Genotype testing may predict efficacy of tamoxifen

San Antonio Breast Cancer Symposium

SAN ANTONIO — Testing women for CYP2D6 may assist in directing therapy for those considering tamoxifen.

Mayo Clinic researchers sought to validate their prior published data regarding CYP2D6 in the ABCSG 8 trial. Matthew P. Goetz, MD, clinical assistant professor of pharmacology and oncology at the Mayo Clinic in Rochester, Minn., presented the data at the San Antonio Breast Cancer Symposium.

The ABCSG 8 trial randomly assigned 2,926 patients to five years of tamoxifen or to a sequence of tamoxifen for two years and anastrozole for three years. In the current trial, researchers performed a case-control study in which 67 of the cases occurring in the tamoxifen alone arm and 55 cases of those assigned to the sequence were matched with two controls.

In the tamoxifen arm, researchers found a RR of 3.83 (95% CI, 1.27-11.55) for poor metabolizers of CYP2D6, relative to extensive metabolizers. In the sequence arm, RR was 1.02 (95% CI, 0.21-4.83) for poor metabolizers of CYP2D6, according to Goetz.

In order to determine whether the risk for recurrence for poor metabolizers was different for those patients continued on tamoxifen vs. those switched to anastrozole, Goetz and his colleagues examined the risk for recurrence in the last three years in both arms. Compared with CYP2D6 extensive metabolizers, continuation of tamoxifen for years three to five for poor metabolizers of CYP2D6 was associated with a 2.8-fold higher risk of recurrence (P=.08). However, those poor metabolizers who were recurrence-free after two years and who switched to anastrozole did not have an increased risk for recurrence relative to extensive metabolizers (RR 0.71, P=.782).

“Postmenopausal women considering tamoxifen should be tested for CYP2D6 and CYP2D6 poor metabolizers should not be prescribed tamoxifen either as monotherapy or as part of a planned sequencing strategy,” Goetz said. “Additionally postmenopausal women currently taking tamoxifen should be genotyped for CYP2D6 with consideration for switching to an aromatase inhibitor if poor metabolizer status is identified.”

He added that because a substantial proportion of events in the tamoxifen arm occurred in a small minority of the population (CYP2D6 poor metabolizers), comprising only 6% to 8% of a white population, there may be little or no difference between tamoxifen and the aromatase inhibitors if CYP2D6 poor metabolizers are excluded from tamoxifen therapy.

The researchers also evaluated all distant recurrence events in both arms (n=73) for molecular grade and HOXB13/IL17BR index. Those who were high risk by this index yielded a 2.87 (95% CI, 1.27-6.49) RR to the low risk index, according to Goetz. – by Tina DiMarcantonio

For more information:

Goetz MP. #57. Presented at: the 31st Annual CTRC-AACR San Antonio Breast Cancer Symposium; Dec. 10-14, 2008; San Antonio.