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A turning point in adjuvant therapy: Optimizing use of aromatase inhibitors

Invasive Breast Cancer by Age and ER-PR status. (Year 1998) . Li CL et al. J Clin Oncol 2003, 1:28. Mortalit

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A turning point in adjuvant therapy: Optimizing use of aromatase inhibitors

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    1. A turning point in adjuvant therapy: Optimizing use of aromatase inhibitors P Pronzato Genova

    3. Mortalit per cancro negli ultimi 50 anni Nei Paesi Occidentali si sta assistendo ad un decremento della mortalit per carcinoma mammario (nonostante lincremento in incidenza). Il fenomeno comunemente attribuito alla applicazione dello screening mammografico e allimpiego su larga scala delle terapie adiuvanti.Nei Paesi Occidentali si sta assistendo ad un decremento della mortalit per carcinoma mammario (nonostante lincremento in incidenza). Il fenomeno comunemente attribuito alla applicazione dello screening mammografico e allimpiego su larga scala delle terapie adiuvanti.

    12. Optimization Premenopause (+ LHRHa) Upfront vs early switch Duration after switch Which AI Selection of pts Tumor characteristics Pt Characteristics

    14. SPEAKERS NOTES This slide displays the benefit of exemestane administered after prior tamoxifen in the advanced breast cancer setting.1 This Kaplan-Meier curve shows a significant overall survival advantage for exemestane when compared with megestrol acetate (P=0.039).1 Exemestane is the only drug in its class to reach all efficacy end points, including overall survival. Reference Kaufmann M, Bajetta E, Dirix LY, et al. Exemestane is superior to megestrol acetate after tamoxifen in postmenopausal women with advanced breast cancer: results of a phase III randomized double-blind trial. J Clin Oncol. 2000;18:1399-1411. SPEAKERS NOTES This slide displays the benefit of exemestane administered after prior tamoxifen in the advanced breast cancer setting.1 This Kaplan-Meier curve shows a significant overall survival advantage for exemestane when compared with megestrol acetate (P=0.039).1 Exemestane is the only drug in its class to reach all efficacy end points, including overall survival. Reference Kaufmann M, Bajetta E, Dirix LY, et al. Exemestane is superior to megestrol acetate after tamoxifen in postmenopausal women with advanced breast cancer: results of a phase III randomized double-blind trial. J Clin Oncol. 2000;18:1399-1411.

    15. Exemestane as Initial Therapy for MBC: Randomized EORTC Phase II/III Trial

    17. 10-Year Follow-up: Long-Term Efficacy of ~2 Years of Adjuvant Tamoxifen SPEAKER'S NOTES These data show the 10-year recurrence and mortality derived from a combined analysis of trials of women receiving about 2 years of adjuvant tamoxifen.1 These data demonstrate that the benefits of being treated with tamoxifen are substantial and persistent.1 Reference 1. Early Breast Cancer Trialists' Collaborative Group. Tamoxifen for early breast cancer: an overview of the randomized trials. Lancet. 1998;351:1451-1467. SPEAKER'S NOTES These data show the 10-year recurrence and mortality derived from a combined analysis of trials of women receiving about 2 years of adjuvant tamoxifen.1 These data demonstrate that the benefits of being treated with tamoxifen are substantial and persistent.1 Reference 1. Early Breast Cancer Trialists' Collaborative Group. Tamoxifen for early breast cancer: an overview of the randomized trials. Lancet. 1998;351:1451-1467.

    18. Results of the Intergroup Exemestane Study (IES)

    19. SPEAKERS NOTES: This slide summarizes the study design and follow-up for the mature results of the IES trial. IES was designed to evaluate whether patients who remained disease free after 2 to 3 years of tamoxifen were more effectively treated by switching to exemestane than by continuing tamoxifen for the remainder of their 5-year treatment. Median follow-up for the trial analysis presented at ASCO on June 5, 2006 was 56 months. Data were available for patients followed for more than 2 years after the discontinuation of treatment. Currently, more than 99% of patients have completed their study treatment. There were more than 5000 patient years on treatment for exemestane and for tamoxifen. Over 10,000 patient years were included in post-treatment follow-up. Reference 1. Coombes RC, et al. First mature analysis of the Intergroup Exemestane Study. Presented at: Annual Meeting of the American Society of Clinical Oncology; June 2-6, 2006; Atlanta, Ga. SPEAKERS NOTES: This slide summarizes the study design and follow-up for the mature results of the IES trial. IES was designed to evaluate whether patients who remained disease free after 2 to 3 years of tamoxifen were more effectively treated by switching to exemestane than by continuing tamoxifen for the remainder of their 5-year treatment. Median follow-up for the trial analysis presented at ASCO on June 5, 2006 was 56 months. Data were available for patients followed for more than 2 years after the discontinuation of treatment. Currently, more than 99% of patients have completed their study treatment. There were more than 5000 patient years on treatment for exemestane and for tamoxifen. Over 10,000 patient years were included in post-treatment follow-up. Reference 1. Coombes RC, et al. First mature analysis of the Intergroup Exemestane Study. Presented at: Annual Meeting of the American Society of Clinical Oncology; June 2-6, 2006; Atlanta, Ga.

