic)
B35.1 Dermatophitosis (Tinea unquium)
B37.2 Candidiasis of skin and nail
B52.0 Plasmodium malariae with neuropathy
E08.00 – E13.9 Diabetes Mellitus
O24.011 – O24.93 Diabetes mellitus in pregnancy
G13.0 – G13.1 Systemic atrophy and neuropathy
G6281 – G65.2 Polyneuropathies


Code Description
G73.3 Myasthenic syndromes in other diseases classified elsewhere
G90.09 Peripheral neuropathy
G99.0 Autonomic neuropathy
I70.201 – I70.799 Atherosclerosis of arteries, lower extremities
I73.00 – I79.8 Peripheral vascular disease
I80.00 – I80.3 Phlebitis and thrombophlebitis, lower extremities
I82.501 – I87.9 Chronic embolism and thrombosis, lower extremities
I89.0 Lymphedema
I99.8 Circulatory system disorder
L02.415 – L03.129 Infections of skin and subcutaneous tissue, lower limb
L11.0 Acquired keratosis follicularis
L60.0 – L60.9 Nail disorders
L84 – L85.2, L86, L87.0, L87.2, L97.501 – L97.529
Disorders of skin and subcutaneous tissue
M05.571 – M05.59 Polyarthropathies
M14.671 – M14.69 Arthropathies, Charcot's joint, ankle and foot  
M20.10 – M02.12 Hallus valgus
M34.83 Systemic sclerosis with polyneuropathy
M90.561 – M90.59 Osteonecrosis, lower ley, ankle and foot
M90.861 – M90.89 Osteopathy, lower leg, ankle and foot
Q82.0 Hereditary lymphedema
R20.0 – R20.9 Disorders of skin and subcutaneous tissue
R60.0 – R60.9 Edema
Note:  CPT codes, descriptions and materials are copyrighted by the American Medical Association (AMA). HCPCS codes, descriptions and materials are copyrighted by Centers for Medicare Services (CMS).


This coverage guideline describes the clinical indications for routine foot care services.  

Routine foot care includes:

* Cutting or removal of corns and calluses
* Trimming, cutting/clipping and debridement of nails

Generally, routine foot care services are performed by the member or the caregiver. However, if certain medical conditions are present they may pose a hazard when foot care is performed by a non-professional. 

The following conditions may pose a risk to life or limb loss, so a qualified provider of foot care services should perform the routine foot care. Conditions that may require a qualified provider to perform routine foot care include but are not limited to any of the following:

* Arteriosclerosis of the extremities
* Buerger’s disease (ie, thromboangiitis obliterans)
* Chronic thrombophlebitis of lower extremities
* Diabetes
* Peripheral neuropathies
* Peripheral vascular disease

This policy only addresses routine foot care. It does not address the treatment of symptomatic diseases and medical conditions of the feet, which may include:
* Bunion
* Bursitis
* Hammer toe
* Heel spur
* Ingrown toenail
* Neuroma
* Plantar fasciitis
* Sprain/strain of the foot
* Warts, including

Tuesday, February 5, 2019

CPT 37243, 75894, 79445, S2095 - Radioembolization for Primary and Metastatic Tumors of the Liver

Code Description CPT

37243 Vascular embolization or occlusion, inclusive of all radiological supervision and interpretation, intraprocedural roadmapping, and imaging guidance necessary to complete the intervention; for tumors, organ ischemia, or infarction.

75894 Transcatheter therapy, embolization, any method, radiological supervision and interpretation

79445 Radiopharmaceutical therapy, by intra-arterial particulate administration

Code Description HCPCS

S2095 Transcatheter occlusion or embolization for tumor destruction, percutaneous, any method, using ytrrium-90 microspheres


Introduction

Embolization is procedure to block blood flow. Combined with radiation, it is a way to treat cancer in the liver in some situations. In this procedure a catheter (a long, thin, hollow tube) is inserted in an artery near the groin. It’s threaded to the tumor’s blood supply. Tiny radioactive particles are released into the artery that feeds the tumor. The particles travel into the tumor and block off — embolize — the blood supply feeding the tumor, causing it to shrink. The radiation works to kill the cancer cells. The radiation dissipates in a few weeks and the particles stay in the liver permanently. The radiation usually doesn’t affect the healthy liver tissue around the tumor very much. This policy describes when radioembolization may be considered medically necessary.

