MP 2.04.51

Genetic Testing for Tamoxifen Treatment

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Section Medicine	Original Policy Date 3/2008	Last Review Status/Date Created with Literature Search/7:2009
Issue 7:2009		Return to Medical Policy Index

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Disclaimer

Our medical policies are designed for informational purposes only and are not an authorization, or an explanation of benefits, or a contract.  Receipt of benefits is subject to satisfaction of all terms and conditions of the coverage.  Medical technology is constantly changing, and we reserve the right to review and update our policies periodically.

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Description

• aromatase inhibitors (AI) for 5 years
• TAM for 2-3 years, followed by AI to complete 5 years or longer
• TAM to 4.5-6 years, followed by AI for 5 years
• TAM for 5 years in women with contraindications to AI treatment, who decline AI treatment, or who are intolerant to AI treatment.

In clinical practice, AIs may eventually replace TAM because of fewer adverse effects and equal or better efficacy. However, it is not yet clear that AI treatment alone maintains or improves long-term outcomes compared to sequential use of TAM and AI. (11) Nor is there evidence as yet to support AI use in pre-menopausal women. Finally, TAM is important in the treatment of metastatic cancer, where either TAM or AI resistance may develop. Therefore the use of pharmacogenomics to improve the likelihood of tamoxifen benefit is of current interest.

Pharmacologic Inhibitors of Metabolic Enzymes
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 (SSRIs) in particular have shown that fluoxetine and paroxetine, but not sertraline, fluvoxamine or venlafaxine, are potent CYP2D6 inhibitors. (12 - 14) Some individuals treated with fluoxetine or paroxetine changed from EM phenotype to PM. (12) The degree of inhibition may depend upon the SSRI dose.

Thus, CYP2D6 inhibitor use must be considered in assigning CYP2D6 functional status, and potent CYP2D6 inhibitors may need to be avoided when TAM is administered.

Regulatory Status
The Roche AmpliChip CYP450 Test is cleared by the U.S. Food and Drug Administration (FDA) and can be used to identify a patient's CYP2D6 genotype.

CYP2D6 genotyping assays are also available as non-FDA-cleared laboratory-developed services; laboratories offering such tests as a clinical service must meet the general regulatory standards of the Clinical Laboratory Improvement Act (CLIA) and must be licensed by CLIA for high-complexity testing.

Policy

Genotyping to determine cytochrome p450 (CYP2D6) genetic polymorphisms is considered investigational for the purpose of managing treatment with tamoxifen for women at high risk for or with breast cancer.

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Policy Guidelines

Coding

There are specific CPT codes for array-based evaluation of multiple molecular markers:

88384: Array-based evaluation of multiple molecular probes: 11 through 50 probes

88385: 51 through 250 probes

88386: 251 through 500 probes

When less than 11 probes are prepared and evaluated, the services are coded using CPT codes 83890-83914 as appropriate.

There is also a CPT genetic testing modifier that is specific to CYP2 genes:

-9B: CYP2 genes, commonly called cytochrome p 450 (drug metabolism)

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Benefit Application

BlueCard/National Account Issues

State or federal mandates (e.g., FEP) may dictate that all FDA-approved devices may not be considered investigational and thus these devices may be assessed only on the basis of their medical necessity.

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Rationale

This policy is based on a February 2008 TEC Assessment. (15) Additional details concerning the studies described in this section are available in the Assessment.

Potential indications for CYP2D6 pharmacogenomic testing include patients who are to be treated with tamoxifen (alone or prior to treatment with an aromatase inhibitor) for prevention of breast cancer in high risk women or women with DCIS, for adjuvant treatment to prevent breast cancer recurrence, or for treatment of metastatic disease, and who have no contraindications to treatment with aromatase inhibitors (for treatment of existing disease) or raloxifene (for prevention of disease). Post-menopausal patients determined to be CYP2D6 poor metabolizers could avoid tamoxifen therapy and be treated with aromatase inhibitors alone. Pre-menopausal patients might consider ovarian ablation. For any indication, co-administration of drugs that inhibit CYP2D6 activity should be taken into account.

Analytic Validity (technical performance of the assay)
The Roche AmpliChip CYP450 Test (for detecting variants in CYP2D6 and CYP2C19 enzymes) has been fully validated for analytic validity; a summary of the results submitted for FDA clearance is provided in the product insert (available at http://www.amplichip.us/documents/CYP450_P.I._US-IVD_Sept_15_2006.pdf).

While comparable information on the analytic validity of laboratory-developed tests is usually not available, in an experienced laboratory and with validation of in-house results compared to either sequencing or to AmpliChip, accurate and reliable performance should be achievable.

Clinical Validity (association of genetic marker with intermediate or clinical outcomes)

Three studies evaluated CYP2D6 genotype as a prognostic marker in patients not treated with TAM, to ensure that a prognostic association would not confound the effect of genotype on TAM outcomes. (16 -18). None of the studies found evidence that CYP2D6 genotype is prognostic, but limitations to the analyses of each warrant further study.