    20. IES: The Pivotal Study of Switching Adjuvant Therapy in Breast Cancer Double-blind, prospective randomized trial 4724 patients* 20 cooperative groups 37 countries 366 centers SPEAKERS NOTES IES is the pivotal study in switching adjuvant therapy in breast cancer. IES is the only double-blind, large, multinational, prospective, randomized trial in the switch setting. The ITT analysis included a total of 4724 patients in 366 study sites from 37 countries spanning 5 continents. Reference 1. Coombes RC, et al. First mature analysis of the Intergroup Exemestane Study. Presented at: Annual Meeting of the American Society of Clinical Oncology; June 2-6, 2006; Atlanta, Ga. SPEAKERS NOTES IES is the pivotal study in switching adjuvant therapy in breast cancer. IES is the only double-blind, large, multinational, prospective, randomized trial in the switch setting. The ITT analysis included a total of 4724 patients in 366 study sites from 37 countries spanning 5 continents. Reference 1. Coombes RC, et al. First mature analysis of the Intergroup Exemestane Study. Presented at: Annual Meeting of the American Society of Clinical Oncology; June 2-6, 2006; Atlanta, Ga.

    21. IES Eligibility Criteria Key inclusion criteria: 2 to 3 years of adjuvant tamoxifen therapy ER-positive or unknown breast cancer Confirmed postmenopausal status Previous chemotherapy permitted Key exclusion criteria: Known ER-negative status Clinical evidence of local relapse or distant metastases Osteoporosis and/or osteoporotic fractures SPEAKERS NOTES The IES trial included estrogen-receptor (ER) positive or unknown patients who were disease free after 2 to 3 years of tamoxifen. Other key eligibility requirements included postmenopausal status at the time of diagnosis, defined as being at least 55 years old with amenorrhea for >2 years, or natural amenorrhea for =1 year at the time of breast cancer diagnosis, or radiation menopause, or surgical oophorectomy. Patients with previous chemotherapy treatment were permitted to enter the trial. Key exclusion criteria included known hormone-receptor negative status; clinical evidence of local relapse or distant metastasis since initial diagnosis; and patients with osteoporosis and/or osteoporotic fractures. Reference 1. Coombes RC, et al. First mature analysis of the Intergroup Exemestane Study. Presented at: Annual Meeting of the American Society of Clinical Oncology; June 2-6, 2006; Atlanta, Ga. SPEAKERS NOTES The IES trial included estrogen-receptor (ER) positive or unknown patients who were disease free after 2 to 3 years of tamoxifen. Other key eligibility requirements included postmenopausal status at the time of diagnosis, defined as being at least 55 years old with amenorrhea for >2 years, or natural amenorrhea for =1 year at the time of breast cancer diagnosis, or radiation menopause, or surgical oophorectomy. Patients with previous chemotherapy treatment were permitted to enter the trial. Key exclusion criteria included known hormone-receptor negative status; clinical evidence of local relapse or distant metastasis since initial diagnosis; and patients with osteoporosis and/or osteoporotic fractures. Reference 1. Coombes RC, et al. First mature analysis of the Intergroup Exemestane Study. Presented at: Annual Meeting of the American Society of Clinical Oncology; June 2-6, 2006; Atlanta, Ga.

    22. IES Study End Points Primary end point: Disease-free survival (DFS), defined as: Breast cancer recurrence (local or distant) Contralateral breast cancer Death from any cause Secondary end points: Overall survival (OS) Contralateral breast cancer Long-term tolerability and safety Additional end points: Breast Cancer Free Survival (BCFS) Time To Distant Recurrence (TTDR) SPEAKERS NOTES The primary end point of the IES study is disease-free survival (DFS), which is defined as time from randomization to local or distant recurrence, diagnosis of a second primary invasive breast cancer, or death from any cause. Secondary end points included overall survival, time to contralateral breast cancer, and long-term tolerability. Additional end points included breast cancer-free survival (BCFS) and time to distant recurrence (TTDR). Reference 1. Coombes RC, et al. First mature analysis of the Intergroup Exemestane Study. Presented at: Annual Meeting of the American Society of Clinical Oncology; June 2-6, 2006; Atlanta, Ga. SPEAKERS NOTES The primary end point of the IES study is disease-free survival (DFS), which is defined as time from randomization to local or distant recurrence, diagnosis of a second primary invasive breast cancer, or death from any cause. Secondary end points included overall survival, time to contralateral breast cancer, and long-term tolerability. Additional end points included breast cancer-free survival (BCFS) and time to distant recurrence (TTDR). Reference 1. Coombes RC, et al. First mature analysis of the Intergroup Exemestane Study. Presented at: Annual Meeting of the American Society of Clinical Oncology; June 2-6, 2006; Atlanta, Ga.

    23. IES Patient Demographics SPEAKERS NOTES: In the IES trial, the exemestane and tamoxifen groups were well balanced with respect to demographics. The trial included most patient types commonly seen in clinical practice including node-positive and -negative patients, and patients who had previously received chemotherapy and those who had not. The median age for both arms was approximately 64 years, with patients aged up to 96 years included in the study. Over 97% of patients were ER-positive or unknown. A small percentage of ER-negative patients were identified during testing of patients considered ER unknown at study entry. Fewer than 3% of patients were found to be ER negative. Reference Coombes RC, et al. First mature analysis of the Intergroup Exemestane Study. Presented at: Annual Meeting of the American Society of Clinical Oncology; June 2-6, 2006; Atlanta, Ga. SPEAKERS NOTES: In the IES trial, the exemestane and tamoxifen groups were well balanced with respect to demographics. The trial included most patient types commonly seen in clinical practice including node-positive and -negative patients, and patients who had previously received chemotherapy and those who had not. The median age for both arms was approximately 64 years, with patients aged up to 96 years included in the study. Over 97% of patients were ER-positive or unknown. A small percentage of ER-negative patients were identified during testing of patients considered ER unknown at study entry. Fewer than 3% of patients were found to be ER negative. Reference Coombes RC, et al. First mature analysis of the Intergroup Exemestane Study. Presented at: Annual Meeting of the American Society of Clinical Oncology; June 2-6, 2006; Atlanta, Ga.

