Controversies in the hormonal adjuvant therapy of postmenopausal patients

Over 80% of primary breast cancers in postmenopausal women present as ER⁺. It is clear that aromatase inhibitors (AIs) are more effective than tamoxifen as initial adjuvant therapy for such patients. Overview analysis indicates that this proportional enhancement in benefit is seen across all common clinical subgroups [1]. Recent data from the BIG1-98 trial [2] revealed that initial therapy with tamoxifen with a switch after 2 years to letrozole was not as effective as continued letrozole, an important refutation of earlier modelling that suggested the sequential approach might be at least as effective as 5 years' AI treatment. The indication that 2 years of letrozole followed by 3 years of tamoxifen therapy is as effective as 5 years of letrozole provokes new thinking about the possible best use of these agents.

Tamoxifen has some serious side effects (for example, increased risk of endometrial cancer and thromboembolism) that AIs do not, but the deleterious bone and joint effects of AIs make tamoxifen a continued choice of treatment in some patients, particularly those at low risk of relapse.

The early indications that AIs might be relatively more effective than tamoxifen in PgR^- versus PgR⁺ patients and HER2⁺ versus HER2^- tumours have not been confirmed. Similarly, the Oncotype DX Recurrence Score (RS) showed similar relationships with risk of distant recurrence in both anastrozole and tamoxifen arms of the ATAC trial. Although data from BIG1-98 show a greater effect of AIs over tamoxifen at higher levels of Ki67, there is no significant interaction between the Ki67 and treatment effects – suggesting that this is largely an effect of high Ki67 being associated with poorer prognosis. There are conflicting data on whether polymorphisms in the CYP2D6 gene, which reduce the efficiency of conversion of tamoxifen to the more potent endoxifen, indicate a poorer efficacy for tamoxifen and therefore greater relative benefit from an AI.

The decision to deliver adjuvant chemotherapy in addition to endocrine treatment is judged largely on the basis of prognosis after considering the impact of the endocrine therapy. While the RS is a validated instrument for this purpose, the prognostic effect of markers such as PgR, HER2 and Ki67 is substantial and may allow the development of widely applicable immunohistochemical approaches to risk evaluation.