1. Breast Cancer Treatment : Aromatase Inhibitors vs. Tamoxifen Elizabeth Geddes March 9, 2006 Advisor - Dr. Hadley

2. Breast Cancer Brief Breast cancer is the MOST common cancer in womenBreast cancer is the MOST common cancer in women 2 nd leading cause of cancer deaths in women2 nd leading cause of cancer deaths in women Over 212,000 women will be diagnosed with breast cancer and over 40,000 will die in 2006Over 212,000 women will be diagnosed with breast cancer and over 40,000 will die in 2006

3. Types of Cancer Ductal vs. LobularDuctal vs. Lobular Lobular – can be in lobes or lobulesLobular – can be in lobes or lobules In Situ vs. InvasiveIn Situ vs. Invasive Ductal Invasive is most commonDuctal Invasive is most common Hormone receptor positive or negativeHormone receptor positive or negative Estrogen receptor / Progesterone receptorEstrogen receptor / Progesterone receptor Hormone receptor positive cancers are dependent on estrogen/progesterone for growthHormone receptor positive cancers are dependent on estrogen/progesterone for growth

4. Treatment Options ChemotherapyChemotherapy RadiationRadiation MastectomyMastectomy LumpectomyLumpectomy Alternative MedicineAlternative Medicine HORMONE THERAPYHORMONE THERAPY

5. Hormone Therapy Hormone therapy is effective in hormone receptor positive tumorsHormone therapy is effective in hormone receptor positive tumors 75% of all breast cancers are receptor positive75% of all breast cancers are receptor positive Treatment is non-invasive, fairly non- toxicTreatment is non-invasive, fairly non- toxic Used to inhibit progression or recurrence of diseaseUsed to inhibit progression or recurrence of disease

6. Tamoxifen Selective estrogen receptor modulatorSelective estrogen receptor modulator Estrogen agonist and antagonistEstrogen agonist and antagonist Reversibly blocks estrogen binding to receptor in tumor cellsReversibly blocks estrogen binding to receptor in tumor cells Agonist effects include decreased blood lipid changes, and increased bone densityAgonist effects include decreased blood lipid changes, and increased bone density

7. Adverse Effects Thromboembolic eventsThromboembolic events Endometrial cancerEndometrial cancer Hepatic carcinomasHepatic carcinomas Menstrual dysregularitiesMenstrual dysregularities Vaginal dryness and bleedingVaginal dryness and bleeding Hot flushesHot flushes

8. Tamoxifen Resistance Tamoxifen has only been proven effective for a maximum of 5 yearsTamoxifen has only been proven effective for a maximum of 5 years The risks are greater than the benefits past this time frameThe risks are greater than the benefits past this time frame Resistance of the tumors is attributed to this decrease in efficacyResistance of the tumors is attributed to this decrease in efficacy Resistance is thought to be due to the tumor becoming estrogen independentResistance is thought to be due to the tumor becoming estrogen independent

9. Aromatase Inhibitors Block aromatase, inhibiting estrogen synthesisBlock aromatase, inhibiting estrogen synthesis SteroidalSteroidal ExemestaneExemestane Irreversibly inhibitIrreversibly inhibit Non-SteroidalNon-Steroidal Anastrozole and LetrozoleAnastrozole and Letrozole Reversibly inhibitReversibly inhibit

10. Aromatase Inhibitors Only useful in postmenopausal womenOnly useful in postmenopausal women Production of estrogen in premenopausal women overrides aromatase inhibitorsProduction of estrogen in premenopausal women overrides aromatase inhibitors

11. Adverse Effects OsteoporosisOsteoporosis Thromboembolic EventsThromboembolic Events Cardiac EventsCardiac Events Vaginal drynessVaginal dryness

12. Clinical Trials Aromatase Inhibitors vs. Tamoxifen ATAC trialATAC trial 68 months follow-up there was improved disease free survival with Anastrozole over Tamoxifen68 months follow-up there was improved disease free survival with Anastrozole over Tamoxifen Big 1-98Big 1-98 25.8 months follow-up there was improved disease free survival with Letrozole over Tamoxifen25.8 months follow-up there was improved disease free survival with Letrozole over Tamoxifen

