Doctors have known for years that hormonal therapies are effective at treating
women with hormone-sensitive breast cancers (those positive for the estrogen or
progesterone receptors).
But questions remained about switching from one type of drug to another for
postmenopausal women: Is it best to start with tamoxifen and then switch to an
aromatase inhibitor (AI), or should the AI come first? And is the sequential use
of both agents better than treatment with either one alone?
Offering some answers were new data from the BIG (Breast International Group)
1-98 trial, a phase III study involving more than 8,000 women with early-stage
breast cancer, which were presented this past December at the 31st Annual
CTRC-AACR San Antonio Breast Cancer Symposium. Previous results reported in 2005
showed five years of Femara (letrozole) was more effective than five years of
tamoxifen, so the purpose of the updated analyses was to determine whether
giving both agents in a sequence would work better than Femara alone.
The amended BIG 1-98 trial compared five years of Femara, two years of Femara
followed by three years of tamoxifen, and two years of tamoxifen followed by
three years of Femara. There was no evidence that the sequential treatments
improved disease-free survival compared with Femara alone. But after two years
of initial treatment with Femara, the patients who switched to tamoxifen for
three years “couldn’t be distinguished” from patients treated with Femara for
the entire five years, study investigator Alan Coates, MD, of the University of
Sydney in Australia, told CURE at the meeting.
This is important, Coates said, “because if you need to switch [because of the
side effects or cost of Femara], you can afford to switch” without compromising
efficacy.
Other data presented at SABCS addressed a related question: Is tamoxifen as
effective in patients whose bodies do not fully metabolize the drug?
It turns out that tamoxifen has to be metabolized to a compound called endoxifen
to be fully active, and one of the key enzymes responsible for this is CYP2D6.
Individuals inherit slightly different versions of genes that encode all
proteins, including CYP2D6. In some studies looking at patients taking tamoxifen,
those who inherited less active versions of these genes were found to have a
higher recurrence rate compared with those who have versions with normal enzyme
activity.
American researchers found that in patients treated with tamoxifen only, those
who had “slow metabolizing” CYP2D6 had a nearly four-fold higher chance of early
recurrence compared with high metabolizers.
Experts say this finding provides more evidence supporting routine CYP2D6
assessment in patients receiving tamoxifen, and possibly the use of AIs in
postmenopausal patients who are slow metabolizers. Ovarian removal or
suppression would be necessary in premenopausal patients since AIs are only
effective when the ovaries are not producing estrogen.
There is still controversy as to how this test should be interpreted and whether
it should be routinely used to make treatment decisions. (Other enzymes
metabolize tamoxifen, and several parts of the CYP2D6 gene harbor variations.)
It is likely the research community will come together to deliberate on whether
this and other findings warrant changes in recommendations for CYP2D6 testing.
