Estrogen Receptor and Receptor Tyrosine Kinase Signaling: Use of Combinatorial Hormone and Epidermal Growth Factor Receptor/Human Epidermal Growth Factor Receptor 2–Targeted Therapies for Breast Cancer

Estrogen receptor (ER ) is expressed in nearly 70% of breast cancers and is a key driver of growth in ER-positive breast tumors. ER is primarily a nuclear protein that, when activated by estrogens, acts as a ligand-dependent transcription factor and promotes the expression of several genes that enhance cell survival, proliferation, and tumor progression (Fig 1). Examples of gene products upregulated by ER’s genomic actions include Bcl-2, cyclin D1, and the insulin-like growth factor 1 (IGF-1) receptor. Activated ER can also be localized to the cellular membrane and exert rapid, nongenomic effects. Here ER can colocalize with numerous different signaling molecules that lead to activation of growth and survival-promoting pathways, including the mitogen-activated protein kinase (MAPK) and Akt pathways. The use of hormone therapies, including aromatase inhibitors and selective estrogen receptor modulators, that target and downregulate ER signaling in the breast is a mainstay of treatment for patients with ER-positive breast cancers. Although these agents are extremely effective, a significant proportion of patients exhibit de novo or acquired resistance to hormone therapy. A proposed mechanism of resistance to hormone therapy is signaling crosstalk between ER and growth factor receptor tyrosine kinases (RTKs). In an accompanying article, Guarneri et al report the results of a randomized, double-blind, placebo-controlled, multicenter phase IIb neoadjuvant study of the aromatase inhibitor letrozole combined with the dual epidermal growth factor receptor/human epidermal growth factor receptor 2 (EGFR/ HER2) inhibitor lapatinib in postmenopausal hormone receptor– positive, HER2-negative early-stage breast cancer. Their results show that clinical response rates were similar for patients who received a combination of letrozole and lapatinib compared with patients receiving letrozole and placebo (70% v 63%, respectively). However, on further subset analysis, they found that patients with a PIK3CA mutation (37%) had a significantly higher likelihood of clinical response to the letrozole-lapatinib combination therapy versus those patients without PIK3CA mutations (overall response rate of 93% for patients with mutant PIK3CA v 63% for patients with wild-type PIK3CA). PIK3CA is the gene that encodes the PI3K catalytic subunit p110 , and the PI3K pathway is the most commonly mutated pathway in breast cancers, with PIK3CA recurrent hotspot mutations found at high frequency in ER-positive breast tumors. PI3K has been implicated as a key mediator of hormone resistance in preclinical models, and evidence suggests that hyperactivation of PI3K may enhance estrogen-independent and -dependent ER transcriptional activity. Although inhibition of the PI3K pathway has been postulated to sensitize cells to hormone therapy, several retrospective clinical studies have shown that activating mutations in PIK3CA paradoxically predict for a better long-term prognosis in patients with ER-positive breast cancers treated with hormonal therapy although other studies have shown contradictory results. It is known that activated RTKs and their downstream signaling partners can directly interact with ER and cause phosphorylation of key residues in the AF-1 domain of ER. This phosphorylation results in activation of ER in a ligand-independent fashion to promote cell growth and survival. In addition, membrane-activated ER can activate the EGFR pathway by increasing the production of the EGFR ligand heparin-binding epidermal growth factor. Furthermore, in vitro studies have shown that breast cancer cell lines with acquired resistance to hormone therapy have increased expression and activation of EGFR and HER2 along with their downstream signaling pathways. The use of ErbB-targeted tyrosine kinase inhibitors or the anti-HER2 monoclonal antibody trastuzumab significantly inhibits the growth of these cells after development of resistance to hormone therapies. In addition, sensitivity to hormone therapies can be restored when resistant cells are treated with lapatinib, a dual EGFR/ HER2 inhibitor. Together, these data suggest that enhanced RTK signaling and activationofPI3Ksignalingmaybekeycontributorstoresistancetohormone therapies in breast cancer. This provides the rationale for the dual JOURNAL OF CLINICAL ONCOLOGY U N D E R S T A N D I N G T H E P A T H W A Y VOLUME 32 NUMBER 10 APRIL 1 2014