Indirect Association of Genotype with Clinical Outcomes. Three prospective cohort studies of adjuvant TAM treatment provide consistent evidence that CYP2D6 non-functional variant alleles, which render patients intermediate (one variant allele) or poor (two variant alleles) metabolizers, are associated with significantly reduced plasma endoxifen levels. However, endoxifen levels overlap across all genotypes, suggesting that CYP2D6 genetic variability does not explain all variability in endoxifen levels. One study suggests that reduced function variant homozygotes, but not heterozygotes, also have significantly reduced circulating endoxifen. Co-administration of a potent CYP2D6 inhibitor to CYP2D6 homozygous wild-type patients (extensive metabolizers) is associated with endoxifen levels near those of PMs.

Whether reduced levels of endoxifen, either because of genotype or use of CYP2D6 inhibitor medication, result in poorer outcomes of TAM treatment is not known from the published literature. The relationship between endoxifen (or 4-OH TAM) plasma concentrations and clinical outcomes has not been established. (19) Therefore, this indirect evidence pathway fails.

Association of Genotype with Clinical Outcomes. Seven studies evaluated the association between CYP2D6 genotype and clinical outcomes in women treated with TAM. Six were studies of adjuvant TAM treatment; one (20) studied 21 patients with metastatic disease.

One way to evaluate the effect of genotype on TAM response is to compare TAM-treated women vs. those not receiving TAM, with stratification by CYP2D6 genotype. Wegman et al. conducted such a study retrospectively, on archived samples from a TAM randomized controlled trial. (18) Paradoxically, they found that EMs treated with TAM received no statistically significant clinical benefit compared to EMs not treated with TAM, and that carriers of a CYP2D6*4 variant allelle obtained significant benefit from TAM treatment. There were several limitations to this study: tissue samples were available for only 33% of originally enrolled patients; only 47 patients carried a *4 allele (only 4 were homozygous PMs); TAM dose was 40 mg/day instead of the standard 20 mg/day and was administered for only 2 years instead of the standard 5 years. Because of these limitations, the study results are questionable.

The other 10 studies evaluated only TAM-treated women and outcomes by CYP2D6 genotype. The best evidence for whether CYP2D6 genotype predicts outcomes of TAM treatment comes from Goetz et al (21) and Schroth et al (17). Both studies retrospectively enrolled relatively homogeneous populations of patients who were estrogen-receptor-positive, node-positive in 63%–64%, and grade 1–2 in 78%–91% of women, and for the primary analyses had been treated with TAM alone (no chemotherapy) following resection of the tumor. Target treatment duration was 5 years in Goetz et al, but was not reported in Schroth et al. The studies differed in that Goetz et al only genotyped for the CYP2D6*4 non-functional variant (most common), whereas Schroth et al also tested for the *5 nonfunctional variant, and for the *10 and *41 reduced function variants. In both studies, negative results for the tested variants were assumed to represent wild-type genotypes. Schroth and coworkers also adjusted p-values of risk estimates for multiple comparisons.

Goetz et al. reported a re-analysis of a 2005 study, incorporated information on CYP2D6 inhibitor medication use (6% of patients) and assigned CYP2D6 metabolizer status based on both genotype and use of inhibitor medications. (21) Cox proportional hazards (PH) analysis of survival outcomes demonstrated that only tumor size greater than 3 cm and positive nodes were significant. Cox PH analyses of the effect of CYP2D6 metabolizer status (PM or IM vs. EM) on survival outcomes were adjusted for tumor size and nodal status, with statistically significant results for time to recurrence (TTR) and recurrence-free survival (RFS), but not for overall survival (OS):

• TTR:  HR = 1.91; 95% CI 1.05-3.45; p=0.034
• RFS: HR = 1.74; 95% CI 1.10-2.74; p=0.017
• OS:   HR = 1.34; 95% CI 0.83-2.16; p=0.223.

The population attributable risks (PAR), or the approximate proportions of outcomes accounted for by PM/IM status were 23%, 20%, and 10% for TTR, RFS, and OS, respectively.

The results represent a potentially weaker effect than might otherwise have been found, because IMs are included in the decreased CYP2D6 activity group. When PMs alone were compared to EMs alone in univariate analyses, the results were highly significant for TTR (HR = 3.20; 95% CI 1.37-7.55; p =0.007) and RFS (HR = 2.69; 95% CI 1.34-5.37; p =0.005), although not for OS. Multivariate analyses for PM vs. EM were not reported, likely because the numbers of PMs (n =16) were insufficient. Study results may also be affected by the incorrect assignment of less common variants (that were not genotyped) to the EM category, which could bias the results toward the null.

Schroth et al. conducted a retrospective cohort analysis of patients diagnosed with primary, ER-positive invasive breast cancer who had received adjuvant TAM alone. (17) The authors also combined all homozygous variants with heterozygous non-functional variant genotypes (decreased metabolizers) and compared them to the combined group of homozygous wild type or heterozygous reduced function variant genotypes (extensive metabolizers). The adjusted Cox HRs and PARs for TTR and RFS of TAM-treated decreased metabolizers compared to extensive metabolizers were significantly poorer:

• TTR: HR=2.24; 95% CI, 1.16-4.33; p= 0.02; PAR= 33%
• RFS: HR=1.89; 95% CI, 1.10-3.25; p= 0.02; PAR= 26%.

