Notification



Notification Issue Date:



Policy Attachment

Attachment to Policy # MA06.008b


Attachment:D

Policy #:MA06.008b

Description:Pharmacogenetic Testing to Determine Cytochrome p450 (CYP2D6) Genetic Polymorphisms for Management of Tamoxifen Treatment for Women with, or at High Risk for Breast Cancer

Title:Pharmacogenetic Testing to Determine Drug Sensitivity

The Coding Table lists any CPT, ICD-9, ICD-10, and HCPCS billing codes related only to the specific policy in which they appear.


Title: Pharmacogenetic Testing to Determine Cytochrome p450 (CYP2D6) Genetic Polymorphisms for Management of Tamoxifen Treatment for Women with, or at High Risk for Breast Cancer


POLICY

Coverage is subject to the terms, conditions, and limitations of the member's Evidence of Coverage.

Pharmacogenetic testing to determine cytochrome p450 (CYP2D6) genetic polymorphisms for management of tamoxifen treatment for women with, or at high risk for, breast cancer is considered experimental/investigational, and, therefore, not covered for the purpose of managing treatment with tamoxifen for women at high risk for or with breast cancer.


POLICY GUIDELINES

There is no Medicare coverage determination addressing this service; therefore, the Company policy is applicable.

BENEFIT APPLICATION

Subject to the terms and conditions of the applicable Evidence of Coverage, pharmacogenetic testing to determine cytochrome p450 (CYP2D6) genetic polymorphisms for management of tamoxifen treatment for women with, or at high risk for, breast cancer is not eligible for payment under the medical benefits of the Company's Medicare Advantage products because the service is considered experimental/investigational and, therefore, not covered.

Services that are experimental/investigational are excluded from the Company's Medicare Advantage products. Therefore, they are not eligible for reimbursement consideration.

US FOOD AND DRUG ADMINISTRATION STATUS

Genetic testing is a laboratory procedure and is historically not regulated by the US Food and Drug Administration (FDA). Clinical Laboratory Improvement Amendments (CLIA) establishes quality standards for all laboratory testing. However, recently, the FDA is reported to be involved in the evaluation of the service of genetic testing.

DESCRIPTION

Tamoxifen is prescribed for use as an adjuvant treatment of estrogen receptor--positive (ER+) primary breast cancer for prevention of recurrence, prevention of breast cancer for women without disease but at high risk for disease occurrence, for women with ductal carcinoma in situ (DCIS), and for treatment of metastatic breast cancer.

The CYP2D6 gene is believed to be polymorphic with variant DNA gene sequences. This polymorphism may result in variant alleles that result in enzymes with no activity or reduced activity in the metabolism of tamoxifen. Consequently, this could result in a lessened impact of the efficacy of tamoxifen in treatment.

Various ethnic groups have been identified as having a CYP2D6 variant, including northern European Caucasians, African-Americans, and Asians. Within these groups, several different variants have been discovered. Some conclusions in published literature hypothesize that these groups may be at risk to be potential poor metabolizers (PM) of tamoxifen.

At the present time, there is only indirect evidence available to evaluate the clinical utility of CYP2D6 genotyping for tamoxifen treatment in women with breast cancer or those at high risk for this disease. This state of evidence is insufficient to establish the role of this testing on direct patient management. Properly designed clinical trials are needed for direct evidence that speaks to clinical utility of this genetic testing.

A review of the National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology for treatment of breast cancer (V.2.2011) indicates that, relative to genetic testing prior to the start of tamoxifen treatment, "at this time, based on current data, the panel does not endorse routine CYP2D6 testing for women being considered for tamoxifen therapy." In addition, the American Society of Clinical Oncology (ASCO) issued 2009 updated clinical practice guidelines on the topic of adjuvant endocrine therapy for women with hormone receptor--positive breast cancer. Relative to CYP2D5 testing, ASCO indicates "The Update Committee recommends against using CYP2D6 genotype to select adjuvant endocrine therapy."

