Highmark Commercial Medical Policy - Pennsylvania
Medical Policy: L-148-006
Topic: CYP2D6 Variant Analysis for Drug Response
Section: Laboratory
Effective Date: July 1, 2018
Issue Date: July 2, 2018
Last Reviewed: March 2018

The cytochrome P450 2D6 (CYP2D6) enzyme is involved in metabolizing many medications including tamoxifen, tetrabenazine, deutetrabenazine, and eliglustat. CYP2D6 gene result in reduced or absent enzyme function, which may lead to lower levels of active tamoxifen metabolites and reduced treatment efficacy. Testing is not indicated for perimenopausal and premenopausal women with hormone-positive breast cancer. Tamoxifen is the current standard of care for these patients, and no alternative treatment plans have been approved.

This policy is designed to address medical guidelines that are appropriate for the majority of individuals with a particular disease, illness, or condition. Each person's unique clinical circumstances may warrant individual consideration, based on review of applicable medical records.

Policy Position Coverage is subject to the specific terms of the member’s benefit plan.

Testing for Tetrabenazine Response

CYP2D6 testing for tetrabenazine response may be considered medically necessary when the following criteria are met:

Procedure Codes
81226


Testing for Deutetrabenazine Response

CYP2D6 testing for Deutetrabenazine response may be considered medically necessary when the following criteria are met:

Procedure Codes
81226


Testing for Eliglustat Response

CYP2D6 testing for eliglustat response may be considered medically necessary when the following criteria are met:

Procedure Codes
81226


Testing for Tamoxifen Response

CYP2D6 testing for tamoxifen response is considered experimental/investigational and therefore, non-covered due to lack of scientific-based evidence published in the peer reviewed literature.

Procedure Codes
81226, 0028U


Testing for All Other Indications

CYP2D6 testing for any other indication is considered experimental/investigational and, therefore, non-covered due to lack of scientific-based evidence published in the peer reviewed literature.

CYP2D6 Genotype Cascade from Mayo Clinic is considered experimental/investigational and, therefore, not non-covered due to lack of scientific-based evidence published in the peer reviewed literature.

Procedure Codes
81226, 0028U

Professional Statements and Societal Positions

Tetrabenazine, deutetrabenazine and eliglustat:

  • CYP2D6 is listed as an FDA-approved biomarker for both tetrabenazine and eliglustat.
  • Product labeling for tetrabenazine, deutetrabenazine, and eliglustat address CYP2D6 testing.

Tamoxifen

  • Evidence-based guidelines from the National Comprehensive Cancer Network (NCCN, 2016) state: "At this time, based on current data the [NCCN Breast Cancer] panel recommends against CYP2D6 testing for women being considered for tamoxifen therapy." (category 2A: The recommendation is based on lower level evidence and there is uniform NCCN consensus).
  • Practice guidelines from the American Society of Clinical Oncologists (ASCO, 2009) state: "Given the limited evidence, CYP2D6 testing is currently not recommended in the preventive setting."
  • Two important large clinical trials have most directly addressed clinical utility of CYP2D6 testing for tamoxifen response.  Both found that CYP2D6 genotype did not predict long-term outcome among tamoxifen users.
    • Regan et al. performed CYP2D6 variant testing on tumor tissue from 4393 patients enrolled in the BIG 1-98 trial and evaluated the association with breast cancer recurrence. BIG 1-98 was an international, randomized double-blind trial that compared tamoxifen monotherapy, letrozole (an aromatase inhibitor) monotherapy, and sequential therapy (2 years of one and 3 years of another). Patients were mostly Caucasian and all had postmenopausal, hormone receptor-positive, operable breast cancer. Results found a non-statistically significant association between metabolizer phenotype and recurrence (poor metabolizer vs. extensive metabolizer HR = 0.58, 95% CI = 0.28 to 1.21). The authors concluded "The results of this study do not support using the presence or absence of hot flushes or the pharmacogenetic testing of CYP2D6 to determine whether to treat postmenopausal breast cancer patients with tamoxifen.
    • Similarly, Rae et al. found no association between CYP2D6 genotype and breast cancer recurrence in people treated with tamoxifen from the randomized double-blind Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial (n=1203; poor metabolizer vs. extensive metabolizer HR = 1.25, 95% CI = 0.55 to 3.15). The authors conclude "The results do not support the hypothesis that CYP2D6 genotype predicts clinical benefit of adjuvant tamoxifen treatment among postmenopausal breast cancer patients."

Place of Service: Outpatient

Experimental/Investigational (E/I) services are not covered regardless of place of service.

CYP2D6 variant analysis for drug response is typically an outpatient procedure which is only eligible for coverage as an inpatient procedure in special circumstances, including, but not limited to, the presence of a co-morbid condition that would require monitoring in a more controlled environment such as the inpatient setting.


The policy position applies to all commercial lines of business


Denial Statements

Services that do not meet the criteria of this policy will not be considered medically necessary. A network provider cannot bill the member for the denied service unless: (a) the provider has given advance written notice, informing the member that the service may be deemed not medically necessary; (b) the member is provided with an estimate of the cost; and (c) the member agrees in writing to assume financial responsibility in advance of receiving the service. The signed agreement must be maintained in the provider’s records.

Services that do not meet the criteria of this policy will be considered experimental/investigational (E/I). A network provider can bill the member for the experimental/investigational service. The provider must give advance written notice informing the member that the service has been deemed E/I. The member must be provided with an estimate of the cost and the member must agree in writing to assume financial responsibility in advance of receiving the service. The signed agreement must be maintained in the provider’s records.

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