13. Sequential Treatments It has been proven that there is an increased disease free survival after 5 years of therapy in patients who switched to aromatase inhibitors after 2-3 years of Tamoxifen compared to those who remained on TamoxifenIt has been proven that there is an increased disease free survival after 5 years of therapy in patients who switched to aromatase inhibitors after 2-3 years of Tamoxifen compared to those who remained on Tamoxifen ABSCG/ARNO - AnastrozoleABSCG/ARNO - Anastrozole ITA - AnastrozoleITA - Anastrozole IES – ExemestaneIES – Exemestane

14. Long term treatments Early results of the MA.17 clinical trial show promise for aromatase inhibitor effectiveness after 5 years of treatmentEarly results of the MA.17 clinical trial show promise for aromatase inhibitor effectiveness after 5 years of treatment Increased disease free survival in patients continuing treatments compared to those on no treatmentIncreased disease free survival in patients continuing treatments compared to those on no treatment Letrozole has shown positive effect in overall survivalLetrozole has shown positive effect in overall survival

15. Current Debates Aromatase inhibitors as initial treatment versus post-Tamoxifen treatmentAromatase inhibitors as initial treatment versus post-Tamoxifen treatment How many years of Tamoxifen before beginning aromatase inhibitors?How many years of Tamoxifen before beginning aromatase inhibitors? Effective length of treatment with aromatase inhibitorsEffective length of treatment with aromatase inhibitors Efficacy between different aromatase inhibitorsEfficacy between different aromatase inhibitors

16. Tolerability In ATAC trial fewer patients withdrew and there were less reported side effects in the aromatase inhibitor populationIn ATAC trial fewer patients withdrew and there were less reported side effects in the aromatase inhibitor population

17. Why should a primary care PA care? Some of our patients will be diagnosed with breast cancerSome of our patients will be diagnosed with breast cancer Patients will follow-up with PCP after seeing oncologistPatients will follow-up with PCP after seeing oncologist We need to be aware of these drugsWe need to be aware of these drugs When to use themWhen to use them Which is the best option for our patientWhich is the best option for our patient Adverse EffectsAdverse Effects Be knowledgeable for patient educationBe knowledgeable for patient education

18. Conclusion Tamoxifen was gold standardTamoxifen was gold standard Aromatase inhibitors are proving to be more effectiveAromatase inhibitors are proving to be more effective Increased disease free survivalIncreased disease free survival Longer treatment optionsLonger treatment options Better tolerabilityBetter tolerability Several questions remain unansweredSeveral questions remain unanswered Hormonal therapies are effective in halting the progression and recurrence of breast cancerHormonal therapies are effective in halting the progression and recurrence of breast cancer

