Oncologists concerned about cytochrome P450 2D6 (CYP2D6)
metabolism in patients taking tamoxifen for breast cancer can relax
a bit, based on two key studies and expert commentary from the 33rd
Annual San Antonio Breast Cancer Symposium in December.
CYP2D6 is intricately involved in the metabolism of tamoxifen
and its bioactive form, endoxifen. As the BIG 1-98 study (discussed
below) showed, 9% of Caucasian women have an absence of activity of
this enzyme and 27% have low enzyme activity. Several studies have
suggested that patients who are poor metabolizers of CYP2D6 may not
derive optimal benefit from tamoxifen. In addition, CYP2D6 can be
inhibited by concomitant medicines, particularly selective
serotonin-reuptake inhibitors (SSRIs).
It has been proposed that knowing a patient's CYP2D6 levels
could help clinicians to individualize endocrine therapy, but the
adjuvant studies presented at the San Antonio meeting call this
into question. The Arimidex, Tamoxifen, Alone or in Combination
(ATAC) trial and Breast International Group (BIG) 1-98 trial found
little association between variations in CYP2D6 levels and
tamoxifen's efficacy, leaving the value of CYP2D6 monitoring an
open question.
ATAC
"Does the CYP2D6
genotype predict tamoxifen response? We thought it would be
important to test this hypothesis in the ATAC trial," said
James Rae, PhD, of the University of Michigan, Ann
Arbor.1
ATAC compared 5 years of adjuvant anastrozole against tamoxifen
in 9,366 patients with early breast cancer. CYP2D6 genotype data
for the seven most common alleles, including CYP2D6*4, were used to
assign each patient a CYP2D6 score based on predicted allele
activities, from 0 (no activity) to 2 (high activity).
The CYP2D6 scoring system separates patients into poor,
intermediate, and extensive endoxifen metabolizers. The study
looked at an activity/dose-response relationship in 588 patients
randomly assigned to receive tamoxifen and 615 who received
anastrozole.
After 10 years median follow-up, the investigators found 115
recurrences in the tamoxifen cohort, but these were not associated
with CYP2D6 score. The hazard ratios were 1.06 for poor
metabolizers, 0.92 for intermediate metabolizers, and 1.0 for
extensive metabolizers, which were not significantly different.
Also, no association was found between the 92 recurrences in the
anastrozole cohort and CYP2D6 score.
The use of SSRIs also had no discernible effect on CYP2D6
levels. "We controlled for potent CYP2D6 inhibitors, and we did not
see an influence on outcomes," Dr. Rae said.
Dr. Rae concluded that there is insufficient evidence for
recommending CYP2D6 genotyping for patients initiated on tamoxifen,
nor is there a reason to avoid CYP2D6 inhibitors in these
patients.
BIG 1-98
Similarly, for the BIG 1-98 trial, Brian
Leyland-Jones, MD, PhD, of Emory Winship Cancer Institute,
of Emory University, Atlanta, reported that CYP2D6 phenotype as
well as reduced enzyme activity did not compromise disease
control.2
BIG 1-98 compared 5 years of letrozole (Femara), tamoxifen, and
sequences of letrozole and tamoxifen in 8,010 patients, of whom
4,628 were genotyped for CYP2D6 and classified (according to the
CYP2D6 scoring system) as poor, intermediate, or extensive
metabolizers.
Again, no association was observed between CYP2D6 phenotype and
breast cancer-free interval, the primary endpoint. Poor and
intermediate metabolizers did not have worse disease control than
the extensive metabolizers, Dr. Leyland-Jones reported.
In the multivariate analysis in the tamoxifen cohort (adjusted
for nodal involvement, tumor size, local therapy, race, and other
factors), the hazard ratio was 0.58 for poor metabolizers, 0.95 for
intermediate metabolizers, and 1.0 for extensive metabolizers
(P = .35).
Moreover, the BIG 1-98 study was one of the first studies to
report a distinct population (564 patients) receiving chemotherapy
in this setting. Again, no association was observed between CYP2D6
phenotype and breast cancer-free interval; the hazard ratio was
0.76 for poor metabolizers, 0.57 for intermediate metabolizers, and
1.0 for extensive metabolizers (P = .23).
The investigators also examined the occurrence of hot flushes in
association with enzyme metabolism, and observed incidences of 48%
of poor metabolizers, 49% of intermediate metabolizers, and 42% of
extensive metabolizers, which were not significantly different.
"The lowest hot flush incidence was in extensive metabolizers,
and this does not support the hypothesis that poor [endoxifen]
metabolism is associated with reduced hot flushes," Dr.
Leyland-Jones said.
He joined Dr. Rae in concluding that CYP2D6 testing is not
justified to determine whether tamoxifen should be given, and
further maintained that the incidence of hot flushes should not be
used to gauge tamoxifen efficacy. ■
References
1. Rae JM, Drury S, Hayes DF, et al: Lack of correlation between
gene variants in tamoxifen metabolizing enzymes with primary
endpoints in the ATAC trial. 33rd Annual San Antonio Breast Cancer
Symposium. Abstract S1-7. Presented December 9, 2010.
2. Leyland-Jones B, Regan MM, Bouzk M, et al: Outcome according
to CYP2D6 genotype among postmenopausal women with
endocrine-responsive early invasive breast cancer randomized in the
BIG 1-98 trial. 33rd Annual San Antonio Breast Cancer
Symposium. Abstract S1-8. Presented December 9, 2010.
