CYP2D6 DEBATE FOR TAMOXIFEN CONTINUES

Although previous studies have been somewhat inconsistent, a new study shows that breast cancer patients taking tamoxifen who have genetic alterations in CYP2D6 have a higher likelihood of both disease recurrence and death.

Approximately 5% to 7% of European and North American populations are considered to be poor metabolizers of tamoxifen, and there is a simple test that can identify these patients. But there has been "hesistancy" over moving this test into routine clinical use because of the inconsistency of the data supporting its use, and 2 recent analyses of large clinical trail data concluded that CYP2D6 did not predict tamoxifen effectiveness.

The new study suggests that CYP2D6 can predict ineffectiveness. The results show that after 5 years of taking tamoxifen, breast cancer patients with genetic alterations of CYP2D6 who are considered to be poor metabolizers of tamoxifen experienced disease recurrence or died at a rate that was 2.5 times higher than women with normal CYP2D6 enzyme activity.

In addition, women with intermediate levels of the CYP2D6 enzyme had rates of recurrence or death that were 1.7 times higher than those with normal CYP2D6 activity.

The study was conducted by researchers from the Mayo Clinic Cancer Center and the Austrian Breast and Colorectal Cancer Study Group (ABCSG) and was published in OnlineFirst on December 4 inClinical Cancer Research.

"Our findings confirm that in early breast cancer treated with tamoxifen, genetic alterations in CYP2D6 lead to a higher likelihood of recurrence and death," said lead author Matthew Goetz, MD, an oncologist at the Mayo Clinic, Rochester, Minnesota, who has been a vocal proponent of CYP2D6 testing.

However, the genetic alterations in CYP2D6 did not affect the likelihood of recurrence or death in patients who switched to anastrozole following 2 years of tamoxifen therapy. In fact, in the women who switched to anastrozole, he added, "We actually saw the opposite — a tendency towards a reduction in the odds of reduction for a recurrence."

In view of these latest results, the current recommendation of switching from tamoxifen to an aromatase inhibitor is likely to result in the greatest benefit in women with decreased CYP2D6 metabolism, Dr. Goetz said. However, for women who are poor metabolizers of CYP2D6, avoiding tamoxifen altogether and starting out with an aromatase inhibitor may be the best approach, he added.

"Our approach has been to test postmenopausal women who have a diagnosis of invasive ER [estrogen-receptor]–positive breast cancer in which we are considering adjuvant tamoxifen," he toldMedscape Medical News. "In the event that the patient is determined to be a CYP2D6 poor metabolizer, we advocate either starting on an AI [aromatase inhibitor], or switching to an AI if they are already on tamoxifen, since these medications, like tamoxifen, are FDA approved and are not metabolized by CYPD6."

"An important question is whether a CYP2D6 extensive metabolizer would do just as well on tamoxifen for 5 years as an AI for 5 years," he added. "However, we don't have those data, and they would need to be generated prospectively."

Previous Data Inconsistent

Senior author James Ingle, MD, of Mayo Clinic, added that the switching may explain some of the previous inconsistent results. "Switching from tamoxifen to an aromatase inhibitor may be one reason for the discrepant studies surrounding CYP2D6 and tamoxifen — as information about whether a patient took an aromatase inhibitor after tamoxifen was not available in most of the prior studies," he said in a statement.

As previously reported by Medscape Medical News, the results of 2 very large trials — the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial and the Breast International Group (BIG) 1-98 trial — both concluded that CYP2D6 does not predict tamoxifen effectiveness. However, in both studies, only postmenopausal women were evaluated.

New guidelines from the National Comprehensive Cancer Network (NCCN), which were presented at their 2011 annual meeting, did not make a recommendation about using CYP2D6 as a marker to predict tamoxifen response because "available studies are inconsistent."

In contrast, results from a randomized trial of women treated with tamoxifen monotherapy for early-stage ER-positive breast cancer ( J Clin Oncol 2005;23:9312-8), along with a pooled analysis of the women from the same study and a respective German cohort ( JAMA 2009;302:1429-36), have shown an association between CYP2D6 genotype and disease-free survival.

"As far as the guidelines are concerned, I would advocate that they be revisited by an independent review committee, and with recommendations for testing (yes/no) based on the quality of the published data generated from ATAC, BIG 1-98, and ABCSG 8," explained Dr. Goetz.

Study Details

In this current study, Dr. Goetz and colleagues conducted a matched case-control study that randomly assigned postmenopausal women with ER-positive breast cancer to receive tamoxifen for 5 years (Arm A; n = 1849) or tamoxifen for 2 years followed by anastrozole for 3 years (Arm B; n = 1865). Within the entire cohort, there were 790 patients from Arm A and 799 patients from Arm B with tissue blocks available.

CYP2D6 phenotype groups were defined as "extensive" metabolizers who did not carry a null or reduced allele (EM/EM); those with 1 or 2 reduced alleles without a null allele (EM/IM, IM/IM); those with 1 null allele (PM/IM, PM/EM); and "poor" metabolizers, or those with 2 null alleles (PM/PM).

Among patients in Arm A, those who were classified as PM/PM had higher odds of a disease event relative to those who were classified as EM/EM (OR, 2.45; P = .04). In addition, there was also a trend for higher odds of a disease event in patients classified as IM/PM or EM/PM as compared with patients classified as EM/EM (OR, 1.67; P = .07). This was not observed, however, in those classified as EM/IM or IM/IM relative to EM/EM (OR, 1.23; P = .60).

In contrast, among patients in Arm B, no significant association was found between CYP2D6 genotype and the likelihood of a disease event during the 5 years of treatment.

Trend in First 2 Years

The authors also conducted a secondary analysis to evaluate this association during the first 2 years of treatment, during which all patients received tamoxifen, as well in years 3 to 5, when patients in Arm B changed therapy to anastrozole.

Overall, there was a limited number of events during the first 2 years, but the authors observed a similar nonsignificant higher odds of a disease event for PM/PM relative to EM/EM during that time for both arms (Arm A: OR = 2.54; P = .25; Arm B: OR, 2.60; P = .46).

For years 3 to 5, for patients in Arm A who remained event free during the first 2 years of tamoxifen therapy, PM/PM (OR, 2.40; P = .09), and IM/PM or EM/PM (OR, 1.70; P = .09), a trend was observed toward increased odds of a disease event compared with EM/EM. Conversely, among those in Arm B who remained free of events during the first 2 years of tamoxifen therapy, the odds of a disease event for PM/PM (OR 0.28, p = 0.23) and the IM/PM or EM/PM group (OR, 0.63; P = .22) were nonsignificantly decreased as compared with EM/EM.

The study is partially funded by the National Institutes of Health.

Clin Cancer Res. Published December 4, 2012. Abstract