Liarozole fumarate (R85246): a novel imidazole in the treatment of receptor positive postmenopausal metastatic breast cancer

Abstract

This phase II study of liarozole fumarate (R85246, liarozole), a novel imidazole with retinomimetic and aromatase inhibitory effects, was designed to determine the efficacy and tolerability in postmenopausal women with advanced breast cancer in progression, to correlate these effects with hormonal levels, and to evaluate quality of life. Twenty-nine women with ER-positive or unknown metastatic disease who received > or = 2 prior hormonal therapies were treated with 150-300 mg liarozole twice daily until disease progression. All patients were evaluable for toxicity and 25 for response. Four patients (16.0%, 95% CI 5.3-37.4%) had partial remission (PR) of their disease for a median of 7.4 months (range 1.2-12.9) and 7 (28%) had disease stabilization for a median of 4.8 months (1.6-16.0). Estradiol decreased from pre-treatment levels of 9.2-52 pM (mean 17.1) to below detection (9.2 pM, p = 0.0005) after 1 month. Similarly estrone levels fell from 14-307 pM (mean 92.7) to below detection (9.2 pM, p = 0.0001). The most common toxicity was dermatological (96.6%) with features compatible with hypervitaminosis A syndrome such as rash, pruritus, dry skin, and brittle nails. The majority of these were mild to moderate in severity. No significant improvement in quality of life scores (FLI-C) were noted. Liarozole is an active new treatment for breast cancer in patients heavily pre-treated with hormone therapies. Further studies are needed to confirm its relative efficacy in both receptor positive and negative postmenopausal breast cancer.

Antiestrogen resistance in breast cancer and the role of estrogen receptor signaling

“…Nonetheless, several observations suggest that various forms of both estrogen independence and antiestrogen resistance exist and that these may be biologically and clinically very different. For example, second-line responses to aromatase inhibitors after response and recurrence on TAM are common (Goss et al, 1995;Buzdar et al, 1996). Crossover between more similar compounds, such as other nonsteroidal antiestrogens, rarely produces secondary responses (Johnston, 2001), although crossover to structurally different antiestrogens can produce secondary responses in patients.…”

Effects of Novel Retinoic Acid Metabolism Blocking Agent (VN/14-1) on Letrozole-Insensitive Breast Cancer Cells

“…Cancer Res 2006; 66: (23 Effect of VN/14-1 on growth factor signaling pathways. As seen from the growth study results, LTLC cells were more sensitive to growth-inhibitory effects of VN/14-1 compared with the parental MCF-7Ca cells.…”

“…However, the rapid metabolism of ATRA in the body is believed to be one of the major reasons for limited efficacy of ATRA. Thus, retinoic acid metabolism blocking agents (RAMBA) represent a promising approach for various diseases responsive to ATRA, including breast cancer, especially in patients heavily pretreated with hormone therapies (23).…”

Therapeutic Potential of the Inhibition of the Retinoic Acid Hydroxylases CYP26A1 and CYP26B1 by Xenobiotics

“…Since then, researchers have explored the possibility that liarozole could be used in the treatment of other types of cancer. However, liarozole was ineffective in non-small cell lung cancer [105] and was beneficial only in a small fraction of breast cancer patients (10–35% of patients were responsive, [106–108]) when administered as single agent (Table 1). Whether efficacy of liarozole would be improved with co-administration with ATRA is not known.…”