TORONTO—Postmenopausal women with early-stage breast cancer who took the aromatase inhibitor letrozole(Drug information on letrozole) (Femara) after completing 5 years of tamoxifen(Drug information on 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 node-positive disease.
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 events).
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.
Adverse Events
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 = .11).
