Changing clinical practice: extending the benefits of adjuvant endocrine therapy in breast cancer

Five years of tamoxifen is standard adjuvant therapy for hormone-sensitive early breast cancer, but women remain at appreciable risk of recurrence for many years following that therapy, and further tamoxifen does not appear to be beneficial. Trial MA.17 was designed to determine whether, following 5 years of tamoxifen, switching disease-free postmenopausal women to the aromatase inhibitor letrozole for 5 years improved disease-free survival compared with switching to placebo. The rationale was that as residual cancer cells become tamoxifen resistant, their growth may be stimulated by the minor agonist effect of tamoxifen as well as by very low estrogen concentrations. Those cells might be particularly sensitive to tamoxifen withdrawal coupled with treatment with a potent suppressor of estrogen synthesis. At the first planned interim analysis of MA.17, "extended adjuvant" letrozole significantly improved estimated 4-year disease-free survival overall (93% for letrozole v 87% for placebo; P < .001), irrespective of nodal status. Recurrences were reduced to a comparable extent for all included events, locoregional and distant recurrences (53% and 38%, respectively) and new primary cancers in the contralateral breast (46%). Breast cancer deaths were reduced by 47% with letrozole versus placebo. Letrozole treatment was well tolerated, with most adverse events mild and expected as symptoms of estrogen deprivation. This is the first demonstration that extended adjuvant therapy after standard tamoxifen in postmenopausal women with early breast cancer has a clinically significant impact on outcome.