Genotyping errors plague testing for tamoxifen therapy

Volume 4, Issue 1, 2015


Patients, clinicians need more data to assess the value of CYP2D6 testing.

Photograph of Matthew P. Goetz, M.D.

Matthew P. Goetz, M.D.

Clinical recommendations discouraging the use of CYP2D6 gene testing to guide tamoxifen therapy in breast cancer patients are based on studies with flawed methodology and should be reconsidered, according to the results of a Mayo Clinic Cancer Center study published in the Journal of the National Cancer Institute.

For years, controversy has surrounded the CYP2D6 gene test for breast cancer.

Women with certain inherited genetic deficiencies in the CYP2D6 gene metabolize tamoxifen less efficiently, and thus have lower levels of endoxifen, tamoxifen's active cancer-fighting metabolite. Numerous studies have shown that these women gain less benefit from tamoxifen therapy and have higher rates of recurrence.

However, two large clinical trials found no link between the CYP2D6 genotype and tamoxifen effectiveness, prompting recommendations against testing.

In the new Mayo Clinic Cancer Center study, researchers found that previous studies were prone to error.

That's because the older studies used tumor tissue instead of healthy tissue to determine the CYP2D6 genotype. The new study found that up to 45 percent of breast tumors exhibit genetic alterations affecting the CYP2D6 gene. Thus, the use of tumor tissue to obtain DNA leads to a distortion of the patient's true, or inherited, CYP2D6 genotype.

"The potential benefit of CYP2D6 testing is obvious but has been difficult to establish. One major reason appears to be the lack of analytical validity," said Matthew P. Goetz, M.D., an oncologist at the Mayo Clinic Cancer Center and senior author of the study. "We found that if you use tumor tissue to determine the CYP2D6 genotype a patient was born with, you are going to get it wrong a substantial portion of the time."

CYP2D6, which stands for cytochrome P450 2D6, is one of the most important enzymes involved in drug metabolism. It is responsible for the breakdown of nearly a quarter of all medicines prescribed.

The CYP2D6 gene is highly variable. That variability is the main genetic factor affecting how the liver metabolizes tamoxifen, and the blood levels of the important metabolite endoxifen.

"It is sobering to consider that a decade of work by the oncology community has not produced a clear resolution of the value of CYP2D6 genotype for predicting tamoxifen efficacy," said James N. Ingle, M.D., an oncologist at Mayo Clinic Cancer Center and co-author of the study.

"The potential impact of the delay in resolving this issue is quite large in that during this time over half a million women worldwide would have been expected to be poor metabolizers, and if the relationship between CYP2D6 genotype and tamoxifen efficacy is correct, these women would have been given less than optimal adjuvant therapy had they received tamoxifen," he said.

The researchers say their results should prompt a careful reassessment of the data necessary to inform patients and clinicians properly about the value of CYP2D6 testing.