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The Role of CDK4/6 in Breast Cancer

The Role of CDK4/6 in Breast Cancer. Note to Viewers/Users. These slides have been developed by Pfizer and are provided as an informational resource The slides may be used for noncommercial presentations. Presentation Overview. Brief overview of breast cancer

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The Role of CDK4/6 in Breast Cancer

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  1. The Role of CDK4/6 in Breast Cancer

  2. Note to Viewers/Users • These slides have been developed by Pfizer and are provided as an informational resource • The slides may be used for noncommercial presentations

  3. Presentation Overview • Brief overview of breast cancer • Role of cyclin-dependent kinases 4 and 6 (CDK4/6)in normal and tumor cells • Role of CDK4/6 in estrogen receptor-positive (ER+) breast cancer

  4. Brief Overview of Breast Cancer

  5. Breast Cancer Epidemiology (United States) • Breast cancer is one of the most common cancers affecting women in the United States, with a lifetime risk of »1 in 8 (12%)1 • Nearly 30% of women diagnosed with early breast cancer will eventually progress to advanced disease2 • It is estimated that »250,000 women in the United States are living with advanced breast cancer3 • Exceeded only by lung cancer, breast cancer is the second leading cause of cancer death in women1 • »39,620: the estimated number of US women who died from breast cancer in 20131 1. American Cancer Society.www.cancer.org/acs/groups/cid/documents/webcontent/003090-pdf.pdf. Accessed December 16, 2013; 2. O’Shaughnessy J. Oncologist. 2005;10(suppl 3):20-29; 3. AdvancedBC.org. www.advancedbc.org/node/26. Accessed December 9, 2013.

  6. What Is ER+ Breast Cancer? • Breast cancer tumors can be characterized by the presence or absence of specific receptors, including: • Estrogen receptor (ER) • Progesterone receptor (PR) • Human epidermal growth factor receptor 2 (HER2) • »2 out of 3 US women with breast cancer are hormone receptor-positive (HR+), with cancerous cells that express ER (ER+) and/or PR (PR+) • Growth of ER+ breast cancer is driven by estrogen American Cancer Society.www.cancer.org/acs/groups/cid/documents/webcontent/003090-pdf.pdf. Accessed December 16, 2013.

  7. Treatment Options for ER+ Breast Cancer • Treatment options for ER+ breast cancer include local therapy (eg, surgery, radiation therapy) and systemic therapy (eg, chemotherapy, endocrine/hormonal therapy)1,2 • Hormonal therapy can be used as recommended for women with ER+ breast cancer and is used as1,2: • Adjuvant treatment • Neoadjuvant treatment • Treatment of metastatic breast cancer • When selecting a hormonal therapy, a woman’s menopausal status is taken into consideration1,2 Aromatase Inhibitors (AIs) decrease the amount of available estrogen by inhibiting the conversion of androgens to estrogen, a primary source of estrogen in post-menopausal women1,2 Antiestrogens prevent estrogen from binding to the ER, regardless of estrogen source, and may be used to treat women prior to or after menopause1,2 • 1. American Cancer Society.www.cancer.org/acs/groups/cid/documents/webcontent/003090-pdf.pdf. Accessed December 16, 2013; 2. National Cancer Institute. www.cancer.gov/cancertopics/factsheet/Therapy/hormone-therapy-breast. Accessed December 19, 2013.

  8. Examples of Hormonal Therapies for ER+ Breast Cancer (and Year of FDA Approval) Letrozole3(1997) Fulvestrant6(2002) Toremifene4(1997) Exemestane5(1999) Anastrozole2(1995) Tamoxifen1(1977) 1980 1995 2000 2010 2014 1990 , antiestrogen; , aromatase inhibitor. 1. Drugs@FDA. www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails. Accessed January 27, 2014; 2. Arimidex [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals; 2013; 3. Femara [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp.; 2014; 4. Fareston [package insert]. Bridgewater, NJ: ProStraken Inc.; 2012; 5. Aromasin [package insert]. New York, NY: Pfizer Inc; 2013. 6. Faslodex [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals; 2012.

