The third-generation
aromatase inhibitors,
letrozole,
anastrozole, and
exemestane, have been shown to be effective both as alternatives to
tamoxifen in first-line treatment of
hormone-sensitive advanced
breast cancer in postmenopausal women and following failure of first-line
tamoxifen for endocrine
therapy. These 3 agents are now being investigated as adjuvant
therapy of early
breast cancer, as alternative or complementary treatments to the standard,
tamoxifen. Three treatment strategies are under investigation: replacement of
tamoxifen as adjuvant
therapy for 5 years (early adjuvant
therapy), sequencing of
tamoxifen before or after an
aromatase inhibitor during the first 5 years (early sequential adjuvant
therapy), or following 5 years of
tamoxifen (extended adjuvant
therapy). In the first adjuvant trial (
Arimidex,
Tamoxifen Alone or in Combination [ATAC]),
anastrozole was significantly superior to
tamoxifen in reducing risk of disease recurrence, and recently, the Breast International Group (BIG) trial BIG 1-98 demonstrated the significant superiority of
letrozole over
tamoxifen in improving disease-free survival. A large trial (International Collaborative
Cancer Group [ICCG] trial 96) investigated sequencing of 2 to 3 years of
exemestane after 2 to 3 years of
tamoxifen and found that switching to
exemestane was significantly superior in disease-free survival compared with continuing on
tamoxifen. The
Arimidex or
Nolvadex (ARNO) and the small ITA (Italian
Tamoxifen Arimidex) trials similarly sequenced
anastrozole after
tamoxifen and also found that sequencing reduced the hazard of recurrence compared with remaining on
tamoxifen. Trial MA.17 evaluated extended adjuvant
therapy with
letrozole vs placebo following 5 years of
tamoxifen. Disease-free survival was significantly improved with
letrozole vs placebo, irrespective of whether patients had lymph node-positive or node-negative
tumors. All 3
aromatase inhibitors were generally well tolerated. Results of these trials indicate that
aromatase inhibitors provide important benefits relative to
tamoxifen in each of these adjuvant treatment settings, but the optimal approach still needs to be defined. Other trials continue to investigate some of these adjuvant treatment strategies.