Endocrine resistance in advanced breast cancer

Although about half of patients with advanced breast cancer show either an objective response or disease stabilization on first line endocrine therapy, virtually all eventually relapse. Few of those patients that fail to respond to first-line treatment, respond to challenge with a second agent. In most cases, the cause of this de novo resistance appears to be the presence of only very low levels of oestrogen receptor (ER) and presumed growth dependence on other pathways. Patients who develop acquired resistance after an initial response, have approximately a 50% chance of responding to a further agent. The most frequently used first-line agent is tamoxifen, and the understanding of acquired endocrine resistance mainly relates to this agent. Selection of ER-ve clones of cells does not appear to occur frequently, and there is little clinical evidence to support the role of ER variants or mutants. There is evidence, however, that in some patients the intratumoural concentration of tamoxifen is substantially reduced at relapse, despite no change in plasma levels.