Researchers from the Dana Farber Cancer Center, Brigham and Women's Hospital, and Harvard Medical School have reported that mutations within the CYP2D6 gene may affect the way in which a patient with hormone-positive breast cancer responds to tamoxifen (Nolvadex®). These results were recently published in the May 7, 2008 issue of the Journal of the National Cancer Institute.¹

Historically, tamoxifen was the most widely used hormone agent for the treatment of hormone-positive breast cancer. Newer agents, however, referred to as aromatase agents (Femara® [letrozole], Arimidex® [anastrozole], and Aromasin® [exemestane]), are now commonly used for treatment of this disease. Large trials have demonstrated that treatment with aromatase inhibitors in postmenopausal women with early-stage hormone-positive breast cancer improves progression-free survival compared with tamoxifen in this setting. It might be anticipated that breast cancers with differing characteristics would respond differently to hormonal therapy.

At the 2007 San Antonio Breast Cancer Symposium (SABCS), data were presented showing that the effectiveness of tamoxifen in preventing breast cancer was lower among women who carry a gene variant linked with poor tamoxifen metabolism. Researchers reported that response to tamoxifen is influenced in part by a gene known as CYP2D6 that controls tamoxifen metabolism. A majority of people have two functional versions of this gene and are able to effectively process tamoxifen. Some people, however, have versions of the gene that appear to reduce tamoxifen effectiveness. An Italian study showed that women who were classified as poor metabolizers of tamoxifen on the basis of their CYP2D6 genotype were more likely to develop breast cancer than other women.²

In another study presented at SABCS, researchers evaluated how CYP2D6 genotype influenced tamoxifen adherence.³ Women who effectively metabolize tamoxifen may be more likely to experience not only the benefits of tamoxifen therapy but also the side effects (such as hot flashes). This could lead to higher rates of tamoxifen discontinuation among effective metabolizers. The study involved 297 women with breast cancer, 28 of whom stopped taking tamoxifen during the first year of treatment as a result of side effects. Women who effectively metabolized tamoxifen were more likely to stop taking tamoxifen than women who were poor metabolizers. This study suggests that the patients who are most likely to benefit from tamoxifen are also the ones who are most likely to stop taking tamoxifen due to side effects. Identifying these patients in advance, and taking steps to manage tamoxifen side effects, may improve tamoxifen adherence and effectiveness.

The current study explored a potential relationship between mutations within the CYP2D6 gene and how it may affect a breast cancer patient’s response to different hormone therapies. The researchers gathered data from a previous large clinical trial, referred to as the BIG 1-98 trial, in which women with early-stage hormone-positive breast cancer were treated either with tamoxifen or an aromatase agent and were directly compared. Researchers gathered information from the BIG 1-98 trial regarding the CYP2D6 gene and patient outcomes with both agents.

At five years it was estimated that approximately 84% of patients with a normal CYP2D6 gene had cancer-free survival, which is the same survival rate as patients treated with aromatase agents in the BIG 1-98 trial.

The researchers concluded: “Modeling suggests that among patients who [have normal] CYP2D6, 5-year disease-free survival outcomes are similar to or perhaps even superior with tamoxifen than with aromatase inhibitors. Endocrine therapy tailored to CYP2D6 [gene] could be considered for women who are newly diagnosed with breast cancer, particularly those who have concerns about either the relative toxicity or the increased cost of aromatase inhibitors.”

Comments: Although further evaluation of these findings is necessary, these results provide additional evidence that individualized treatment approaches likely offer the best chance of optimal outcomes. Another question is whether or not the effect of the CYP2D6 gene effect is detected in the newer gene profiling assays that are in commercial use.

Related News:

Status of Gene Expression Profiling Assays for Early-Stage Breast Cancer Reviewed (02/25/2008)

Reference: 

¹ Punglia R, Burstein H, Winer E, Weeks J. Pharmacogenomic variation of CYP2D6 and the choice of optimal adjuvant endocrine therapy for postmenopausal breast cancer: a modeling analysis. Journal of the National Cancer Institute. 2008;100:642-648.

² Bonanni B, Maisonneuve P, Johannsson H et al. Risk stratification based on the CYP2D6 tamoxifen metabolizing gene within the Italian tamoxifen prevention trial. Presented at the 30th Annual San Antonio Breast Cancer Symposium. San Antonio, TX, December 13-16, 2007. Abstract #29.

³ Rae JM, Sikora MJ, Henry NL et al. Cytochrome P450 2D6 activity predicts adherence to tamoxifen therapy. Presented at the 30th Annual San Antonio Breast Cancer Symposium. San Antonio, TX, December 13-16, 2007. Abstract #77.