Update on Novel Drug Targets in Metastatic Breast Cancer | Page 2

Massimo Cristofanilli, MD, FACP
Published Online: Friday, May 16, 2014
Two other studies have evaluated the combination of fulvestrant with an AI in advanced setting.12,13 The Fulvestrant and Anastrozole Combination Therapy (FACT) trial was a multicenter, international, randomized study that enrolled 514 patients treated with either the combination regimen or single agent anastrozole.12 Approximately a third of patients were endocrine therapy naïve (34.4% vs 30.2% anastrozole vs combination respectively). Prior adjuvant chemotherapy exposure was also more frequent in the anastrozole group (49.6% vs 41.9%). There was no statistically significant difference in overall response rate (ORR) (33.6% vs 31.8% for anastrozole vs combination respectively) and median time to progression (TTP) of 10.2 months for anastrozole compared with 10.8 months for anastrozole plus fulvestrant (hazard ratio [HR] = 0.99, 95% CI, 0.81-1.20; P = .91). The Study of Faslodex with or without Arimidex vs Exemestane following progression on non-steroidal Aromatase inhibitors (SoFEA) was a multicenter, phase III randomized controlled trial.13

Participants were randomly assigned (1:1:1) to receive fulvestrant (500 mg intramuscular injection on day 1, followed by 250-mg doses on days 15 and 29, and then every 28 days) plus daily oral anastrozole (1 mg); fulvestrant plus anastrozole-matched placebo; or daily oral exemestane (25 mg). A total of 723 patients underwent randomization: 243 were assigned to receive fulvestrant plus anastrozole, 231 to fulvestrant plus placebo, and 249 to exemestane. Median PFS was 4.4 months (95% CI 3.4- 5.4) in patients assigned to fulvestrant plus anastrozole, 4.8 months (3.6-5.5) in those assigned to fulvestrant plus placebo, and 3.4 months (3.0-4.6) in those assigned to exemestane. No difference was recorded between the patients assigned to fulvestrant plus anastrozole and fulvestrant plus placebo (HR = 1.00, 95% CI 0.83-1.21; log-rank P = .98), or between those assigned to fulvestrant plus placebo and exemestane (HR = 0.95, 95% CI, 0.79-1.14; log-rank P = .56).

In summary, these studies suggest that a combination of fulvestrant and AI should be considered an appropriate choice only for a selected population of de novo stage IV or endocrine-naïve HR-positive postmenopausal patients. Unfortunately, after an initial response to hormonal therapy, most ER-positive tumors develop resistance leading to disease progression.14 Preclinical models have shown that an adaptive upregulation of growth factor signaling is associated with acquired resistance to endocrine therapies, whereas overexpression of human epidermal growth factor receptor 2 (HER2) in ER-positive breast cancer is responsible for de novo resistance to tamoxifen and AIs.15,16

Furthermore, studies on ER biology have highlighted the fundamental role of other signaling pathways in the development of resistance to hormone therapies.17 It has been suggested that overactive growth factor receptor signaling through multiple intracellular pathways may contribute to the evolution of an endocrine resistance phenotype. Manipulation of growth factor signaling networks has emerged as an attractive strategy to delay the onset, or potentially even overcome the resistance to endocrine therapy in breast cancer.18 In this context, a number of clinical trials have tested the use of HER2/neu antagonists, insulin-like growth factor 1 receptor (IGF1R) inhibitors, tyrosine kinase inhibitors (TKIs), multikinase inhibitors, cyclin- dependent inhibitors, mTOR antagonists, and src-inhibitors19,20 together with hormone therapy. More recently, new ER alpha mutations were described in tumor samples from patients with endocrine-resistant disease, particularly in cases of long-term exposure to antiestrogen therapy.21-23

These studies suggest that the increased routine use of molecular diagnostics platforms in the evaluation of patients with MBC will contribute to improving our understanding of the complex biology of this disease, particularly in ER-positive breast cancer considering the availability of multiple molecularly targeted therapies.

Growth-Factor Receptor Modulation

Preclinical data have provided evidence that crosstalk between growth factor receptor and ER pathways may mediate the development of resistance to endocrine therapy in HR-positive disease.17,18 For example, increased expression of epidermal growth factor receptor (EGFR), human ErbB2 (HER2), and insulin- like growth factor 1 receptors can elicit tamoxifen resistance, as can activation of their downstream signaling pathway components, particularly extracellular signal-regulated kinase and phosphoinositol-3-kinase.16,24 EGFR overexpression is also predictive of a decreased benefit from tamoxifen,18,19 and patients with higher EGFR expression are less likely to respond to tamoxifen and have a significantly shorter time to treatment failure.25

The combination of endocrine therapy and trastuzumab (Herceptin) or lapatinib (Tykerb) is a first-line therapeutic option in patients with HER2-positive/HR-positive metastatic tumors based of the results of two prospective randomized studies.26,27

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