    24. Efficacy in the Intergroup Exemestane Study (IES)

    25. Does Exemestane Improve Disease-Free Survival? SPEAKERS NOTES This slide shows the Kaplan-Meier disease-free survival (DFS) curve in the intent-to-treat (ITT) population of the IES trial. The shaded bar indicates treatment completion at 2 to 3 years. DFS was significantly better in the exemestane group versus the tamoxifen group. A 24% improvement in the probability of DFS was seen with exemestane. The absolute difference between tamoxifen and exemestane at 2.5 years was 3.2%. This benefit was maintained after the end of treatment, with a 3.4% absolute benefit at 5 years of follow-up. Reference 1. Coombes RC, et al. First mature analysis of the Intergroup Exemestane Study. Presented at: Annual Meeting of the American Society of Clinical Oncology; June 2-6, 2006; Atlanta, Ga.SPEAKERS NOTES This slide shows the Kaplan-Meier disease-free survival (DFS) curve in the intent-to-treat (ITT) population of the IES trial. The shaded bar indicates treatment completion at 2 to 3 years. DFS was significantly better in the exemestane group versus the tamoxifen group. A 24% improvement in the probability of DFS was seen with exemestane. The absolute difference between tamoxifen and exemestane at 2.5 years was 3.2%. This benefit was maintained after the end of treatment, with a 3.4% absolute benefit at 5 years of follow-up. Reference 1. Coombes RC, et al. First mature analysis of the Intergroup Exemestane Study. Presented at: Annual Meeting of the American Society of Clinical Oncology; June 2-6, 2006; Atlanta, Ga.

    26. Does Exemestane Improve Disease-Free Survival? SPEAKERS NOTES This slide shows disease-free survival (DFS) data in the ER positive/unknown population of the IES trial. The shaded bar indicates treatment completion at 2 to 3 years. As in the ITT population, DFS in the ER+/unknown population was also significantly better in the exemestane group versus the tamoxifen group. A 25% improvement in the probability of DFS was seen with exemestane. The absolute difference between tamoxifen and exemestane at 2.5 years was 3.4%. This benefit was maintained after the end of treatment, with a 3.5% absolute benefit at 5 years of follow-up. Reference 1. Coombes RC, et al. First mature analysis of the Intergroup Exemestane Study. Presented at: Annual Meeting of the American Society of Clinical Oncology; June 2-6, 2006; Atlanta, Ga. SPEAKERS NOTES This slide shows disease-free survival (DFS) data in the ER positive/unknown population of the IES trial. The shaded bar indicates treatment completion at 2 to 3 years. As in the ITT population, DFS in the ER+/unknown population was also significantly better in the exemestane group versus the tamoxifen group. A 25% improvement in the probability of DFS was seen with exemestane. The absolute difference between tamoxifen and exemestane at 2.5 years was 3.4%. This benefit was maintained after the end of treatment, with a 3.5% absolute benefit at 5 years of follow-up. Reference 1. Coombes RC, et al. First mature analysis of the Intergroup Exemestane Study. Presented at: Annual Meeting of the American Society of Clinical Oncology; June 2-6, 2006; Atlanta, Ga.

    27. Does Exemestane Improve Disease-Free Survival? SPEAKERS NOTES: This slide shows the cumulative hazard rate curves for disease-free survival (DFS) data in the intent-to-treat (ITT) population of the IES trial. The shaded bar indicates treatment completion at 2 to 3 years. DFS was significantly better in the exemestane group versus the tamoxifen group. Annual hazard rates, shown at the bottom of the slide, demonstrate the early divergence with the difference in hazard rates increasing during the first 2 years of treatment. Benefit was then maintained after treatment. Reference 1. Coombes RC, et al. First mature analysis of the Intergroup Exemestane Study. Presented at: Annual Meeting of the American Society of Clinical Oncology; June 2-6, 2006; Atlanta, Ga. SPEAKERS NOTES: This slide shows the cumulative hazard rate curves for disease-free survival (DFS) data in the intent-to-treat (ITT) population of the IES trial. The shaded bar indicates treatment completion at 2 to 3 years. DFS was significantly better in the exemestane group versus the tamoxifen group. Annual hazard rates, shown at the bottom of the slide, demonstrate the early divergence with the difference in hazard rates increasing during the first 2 years of treatment. Benefit was then maintained after treatment. Reference 1. Coombes RC, et al. First mature analysis of the Intergroup Exemestane Study. Presented at: Annual Meeting of the American Society of Clinical Oncology; June 2-6, 2006; Atlanta, Ga.

    28. Does Exemestane Improve Disease-Free Survival? SPEAKERS NOTES: This slide shows the cumulative hazard rate curves for disease-free survival (DFS) data in the ER positive/unknown population of the IES trial. The shaded bar indicates treatment completion at 2 to 3 years. DFS was significantly better in the exemestane group versus the tamoxifen group. Reference 1. Coombes RC, et al. First mature analysis of the Intergroup Exemestane Study. Presented at: Annual Meeting of the American Society of Clinical Oncology; June 2-6, 2006; Atlanta, Ga.SPEAKERS NOTES: This slide shows the cumulative hazard rate curves for disease-free survival (DFS) data in the ER positive/unknown population of the IES trial. The shaded bar indicates treatment completion at 2 to 3 years. DFS was significantly better in the exemestane group versus the tamoxifen group. Reference 1. Coombes RC, et al. First mature analysis of the Intergroup Exemestane Study. Presented at: Annual Meeting of the American Society of Clinical Oncology; June 2-6, 2006; Atlanta, Ga.

