Aromatase inhibitors: combinations with fulvestrant or signal transduction inhibitors as a strategy to overcome endocrine resistance.
There is an increasing rationale for effective combinations of endocrine therapy with novel drugs that target aberrant signal transduction pathways in estrogen receptor (ER) positive breast cancer. Prolonged endocrine therapy can be associated with an acquired increase in peptide growth factor signaling (EGFR, HER2), together with cross-talk activation of ER-dependent gene transcription and cell growth that leads to endocrine resistance. Current approaches to target these pathways include both the selective ER downregulator fulvestrant, and various signal transduction inhibitors (STIs). Fulvestrant can overcome resistance to tamoxifen (TAM-R) and long-term estrogen deprivation (LTED-R) in experimental models by reducing ER expression, and represents a current option for post-menopausal women with endocrine resistant ER+ve breast cancer. Emerging data suggest that fulvestrant's effect may be greater when combined with estrogen deprivation, and several phase III trials are assessing fulvestrant combined with aromatase inhibitors (AIs). Small molecule STIs such as tyrosine kinase inhibitors (TKIs), farnesyltransferase inhibitors (FTIs) and mTOR antagonists are also active in breast cancer. Pre-clinical data suggest that combined endocrine/STI therapy may result in greater growth inhibition than either therapy alone, and thus delay emergence of resistance. Several clinical trials are now examining STIs combined with AIs both in the tamoxifen-resistant and first-line advanced breast cancer setting, while pre-surgical studies are investigating the efficacy of combined endocrine/STI therapy utilising biological primary endpoints. This article reviews the pre-clinical rationale for this strategy and the clinical trials in this area.
Johnston
Stephen R D
SR
Department of Medicine-Breast Unit, The Royal Marsden NHS Trust, 233 Fulham Road, London SW3 6JJ, UK. stephen.johnston@rmh.nthames.nhs.uk
Martin
Lesley-Ann
LA
Head
Julia
J
Smith
Ian
I
Dowsett
Mitch
M
D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology / Q000627:therapeutic use*; D047072:Aromatase Inhibitors / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000276:immunology; D004351:Drug Resistance; D004359:Drug Therapy, Combination; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D020847:Estrogen Receptor Modulators / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D000077267:Fulvestrant; D006801:Humans; D011960:Receptors, Estrogen / Q000032:analysis / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
D018931:Antineoplastic Agents, Hormonal; D047072:Aromatase Inhibitors; D020847:Estrogen Receptor Modulators; D011960:Receptors, Estrogen; D000077267:Fulvestrant; D004958:Estradiol