As with the Goetz study (21), these results were potentially biased toward the null by inclusion of heterozygous wild-type/non-functional variants in the decreased CYP2D6 activity group. This study did not take CYP2D6 inhibitor co-medication into account; the association might be stronger if a significant proportion of EM patients had been taking potent CYP2D6 inhibitors and could have been correctly classified as functional PMs rather than EMs. It should also be noted that the authors corrected their p-values for multiple comparisons. Considering all these points, the results likely represent the minimum strength of association between genotype and outcomes.

Newman et al (22) studied 115 patients with familial, early-onset breast cancer (47 BRCA1 and 68 BRCA2 mutations) treated with adjuvant TAM. Of these, 7% were CYP2D6 PMs, and 3.5% were considered PMs due to administration of CYP2D6 inhibitor drugs. CYP2D6 PMs had reduced time to recurrence, disease-free, and overall survival, but this effect was significant only for those with BRCA2 mutations. The results of this study cannot be generalized to women with sporadic breast cancer.
Okishiro et al (23) studied the impact of the CYP2D6*10 reduced activity variant in Japanese breast cancer patients treated with adjuvant TAM. Patients who were homozygous for the CYP2D6*10 variant (n =40), compared to heterozygous or wild type patients (n =133) did not differ in recurrence-free survival even after adjustment for established prognostic factors. Patients administered CYP2D6 inhibitor medication were excluded from this study. The authors also conducted a meta-analysis of their results plus previously reported results of similar studies conducted in Japanese and Chinese patients (24, 25) and similarly found no significant effect of homozygous CYP2D6*10 on recurrence-free survival.
In summary, evidence from 2 higher quality trials of adjuvant TAM in relatively homogeneous patient populations suggests that women who are functional PMs or IMs, whether by genotype or by co-medication with CYP2D6 inhibitors, treated with TAM have significantly reduced time to recurrence and RFS (but not OS) compared to EMs. The significance levels are marginal but might have been stronger and more convincing if PMs alone could have been compared to EMs, but numbers of PMs were insufficient. Few variant alleles have been typed in these studies; more extensive genotyping and better categorization might also strengthen results. Three other studies provide conflicting evidence; results were not sufficiently adjusted for variable treatment and TAM dose. (16, 20, 26) Individual studies of a reduced activity CYP2D6 variant in Asian women treated with TAM are conflicting but in aggregate show no significant effect on RFS. One study conducted in patients with familial breast cancer reported a significant effect only for PMs with BRCA2 mutations.

Clinical Utility

No clinical trials have been conducted that would provide direct evidence of clinical utility. Such a trial might prospectively enroll patients who would be prescribed endocrine therapy including TAM, but who would also be eligible for AI treatment. Patients would be randomized to usual methods of treatment selection, or to CYP2D6 genotyping after which poor metabolizers would receive AI treatment alone.

In the absence of direct evidence of clinical utility, an evidence chain could link clinical validity to other evidence of treatment benefit to infer outcomes from genotyping patients and making non-TAM treatment choices for CYP2D6 PMs, however, the evidence for clinical validity was insufficient.

Conclusion

There is no direct evidence of clinical utility. As noted above, chain of indirect evidence is insufficient to support demonstrating clinical utility. There is insufficient evidence to permit conclusions regarding the use of CYP2D6 genotyping for directing endocrine therapy regimen selection for women at high risk for or with breast cancer; this testing is considered investigational.

References:

1. 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.
2. 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.
3. 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.
4. 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.
5. 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
6. 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.
7. Beverage JN, Sissung TM, Sion AM et al. CYP2D6 polymorphisms and the impact on tamoxifen therapy. J Pharm Sci 2007; 96(9):2224-31.
8. 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.
9. 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. Last accessed, January 23, 2008.
10. National Comprehensive Cancer Network (NCCN). Clinical Practice Guidelines in Oncology™: Breast Cancer V.2.2008. Available at www.nccn.org. Last accessed January 22, 2008.
11. Lin NU, Winer EP. Optimal use of aromatase inhibitors: to lead or to follow? J Clin Oncol 2007; 25(19):2639-41.
12. 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.
13. 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
14. 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.
15. TEC Assessments 2008; Pharmacogenomics of Tamoxifen Treatment.
16. 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.
17. 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.
18. 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.
19. Desta Z, Flockhart DA. Germline pharmacogenetics of tamoxifen response: have we learned enough? J Clin Oncol 2007; 25(33):5147-9.
20. 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.
21. 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
22. 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.
23. 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.
24. 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.
25. 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.
26. 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.

 

Codes	Number	Description
CPT		See Policy Guidelines section
ICD-9 Diagnosis		Investigational for all codes

Policy History

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