    29. Does Exemestane Reduce First Events? SPEAKERS NOTES This slide summarizes the events contributing to DFS for the IES trial. DFS assessment was based on first events. There were fewer first events for exemestane (354) compared with tamoxifen (454). Exemestane reduces both distant and local recurrences as well as the incidence of contralateral breast cancer. In this setting, distant recurrences are more common than local recurrences. The number of non-breast cancer deaths (intercurrent deaths) is also lower for exemestane. Reference 1. Coombes RC, et al. First mature analysis of the Intergroup Exemestane Study. Presented at: Annual Meeting of the American Society of Clinical Oncology; June 2-6, 2006; Atlanta, Ga. SPEAKERS NOTES This slide summarizes the events contributing to DFS for the IES trial. DFS assessment was based on first events. There were fewer first events for exemestane (354) compared with tamoxifen (454). Exemestane reduces both distant and local recurrences as well as the incidence of contralateral breast cancer. In this setting, distant recurrences are more common than local recurrences. The number of non-breast cancer deaths (intercurrent deaths) is also lower for exemestane. Reference 1. Coombes RC, et al. First mature analysis of the Intergroup Exemestane Study. Presented at: Annual Meeting of the American Society of Clinical Oncology; June 2-6, 2006; Atlanta, Ga.

    30. Is Exemestane Consistent Across Subgroups for DFS? SPEAKERS NOTES Exemestane demonstrates consistent efficacy across patient subgroups in the IES trial. On DFS analysis, no apparent difference in exemestane efficacy was found in the ER+/unknown population between groups by nodal status, use of previous chemotherapy, or duration of tamoxifen treatment prior to switch (more than or less than 2.5 years), supporting broad applicability of these data. Note: The size of the square is proportional to the number of the patients in the subgroup analyzed. Reference 1. Coombes RC, et al. First mature analysis of the Intergroup Exemestane Study. Presented at: Annual Meeting of the American Society of Clinical Oncology; June 2-6, 2006; Atlanta, Ga. SPEAKERS NOTES Exemestane demonstrates consistent efficacy across patient subgroups in the IES trial. On DFS analysis, no apparent difference in exemestane efficacy was found in the ER+/unknown population between groups by nodal status, use of previous chemotherapy, or duration of tamoxifen treatment prior to switch (more than or less than 2.5 years), supporting broad applicability of these data. Note: The size of the square is proportional to the number of the patients in the subgroup analyzed. Reference 1. Coombes RC, et al. First mature analysis of the Intergroup Exemestane Study. Presented at: Annual Meeting of the American Society of Clinical Oncology; June 2-6, 2006; Atlanta, Ga.

    31. How Does Exemestane Impact Different Efficacy End Points? SPEAKERS NOTES: This slide summarizes exemestanes effects on efficacy end points for the mature analysis of the IES trial. All efficacy end points favor exemestane. The risk reduction for relapse and death was 24% to 25% (ITT vs ER+/unknown). The risk reduction for breast cancer-free relapse was also 24% to 25%. The risk reduction for time to distant recurrence was 17% to 18%. The risk reduction for time to contralateral breast cancer was 43% to 44%. All 95% confidence intervals were <1. This suggests a clear efficacy benefit for exemestane. Reference 1. Coombes RC, et al. First mature analysis of the Intergroup Exemestane Study. Presented at: Annual Meeting of the American Society of Clinical Oncology; June 2-6, 2006; Atlanta, Ga. SPEAKERS NOTES: This slide summarizes exemestanes effects on efficacy end points for the mature analysis of the IES trial. All efficacy end points favor exemestane. The risk reduction for relapse and death was 24% to 25% (ITT vs ER+/unknown). The risk reduction for breast cancer-free relapse was also 24% to 25%. The risk reduction for time to distant recurrence was 17% to 18%. The risk reduction for time to contralateral breast cancer was 43% to 44%. All 95% confidence intervals were <1. This suggests a clear efficacy benefit for exemestane. Reference 1. Coombes RC, et al. First mature analysis of the Intergroup Exemestane Study. Presented at: Annual Meeting of the American Society of Clinical Oncology; June 2-6, 2006; Atlanta, Ga.

    32. Does Exemestane Improve Overall Survival? SPEAKERS NOTES This slide shows the Kaplan-Meier (K-M) overall survival curves in the intent-to-treat (ITT) population of the IES trial. Treatment with exemestane improves the chance of living longer by 15% (P=0.08). The shaded bar indicates treatment completion at 2 to 3 years. These results are building upon the overall survival benefit established for up to 2 years of tamoxifen. The magnitude of absolute benefit increases over time on therapy and is maintained in follow-up. Reference 1. Coombes RC, et al. First mature analysis of the Intergroup Exemestane Study. Presented at: Annual Meeting of the American Society of Clinical Oncology; June 2-6, 2006; Atlanta, Ga.SPEAKERS NOTES This slide shows the Kaplan-Meier (K-M) overall survival curves in the intent-to-treat (ITT) population of the IES trial. Treatment with exemestane improves the chance of living longer by 15% (P=0.08). The shaded bar indicates treatment completion at 2 to 3 years. These results are building upon the overall survival benefit established for up to 2 years of tamoxifen. The magnitude of absolute benefit increases over time on therapy and is maintained in follow-up. Reference 1. Coombes RC, et al. First mature analysis of the Intergroup Exemestane Study. Presented at: Annual Meeting of the American Society of Clinical Oncology; June 2-6, 2006; Atlanta, Ga.

