LONDON--Interim analyses of two randomized European trials of
tamoxifen (Nolvadex) prophylaxis in healthy women have failed to show
a significant reduction in the incidence of breast cancer, in
contrast to the US Breast Cancer Prevention Trial (BCPT), which
showed a 45% reduction with tamoxifen.
The two European reports both appeared in The Lancet
(352:93-97, 98-101, 1998), along with a commentary by Dr. Kathleen I.
Pritchard, of the University of Toronto, in which she suggested that
the discrepancy may stem largely from differences in patient populations.
Trevor Powles, MD, of the Royal Marsden Hospital, reported on 2,471
women with a family history of breast cancer randomized to tamoxifen,
20 mg/d, or placebo for 8 years. With a median follow-up of 70
months, the researchers have found no difference in overall breast
cancer frequency (34 cases in the tamoxifen arm vs 36 for placebo).
The trial has a 90% power to detect a significant 50% reduction in
breast cancer frequency at the 5% level. Compliance was good, he
said, and unlikely to be a cause of the negative result.
More likely causes of the discrepancy are the differences in
eligibility criteria, with entry into the London trial based
predominantly on a strong family history and thus a strong likelihood
of including patients with an inherited BRCA1 mutation. In contrast,
the BCPT entry criteria were based primarily on nongenetic risk
factors. "Estrogen promotion, which we would be expecting
tamoxifen to oppose, may not be important in the genesis of clinical
breast cancer in high-risk gene carriers," Dr. Powles said.
A further issue is the duration of follow-up: an average of 3½
years for the BCPT, compared with a median of nearly 6 years in the
London trial. "The relatively early frequency data in the NSABP
trial would largely reflect treatment of occult primary cancers,
rather than prevention by blocking estrogen promotion of a
transformed cell into an active cancer," he said.
Dr. Powles said that treatment and follow-up in the London trial
continue, and that the data will eventually contribute to a
metaanalysis of all tamoxifen chemoprevention trials.
Italian Study Results
The Italian Tamoxifen Prevention Study included 5,408 hysterectomized
women (at low to normal breast cancer risk) randomized to tamoxifen
20 mg/d or placebo for 5 years. At median follow-up of 46 months,
there is no difference in breast cancer frequency between placebo (22
cases) and tamoxifen (19 cases).
The trial did have a problem with compliance, with 26% of patients
dropping out of the study, most within the first year after
randomization. There was a trend toward a reduction in breast cancer
incidence among those women who took tamoxifen for more than a year
(11 cases), compared with placebo recipients who stayed on trial that
long (19 cases).
As with the London trial, treatment and follow-up continue, said Dr.
Umberto Veronesi, of the European Institute of Oncology, Milan. The
power of the study at present is low, he said, "and it is
possible that the finding will be overturned by continued
follow-up," especially among those women who stay on treatment
for more than a year. The Italian group also anticipates taking part
in a pooled analysis with other trials.
Dr. Pritchard noted that the Italian trial--in addition to compliance
problems and enrollment of patients who were not at high risk--had
far fewer women age 60 and above (12%) than the BCPT (30%). This age
group had slightly greater benefits from tamoxifen in the BCPT, and
also are more likely to have ER-positive tumors, which are more
susceptible to tamoxifens effects. She pointed out that the
London study included more younger women than either of the other
studies (62% under age 50 vs about 40% in the BCPT and 36% in the
"The seemingly different results may be largely due to a younger
population in both trials, to poor compliance in the Veronesi study,
and to differences in the populations studied (most importantly,
those in risk levels and family history)," she said. Dr.
Pritchard emphasized that longer follow-up of completed and current
trials is needed. "The decision of the investigators and data
monitoring committee of a fourth large tamoxifen preventive trial to
keep that trial masked and to continue accruing participants seems
wiser day by day," she said, referring to the International
Breast Cancer Intervention Study (IBIS) that has now enrolled 4,000
of a targeted 7,000 women.