Policy Coverage Criteria

Service Medical Necessity
 

Radioembolization Radioembolization may be considered medically necessary in the following situations: * Treatment of primary hepatocellular carcinoma that is  unresectable and limited to the liver (size of 3cm or larger, and patient with good performance status)   OR * Treatment of primary hepatocellular carcinoma as a bridge to  liver transplantation OR * Treatment of primary intrahepatic cholangiocarcinoma in  patients with unresectable tumors OR * Treatment of hepatic metastases from neuroendocrine tumors  (carcinoid and noncarcinoid) with diffuse and symptomatic disease when systemic therapy has failed to control symptoms. (symptoms related to excess hormone production)  OR * Treatment of unresectable hepatic metastases 

o From breast, colorectal or melanoma (ocular or cutaneous)       AND  o That are progressive and unresectable in patients with liver dominant disease
AND o That are refractory to chemotherapy or are not candidates  for chemotherapy   Service Investigational  Radioembolization Radioembolization is considered investigational for all other hepatic metastases except as noted in the Medical Necessity section above. 


Service Investigational

Documentation Requirements

Radioembolization is considered investigational for all other indications not described in the Medical Necessity section above.
The patient’s medical records submitted for review for all conditions should document that medical necessity criteria are met. The record should include office visit notes that contain the relevant history and physical supporting ANY of the following situations: * Patient with primary liver cancer that cannot be removed by surgery and limited to the liver  (size of 3 cm or larger, and patient with good performance status) * Treatment for hepatocellular carcinoma before a liver transplant *
Treatment of primary   intrahepatic cholangiocarcinoma that cannot be removed by surgery * Treatment of hepatic metastases from neuroendocrine tumors (carcinoid and noncarcinoid)  with diffuse and symptomatic disease when systemic therapy has failed to control symptoms (symptoms related to excess hormone production)

* Treatment of hepatic metastases that cannot be removed by surgery: o From breast, colorectal, or melanoma (ocular or cutaneous)
AND o That are progressive and unresectable in patients with liver dominant disease ND * Has failed chemotherapy or are not candidates for chemotherapy

Coding


The coding for radioembolization may depend on the medical specialty providing the therapy.



Related Information


In general, radioembolization is used for unresectable hepatocellular carcinoma that is greater than 3 cm.

There is little information on the safety or efficacy of repeated radioembolization treatments or about the number of treatments that should be administered.
Radioembolization should be reserved for patients with adequate functional status (Eastern Cooperative Oncology Group Performance Status 0-2), adequate liver function and reserve, Child-Pugh class A or B, and liver-dominant metastases.
Symptomatic disease from metastatic neuroendocrine tumors refers to symptoms related to excess hormone production.

Definition of Terms

Child-Pugh Score: This score is used to assess the prognosis of chronic liver disease, usually cirrhosis. 
Eastern Cooperative Oncology Group (ECOG): The ECOG performance status is used to assess the patient’s disease progression and how the disease impacts the patient’s activities of daily living (ADLs). http://www.ecog.org/  (Accessed September 2018)


Description

Radioembolization (RE), also referred to as selective internal radiotherapy, delivers small beads (microspheres) impregnated with yttrium 90 intra-arterially via the hepatic artery. The microspheres, which become permanently embedded, are delivered to tumors preferentially, because the hepatic circulation is uniquely organized, whereby tumors greater than 0.5 cm rely on the hepatic artery for blood supply while the normal liver is primarily perfused via the portal vein. Radioembolization has been proposed as a therapy for multiple types of primary and metastatic liver tumors.

Background

Treatments for Hepatic and NeuroEndocrine Tumors


The use of external-beam radiotherapy and the application of more advanced radiotherapy approaches (eg, intensity-modulated radiotherapy) may be of limited use in patients with multiple diffuse lesions due to the low tolerance of normal liver to radiation compared with thehigher doses of radiation needed to kill the tumor.