    33. Does Exemestane Improve Overall Survival? SPEAKERS NOTES This slide shows the Kaplan-Meier overall survival curves in the ER positive/unknown population of the IES trial. Treatment with exemestane improves the chance of living longer in the ER+/unknown population by 17% (P=0.05). The shaded bar indicates treatment completion at 2 to 3 years. These results are building upon the overall survival benefit established for up to 2 years of tamoxifen. The magnitude of absolute benefit increases over time on therapy and is maintained in follow-up. Reference 1. Coombes RC, et al. First mature analysis of the Intergroup Exemestane Study. Presented at: Annual Meeting of the American Society of Clinical Oncology; June 2-6, 2006; Atlanta, Ga.SPEAKERS NOTES This slide shows the Kaplan-Meier overall survival curves in the ER positive/unknown population of the IES trial. Treatment with exemestane improves the chance of living longer in the ER+/unknown population by 17% (P=0.05). The shaded bar indicates treatment completion at 2 to 3 years. These results are building upon the overall survival benefit established for up to 2 years of tamoxifen. The magnitude of absolute benefit increases over time on therapy and is maintained in follow-up. Reference 1. Coombes RC, et al. First mature analysis of the Intergroup Exemestane Study. Presented at: Annual Meeting of the American Society of Clinical Oncology; June 2-6, 2006; Atlanta, Ga.

    34. Does Exemestane Improve Overall Survival? SPEAKERS NOTES This slide shows the cumulative hazard rate curves for overall survival data in the intent-to-treat (ITT) population of the IES trial. The shaded bar indicates treatment completion at 2 to 3 years. These results are building upon the overall survival benefit established for up to 2 years of tamoxifen. Annual hazard rates, shown at the bottom of the slide, demonstrate the difference in hazard rates at 1 to 2 years of treatment. Benefit was then maintained after treatment. Reference 1. Coombes RC, et al. First mature analysis of the Intergroup Exemestane Study. Presented at: Annual Meeting of the American Society of Clinical Oncology; June 2-6, 2006; Atlanta, Ga.SPEAKERS NOTES This slide shows the cumulative hazard rate curves for overall survival data in the intent-to-treat (ITT) population of the IES trial. The shaded bar indicates treatment completion at 2 to 3 years. These results are building upon the overall survival benefit established for up to 2 years of tamoxifen. Annual hazard rates, shown at the bottom of the slide, demonstrate the difference in hazard rates at 1 to 2 years of treatment. Benefit was then maintained after treatment. Reference 1. Coombes RC, et al. First mature analysis of the Intergroup Exemestane Study. Presented at: Annual Meeting of the American Society of Clinical Oncology; June 2-6, 2006; Atlanta, Ga.

    35. Does Exemestane Improve Overall Survival? SPEAKERS NOTES This slide shows the cumulative hazard curves for overall survival data in the ER positive/unknown population of the IES trial. The shaded bar indicates treatment completion at 2 to 3 years. These results are building upon the overall survival benefit established for up to 2 years of tamoxifen. Reference 1. Coombes RC, et al. First mature analysis of the Intergroup Exemestane Study. Presented at: Annual Meeting of the American Society of Clinical Oncology; June 2-6, 2006; Atlanta, Ga. SPEAKERS NOTES This slide shows the cumulative hazard curves for overall survival data in the ER positive/unknown population of the IES trial. The shaded bar indicates treatment completion at 2 to 3 years. These results are building upon the overall survival benefit established for up to 2 years of tamoxifen. Reference 1. Coombes RC, et al. First mature analysis of the Intergroup Exemestane Study. Presented at: Annual Meeting of the American Society of Clinical Oncology; June 2-6, 2006; Atlanta, Ga.

    36. IES Efficacy Summary* Death: 17% (P=0.05) 17% (P=0.04), adjusted Recurrence and deaths: 25% (P=0.0001) Contralateral breast cancer: 44% (95% CI, 0.33-0.98) Distant recurrence: 18% (95% CI, 0.69-0.98) SPEAKERS NOTES In the ER positive and unknown patient population, switching to exemestane reduces the risk of mortality by 17%. The P value is 0.05 in the unadjusted analysis and is 0.04 in the adjusted analysis. Exemestane reduces the risk of recurrence and deaths (25%, P=0.0001), contralateral breast cancer (44%, 95% CI, 0.33-0.98), and distant recurrence (18%, 95% CI, 0.69-0.98). Reference 1. Coombes RC, et al. First mature analysis of the Intergroup Exemestane Study. Presented at: Annual Meeting of the American Society of Clinical Oncology; June 2-6, 2006; Atlanta, Ga. SPEAKERS NOTES In the ER positive and unknown patient population, switching to exemestane reduces the risk of mortality by 17%. The P value is 0.05 in the unadjusted analysis and is 0.04 in the adjusted analysis. Exemestane reduces the risk of recurrence and deaths (25%, P=0.0001), contralateral breast cancer (44%, 95% CI, 0.33-0.98), and distant recurrence (18%, 95% CI, 0.69-0.98). Reference 1. Coombes RC, et al. First mature analysis of the Intergroup Exemestane Study. Presented at: Annual Meeting of the American Society of Clinical Oncology; June 2-6, 2006; Atlanta, Ga.

