PITTSBURGH--Five years of prophylactic tamoxifen (Nolvadex) cut the
risk of breast cancer almost in half in women at high risk for the
disease. D. Lawrence Wickerham, MD, associate chairman of the
National Surgical Adjuvant Breast and Bowel Project (NSABP), gave the
first formal presentation of the results of the Breast Cancer
Prevention Trial (BCPT) at the ASCO plenary session.
The trial was stopped last March when an interim analysis showed that
the primary endpoint had been reached.
The study enrolled 13,388 women who were otherwise healthy but at
high risk for developing breast cancer (see box below). The most
common risk factor was family history of breast cancer (about 70% of
patients had one or more relatives with the disease). Six percent of
subjects had prior history of LCIS.
Risk Factors for Inclusion in the BCPT
In women less than age 60, at least one of the following:
Patients were randomized to receive two 10-mg tablets of tamoxifen
daily or two placebo tablets daily for 5 years. More than 57% of the
patients in this study have been followed for more than 4 years, and
median follow-up is 3.6 years.
Treatment with tamoxifen reduced the development of invasive breast
cancer--154 cases in the placebo group vs 85 cases in the tamoxifen
group (risk ratio 0.55, P < .00001). The benefit was seen in all
age groups (Table). The
greatest benefit was seen in women over age 60. Tamoxifen also
reduced the rate of noninvasive breast cancers, with 59 cases seen in
the placebo arm vs 31 in the tamoxifen group (risk ratio 0.52, P = .002).
Dr. Wickerham said the tamoxifen group had a significant reducetion
in estrogen-receptor-positive (ER-positive) tumors (38 vs 112 in the
placebo arm), while no significant differences were seen in the
number of ER-negative cancers. Tamoxifen reduced the number of breast
cancers in women with a history of LCIS (7 vs 16) and in women with
prior atypical hyperplasia (1 vs 18).
The tamoxifen group also had a significant decrease in risk of
fractures but no change in risk of is-chemic heart disease events.
The risk of invasive endometrial cancer was increased about 2.5-fold
among those treated with tamoxifen (33 cases vs 14 cases for
placebo), but the excess number was limited to women over age 50 at
time of entry (26 vs 6 cases).
"The excess risk of endometrial cancer was not evident among
those who were less than 49 years of age at entry," Dr.
Wickerham said. He also noted that all cases of endometrial cancer in
the tamoxifen-treated group were stage I at diagnosis.
There was no increased risk of stroke in the tamoxifen arm. The risk
of pulmonary embolism and deep-vein thrombosis increased
significantly from 25 with placebo to 47 with tamoxifen, and this
increase was concentrated in those over 50 years of age at entry.
"There is no increased risk of serious side effects in women
under the age of 50," he commented.
Dr. Wickerham said that two questions remain in the wake of the BCPT:
Is 5 years of tamoxifen enough to get the optimum effect, and is this
effect due to true prevention of breast cancer or merely to delaying
Some clues as to optimal duration of treatment can be gleaned from
another NSABP protocol, B-14, in which breast cancer patients treated
with adjuvant tamoxifen for 5 years could elect to stop at that point
or to continue.
"During the first 5 years there was a 50% reduction in
contralateral breast cancer. Those who stopped after 5 years did not
then have a dramatic acceleration of contralateral breast cancer, and
continuing beyond 5 years does not appear to provide significant
additional protection," he said.
As to the second question, the discussant C. Kent Osborne, MD, of the
University of Texas Health Science Center, San Antonio, said that he
believes the early results in this study and in the raloxifene
(Evista) trial "are due primarily to the known treatment
effect of the antiestrogens on ER-positive established breast
cancer." It may be that the agents are having an early treatment
effect on subclinical cancers present in some patients at the time of
"This would explain tamoxifens failure to reduce the
number of ER-negative tumors that became clinical and the somewhat
greater effect of these drugs on older patients who would be expected
to have a higher incidence of ER-positive subclinical cancer,"
he said. "We dont know yet whether these drugs block
progression at earlier stages, which might be considered a true