Various nonsurgical ablative techniques have been investigated that seek to cure or palliate unresectable hepatic tumors by improving locoregional control. These techniques rely on extreme temperature changes (cryosurgery or radiofrequency ablation), particle and wave physics (microwave or laser ablation), or arterial embolization therapy including chemoembolization, bland embolization, or radioembolization.

Radioembolization

Radioembolization, (radiotherapy in older literature) delivers small beads (microspheres) impregnated with yttrium 90 intra-arterially via the hepatic artery. The microspheres, which become permanently embedded, are delivered to tumors preferentially because thehepatic circulation is uniquely organized, whereby tumors greater than 0.5 cm rely on the hepatic arteryfor blood supply while normal liver is primarily perfused via the portal vein. Yttrium-90 is a pure beta-emitter with a relatively limited effective range and short half-life that helps focus the radiation and minimize its spread. Candidates for radioembolizationare initially examined by hepatic angiogram to identify and map the hepatic arterial system. At that time, a mixture of technetium 99-labeled albumin particles is delivered via the hepatic artery to simulate  microspheres. Single-photon emission computed tomography is used to detect possible shunting of the albumin particles into gastrointestinal or pulmonary vasculature.

Currently 2 commercial forms of yttrium-90 microspheres are available: a glass sphere, (TheraSphere) and a resin sphere (SIR-Spheres). Noncommercial forms are mostly used outside the United States. While the commercial products use the same radioisotope (yttrium-90) and have the same target dose (100 Gy), they differ in microsphere size profile, base material (ie, resin vs glass), and size of commercially available doses. The physical characteristics of the active and inactive ingredients affect the flow of microspheres during injection, their retention at the tumor site, spread outside the therapeutic target region, and dosimetry calculations. The  Food and Drug Administration (FDA) granted premarket approval of SIR-Spheres for use in combination with 5-floxuridine chemotherapy by hepatic arterial infusion to treat unresectable hepatic metastases from colorectal cancer. In contrast, TheraSphere’s glass sphere was approved under a humanitarian device exemption for use as monotherapy to treat unresectable hepatocellular carcinoma. In 2007, this humanitarian device exemption was expanded to include patients with hepatocellular carcinoma who have partial or branch portal vein thrombosis. For these reasons, results obtained with 1 product do not necessarily apply to other commercial (or non-commercial) products (see Regulatory Status section). 

Sunday, January 27, 2019

CPT 81504, 81540, 81599 - Assays for Cancers of Unknown Primary

Policy Coverage Criteria 

Type of Test Investigational

Gene expression profiling Gene expression profiling is considered investigational to evaluate the site of origin of a tumor of unknown primary, or to distinguish a primary from a metastatic tumor.

Coding   code Description CPT

81479 Unlisted molecular pathology procedure

81504 Oncology (tissue of origin), microarray gene expression profiling of > 2000 genes, utilizing formalin-fixed paraffin embedded tissue, algorithm reported as tissue similarity scores

81540 Oncology (tumor of unknown origin), mRNA, gene expression profiling by real-time RT-PCR of 92 genes (87 content and 5 housekeeping) to classify tumor into main cancer type and subtype, utilizing formalin-fixed paraffin-embedded tissue, algorithm reported as a probability of a predicted main cancer type and subtype

81599 Unlisted multianalyte assay with algorithmic analysis


Introduction

A primary site is the part of the body where cancer started. Cancers are named on this primary site, even when they spread to other parts of the body. For example, if cancer starts in the breast but spreads to the bones, lungs, or liver, it is still classified as breast cancer. Cancer treatment is often based on the primary cancer. In rare cases, a cancer may have already spread before the original cancer is found. This is known as cancer of unknown primary. Cancers of unknown primary happen in three to four percent of all cancers in the United States. Certain genetic tests are being studied as one way to try to find the original site of the cancer. There is not yet enough scientific evidence about how these genetic tests might affect overall health outcomes. These tests are considered unproven (investigational).