    37. Safety and Tolerability in the Intergroup Exemestane Study (IES)

    38. Cardiovascular and Thromboembolic Adverse Events SPEAKERS NOTES: This slide summarizes the cardiovascular and thromboembolic adverse events for patients on the IES at 55.7 months follow-up. Note: Box sizes in the plot indicate the precision of the estimate, with a larger box indicating better precision. Reference 1. Coombes RC, et al. First mature analysis of the Intergroup Exemestane Study. Presented at: Annual Meeting of the American Society of Clinical Oncology; June 2-6, 2006; Atlanta, Ga.SPEAKERS NOTES: This slide summarizes the cardiovascular and thromboembolic adverse events for patients on the IES at 55.7 months follow-up. Note: Box sizes in the plot indicate the precision of the estimate, with a larger box indicating better precision. Reference 1. Coombes RC, et al. First mature analysis of the Intergroup Exemestane Study. Presented at: Annual Meeting of the American Society of Clinical Oncology; June 2-6, 2006; Atlanta, Ga.

    39. Musculoskeletal and Other Adverse Events SPEAKERS NOTES: This slide summarizes the musculoskeletal and other adverse events for patients on the IES at 55.7 months follow-up. Incidence rates per 1000 women years (99% CI) for fractures (allowing more than one fracture event per patient) are E=19.2 (15.9, 23.1) and T=15.1 (12.2, 18.7). Fracture rates, osteoporosis, and musculoskeletal adverse events all differ between treatment arms, with the majority in favor of tamoxifen. Muscle cramps significantly favors exemestane (P=0.001). Note: Box sizes in the plot indicate the precision of the estimate, with a larger box indicating better precision. Reference 1. Coombes RC, et al. First mature analysis of the Intergroup Exemestane Study. Presented at: Annual Meeting of the American Society of Clinical Oncology; June 2-6, 2006; Atlanta, Ga. . SPEAKERS NOTES: This slide summarizes the musculoskeletal and other adverse events for patients on the IES at 55.7 months follow-up. Incidence rates per 1000 women years (99% CI) for fractures (allowing more than one fracture event per patient) are E=19.2 (15.9, 23.1) and T=15.1 (12.2, 18.7). Fracture rates, osteoporosis, and musculoskeletal adverse events all differ between treatment arms, with the majority in favor of tamoxifen. Muscle cramps significantly favors exemestane (P=0.001). Note: Box sizes in the plot indicate the precision of the estimate, with a larger box indicating better precision. Reference 1. Coombes RC, et al. First mature analysis of the Intergroup Exemestane Study. Presented at: Annual Meeting of the American Society of Clinical Oncology; June 2-6, 2006; Atlanta, Ga. .

    40. Gynecologic Adverse Events SPEAKERS NOTES: This slide summarizes the gynecologic adverse events for patients on the IES at 55.7 months of follow-up. Most gynecologic adverse events were significantly in favor of exemestane. Note: Box sizes in the plot indicate the precision of the estimate, with a larger box indicating better precision. Reference 1. Coombes RC, et al. First mature analysis of the Intergroup Exemestane Study. Presented at: Annual Meeting of the American Society of Clinical Oncology; June 2-6, 2006; Atlanta, Ga.SPEAKERS NOTES: This slide summarizes the gynecologic adverse events for patients on the IES at 55.7 months of follow-up. Most gynecologic adverse events were significantly in favor of exemestane. Note: Box sizes in the plot indicate the precision of the estimate, with a larger box indicating better precision. Reference 1. Coombes RC, et al. First mature analysis of the Intergroup Exemestane Study. Presented at: Annual Meeting of the American Society of Clinical Oncology; June 2-6, 2006; Atlanta, Ga.

    41. Sites of Other Invasive Cancers SPEAKERS NOTES: This slide displays the number of secondary non-breast primary tumors reported in IES. More non-breast primary tumors occurred on tamoxifen than on exemestane treatment. More uterine cancers were reported on tamoxifen, as would be expected. More GI and lung cancers were observed on tamoxifen. These differences are unexplained and may be considered hypothesis generating. Reference 1. Coombes RC, et al. First mature analysis of the Intergroup Exemestane Study. Presented at: Annual Meeting of the American Society of Clinical Oncology; June 2-6, 2006; Atlanta, Ga.SPEAKERS NOTES: This slide displays the number of secondary non-breast primary tumors reported in IES. More non-breast primary tumors occurred on tamoxifen than on exemestane treatment. More uterine cancers were reported on tamoxifen, as would be expected. More GI and lung cancers were observed on tamoxifen. These differences are unexplained and may be considered hypothesis generating. Reference 1. Coombes RC, et al. First mature analysis of the Intergroup Exemestane Study. Presented at: Annual Meeting of the American Society of Clinical Oncology; June 2-6, 2006; Atlanta, Ga.

    42. IES Substudy Results

    43. IES Quality of Life Substudy SPEAKERS NOTES The purpose of this assessment was to compare and describe the QOL of women randomized to tamoxifen or exemestane treatment in the IES.1 The primary end point of the trial subprotocol was trial outcome index (TOI), which incorporates Physical Well-Being, Functional Well-Being, and Breast Cancer Subscale.1 Secondary end points include: Total Functional Assessment of Cancer Therapy-Breast (FACT-B) and endocrine subscale (ES) scores and individual endocrine symptoms.1 Reference 1. Fallowfield LJ, Bliss JM, Porter LS, et al. Quality of life in the intergroup exemestane study: a randomized trial of exemestane versus continued tamoxifen after 2 to 3 years of tamoxifen in postmenopausal women with primary breast cancer. J Clin Oncol. 2006;24:910-917. SPEAKERS NOTES The purpose of this assessment was to compare and describe the QOL of women randomized to tamoxifen or exemestane treatment in the IES.1 The primary end point of the trial subprotocol was trial outcome index (TOI), which incorporates Physical Well-Being, Functional Well-Being, and Breast Cancer Subscale.1 Secondary end points include: Total Functional Assessment of Cancer Therapy-Breast (FACT-B) and endocrine subscale (ES) scores and individual endocrine symptoms.1 Reference 1. Fallowfield LJ, Bliss JM, Porter LS, et al. Quality of life in the intergroup exemestane study: a randomized trial of exemestane versus continued tamoxifen after 2 to 3 years of tamoxifen in postmenopausal women with primary breast cancer. J Clin Oncol. 2006;24:910-917.

