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A distinct mechanism of action and a different way of overcoming disease resistance

FASLODEX 500 mg MOA

FASLODEX (fulvestrant) is the first in a class of endocrine agents for postmenopausal women with hormone receptor-positive advanced breast cancer failing on prior anti-oestrogen therapy. It is a unique oestrogen receptor downregulator with no known agonist effects1 and a mechanism of action distinct from that of other endocrine agents.2

FASLODEX MOA—reducing chance of oestrogen receptor being activated by alternative pathways

FASLODEX binds, blocks and, unlike tamoxifen or other SERMs, degrades the oestrogen receptor, completely inhibiting oestrogen receptor signalling.3

FASLODEX MOA—reducing chance of oestrogen receptor being activated by alternative pathways

As a result, there is less chance of the oestrogen receptor being activated by alternative pathways that are believed to cause resistance (eg, growth factor–mediated mechanisms).3

  • FASLODEX degrades the oestrogen receptor in a dose dependent manner resulting in its down regulation, and the 250-mg dose does so to a greater extent than tamoxifen (20 mg/day for 14-21 days p.o.) (P=0.024).4 Similarly, it has been observed that FASLODEX doses up to 250 mg reduce progesterone receptor expression and Ki67 in a dose-dependent manner4
  • In the NEWEST neoadjuvant trial,5 FASLODEX 500 mg reduced mean Ki67 labelling index to a significantly greater extent than FASLODEX 250 mg (P<0.0001) following 4 weeks of treatment. This was associated with a significantly greater (P<0.0003) reduction in oestrogen receptor with the 500 mg dose
  • The molecular effects of FASLODEX are different than those of the selective oestrogen receptor modulator (SERM) tamoxifen, which results in FASLODEX leading to total inactivation of oestrogen receptor-regulated transcription; by contrast, tamoxifen leads to only a partial inactivation4
  • FASLODEX also inhibits oestrogen receptor dimerisation, reduces uptake of drug-receptor complex and prevents the oestrogen receptor from binding to oestrogen-responsive genes6

References

  1. Addo S et al. A phase I trial to assess the pharmacology of the new oestrogen receptor antagonist fulvestrant on the endometrium in healthy postmenopausal volunteers. Br J Cancer 2002; 87(12): 1354–9.
  2. Wakeling AE. Similarities and distinctions in the mode of action of different classes of antioestrogens. Endocr Relat Cancer 2000; 7(1): 17–28.
  3. Nicholson RI, Johnston SR. Endocrine therapy—current benefits and limitations. Breast Cancer Res Treat 2005; 93(suppl 1): S3–S10.
  4. Robertson JF et al. Comparison of the short-term biological effects of 7alpha-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)-nonyl]estra-1,3,5, (10)-triene-3,17beta-diol (Faslodex) versus tamoxifen in postmenopausal women with primary breast cancer. Cancer Res 2001; 61(18): 6739–46.
  5. Singer CF et al. NEWEST: a Phase II, randomised, neoadjuvant trial comparing fulvestrant 500 mg vs 250 mg in postmenopausal women with locally advanced, oestrogen receptor-positive (ER+) breast cancer. Eur J Cancer 2008; 6(suppl): 115. Abstract 227.
  6. Possinger K. Fulvestrant—a new treatment for postmenopausal women with hormone-sensitive advanced breast cancer. Expert Opin Pharmacother 2004; 5(12): 2549–58.