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Medical Policy: 02.04.19
Original Effective Date: October 2008
Reviewed: August 2011
Revised:
Benefit Application
Benefit determinations are based on the applicable contract language in effect at the time the
services were rendered. Exclusions, limitations or exceptions may apply. Benefits may vary
based on contract, and individual member benefits must be verified. Wellmark determines medical
necessity only if the benefit exists and no contract exclusions are applicable. This medical
policy may not apply to FEP. Benefits are determined by the Federal Employee Program.
This Medical Policy document describes the status of medical technology at the time the document
was developed. Since that time, new technology may have emerged or new medical literature may
have been published. This Medical Policy will be reviewed regularly and be updated as scientific
and medical literature becomes available.
Description:
Tamoxifen is prescribed as a component of adjuvant endocrine therapy to prevent endocrine receptor-positive breast cancer recurrence, as treatment of metastatic breast cancer, and to prevent disease in high-risk populations and in women with ductal carcinoma in situ (DCIS). The cytochrome P450 (CYP) metabolic enzyme CYP2D6 has a major role in tamoxifen metabolism. The CYP2D6 gene is polymorphic; variant DNA gene sequences resulting in proteins with reduced or absent enzyme function may be associated with lower plasma levels of active tamoxifen metabolites, which could have an impact on tamoxifen treatment efficacy.
Tamoxifen metabolites, rather than tamoxifen itself, are likely the primary effectors of tamoxifen benefit. Tamoxifen undergoes extensive primary and secondary metabolism, and the plasma concentrations of tamoxifen and its metabolites vary widely.
Tamoxifen has several prescribing 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, and treatment of metastatic disease. In women with breast cancer, endocrine-receptor-positive disease predicts likely benefit from tamoxifen treatment.
Tamoxifen is the only adjuvant treatment approved for preventing breast cancer in women with ductal carcinoma in situ and for preventing disease in pre- or perimenopausal women at high risk. Thus, pharmacogenomics evaluation would not change treatment in these women.
Tamoxifen is currently the most commonly prescribed adjuvant treatment to prevent recurrence of endocrine-receptor-positive breast cancer in pre- or perimenopausal women. For prevention of cancer in postmenopausal women, who make up the majority of patients with breast cancer, raloxifene is an alternative treatment option, with equal efficacy and markedly reduced risk of endometrial hyperplasia. Raloxifene is currently not indicated for the treatment of invasive breast cancer, reduction of the risk of breast cancer, or reduction of risk of noninvasive breast cancer.
The pharmacogenomics of tamoxifen have been most often studied in post-menopausal women with endocrine receptor-positive tumors who require endocrine therapy to prevent recurrence. For this population, the NCCN breast cancer guidelines make no preferential treatment recommendations among the following choices:
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Aromatase inhibitors for 5 years
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Tamoxifen for 2-3 years, followed by aromatase inhibitor to complete 5 years or longer
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Tamoxifen to 4.5-6 years, followed by aromatase inhibitor for 5 years
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Tamoxifen for 5 years in women with contraindications to aromatase inhibitor treatment, who decline or are intolerant to aromatase inhibitor treatment
CYP2D6 activity may be affected not only by genotype, but also by co-administration of drugs that block the metabolic activity of CYP2D6. Studies of selective serotonin reuptake inhibitors in particular have shown that fluoxetine and paroxetine, but not sertraline, fluvoxamine, or venlafaxine, are potent CYP2D6 inhibitors.
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Prior Approval:
Not applicable
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Policy:
Genotyping to determine cytochrome P450 (CYP2D6) is considered investigational for the purpose of managing treatment with tamoxifen for women at high risk for or with breast cancer.
The available evidence does not clearly support a significant association between CYP2D6 genotype and tamoxifen treatment outcome; an indirect evidence chain supporting the clinical utility of CYP2D6 genotyping for directing endocrine therapy regimen selection for women at high risk for or with breast cancer cannot be constructed. Thus, because the impact of testing on net health outcome is not known, this is considered investigational.
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Procedure Codes and Billing Guidelines:
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To report provider services, use appropriate CPT* codes, Modifiers, Alpha Numeric (HCPCS level 2) codes, Revenue codes, and/or ICD-9-CM diagnostic codes.
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88384 Array-based evaluation of multiple molecular probes; 11 through 50 probes
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88385 Array-based evaluation of multiple molecular probes; 51 through 250 probes
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88386 Array-based evaluation of multiple molecular probes; 251 through 500 probes
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Selected References:
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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.
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Beverage JN, Sissung TM, Sion AM et al. CYP2D6 polymorphisms and the impact on tamoxifen therapy. J Pharm Sci 2007; 96(9):2224-31.
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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(2):249-58.
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Desta Z, Flockhart DA. Germline pharmacogenetics of tamoxifen response: have we learned enough? J Clin Oncol 2007; 25(33)5147-9.
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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.
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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.
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Schroth W, Goetz MP, Hamann U et al. Association between CYP2D6 polymorphisms and outcomes among women with early stage breast cancer treated with Tamoxifen. JAMA. 2009; 302(13):1429-36.
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Higgins MJ, Rae JM, Flockhart DA et al. Pharmacogenetics of Tamoxifen: Who should undergo CYP2D6 Genetic Testing? JNCCN 2009; 7:203-13.
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Blue Cross Blue Shield Association Technology Evaluation Center (TEC). CYP2D6 Pharmacogenomics of Tamoxifen Treatment. TEC Assessments 2011, Volume 26, Tab TBA.
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Kiyotani K, Mushiroda T, Imamura CK et al. Significant effect of polymorphisms in CYP2D6 and ABCC2 on clinical outcomes of adjuvant tamoxifen therapy for breast cancer patients. J Clin Oncol. 2010 Mar 10;28(8):1287-93. Epub 2010 Feb 1.
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Lammers LA, Mathijssen RH, van Gelder T et al. The impact of CYP2D6-predicted phenotype on tamoxifen treatment outcome in patients with metastatic breast cancer. Br J Cancer. 2010 Sep 7;103(6):765-71. Epub 2010 Aug 10.
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Lash TL, Cronin-Fenton D, Ahern TP et al. CYP2D6 inhibition and breast cancer recurrence in a population-based study in Denmark. J Natl Cancer Inst. 2011 Mar 16;103(6):489-500. Epub 2011 Feb 15.
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Cronin-Fenton DP, Lash TL. Clinical epidemiology and pharmacology of CYP2D6 inhibition related to breast cancer outcomes. Expert Rev Clin Pharmacol. 2011 May;4(3):363-77.
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Ramon y Cajal T, Altes A, Pare L et al. Impact of CYP2D6 polymorphisms in tamoxifen adjuvant breast cancer treatment. Breast Cancer Res Treat. 2010 Jan;119(1):33-8. Epub 2009 Feb 3.
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Burstein HJ, Prestrud AA, Seidenfeld J et al. American Society of Clinical Oncology clinical practice guideline: update on adjuvant endocrine therapy for women with hormone receptor-positive breast cancer. J Clin Oncol. 2010 Aug 10;28(23):3784-96. Epub 2010 Jul 12.
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Policy History:
Date Reason Action
August 2011 Annual review Policy renewed
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Wellmark medical policies address the complex issue
of technology assessment of new and emerging treatments, devices,
drugs, etc. They are developed to
assist in administering plan benefits and constitute neither offers of
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advice and treatment of members. Our medical policies may be updated
and therefore are subject to change without notice.
*Current Procedural Terminology © 2010 American Medical Association. All Rights Reserved.
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