    44. IES Quality of Life Substudy Methods 582 consenting patients from 8 countries SPEAKERS NOTES The IES QOL substudy enrolled 582 patients. The QOL questionnaires were administered at 3, 6, 9, and 12 months and then every 6 months until 36 months.1 After 36 months, assessments were conducted annually until 60 months or 1 month post-recurrence.1 The follow-up is for 5 years, however, this interim analysis was conducted on all data available up to 2 years.1 Reference 1. Fallowfield LJ, Bliss JM, Porter LS, et al. Quality of life in the intergroup exemestane study: a randomized trial of exemestane versus continued tamoxifen after 2 to 3 years of tamoxifen in postmenopausal women with primary breast cancer. J Clin Oncol. 2006;24:910-917. SPEAKERS NOTES The IES QOL substudy enrolled 582 patients. The QOL questionnaires were administered at 3, 6, 9, and 12 months and then every 6 months until 36 months.1 After 36 months, assessments were conducted annually until 60 months or 1 month post-recurrence.1 The follow-up is for 5 years, however, this interim analysis was conducted on all data available up to 2 years.1 Reference 1. Fallowfield LJ, Bliss JM, Porter LS, et al. Quality of life in the intergroup exemestane study: a randomized trial of exemestane versus continued tamoxifen after 2 to 3 years of tamoxifen in postmenopausal women with primary breast cancer. J Clin Oncol. 2006;24:910-917.

    45. IES Quality of Life Substudy Outcomes SPEAKERS NOTES There were no significant differences in Trial Outcome Index (TOI) scores over the total time period for exemestane and tamoxifen.1 There were no significant differences in Endocrine Subscale (ES) scores over time.1 These data indicate similar and favorable QOL measured for both patient groups.1 Reference 1. Fallowfield LJ, Bliss JM, Porter LS, et al. Quality of life in the intergroup exemestane study: a randomized trial of exemestane versus continued tamoxifen after 2 to 3 years of tamoxifen in postmenopausal women with primary breast cancer. J Clin Oncol. 2006;24:910-917. SPEAKERS NOTES There were no significant differences in Trial Outcome Index (TOI) scores over the total time period for exemestane and tamoxifen.1 There were no significant differences in Endocrine Subscale (ES) scores over time.1 These data indicate similar and favorable QOL measured for both patient groups.1 Reference 1. Fallowfield LJ, Bliss JM, Porter LS, et al. Quality of life in the intergroup exemestane study: a randomized trial of exemestane versus continued tamoxifen after 2 to 3 years of tamoxifen in postmenopausal women with primary breast cancer. J Clin Oncol. 2006;24:910-917.

    46. IES Quality of Life Substudy: Endocrine Symptoms SPEAKERS NOTES: No significant differences were observed between patients in the tamoxifen and exemestane arms for vasomotor symptoms and neuropsychological symptoms.1 Vasomotor symptoms were common, as was lack of energy.1 Reference 1. Fallowfield LJ, Bliss JM, Porter LS, et al. Quality of life in the intergroup exemestane study: a randomized trial of exemestane versus continued tamoxifen after 2 to 3 years of tamoxifen in postmenopausal women with primary breast cancer. J Clin Oncol. 2006;24:910-917. SPEAKERS NOTES: No significant differences were observed between patients in the tamoxifen and exemestane arms for vasomotor symptoms and neuropsychological symptoms.1 Vasomotor symptoms were common, as was lack of energy.1 Reference 1. Fallowfield LJ, Bliss JM, Porter LS, et al. Quality of life in the intergroup exemestane study: a randomized trial of exemestane versus continued tamoxifen after 2 to 3 years of tamoxifen in postmenopausal women with primary breast cancer. J Clin Oncol. 2006;24:910-917.

    47. IES Quality of Life Substudy: Endocrine Symptoms SPEAKERS NOTES: No significant differences were observed between patients in the tamoxifen and exemestane arms for gastrointestinal and gynecologic symptoms, other than vaginal discharge.1 Vaginal discharge was reported significantly less frequently in exemestane-treated patients (P<0.001).1 Reference 1. Fallowfield LJ, Bliss JM, Porter LS, et al. Quality of life in the intergroup exemestane study: a randomized trial of exemestane versus continued tamoxifen after 2 to 3 years of tamoxifen in postmenopausal women with primary breast cancer. J Clin Oncol. 2006;24:910-917. SPEAKERS NOTES: No significant differences were observed between patients in the tamoxifen and exemestane arms for gastrointestinal and gynecologic symptoms, other than vaginal discharge.1 Vaginal discharge was reported significantly less frequently in exemestane-treated patients (P<0.001).1 Reference 1. Fallowfield LJ, Bliss JM, Porter LS, et al. Quality of life in the intergroup exemestane study: a randomized trial of exemestane versus continued tamoxifen after 2 to 3 years of tamoxifen in postmenopausal women with primary breast cancer. J Clin Oncol. 2006;24:910-917.