Related Information 

Genetics Nomenclature Update 


The Human Genome Variation Society nomenclature is used to report information on variants found in DNA and serves as an international standard in DNA diagnostics (see Table 1). The Society’s nomenclature is recommended by the Human Variome Project, the Human Genome Organization, and by the Human Genome Variation Society itself.


The American College of Medical Genetics and Genomics and the Association for Molecular Pathology standards and guidelines for interpretation of sequence variants represent expert opinion from both organizations, in addition to the College of American Pathologists. These recommendations primarily apply to genetic tests used in clinical laboratories, including genotyping, single genes, panels, exomes, and genomes. Table 2 shows the recommended standard terminology—“pathogenic,” “likely pathogenic,” “uncertain significance,” “likely benign,” and “benign”—to describe variants identified that cause Mendelian disorders.

Table 1. Nomenclature to Report on Variants Found in DNA
Previous  Updated  Definition
Mutation Disease-associated variant Disease-associated change in the DNA sequence
 Variant Change in the DNA sequence 

Familial variant Disease-associated variant identified in a proband for use in subsequent targeted genetic testing in first-degree relatives
Table 2. ACMG-AMP Standards and Guidelines for Variant Classification
Variant Classification  Definition
Pathogenic Disease-causing change in the DNA sequence
Likely pathogenic Likely disease-causing change in the DNA sequence 
Variant of uncertain significance Change in DNA sequence with uncertain effects on disease
Likely benign Likely benign change in the DNA sequence
Benign Benign change in the DNA sequence
American College of Medical Genetics and Genomics; AMP: Association for Molecular Pathology

Genetic Counseling
Experts recommend formal genetic counseling for patients who are at risk for inherited disorders and who wish to undergo genetic testing. Interpreting the results of  genetic tests and understanding risk factors can be difficult for some patients; genetic counseling helps individuals understand the impact of genetic testing,  including the possible effects the test results could have on the individual or their family members. It should be noted that genetic counseling may alter the  utilization of genetic testing substantially and may reduce  inappropriate testing; further, genetic counseling should be performed by an individual with experience and expertise in genetic medicine and genetic testing methods.

Evidence Review 

Description


Cancers of unknown primary represent 3% to 4% of cancers diagnosed in the United States. These cancers are heterogeneous and many accompanied by poor prognoses. A detailed history and physical combined with imaging and tissue pathology can identify some, but not all, primary sources of secondary tumors. It is suggested that identifying the likely primary source with gene expression profiling to direct treatment may improve health outcomes.

Background

Cancers of Unknown Primary


Cancers of unknown primary (CUPs), or occult primary malignancies, are tumors that have metastasized from an unknown primary source; they make up about 3% to 4% of all cancers in the United States. Identifying the primary origin of a tumor can dictate cancer-specific treatment, expected outcome, and prognosis.

Most CUPs are adenocarcinomas or undifferentiated tumors; less commonly, they may be squamous carcinomas, melanoma, soft tissue sarcoma, or neuroendocrine tumors. Osteo- and chondrosarcomas rarely produce CUPs. The most common primary sites of CUPs are the lung and pancreas, followed by colon and stomach, then breast, ovary, prostate, and solid-organ carcinomas of the kidney, thyroid, and liver. Conventional methods used to aid in the identification of the origin of a CUP include a thorough history and physical examination; computed tomography scans of the chest, abdomen, and pelvis; routine laboratory studies; and targeted evaluation of specific signs and symptoms.

Diagnosis and Classification

Biopsy of a CUP with detailed pathology evaluation may include immunohistochemical (IHC) analysis of the tumor. IHC analysis identifies different antigens present in different types of tumors and can usually distinguish an epithelial tumor (ie, carcinoma) from melanoma or sarcoma. Detailed cytokeratin panels often allow further classification of carcinoma; however, tumors of different origins may show overlapping cytokeratin expression. Results of IHC may provide a narrow differential of possible sources of a tumor’s origin, but not necessarily a definitive answer.
Recent advances in the understanding of gene expression in normal and malignant cells have led researchers to explore molecular classification to improve the identification of the site of origin of a CUP. The molecular classification of cancers is based on the premise that, despite different degrees of differentiation, tumors retain sufficient gene expression “signatures” as to their cell of origin, even after metastasis. Theoretically, it is possible to build a gene expression database spanning many different tumor types to compare to the expression profile of very poorly differentiated tumors, or a CUP, to aid in the identification of the tumor type and organ of origin. The feasibility of using molecular classification schemes with gene expression profiling (GEP) to classify these tumors of uncertain origin has been demonstrated in several studies.