  9. Role of CDK4/6 in Normal and Tumor Cells

  10. Cell Cycle Overview • Cellular proliferation is largely controlled by extracellular factors that trigger progression through the cell cycle1,2 • The cell cycle consists of 4 highly regulated phases1,2: • G1: cell growth and checkpoint for S phase • S: DNA synthesis • G2: cell growth and checkpoint for M phase • M: mitosis, cell division • In G1, CDK4/6 activation is required for progression to and passage through the critical Restriction point (R point), when cells commit to pass through the remaining G1 phase and complete the cell cycle1,2 • CDK4/6 are serine/threonine kinases that function in the nucleus, and whose activity depends on forming a complex with a regulatory subunit, called cyclin D11,2 Cell Cycle • 1. Sotillo E, Graña X. In: Cell Cycle Deregulation in Cancer 2010:3-22; 2. Weinberg RA. In: The Biology of Cancer; 2014:275-329.

  11. CDK4/6: Downstream Cell Cycle Regulators • The expression of cyclin D1—a protein that preferentially binds to and activates CDK4/6—is induced by mitogenic growth factors, acting through various upstream signaling pathways1 • Cyclin D1 is a direct transcriptional target of ER2 • These multiple signaling pathways, including mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K), and ER, converge downstream at the cyclin D1-CDK4/6 complex, leading to its activation3 • 1. Weinberg RA. In: The Biology of Cancer; 2014:275-329; 2. Finn RS, et al. Breast Cancer Res. 2009;11(5):R77; 3. Sotillo E, Graña X. In: Cell Cycle Deregulation in Cancer; 2010:3-22

  12. Role of CDK4/6 in Normal Cells Activated CDK4/6 Lead to Phosphorylation of RB and Thereby Regulate Cell Cycle Progression and Cellular Proliferation • Once activated, CDK4/6 lead to phosphorylation (Figure A) and thus inactivation of the retinoblastoma protein (RB; Figure B), which is1,2: • A key tumor-suppressor protein • A critical target of cyclin D1-CDK4/6 • Inactivated RB releases key transcription factors (E2F; Figure B), allowing expression of several genes whose protein products are necessary for S-phase entry and DNA replication1,2 A A B B P , phosphorylation. • 1. Sotillo E, Graña X. In: Cell Cycle Deregulation in Cancer; 2010:3-22;2. Fry DW, et al. Mol Cancer Ther. 2004;3(11):1427-1438.

  13. Role of CDK4/6 in Tumor Cells • Weinberg RA. In: The Biology of Cancer; 2014:275-328.

  14. Role of CDK4/6 in ER+ Breast Cancer

  15. CDK4/6: Downstream Targets of ER Signaling in ER+ Breast Cancer • ER+ breast cancer exhibits a high frequency of cell cycle dysregulation due to aberrant expression of key regulators1 • The increased expression of cyclin D1 is frequently observed in ER+ breast cancer,2,3 which may lead to increased CDK4/6 activity • CDK4/6 are downstream targets of ER signaling in ER+ breast cancer1,4 • Estrogen induces cyclin D1-CDK4/6 activation, which leads to RB phosphorylation and cell cycle progression4,5 • 1. Finn RS, et al. Breast Cancer Res. 2009;11(5):R77; 2. Gillett C, et al. Cancer Res. 1994;54(7):1812-1817; 3. Hui R, et al. Clin Cancer Res. 1996;2(6):923-928; 4. Weinberg RA. In: The Biology of Cancer; 2014:275-329; 5. Kilker RL, et al. J Steroid Biochem Mol Biol. 2004;92(1-2):63-71.

  16. Synergistic Potential of Dual Inhibition in ER+ Breast Cancer Cell Lines • 1. Sutherland RL, Musgrove EA. Breast Cancer Res. 2009;11(6):112; 2. Finn RS et al. Breast Cancer Res. 2009;11(5):R77.

  17. Summary • Breast cancer is one of the most common cancers in US women • »250,000 women in the United States are living with advanced breast cancer • Approximately 2 out of 3 women with breast cancer in the United States have hormone receptor-positive disease • CDK4/6 inhibition, and the role it may play in restoring cell cycle control in cancer, are critical areas of study • Research is focusing on the dual inhibition of ER and CDK4/6 in breast cancer

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