MECHANISM OF DISEASE &
MECHANISM OF ACTION

The estrogen receptor (ER) is a critical target

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Explore the critical role the ER plays in ER+ mBC1-5

The ER is known to drive tumor cell proliferation in several ways, including via cell cycle activation, regardless of the presence or absence of estrogen.6-10 The latest science shows that the ER plays a critical role in ER+ mBC.1-5

ER+=estrogen receptor-positive; mBC=metastatic breast cancer.

Discover how FASLODEX targets the ER11,12
 

FASLODEX remains the only approved hormonal therapy capable of targeting the ER through one distinct mechanism of action with 5 key elements/components11,13-17:

Binds

Binds competitively to the ER with no known agonist effects11,12

Blocks

Blocks ER activating functions, dimerization, and nuclear translocation12,18-20

Degrades

Degrades the ER by accelerating protein and progesterone receptor loss12,19,21-23

Inhibits

Inhibits the growth of estrogen-sensitive and tamoxifen-resistant tumor cell lines in vitro and the potential for ER-mediated signaling11,12,24,25

decrease

Associated with a decrease in Ki67 labeling index, a marker of tumor cell proliferation11

Want to learn more about how FASLODEX targets the ER or the role of the ER in ER+ mBC?1-5,11,12

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References: 1. Osborne CK, Schiff R. Mechanisms of endocrine resistance in breast cancer. Annu Rev Med. 2011;62:233-247. 2. Osborne CK, Shou J, Massarweh S, et al. Crosstalk between estrogen receptor and growth factor receptor pathways as a cause for endocrine therapy resistance in breast cancer. Clin Cancer Res. 2005;11(2, pt 2):865s-870s. 3. Rajbhandari P, Finn G, Solodin NM, et al. Regulation of estrogen receptor α N-terminus conformation and function by peptidyl prolyl isomerase Pin1. Mol Cell Biol. 2012;32(2):445-457. 4. Lamb R, Lehn S, Rogerson L, et al. Cell cycle regulators cyclin D1 and CDK4/6 have estrogen receptor-dependent divergent functions in breast cancer migration and stem cell-like activity. Cell Cycle. 2013;12(15):2384-2394. 5. Hammond MEH, Hayes DF, Dowsett M. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer (unabridged version). Arch Pathol Lab Med. 2010;134:e48-e72. 6. Bunone G, Briand PA, Miksicek RJ, et al. Activation of the unliganded estrogen receptor by EGF involves the MAP kinase pathway and direct phosphorylation. EMBO J. 1996;15(9):2174-2183. 7. Oesterreich S, Zhang P, Guler RL, et al. Re-expression of estrogen receptor α in estrogen receptor α-negative MCF-7 cells restores both estrogen and insulin-like growth factor-mediated signaling and growth. Cancer Res. 2001;61:5771-5777. 8. Razandi M, Pedram A, Merchenthaler I, et al. Plasma membrane estrogen receptors exist and functions as dimers. Mol Endocrinol. 2004;18(12):2854-2865. 9. Finn RS, Aleshin A, Slamon DJ. Targeting the cyclin-dependent kinases (CDK) 4/6 in estrogen receptor-positive breast cancers. Breast Cancer Res. 2016;18(1):17. 10. Miller TW, Balko JM, Fox EM, et al. ERα-dependent E2F transcription can mediate resistance to estrogen deprivation in human breast cancer. Cancer Discov. 2011;1(4):338-351. 11. Prescribing Information for FASLODEX. AstraZeneca Pharmaceuticals LP, Wilmington, DE. 12. Wakeling AE, Dukes M, Bowler J. A potent specific pure antiestrogen with clinical potential. Cancer Res. 1991;51:3867-3873. 13. Afinitor [full Prescribing Information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2016. 14. Prescribing Information for ARIMIDEX. AstraZeneca Pharmaceuticals LP, Wilmington, DE. 15. Ibrance [full Prescribing Information]. New York, NY: Pfizer Inc; 2016. 16. Femara [full Prescribing Information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2014. 17. Prescribing Information for NOLVADEX. AstraZeneca Pharmaceuticals LP, Wilmington, DE. 18. Movérare-Skrtic S, Börjesson AE, Farman HH, et al. The estrogen receptor antagonist ICI 182,780 can act both as an agonist and an inverse agonist when estrogen receptor α AF-2 is modified. Proc Natl Acad Sci USA. 2014;111(3):1180-1185. 19. Kocanova S, Mazaheri M, Caze-Subra S, et al. Ligands specify estrogen receptor alpha nuclear localization and degradation. BMC Cell Biol. 2010;11(98):1-13. 20. Chen D, Pace PE, Coombes RC, et al. Phosphorylation of human estrogen receptor α by protein kinase A regulates dimerization. Mol Cell Biol. 1999;19(2):1002-1015. 21. Robertson JF, Nicholson RI, Bundred NJ, et al. Comparison of the short-term biological effects of 7α-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)-nonyl]estra-1,3,5 (10)-triene-3,17β-diol (Faslodex) versus tamoxifen in postmenopausal women with primary breast cancer. Cancer Res. 2001;61:6739-6746. 22. McClelland RA, Manning DL, Gee JMW, et al. Effects of short-term antiestrogen treatment of primary breast cancer on estrogen receptor mRNA and protein expression and on estrogen-regulated genes. Breast Cancer Res Treat. 1996;41(1):31-41. 23. Watts CKW, Brady A, Sarcevic B, et al. Antiestrogen inhibition of cell cycle progression in breast cancer cells is associated with inhibition of cyclin-dependent kinase activity and decreased retinoblastoma protein phosphorylation. Mol Endocrinol. 1995;9(12):1804-1813. 24. Singh M, Sétáló G Jr, Guan X, et al. Estrogen-induced activation of the mitogen-activated protein kinase cascade in the cerebral cortex of estrogen receptor-α knock-out mice. J Neurosci. 2000;20(5):1694-1700. 25. Chan TW, Pollak M, Huynh H. Inhibition of insulin-like growth factor signaling pathways in mammary gland by pure antiestrogen ICI 182,780. Clin Cancer Res. 2001;7:2545-2554.