Tissue of Origin Testing, Treatment Selection, and Health Outcomes 

Patients with CUP have generally poor prognoses. For example, patients with disease limited to lymph nodes have a median survival of 6 to 9 months, and those with a disease that is extranodal 2 to 4 months.

The premise of tissue of origin testing in CUPs is that identifying a likely primary tumor site will inform treatment selection leading to improved survival and other outcomes or as a predictive test. To evaluate whether treatment selection can be improved, the ability of a test to suggest a likely site of origin (clinical validity) must be first be shown. But demonstrating clinical validity may be problematic because patients with CUPs have no identified primary tumor for a reference standard.
Imperfect reference standards must be relied on such as the available presumptive or a reference pathologic diagnosis, known tumor types, or comparisons IHC. A primary tumor diagnosed during follow-up might also be used as a reference standard, but its use would be subject to potential selection bias. Therefore, even substantial evidence supporting the ability of a test to suggest a likely site of origin will be insufficient to infer benefit. Convincing evidence for benefit requires demonstrating that using a test to select treatment will improve outcomes. 


Tuesday, January 8, 2019

CPT 81225, 81226, 81227, 81599 - Genotype-Guided Tamoxifen Treatment

Policy Coverage Criteria  Test Investigational  Cytochrome P450 2D6 (CYP2D6) testing 

Coding 
 

Genotyping to determine cytochrome P450 2D6 (CYP2D6) variants is considered investigational for the purpose of managing treatment with tamoxifen for women at high risk for or with breast cancer.

Code Description CPT


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) 

81479 Unlisted molecular pathology procedure 

81599
Unlisted multianalyte assay with algorithmic analysis 





Introduction
Certain types of breast cancer are affected by hormones. Cancer cells that are said to be estrogen receptor positive (ER-positive) have receptors that attach to estrogen. Once attached, estrogen then acts like a fertilizer to help the cancer grow. Hormone therapy is used to prevent estrogen from connecting to the receptors. Tamoxifen is a type of hormone therapy that can be used for ER-positive breast cancer to prevent it from coming back and to treat breast cancer that’s already spread to other parts of the body. It’s also used for ER-positive ductal carcinoma in situ (DCIS). To process tamoxifen into its more active form, the body uses a specific, important enzyme (CYP2D6) that’s made by a particular gene. A small percentage of people (about 10%) have a form of the gene that doesn’t make as much of this important enzyme as most other people make. A genetic test has been developed to try to see if a person has the gene form that makes a smaller amount of the needed enzyme. This genetic test is investigational (unproven). Large, well-designed medical studies don’t show a strong link between this gene and tamoxifen’s effectiveness. More studies are needed. 




Related Information 

Genetics Nomenclature Update


The Human Genome Variation Society nomenclature is used to report information on variants found in DNA and serves as an international standard in DNA diagnostics. It is being implemented for genetic testing medical evidence review updates starting in 2017 (see Table 1).


The Society’s nomenclature is recommended by the Human Variome Project, the HUman Genome Organization, and by the Human Genome Variation Society itself.

The American College of Medical Genetics and Genomics and the Association for Molecular Pathology standards and guidelines for interpretation of sequence variants represent expert opinion from both organizations, in addition to the College of American Pathologists. These recommendations primarily apply to genetic tests used in clinical laboratories, including genotyping, single genes, panels, exomes, and genomes. Table 2 shows the recommended standard terminology*“pathogenic,” “likely pathogenic,” “uncertain significance,” “likely benign,” and “benign”*to describe variants identified that cause Mendelian disorders.

