Adjuvant Letrozole Improves DFS, Compared With Tam

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 3 years.

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.