TORONTOPostmenopausal women with early-stage breast
cancer who took the aromatase inhibitor letrozole (Femara) after completing 5
years of tamoxifen therapy had a 43% lower risk of recurrence than those
receiving placebo, an international phase III clinical trial has found.
The interim results of this double-blind, placebo-controlled
study were so striking that the investigators, per protocol, have stopped the
trial and unblinded it so that women who were on placebo can have the option of
taking letrozole. Women in the letrozole group can continue to take the drug
for up to 5 years.
This trial, MA-17, is the first to study extended adjuvant
therapy with an aromatase inhibitor in patients who have completed 5 years of
adjuvant tamoxifen therapy. The Canadian-led trial opened in 1998 and enrolled
more than 5,000 women at 413 sites in the United States, Canada, and Europe
(England, Belgium, Ireland, Italy, Poland, Portugal, and Switzerland).
The trial was funded by the Canadian Cancer Society at a
cost of $20 million (in Canadian dollars) and coordinated by the National
Cancer Institute of Canada Clinical Trials Group at Queen’s University,
Kingston, Ontario, in partnership with the US National Cancer Institute and its
Clinical Trials Cooperative groups. Novartis, which manufactures letrozole,
provided the drug for the trial and $12 million in funding.
Paul Goss, MD, of Princess Margaret Hospital, Toronto, who
conceived and chaired the MA-17 trial, reported the results at a press
conference. The findings were published in the New England Journal of
Medicine on November 6, 2003.
The trial randomized 5,187 women to letrozole 2.5 mg/d
orally or placebo for 5 years. Breast cancer was hormone-receptor positive in
98% of the women and of unknown receptor status in 2%.
Eligible women had to have discontinued tamoxifen less than
3 months before enrollment. Their previous adjuvant tamoxifen therapy had to
have lasted 4.5 to 6 years. They had to be at least 50 years of age, or younger
but postmenopausal; younger than 50 but with both ovaries removed; younger than
50 and premenopausal but amenorrheic due to chemotherapy or their tamoxifen
treatment; or younger than 50 but with postmenopausal levels of LH or FSH.
First Interim Analysis
At the first interim analysis (at a median follow-up of 2.4
years), there were 207 local or metastatic recurrences of breast cancer or new
primary cancers in the contralateral breast: 75 events in the letrozole group
vs 132 in the placebo group, for an overall recurrence reduction of 43% (hazard
ratio vs placebo group 0.57; 95% confidence interval, 0.43 to 0.75, P =
.00008). Efficacy of letrozole was equivalent in women with node-negative vs
There was a 46% reduction in the frequency of new primary
tumors in the contralateral breast, a secondary study endpoint that accounted
for 21% of the difference in events between the treatment groups (12 of 57
The estimated absolute improvement in 4-year disease-free
survival rates was 6% for women in the letrozole group (93% vs 87% for placebo,
P <= .001).
There were 17 deaths from breast cancer in the placebo group
vs 9 in the letrozole group, a finding that, while not statistically
significant, was important when considered together with the disease-free
survival results, Dr. Goss said.
Menopausal-type side effects were common with letrozole but
were mostly low grade. Hot flashes, arthritis, arthralgia, and myalgia were
more common with letrozole than with placebo (P < .05). Vaginal
bleeding was more common with placebo than with letrozole (P = .01).
There were new diagnoses of osteoporosis in 5.8% of women on
letrozole vs 4.5% on placebo (P = .07); fracture rates were similar:
3.6% on letrozole vs 2.9% on placebo (P = .24).
The investigators found a nonsignificant difference in the rate of
cardiovascular events in women on letrozole (4.1%) vs placebo (3.6%); there
were no reports of drug-related hypercholesterolemia. Discontinuation rates due
to side effects were similar: 4.5% of women on letrozole vs 3.6% on placebo (P