Table 1. Nomenclature to Report on Variants Found in DNA 

Previous  Updated  Definition
Mutation Disease-associated variant
Disease-associated change in the DNA sequence
Variant Change in the DNA sequence 
Familial variant Disease-associated variant identified in a proband for use in subsequent targeted genetic testing in first-degree relatives

Table 2. ACMG-AMP Standards and Guidelines for Variant Classification
Variant Classification Definition
Pathogenic Disease-causing change in the DNA sequence
Likely pathogenic Likely disease-causing change in the DNA sequence 
Variant of uncertain significance Change in DNA sequence with uncertain effects on disease
Likely benign Likely benign change in the DNA sequence
Benign Benign change in the DNA sequence
ACMG: American College of Medical Genetics and Genomics; AMP: Association for Molecular Pathology. 


Description

Tamoxifen is prescribed as a component of adjuvant endocrine therapy to prevent endocrine receptor-positive breast cancer recurrence, to treat metastatic breast cancer, and to prevent disease in high-risk populations and in women with ductal carcinoma in situ. Tamoxifen is a prodrug that undergoes extensive metabolism to yield its active form: 4-hydroxy tamoxifen and endoxifen (primary active form) via the CYP2D6 enzyme. Variants in the CYP2D6 gene are associated with significant alterations in endoxifen concentrations leading to the hypothesis that CYP2D6 variation may affect the clinical outcomes of women treated with tamoxifen but not with drugs not metabolized by CYP2D6, such as anastrozole.

Background  Tamoxifen Metabolism 

Tamoxifen is a pro-drug that undergoes extensive metabolism to yield its active form: 4hydroxytamoxifen (4-OH tamoxifen) and 4-hydroxy-N-desmethyltamoxifen (endoxifen).

Among these 2 metabolites, endoxifen is thought to be the major metabolite that exerts the pharmacodynamic effect of tamoxifen. The metabolism of tamoxifen into 4-OH tamoxifen is catalyzed by multiple enzymes, while endoxifen is formed predominantly by the CYP2D6 enzyme. Plasma concentrations of endoxifen exhibit high interindividual variability, as described in breast cancer patients.

Because CYP2D6 enzyme activity is known to vary across individuals, variants in the CYP2D6 gene are of great interest for understanding tamoxifen metabolism variability and variation in levels of circulating active metabolites. Moreover, known variability in endoxifen levels has been hypothesized to result in variable response to tamoxifen treatment.

Metabolic Enzyme Genotypes 

The CYP2D6 gene exhibits a high degree of polymorphism, with more than 100 allelic variants identified. The relations among genotype, phenotype, and clinical implications are summarized in Table 3.

The prevalence of CYP2D6 poor metabolizers is approximately 7% to 10% in whites of Northern European descent, 1.9% to 7.3% in blacks, and 1% or less in most Asian populations studied. The poor metabolizer phenotype in whites is largely accounted for by CYP2D6*3 and *4 nonfunctional variants, and in black and Asian populations, by the *5 nonfunctional variant. Some poor metabolizers may have 1 nonfunctional allele and 1 reduced-function allele. Among reduced function variants, CYP2D6*17, *10, and *8 are the most important in blacks, Asians, and whites, respectively. Few studies have investigated the frequency of CYP2D6-variant alleles or of poor metabolizers in the Hispanic population.

Endocrine Therapy Regimens 

Tamoxifen has several labelled indications


* Chemoprevention of invasive breast cancer in high-risk women without current disease or with ductal carcinoma in situ
* Adjuvant treatment of primary breast cancer
* Treatment of metastatic disease


In women with breast cancer, endocrine receptor-positive disease predicts a likely benefit from tamoxifen treatment. Tamoxifen is currently the most commonly prescribed adjuvant treatment to prevent recurrence of endocrine receptor-positive breast cancer in premenopausal or perimenopausal women. 

For post-menopausal women with osteoporosis or at high risk for invasive breast cancer, raloxifene is an alternative treatment for invasive cancer risk reduction. Currently, raloxifene is indicated for treatment of reduction in the “risk of invasive breast cancer in postmenopausal women with osteoporosis” or those at “high risk for invasive breast cancer.”

