ER ER ER ER - Endocrine Reviews

data showing the ability of lapatinib to reverse hormone resistance and to cooperate with
tamoxifen in providing maximal growth arrest provide the rationale for this study (162).
It will be important in all of the trials mentioned in Table 2 and similar other studies, to
stratify for prior endocrine therapy (usually tamoxifen) given in the adjuvant setting, and,
in particular, the interval since completion of such therapy. This is important, as it may
have implications for the presence or absence of activated growth factor signaling in the
relapsed tumor, which could determine the efficacy of added gefitinib or lapatinib. In
addition, biologic studies are required to help predict those patients who are more likely
to benefit from combined endocrine/antiHER therapy. For example, the
tamoxifen/gefitinib trial (Table 2) will undertake studies to look at downstream
intracellular signaling components of the HER family, in addition to assessment of ER
and ER co-activators such as AIB1.
V. Future challenges
As the complexity of ER biology is being revealed, so is the complexity of the
mechanisms responsible for endocrine sensitivity and resistance in breast cancer. The
genomic and the non-genomic activities of ER, as well as their complex interplay with
many other growth factors and cellular kinase pathways, influence tumor sensitivity to
various types of endocrine therapies. Although ER was first identified more than 30
years ago, we are still trying to clarify and understand its multiple roles in normal
physiology and in disease. In breast cancer there is convincing evidence that ER does not
34