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Treatment of metastatic disease after current adjuvant approaches (taxanes, aromatase inhibitors, trastuzumab)

Metastatic breast cancer patients represent a very heterogeneous population and several factors are important for therapeutic decision: patient characteristics including age, comorbidities, and performance status, tumor biological characteristics, site and extension of metastatic spread, prior adjuvant therapies and disease-free interval. In the past years, adjuvant treatment has been rapidly changing as new cytotoxics, new endocrine agents and targeted therapies are becoming the mainstay of treatment [1]. For endocrine-sensitive breast cancer, several large randomized trials have shown that third-generation aromatase inhibitors, can reduce the risk of relapse of early breast cancer in comparison with tamoxifen. Nowadays, aromatase inhibitors administered up front, as a switch after 2–3 years of tamoxifen or as extended treatment after 5 years of tamoxifen represent the standard treatment in postmenopausal women. As anthracycline and taxanes are the most active cytotoxic agents in breast cancer, anthracycline/taxane-containing regimens are becoming the mainstay of adjuvant chemotherapy. Finally, the growing understanding of the biology of breast cancer cells led to identification of key molecular points that represent possible therapeutic targets. Trastuzumab, the monoclonal antibody against the HER-2 receptor, is approved for the treatment of high-risk early breast cancer overexpressing HER-2 and represents the standard treatment in these patients. With increasing use of very active drugs in the adjuvant setting, there is a greater need for effective therapy at the time of relapse [2]. In endocrine-sensitive breast cancer, sequencing data for anastrozole and tamoxifen have shown that tamoxifen is likely to be effective after progression on anastrozole. Moreover, in recent years Fulvestran, a selective ER downregulator acting as a pure antiestrogen agent, has been developed. Tamoxifen, Fulvestran or an aromatase inactivator are possible options after failure of adjuvant aromatase inhibitors. At present, it is not possible to define the optimal sequence of these endocrine agents. In endocrine-resistant disease, a treatment-free interval (TFI) >12 months after adjuvant chemotherapy has been shown to be an important factor for determining sensitivity to drug rechallenge. If the tumor has been exposed to an anthracycline and a taxane in adjuvant setting and the TFI is >12 months, the re-treatment with the same agents may be an option [3]. If the TFI is <12 months it is preferable to use a different agent. Capecitabine, gemcitabine and vinorelbine have demonstrated substantial activity in metastatic breast cancer. Finally, patients with HER2-positive tumors receiving adjuvant trastuzumab might be refractory (primary resistance) or might become resistant (secondary resistance) to trastuzumab. The mechanisms of primary and secondary trastuzumab resistance are not yet fully elucidated. Lapatinib, a new target agent that simultaneously inhibits both HER-2 and EGFR tyrosine kinases, has been shown to be active in trastuzumab-resistant metastatic breast cancer. Moreover, several new agents targeting HER-2 are currently under clinical development. There are no data on rechallenge with trastuzumab in patients who had received this agent as adjuvant treatment and relapsed after a long TFI, and this issue is a new area of research.


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Conte, P., Guarneri, V. & Bengala, C. Treatment of metastatic disease after current adjuvant approaches (taxanes, aromatase inhibitors, trastuzumab). Breast Cancer Res 9 (Suppl 1), S14 (2007).

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