The FDA has considered updating the label for tamoxifen (brand and generics) with information on recommendations regarding CYP2D6 genotyping and impact on tamoxifen efficacy, but, to date, there has been no updated labeling requested by the Food and Drug Administration (FDA) regarding genetic testing prior to the start of tamoxifen.


REFERENCES

Alfaro CL, Lam YW, Simpson J, et al. CYP2D6 status of extensive metabolizers after multiple-dose fluoxetine, fluvoxamine, paroxetine, or sertraline. J Clin Psychopharmacol. 1999;19(2):155-63.

Alfaro CL, Lam YW, Simpson J, et al. CYP2D6 inhibition by fluoxetine, paroxetine, sertraline, and venlafaxine in a crossover study: intraindividual variability and plasma concentration correlations. J Clin Pharmacol. 2000;40(1):58-66.

American Cancer Society. Breast Cancer Facts & Figures 2007-2008. Atlanta: American Cancer Society, Inc. Available at: http://www.cancer.org/docroot/stt/stt_0.asp. Accessed July 31, 2013.

Bernard S, Neville KA, Nguyen AT, et al. Interethnic differences in genetic polymorphisms of CYP2D6 in the U.S. population: clinical implications. Oncologist. 2006;11(2):126-35.

Beverage JN, Sissung TM, Sion AM, et al. CYP2D6 polymorphisms and the impact on tamoxifen therapy. J Pharm Sci. 2007;96(9):2224-31.

Burstein HL, Prestrud AA, Seidenfeld J, Anderson H, Buchholz TA, Davidson NE, et al. American Society of Clinical Oncology Clinical Practice Guideline: Update on Adjuvant Endocrine Therapy for Women with Homone Receptor-Positive Breast Cancer. J. Clin Oncol. 2010;28 (23):3784-3796. Available at:http://www.asco.org/ASCOv2/Practice+%26+Guidelines/Guidelines/Clinical+Practice+Guidelines/American+Society+of+Clinical+Oncology+Clinical+Practice+Guideline%3A+Update+on+Adjuvant+Endocrine+Therapy+for+Women+with+Hormone+Receptor-Positive+Breast+Cancer. Accessed July 31, 2013.

Desta Z, Flockhart DA. Germline pharmacogenetics of tamoxifen response: have we learned enough? J Clin Oncol. 2007;25(33):5147-9.

Goetz MP, Kamal A, Ames MM. Tamoxifen pharmacogenomics: the role of CYP2D6 as a predictor of drug response. Clin Pharmacol Ther. 2008;83(1):160-6.

Goetz MP, Knox SK, Suman VJ, et al. The impact of cytochrome P450 2D6 metabolism in women receiving adjuvant tamoxifen. Breast Cancer Res Treat. 2007;101(1):113-21.

Griese EU, Zanger UM, Brudermanns U, et al. Assessment of the predictive power of genotypes for the in-vivo catalytic function of CYP2D6 in a German population. Pharmacogenetics. 1998;8(1):15-26.

Johnson MD, Zuo H, Lee KH, et al. Pharmacological characterization of 4-hydroxy-N-desmethyl tamoxifen, a novel active metabolite of tamoxifen. Breast Cancer Res Treat. 2004;85(2):151-9.

Kiyotani K, Mushiroda T, Sasa M, et al. Impact of CYP2D6*10 on recurrence-free survival in breast cancer patients receiving adjuvant tamoxifen therapy. Cancer Sci. 2008;99(5):995-9.

Lam YW, Gaedigk A, Ereshefsky L, et al. CYP2D6 inhibition by selective serotonin reuptake inhibitors: analysis of achievable steady-state plasma concentrations and the effect of ultrarapid metabolism at CYP2D6. Pharmacotherapy. 2002;22(8):1001-6.