Pharmacologic Inhibitors of Metabolic Enzymes 

CYP2D6 activity may be affected not only by genotype but also by co-administered drugs that block or induce CYP2D6 function. Studies of selective serotonin reuptake inhibitors, in particular, have shown that fluoxetine and paroxetine, but not sertraline, fluvoxamine, or venlafaxine, are potent CYP2D6 inhibitors.

Some individuals treated with fluoxetine or paroxetine have changed from extensive metabolizer phenotype to poor metabolizer.

The degree of inhibition may depend on selective serotonin reuptake inhibitors dose.
Thus, CYP2D6 inhibitor use must be considered in assigning CYP2D6 functional status, and potent CYP2D6 inhibitors may need to be avoided when tamoxifen is administered.

Summary of Evidence

For individuals who are treated with tamoxifen for breast cancer or are high risk for breast cancer who receive CYP2D6 genotype-guided tamoxifen treatment, the evidence includes multiple retrospective cohort studies and nonconcurrent prospective studies. Relevant outcomes include overall survival, disease-specific survival, medication use, and treatment-related morbidity. Data in most of these studies derived from a convenient sample, which was further limited by relatively small numbers of patients and lack of comprehensive genotype data, patient data (eg, concomitant medications), and detailed clinical outcomes data. Three influential nonconcurrent prospective studies nested within large prospective, randomized double-blind clinical trials in postmenopausal women with hormone receptor–positive earlystage breast cancer also reported contradictory results. Two larger studies failed to show statistically significant associations between phenotype (patients classified as poor, intermediate, or extensive metabolizer) and recurrence of breast cancer. No trials of genotype-directed dosing or drug choice that compared health outcomes for patients managed with and without the test were identified. It is not known whether CYP2D6 genotype-guided tamoxifen treatment results in the selection of a treatment strategy that would reduce the rate of  breast cancer recurrence, improve disease-free survival or overall survival, or reduce adverse events. The evidence is insufficient to determine the effects of the  technology on health outcomes.

Thursday, December 27, 2018

CPT G9143, 0030U - Genotype-Guided Warfarin Dosing


Code Description CPT

0030U Drug metabolism (warfarin drug response), targeted sequence analysis (ie, CYP2C9, CYP4F2, VKORC1, rs12777823) (new code effective 1/1/18)

HCPCS
G9143 Warfarin responsiveness testing by genetic technique using any method, any number of specimen(s)




Introduction

Warfarin (Coumadin) is a blood thinner that works by reducing the blood’s ability to clot. It’s often prescribed to prevent blood clot formation in people who have conditions like atrial fibrillation. Finding the correct dose can be complicated. Too high a dose can cause bleeding. Too low a dose can result in blood clots being formed. Factors such as age, weight, use of other medications, and smoking go into the calculation of how much is prescribed. Once the drug is prescribed, the doctor then adjusts the dose based on blood tests. Two genes have been associated with how well the body processes warfarin. Genetic tests have been developed to look at these genes to try to determine warfarin dosing. These genetic tests are investigational (unproven). Medical studies do not show whether genetic testing to try to adjust warfarin doses leads to better health results. More studies are needed.



Test Investigational 

Testing of cytochrome p450 2C9 (CYP2C9), P450 4F2 (CYP4F2), and vitamin K epoxide reductase subunit C1 (VKORC1)

Coding Genotyping for CYP2C9, CYP4F2, and VKORC1 variants is considered investigational to manage the administration and dosing of warfarin, including: * Guiding the initial  warfarin dose  * Decreasing the time needed to achieve a stable international  normalized ratio (INR) * Reducing the risk of serious bleeding




Related Information 

Genetics Nomenclature Update


The Human Genome Variation Society nomenclature is used to report information on variants found in DNA and serves as an international standard in DNA diagnostics (see  Table 1). The Society’s nomenclature is recommended by the Human Variome Project, the HUman Genome Organization, and by the Human Genome Variation Society itself.  The American College of Medical Genetics and Genomics and the Association for Molecular Pathology standards and guidelines for interpretation of sequence variants  represent expert opinion from both organizations, in addition to the College of American Pathologists. These  recommendations primarily apply to genetic tests used in clinical laboratories, including genotyping, single genes, panels, exomes, and genomes. Table 2 shows the  recommended standard terminology*“pathogenic,” “likely pathogenic,” “uncertain significance,” “likely benign,” and “benign”*to describe variants identified that cause  Mendelian disorders.

