Research in context
Evidence before this study
Results from clinical trials and overview analyses have established that patients with hormone receptor-positive, early-stage breast cancer are at considerable risk of recurrence long after the first 5 years from diagnosis of breast cancer. We searched PubMed when we designed this study, in March, 2005, to identify randomised clinical trials of adjuvant endocrine therapy in English. At that time, use of adjuvant tamoxifen for 5 years was the standard of care for patients with premenopausal breast cancer. Clinical trials such as the aTTom and ATLAS studies investigated extended adjuvant tamoxifen therapy for 10 years compared with 5 years, but had not reported results at the time we designed this study. These two trials showed that 10 years of tamoxifen improved disease-free survival (and breast cancer-specific mortality in the ATLAS trial), compared with 5 years of tamoxifen. For postmenopausal patients, several clinical trials had shown significant improvement in disease-free survival with the use of aromatase inhibitors, compared with 5 years of tamoxifen. Three different approaches had been used for the incorporation of aromatase inhibitors in the adjuvant setting, all three compared with the standard of 5 years of tamoxifen: 5 years of an upfront aromatase inhibitor (as assessed in the ATAC and BIG-1-98 trials), 2–3 years of an aromatase inhibitor after 2–3 years of tamoxifen (as assessed in the ABCSG-8/ARNO 95 and the ITA trials), or 5 years of an aromatase inhibitor after 5 years of tamoxifen (as assessed in the MA.17 and B-33 trials). All three approaches yielded significant improvements in disease-free survival compared with 5 years of adjuvant tamoxifen. Although the MA.17 and B-33 trials assessed extended aromatase inhibitor therapy after 5 years of tamoxifen, at the time our trial started the benefit of extending adjuvant aromatase inhibitor therapy for longer than 5 years in patients who had received 5 years of an aromatase inhibitor or 2–3 years of tamoxifen followed by 2–3 years of an aromatase inhibitor was unknown. Therefore, the NSABP B-42 (B-42) trial aimed to determine whether extending therapy past 5 years would improve disease-free survival in these patients.
Added value of this study
The B-42 trial showed that letrozole therapy did not significantly prolong disease-free survival after 5 years of hormonal therapy. However, extended letrozole therapy resulted in a significant reduction in breast cancer recurrence and distant recurrence. The B-42 results might appear discordant with those recently reported from the NCIC MA.17R trial, which showed a significant improvement in disease-free survival with extended letrozole therapy in patients who had already received 5 years of letrozole (preceded in most participants by 5 years of tamoxifen treatment). However, disease-free survival in MA.17R included only breast cancer recurrence and contralateral breast cancer as events, which is the definition of breast-cancer-free interval by the STandardized definitions for Efficacy End points (STEEP) criteria. When the disease-free survival endpoint is defined more closely to the STEEP criteria by including deaths as first event in MA.17R, a smaller and non-significant improvement in disease-free survival was observed with extended letrozole treatment. The results of the B-42 trial are further corroborated by two other randomised trials (DATA and IDEAL), which compared longer and shorter durations of extended aromatase inhibitor therapy.
Implications of all the available evidence
Considering all available evidence, it seems that the benefit from extended aromatase inhibitor therapy is modest. Therefore, careful assessment of potential risks and benefits is required before recommending extended letrozole therapy to patients with early-stage breast cancer who are disease-free after 5 years of hormonal therapy, primarily with an aromatase inhibitor. Further research is needed to identify biological markers that might predict risk of late recurrence or magnitude of benefit from extended aromatase inhibitor therapy, to optimise selection of candidates for extended aromatase inhibitor therapy.