19. References Abram, P., Maass, N., Rea, D., Simon, S., Steger, G. Case studies of fulvestrant (‘Faslodex’) in postmenopausal women with advanced breast cancer. Cancer Treatment Reviews 2005; 31: S17-S25.Abram, P., Maass, N., Rea, D., Simon, S., Steger, G. Case studies of fulvestrant (‘Faslodex’) in postmenopausal women with advanced breast cancer. Cancer Treatment Reviews 2005; 31: S17-S25. Benson, J.R. The use of aromatase inhibitors in postmenopausal women with hormone receptor positive breast cancer. J Clin Oncol 2005; 23: 6807-6809Benson, J.R. The use of aromatase inhibitors in postmenopausal women with hormone receptor positive breast cancer. J Clin Oncol 2005; 23: 6807-6809 Breastcancer.org. January 2006. Available at www.breastcancer.org. Accessed November 2005.Breastcancer.org. January 2006. Available at www.breastcancer.org. Accessed November 2005.www.breastcancer.org Brennan, M., Wilcken, N., French, J., Ung, O., Boyages, J. Management of early breastBrennan, M., Wilcken, N., French, J., Ung, O., Boyages, J. Management of early breast cancer—the current approach. Aust Fam Physician 2005; 34: 755-60.cancer—the current approach. Aust Fam Physician 2005; 34: 755-60. de Ziegler, D., Mattenberger, C., Luyet, C., Romoscanu, I., Irion, N., Bianchi-Demicheli,de Ziegler, D., Mattenberger, C., Luyet, C., Romoscanu, I., Irion, N., Bianchi-Demicheli, F. Clinical use of aromatase inhibitors in premenopausal women. J Steroid Biochem Mol Biol 2005; 95: 121-127.F. Clinical use of aromatase inhibitors in premenopausal women. J Steroid Biochem Mol Biol 2005; 95: 121-127. Gould, R., Garcia, A. Update on aromatase inhibitors in breast cancer. Curr Opin Obstet GynecolGould, R., Garcia, A. Update on aromatase inhibitors in breast cancer. Curr Opin Obstet Gynecol 2006; 18: 41-46.2006; 18: 41-46. Howell, A. Selective oestrogen receptor modulators, aromatase inhibitors and the femaleHowell, A. Selective oestrogen receptor modulators, aromatase inhibitors and the female breast. Curr Opin Obstet Gynecol 2005; 17: 429-434.breast. Curr Opin Obstet Gynecol 2005; 17: 429-434. Ingle, J.N., Suman, V.J. Aromatase inhibitors for therapy of advanced breast cancer. JIngle, J.N., Suman, V.J. Aromatase inhibitors for therapy of advanced breast cancer. J Steroid Biochem Mol Biol 2005; 95: 113-119. Steroid Biochem Mol Biol 2005; 95: 113-119. Jonat, W., Hilpert, F. Optimizing the use of aromatase inhibitors in adjuvant therapy forJonat, W., Hilpert, F. Optimizing the use of aromatase inhibitors in adjuvant therapy for postmenopausal patients with hormone-responsive early breast cancer: current and future prospects. J Cancer Res Clin Oncol 2006; 1: 1-13.postmenopausal patients with hormone-responsive early breast cancer: current and future prospects. J Cancer Res Clin Oncol 2006; 1: 1-13. Kaufmann, M., Rody, A. Long-term risk of breast cancer recurrence: the need forKaufmann, M., Rody, A. Long-term risk of breast cancer recurrence: the need for extended adjuvant therapy. J Cancer Res Clin Oncol 2005; 131: 487-494.extended adjuvant therapy. J Cancer Res Clin Oncol 2005; 131: 487-494. Miller, W.R., Anderson, T.J., White, S., Larionov, A., Murray, J., Evans, D., et al.Miller, W.R., Anderson, T.J., White, S., Larionov, A., Murray, J., Evans, D., et al. Aromatase inhibitors: cellular and molecular effects. J Steroid BiochemAromatase inhibitors: cellular and molecular effects. J Steroid Biochem Mol Biol 2005; 95: 83-89. Mol Biol 2005; 95: 83-89. Normanno, N., DiMaio, M., DeMaio, E., DeLuca, A., deMatteis, A., Giordano, A., et al.Normanno, N., DiMaio, M., DeMaio, E., DeLuca, A., deMatteis, A., Giordano, A., et al. Mechanisms of endocrine resistance and novel therapeutic strategies in breast cancer. Endocrine-Related Cancer 2005; 12: 721-747.Mechanisms of endocrine resistance and novel therapeutic strategies in breast cancer. Endocrine-Related Cancer 2005; 12: 721-747. Osborne, C.K., Schiff, R. Aromatase inhibitors: future directions. J Steroid Biochem MolOsborne, C.K., Schiff, R. Aromatase inhibitors: future directions. J Steroid Biochem Mol Biol 2005; 95: 183-187. Biol 2005; 95: 183-187. Sismondi, P., Biglia, N., Giai, M., Sgro, L., Campagnoli, C. Metabolic effects ofSismondi, P., Biglia, N., Giai, M., Sgro, L., Campagnoli, C. Metabolic effects of tamoxifen in postmenopause. Anticancer Res 1994; 14: 2237-2244.tamoxifen in postmenopause. Anticancer Res 1994; 14: 2237-2244. Young, J.L, Fritz, A., Gonghua, L., Thoburn, K., Kres, J., Roffers, S. Breast cancer. September 2005. Available at http://training.seer.cancer.gov/ss_module01_breast/00_bc_home.html. Accessed February 2006.Young, J.L, Fritz, A., Gonghua, L., Thoburn, K., Kres, J., Roffers, S. Breast cancer. September 2005. Available at http://training.seer.cancer.gov/ss_module01_breast/00_bc_home.html. Accessed February 2006. http://training.seer.cancer.gov/ss_module01_breast/00_bc_home.html. Accessed February 2006 http://training.seer.cancer.gov/ss_module01_breast/00_bc_home.html. Accessed February 2006