Researchers affiliated with the BIG I-98 Collaborative Group have reported that sequential treatment with Femara® (letrozole) and tamoxifen (Nolvadex®) does not improve disease-free survival in postmenopausal women with hormone receptor-positive breast cancer when compared with therapy with Femara alone. The details of this study appeared in the August 20, 2009 issue of the New England Journal of Medicine.

The majority of breast cancers are hormone receptor-positive. These cancers are stimulated to grow by the circulating female hormones estrogen and/or progesterone. Treatment of hormone receptor-positive breast cancer often involves hormonal therapies that suppress or block the action of estrogen. These therapies include tamoxifen as well as aromatase inhibitors such as Femara. Tamoxifen acts by blocking estrogen receptors, whereas aromatase inhibitors suppress the production of estrogen.

The Breast International Group (BIG) 1-98 Trial was a randomized, Phase III, double-blind trial involving over 8,000 postmenopausal women with hormone receptor-positive early breast cancer. The women were randomized to one of four groups:

• Five years of treatment with tamoxifen
• Five years of treatment with Femara
• Sequential treatment of two years of treatment with Femara followed by three years of treatment with tamoxifen
• Sequential treatment of two years of treatment with tamoxifen followed by three years of treatment with Femara

Previous analyses of the data from the BIG 1-98 Trial have shown that when compared with tamoxifen, Femara significantly reduces the risk of recurrence, especially at distant sites. Now, at a median follow-up of nearly six years, researchers are evaluating the effects of the sequential treatment options; the results indicate that neither sequential treatment significantly improved disease-free survival compared with treatment with Femara alone.

Notably, the previous analyses of the study indicated that the frequency of recurrence within two years of randomization was significantly reduced in the Femara group compared with the tamoxifen group. With a follow-up of 71 months, overall survival was better for patients receiving Femara (hazard ratio of 0.87), but this difference did not reach statistical significance (p-0.08).

Researchers are now observing a similar pattern in the sequential treatment groups: women who received tamoxifen first followed by Femara had a higher rate of early recurrence than those who received Femara first followed by tamoxifen. As a result of this pattern, the researchers speculate that sequential treatment with Femara for two years followed by the full five years of tamoxifen might be an acceptable option if women need to discontinue Femara for any reason.

Comments: These researchers concluded that sequential treatment with Femara and tamoxifen offered no benefit over treatment with Femara alone.

Reference:  The BIG 1-98 Collaborative Group. Letrozole therapy alone or in sequence with tamoxifen in women with breast cancer. New England Journal of Medicine [early online publication]. August 20, 2009.