Progress in systemic therapy for breast cancer: an overview and perspectives

This review will focus on progress for advanced and early breast cancer in systemic medical therapy, which consists of three main modalities: endocrine therapy (ET), chemotherapy (CT) and biological therapies (BTs). In advanced disease, we did witness two consecutive shifts in our classical sequence of ET: in the first one, the potent third-generation aromatase inhibitors took the second place after tamoxifen failure (a shift that is level 1 evidence based), making megestrol acetate a third option, while in the second, they are challenging tamoxifen as the 'gold standard' first line ET (a shift that is level 2 evidence based). As far as CT is concerned, most of the progress has been seen in anthracycline-resistant disease with the taxanes (docetaxel in particular) becoming the preferred treatment option on a level 1 evidence basis. In patients with no or limited anthracycline exposure, at least 10 randomised clinical trials involving the taxanes have been conducted, but in view of their conflicting results, no new standard of care has emerged. Third-line CT following anthracyclines and taxanes remains a wide-open research opportunity, with oral capecitabine being the only agent approved in this indication. Herceptin(R) (trastuzumab) is the first BTs available for the treatment of breast cancer. Its impressive clinical activity in metastatic breast cancer (MBC) prompted the registration of the drug for use as monotherapy in patients with HER-2 overexpressing MBC who have failed anthracyclines and taxanes, as well as for use upfront in combination with paclitaxel. There is substantial room for further progress with the use of Herceptin(R) in the management of breast cancer and much hope is placed in the combination of Herceptin(R) with other agents targeting important signaling pathways, such as the MAPKinase pathway or the PI3 kinase cell survival pathway. Such strategies will be briefly discussed. In the area of early breast cancer management, BTs (namely Herceptin(R) and bisphosphonates) are being evaluated in randomised clinical trials, while ET has consolidated its prominent role for all women whose tumours express hormone receptors, as outlined in the 2000 NIH Consensus Conference and in the latest treatment guidelines proposed by the St-Gallen consensus panel in 2001. Substantial mutations in our standards of care are also expected in the field of adjuvant ET, with the early positive results of the large ATAC trial showing superior efficacy and tolerability of anastrozole over tamoxifen. The added benefits from adjuvant CT in patients receiving optimal ET remain difficult to ascertain and may be quite small in certain sub-groups. Only translational research efforts carry the hope for a much needed understanding of this complex interplay between ET and CT. With further improvement expected with new hormonal agents, it is possible that the role of CT will diminish in the future management of endocrine-responsive breast cancer, while the role of ET+/-BTs will grow. (C) 2003 Elsevier Ltd. All rights reserved.