ER activation can be achieved through epidermal growth factor (EGF) and the MAPK-signaling pathways (48,61,64,65). Fulvestrant-resistant cells lose ERa expression (61), demonstrate a decline in ER-mediated transcription (62), and appear to have an increased dependence on the EGF/MAPK pathways (61,62). Ful-vestrant resistance can be reversed with the addition of the EGFR tyrosine kinase inhibitor gefitinib (62). Combination treatment with gefitinib and fulvestrant decreased proliferation in MCF-7 cells (66).
Crosstalk between ER and HER2 offers a potential target for combination therapy. Although both single-agent fulvestrant and single-agent trastuzumab inhibit the growth of tamoxifen resistant, HER2 overexpressing cells, the combination is superior (67). Other targeted agents with preclinical evidence of benefit in combination with fulvestrant include lapatinib, a dual kinase inhibitor that disrupts both EGFR and HER2 (68), and tipifarnib, which inhibits farnesyl transferase, an enzyme involved downstream of EGFR and HER2 (10).
Several targeted agents are being combined with fulvestrant in clinical trials. A phase II, open-label Eastern Cooperative Oncology Group (ECOG 4101) trial will assess gefinitib in combination with 250 mg fulvestrant versus gefinitib in combination with anastrozole in hormone-positive postmenopausal women with ABC (10). Trial treatment may be first- or second-line. A separate phase II trial will evaluate the efficacy of trastuzumab alone, high dose fulvestrant alone, and the combination of the two agents in HER2 positive, hormone-positive postmenopausal women with ABC (10).
The combination of lapatinib and loading dose fulvestrant will be assessed in a phase III, placebo-controlled trial by the Cancer and Leukemia Group B (CALGB 40302) (10). The comparator will be fulvestrant alone and eligibility criteria include postmenopausal status, hormone-positive tumors, HER2- or EGFR-positive ABC, and prior exposure to an AI (10). An additional phase II trial will investigate the utility of combining fulvestrant and tipifarnib in the second-line setting after failure of a prior endocrine treatment for postmenopausal, hormone receptor-positive women with ABC (10).
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