 
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Important Safety Information About FASLODEX

Contraindications

  • FASLODEX is contraindicated in patients with known hypersensitivity to the drug or to any of its components. Hypersensitivity reactions, including urticaria and angioedema, have been reported in association with FASLODEX

Risk of Bleeding

  • Because FASLODEX is administered intramuscularly, it should be used with caution in patients with bleeding diatheses, thrombocytopenia, or in patients on anticoagulants

Hepatic Impairment

  • FASLODEX is metabolized primarily in the liver. A 250-mg dose is recommended in patients with moderate hepatic impairment (Child-Pugh class B). FASLODEX has not been evaluated in patients with severe hepatic impairment (Child-Pugh class C)

Injection Site Reaction

  • Use caution while administering FASLODEX at the dorsogluteal injection site due to the proximity of the underlying sciatic nerve. Injection site related events including sciatica, neuralgia, neuropathic pain, and peripheral neuropathy have been reported with FASLODEX injection

Embryo-Fetal Toxicity and Lactation

  • Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during FASLODEX treatment and for 1 year after the last dose. Advise lactating women not to breast-feed during treatment with FASLODEX and for 1 year after the final dose because of the potential risk to the infant

Immunoassay Measurement of Serum Estradiol

  • Due to structural similarity of fulvestrant and estradiol, FASLODEX can interfere with estradiol measurement by immunoassay, resulting in falsely elevated estradiol levels

