ORLANDO Initial adjuvant therapy with the aromatase
inhibitor letrozole (Femara) offered significantly better protection against
further breast cancer, any cancer, or death, compared with tamoxifen, in
patients with hormone-sensitive early-breast cancer, according to results from
the large-scale BIG 1-98 trial. Letrozole also had different side effects than
tamoxifen, but none nearly as consequential for patients as the benefits, said
lead investigator Beat Thürlimann, MD, University of Basel, Switzerland.
Speaking at the 41st Annual Meeting of the American Society
of Clinical Oncology (abstract 511), Dr. Thürlimann said that BIG 1-98,
conducted by the Breast International Group (BIG), enrolled 8,028
postmenopausal women with estrogen-receptor (ER)-positive breast cancer to
receive adjuvant therapy with tamoxifen or letrozole for 5 years, tamoxifen for
2 years then letrozole for 3 years, or letrozole for 2 years then tamoxifen for
Current reporting covers only the primary treatment
comparison of initial tamoxifen vs initial letrozole for 5 or 2 years, and
updates results presented earlier this year (January 2005, St. Gallen) with a
median follow-up of 25.8 months. The primary outcome measure was disease-free
survival (DFS). Assessment of the role of sequential therapy vs monotherapy
will be possible with longer follow-up, he said.
Reduction in Recurrence Risk
At 5 years postrandomization, disease-free survival was
84.0% for letrozole vs 81.4% for tamoxifen, a 19% reduction in risk of
recurrence (P = .003). The cumulative incidence of breast cancer events
was 13.6% (428 events) for tamoxifen vs 10.2% (351 events) for letrozole (P
= .0002). Local and distant failures both significantly favored letrozole.
The risk for distant metastases was lowered by 27% with
letrozole, compared with tamoxifen (P = .0012). "The 27% risk reduction
is important because distant metastases will ultimately lead to death," Dr.
Thürlimann said at an ASCO press conference. That better protection against
distant metastases is expected to translate into improved overall survival.
Importantly, he said, in an exploratory subgroup analysis,
use of letrozole resulted in greater disease-free and overall survival
regardless of whether patients had received or not received chemotherapy or
whether they had lymph-node-positive or negative disease. Side effects, as
expected, reflected differing profiles for the two agents. Significantly higher
in the tamoxifen group were severe thromboembolic events (0.8% vs 2.1%, P
< .0001); vaginal bleeding (3.3% vs 6.6%); and hot flushes (33.5% vs 38%). At
the press conference, Dr. Thürlimann, noted that vaginal bleeding can be a
symptom of endometrial pathology leading to endometrial cancer. Invasive
endometrial cancers were reported in 0.2% of women receiving letrozole and in
0.5% of women receiving tamoxifen, he said.
Letrozole patients had more joint complaints (20.3% vs
12.3%), bone fractures (5.7% vs 4%), and hypercholesterolemia (43.5% vs 19.1%).
Also, cardiac events were significantly higher in the letrozole group, but
percentages were low (grade 3-5 cardiac events: 2.1% vs 1.1%, P =
.0003). He pointed out that the cardiac benefit with tamoxifen may be
attributed, at least in part, to its known 10% to 15% cholesterol-lowering
effects. Putting the cardiac benefits of tamoxifen in perspective, Dr.
Thürlimann underscored that only 19 patients in BIG-1-98 had cardiac deaths (13
for letrozole, 6 for tamoxifen), compared with 358 deaths from all causes (192
on tamoxifen vs 166 on letrozole, a nonsignificant 14% reduction with letrozole)
and 265 cancer-related deaths (154 on tamoxifen vs 111 on letrozole).
Dr. Thürlimann concluded, "Letrozole significantly prolongs
disease-free survival, compared with tamoxifen, for postmenopausal women with
endocrine-positive breast cancer, especially reducing relapse in distant sites.
Compared with tamoxifen in postmenopausal women, more skeletal and grade 3-5
cardiac events and fewer venous thromboembolic and endometrial events occurred
with use of letrozole."
He stated that "letrozole can now be considered part of
standard adjuvant therapy for postmenopausal women with endocrine-positive
breast cancer," noting that among patients given letrozole instead of tamoxifen,
one in five is alive and disease free as a result. "Aromatase inhibitors should
be strongly taken into consideration in treatment plans for postmenopausal
women with hormone-sensitive breast cancer," he said.