Lim HS, Ju Lee H, Seok Lee K, et al. Clinical implications of CYP2D6 genotypes predictive of tamoxifen pharmacokinetics in metastatic breast cancer. J Clin Oncol. 2007;25(25):3837-45.

Lim YC, Desta Z, Flockhart DA, et al. Endoxifen (4-hydroxy-N-desmethyl-tamoxifen) has anti-estrogenic effects in breast cancer cells with potency similar to 4-hydroxy-tamoxifen. Cancer Chemother Pharmacol. 2005;55(5):471-8.

Lim YC, Li L, Desta Z, et al. Endoxifen, a secondary metabolite of tamoxifen, and 4-OH-tamoxifen induce similar changes in global gene expression patterns in MCF-7 breast cancer cells. J Pharmacol Exp Ther. 2006;318(2):503-12.

Lin NU, Winer EP. Optimal use of aromatase inhibitors: to lead or to follow? J Clin Oncol. 2007;25(19):2639-41.
National Comprehensive Cancer Network (NCCN). Clinical Practice Guidelines in Oncology™: Breast Cancer V.2.2011. Available at: http://www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Accessed July 31, 2013.

Newman WG, Hadfield KD, Latif A, et al. Impaired tamoxifen metabolism reduces survival in familial breast cancer patients. Clin Cancer Res. 2008;14(18):5913-8.

Nowell SA, Ahn J, Rae JM, et al. Association of genetic variation in tamoxifen-metabolizing enzymes with overall survival and recurrence of disease in breast cancer patients. Breast Cancer Res Treat. 2005;91(3):249-58.

Okishiro M, Taguchi T, Jin Kim S, et al. Genetic polymorphisms of CYP2D6 10 and CYP2C19 2, 3 are not associated with prognosis, endometrial thickness, or bone mineral density in Japanese breast cancer patients treated with adjuvant tamoxifen. Cancer. 2009;115(5):952-61.

Schroth W, Antoniadou L, Fritz P, et al. Breast cancer treatment outcome with adjuvant tamoxifen relative to patient CYP2D6 and CYP2C19 genotypes. J Clin Oncol. 2007;25(33):5187-93.

Stearns V, Johnson MD, Rae JM, et al. Active tamoxifen metabolite plasma concentrations after coadministration of tamoxifen and the selective serotonin reuptake inhibitor paroxetine. J Natl Cancer Inst. 2003;95(23):1758-64.

Wegman P, Vainikka L, Stal O, et al. Genotype of metabolic enzymes and the benefit of tamoxifen in postmenopausal breast cancer patients. Breast Cancer Res. 2005;7(3):R284-90.

Wegman P, Elingarami S, Carstensen J, et al. Genetic variants of CYP3A5, CYP2D6, SULT1A1, UGT2B15 and tamoxifen response in postmenopausal patients with breast cancer. Breast Cancer Res. 2007;9(1):R7.

Xu Y, Sun Y, Yao L, et al. Association between CYP2D6 *10 genotype and survival of breast cancer patients receiving tamoxifen treatment. Ann Oncol. 2008;19(8):1423-9.


Coding Table

Inclusion of a code in this table does not imply reimbursement. Eligibility, benefits, limitations, exclusions, precertification/referral requirements, provider contracts, and Company policies apply.

The codes listed below are updated on a regular basis, in accordance with nationally accepted coding guidelines. Therefore, this policy applies to any and all future applicable coding changes, revisions, or updates.

In order to ensure optimal reimbursement, all health care services, devices, and pharmaceuticals should be reported using the billing codes and modifiers that most accurately represent the services rendered, unless otherwise directed by the Company.


Code System
Code Number and Code Narrative
CPT 81226
ICD-10 Diagnosis N/A
ICD-10 Procedure N/A
HCPCSG0452 Molecular pathology procedure; physician interpretation and report


Version Effective Date: 07/01/2016
Version Issued Date: 07/01/2016
Version Reissued Date: 10/10/2019

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