Endocrine therapy combined with signal transduction inhibitors – a means to overcome resistance.
Authors: Johnston SR 
Published: December 2010

Abstract
Abstract #P1-1
Signal transduction inhibitors (STIs) are being investigated in combination with endocrine therapy for breast cancer in an attempt to overcome or prevent de-novo / acquired resistance. Estrogen receptor (ER) signalling often survives despite development of acquired resistance, and even for tumors that become ER negative, receptor expression can be restored. The role of type I growth factor receptors EGFR and HER2 in bi-directional cross-talk with ER signalling has been confirmed in pre-clinical studies where various STIs can yield additive or synergistic effects when combined with endocrine agents. Activation of the PI3-K/Akt pathway has also been associated with resistance to either estrogen deprivation or tamoxifen, and inhibitors of mTOR (a downstream target of Akt) can restore tamoxifen sensitivity in-vitro. Despite the pre-clinical promise that such an approach could enhance endocrine response, results from clinical trials testing this concept have been mixed. In metastatic disease, the addition of trastuzumab to the aromatase inhibitor anastrozole significantly improved progression-free survival (PFS) in ER+ve HER+ve advanced breast cancer, although clinical gains were modest. The EGFR tyrosine kinase inhibitor gefitinib combined with tamoxifen as first-line therapy for ER+ve metastatic disease improved PFS (but not objective response rate) for patients with no prior endocrine therapy or completion of prior adjuvant therapy. A second study in a similar setting showed significant improvement in PFS for gefitinib plus anastrozole. While encouraging that this approach could delay resistance, only a small proportion of patients benefit. Attempts to identify likely responders have been made in the neo-adjuvant setting with pre- and post-treatment biopsies being used to study biomarker changes. A recent pre-operative study of letrozole +/- the mTOR inhibitor everolimus reported greater tumour shrinkage for the combination, with changes in proliferation being predictive for response together with high expression of pS6kinase, a downstream marker of activated mTOR. This result was in contrast to a negative study of letrozole +/- temsirolimus in unselected ER+ve metastatic disease. Compensatory pathways and feedback loops which result in enhanced Akt activation during prolonged therapy may explain this negative result. As such, key aspects that need to be addressed include understanding mechanisms of action for each novel agent, best trial design to demonstrate added benefit, appropriate clinical endpoints for different clinical settings, need for selection of patients with activation of the relevant target, and ensuring stratified populations based on prior endocrine exposure and/or sensitivity. Rigorous attempts need to be made to define molecular signatures and biomarkers that may predict tumors most likely to respond. Ultimately this should facilitate better selection of patients for whom the tumor has the required molecular profile / addicted oncogene pathway that leads to endocrine resistance, who in turn may benefit most from specific combinations of STIs with ER targeting.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr P1-1.