Table 1. Nomenclature to Report on Variants Found in DNA
Previous  Updated  Definition

Mutation Disease-associated variant
 

Disease-associated change in the DNA sequence
Variant Change in the DNA sequence 
Familial variant Disease-associated variant identified in a proband for use in subsequent targeted genetic testing in first-degree relatives
Table 2. ACMG-AMP Standards and Guidelines for Variant Classification
Variant Classification Definition
Pathogenic Disease-causing change in the DNA sequence
Likely pathogenic Likely disease-causing change in the DNA sequence 
Variant of uncertain significance Change in DNA sequence with uncertain effects on disease
Likely benign Likely benign change in the DNA sequence
Benign Benign change in the DNA sequence
ACMG: American College of Medical Genetics and Genomics; AMP: Association for Molecular Pathology.

Genetic Counseling

Experts recommend formal genetic counseling for patients who are at risk for inherited disorders and who wish to undergo genetic testing. Interpreting the results of genetic tests and understanding risk factors can be difficult for some patients; genetic counseling helps individuals understand the impact of genetic testing, including the possible effects the test results could have on the individual or their family members. It should be noted that genetic counseling may alter the utilization of genetic testing substantially and may reduce inappropriate testing; further, genetic counseling should be performed by an individual with experience and expertise in genetic medicine and genetic testing methods.



Evidence Review 

Description

Using information about an individual’s genotypes may help in guiding warfarin dosing and could reduce the time to dose stabilization and selection of an appropriate maintenance dose that might avoid the consequences of too much or too little anticoagulation.

Background

Warfarin is administered to prevent and treat thromboembolic events in high-risk patients;   warfarin dosing is a challenging process due to the narrow therapeutic window, variable response to dosing, and serious bleeding events in 5% or more of patients (depending on definition). Patients are typically given a starting dose of 2 to 5 mg and are frequently monitored with dose adjustments until a stable international normalized ratio value (a standardized indicator of clotting time) between 2 and 3 is achieved. During this adjustment period, a patient is at high risk of bleeding.
Stable or maintenance warfarin dose varies among patients by more than an order of magnitude. Factors influencing stable dose include body mass index, age, interacting drugs, and  indication for therapy. 

Warfarin, which is primarily metabolized in the liver by the CYP2C9 enzyme, exerts an anticoagulant effect by inhibiting the protein vitamin K epoxide reductase complex, subunit 1 (VKORC1). Three single nucleotide variants, two in the CYP2C9 gene and one in the VKORC1 gene play key roles in determining the effect of warfarin therapy on coagulation.

 CYP2C9*1 metabolizes warfarin normally, CYP2C9*2 reduces warfarin metabolism by 30%, and CYP2C9*3 reduces warfarin metabolism by 90%. Because warfarin given to patients with *2 or *3 variants will be metabolized less efficiently, the drug will remain in circulation longer, so lower warfarin doses will be needed to achieve anticoagulation. CYP2C9 and VKORC1 genetic variants account for approximately 55% of the variability in warfarin maintenance dose.
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 Recent genome-wide association studies have also identified that a single nucleotide variant in the CYP4F2 gene has been reported to account for a small proportion of the variability in stable dose (the CYP4F2 gene encodes a protein involved in vitamin K oxidation).

Medicare National Coverage

In 2009, the Centers for Medicare and Medicaid Services published a national coverage determination on pharmacogenomic testing for warfarin response.

The Centers for Medicare & Medicaid Services stated 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….” 
However, the Centers also “believes that the available evidence supports that coverage with evidence development (CED) …. 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:
* Have not been previously tested for CYP2C9 or VKORC1 alleles; and

* Have received fewer than five days of warfarin in the anticoagulation regimen for which the testing is ordered; and
* Are enrolled in a prospective, randomized, controlled clinical study when that study meets described standards.”


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