Adverse Reactions

Monotherapy

  • The most common adverse reactions occurring in ≥5% of patients receiving 500 mg FASLODEX were: injection site pain, nausea, bone pain, arthralgia, headache, back pain, fatigue, pain in extremity, hot flash, vomiting, anorexia, asthenia, musculoskeletal pain, cough, dyspnea, and constipation
  • Increased hepatic enzymes (ALT, AST, ALP) occurred in >15% of FASLODEX users and were not dose-dependent

Combination Therapy

  • The most frequently reported serious adverse reactions in patients receiving FASLODEX plus palbociclib were infections (3%), pyrexia (1%), neutropenia (1%) and pulmonary embolism (1%)
  • The most common adverse reactions (≥10%) of any grade reported in patients receiving FASLODEX plus palbociclib were: neutropenia, leukopenia, infections, fatigue, nausea, anemia, stomatitis, headache, diarrhea, thrombocytopenia, constipation, vomiting, alopecia, rash, decreased appetite, and pyrexia

Indications for FASLODEX

Monotherapy

  • FASLODEX is indicated for the treatment of hormone receptor (HR)-positive metastatic breast cancer in postmenopausal women with disease progression following antiestrogen therapy

Combination Therapy

  • FASLODEX in combination with palbociclib is indicated for the treatment of HR-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer in women with disease progression after endocrine therapy

Important Safety Information About FASLODEX  

Contraindications

  • FASLODEX is contraindicated in patients with known hypersensitivity to the drug or to any of its components. Hypersensitivity reactions, including urticaria and angioedema, have been reported in association with FASLODEX

Risk of Bleeding

  • Because FASLODEX is administered intramuscularly, it should be used with caution in patients with bleeding diatheses, thrombocytopenia, or in patients on anticoagulants

Hepatic Impairment

  • FASLODEX is metabolized primarily in the liver. A 250-mg dose is recommended in patients with moderate hepatic impairment (Child-Pugh class B). FASLODEX has not been evaluated in patients with severe hepatic impairment (Child-Pugh class C)

Injection Site Reaction

  • Use caution while administering FASLODEX at the dorsogluteal injection site due to the proximity of the underlying sciatic nerve. Injection site related events including sciatica, neuralgia, neuropathic pain, and peripheral neuropathy have been reported with FASLODEX injection

Embryo-Fetal Toxicity and Lactation

  • Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during FASLODEX treatment and for 1 year after the last dose. Advise lactating women not to breast-feed during treatment with FASLODEX and for 1 year after the final dose because of the potential risk to the infant

Immunoassay Measurement of Serum Estradiol

  • Due to structural similarity of fulvestrant and estradiol, FASLODEX can interfere with estradiol measurement by immunoassay, resulting in falsely elevated estradiol levels

Adverse Reactions

Monotherapy

  • The most common adverse reactions occurring in ≥5% of patients receiving 500 mg FASLODEX were: injection site pain, nausea, bone pain, arthralgia, headache, back pain, fatigue, pain in extremity, hot flash, vomiting, anorexia, asthenia, musculoskeletal pain, cough, dyspnea, and constipation
  • Increased hepatic enzymes (ALT, AST, ALP) occurred in >15% of FASLODEX users and were not dose-dependent

Combination Therapy

  • The most frequently reported serious adverse reactions in patients receiving FASLODEX plus palbociclib were infections (3%), pyrexia (1%), neutropenia (1%) and pulmonary embolism (1%)
  • The most common adverse reactions (≥10%) of any grade reported in patients receiving FASLODEX plus palbociclib were: neutropenia, leukopenia, infections, fatigue, nausea, anemia, stomatitis, headache, diarrhea, thrombocytopenia, constipation, vomiting, alopecia, rash, decreased appetite, and pyrexia

Indications for FASLODEX

Monotherapy

  • FASLODEX is indicated for the treatment of hormone receptor (HR)-positive metastatic breast cancer in postmenopausal women with disease progression following antiestrogen therapy

Combination Therapy

  • FASLODEX in combination with palbociclib is indicated for the treatment of HR-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer in women with disease progression after endocrine therapy

Please see full Prescribing Information with Patient Information.