    48. IES Endometrial Subprotocol Tamoxifen induces uterine abnormalities detectable in postmenopausal women. Does switching to exemestane impact the uterus? Endometrial thickness =5 mm after 2 years of randomized treatment Transvaginal ultrasound changes, mean uterine volume, presence of polyps, fibroids, ovarian cysts Histologic and immunohistochemical findings in patients who undergo biopsy or hysterectomy SPEAKERS NOTES It is well established that tamoxifen induces uterine abnormalities in postmenopuasal women. These abnormalities have not been associated with the aromatase inhibitors. The endometrial subprotocol of the IES was designed to assess the uterine effects of switching from tamoxifen to exemestane. The primary end point was endometrial thickness =5 mm after 2 years of treatment as assessed by transvaginal ultrasound. Secondary end points were transvaginal ultrasound changes, including mean endometrial thickness, mean uterine volume, presence of polyps, fibroids, ovarian cysts, and histologic and immunohistochemical findings in patients who undergo biopsy or hysterectomy. Reference 1. Bertelli, et al. Presented at: the San Antonio Breast Cancer Symposium; December 10, 2004; San Antonio, Tex. SPEAKERS NOTES It is well established that tamoxifen induces uterine abnormalities in postmenopuasal women. These abnormalities have not been associated with the aromatase inhibitors. The endometrial subprotocol of the IES was designed to assess the uterine effects of switching from tamoxifen to exemestane. The primary end point was endometrial thickness =5 mm after 2 years of treatment as assessed by transvaginal ultrasound. Secondary end points were transvaginal ultrasound changes, including mean endometrial thickness, mean uterine volume, presence of polyps, fibroids, ovarian cysts, and histologic and immunohistochemical findings in patients who undergo biopsy or hysterectomy. Reference 1. Bertelli, et al. Presented at: the San Antonio Breast Cancer Symposium; December 10, 2004; San Antonio, Tex.

    49. IES Endometrial Substudy SPEAKERS NOTES: Forty-seven patients in the exemestane group and 43 patients in the tamoxifen group were considered evaluable for the primary end point at 2 years. Preliminary results from the endometrial substudy indicate that after 2 years of treatment, exemestane-treated patients experienced a median decrease in uterine thickness of 31.0% while tamoxifen-treated patients experienced an increase in uterine thickness of 5.3%.1 In 50% of the patients with endometrial thickening at baseline (ie, endometrial thickness of =5mm) who were treated with exemestane, endometrial thickening was reversed to normal (<5mm) at 2 years.1 Reference 1. Data on file, Pfizer Inc. SPEAKERS NOTES: Forty-seven patients in the exemestane group and 43 patients in the tamoxifen group were considered evaluable for the primary end point at 2 years. Preliminary results from the endometrial substudy indicate that after 2 years of treatment, exemestane-treated patients experienced a median decrease in uterine thickness of 31.0% while tamoxifen-treated patients experienced an increase in uterine thickness of 5.3%.1 In 50% of the patients with endometrial thickening at baseline (ie, endometrial thickness of =5mm) who were treated with exemestane, endometrial thickening was reversed to normal (<5mm) at 2 years.1 Reference 1. Data on file, Pfizer Inc.

    50. IES Bone Substudy Tamoxifen may have bone-sparing properties Bone loss has been established for AIs Does switching to exemestane impact bone mineral density and bone biomarkers? Annual changes from baseline in lumbar spine and total hip bone mineral density (BMD) BMD between treatment groups at 12 and 24 months Changes in biochemical markers of bone turnover Assess relationship between change in biochemical markers and BMD Effects on fracture incidence SPEAKERS NOTES While tamoxifen is believed to have bone-sparing properties, bone loss has been observed with the AIs. A total of 206 patients were randomized into the IES bone substudy.1 The IES bone subprotocol was designed to assess BMD and bone biomarker effects of switching from tamoxifen to exemestane versus continuing on tamoxifen.1 Reference 1. Coleman RE, Banks LM, Girgis SI, et al. Skeletal effects of exemestane in the intergroup exemestane study (IES). Presented at: the San Antonio Breast Cancer Symposium; December 2005; San Antonio, Tex. SPEAKERS NOTES While tamoxifen is believed to have bone-sparing properties, bone loss has been observed with the AIs. A total of 206 patients were randomized into the IES bone substudy.1 The IES bone subprotocol was designed to assess BMD and bone biomarker effects of switching from tamoxifen to exemestane versus continuing on tamoxifen.1 Reference 1. Coleman RE, Banks LM, Girgis SI, et al. Skeletal effects of exemestane in the intergroup exemestane study (IES). Presented at: the San Antonio Breast Cancer Symposium; December 2005; San Antonio, Tex.

    51. IES Bone Substudy: Bone Mineral Density SPEAKERS NOTES No significant change in BMD was seen with continuation of tamoxifen.1 In patients switched to exemestane, BMD loss was less than 1% per year of therapy after an initial rapid reduction in BMD seen in the first 6 months after switching.1 This rapid reduction could be due to the withdrawal of tamoxifen, which is considered bone sparing. Reference 1. Coleman RE, Banks LM, Girgis SI, et al. Skeletal effects of exemestane in the intergroup exemestane study (IES). Presented at: the San Antonio Breast Cancer Symposium; December 2005; San Antonio, Tex. SPEAKERS NOTES No significant change in BMD was seen with continuation of tamoxifen.1 In patients switched to exemestane, BMD loss was less than 1% per year of therapy after an initial rapid reduction in BMD seen in the first 6 months after switching.1 This rapid reduction could be due to the withdrawal of tamoxifen, which is considered bone sparing. Reference 1. Coleman RE, Banks LM, Girgis SI, et al. Skeletal effects of exemestane in the intergroup exemestane study (IES). Presented at: the San Antonio Breast Cancer Symposium; December 2005; San Antonio, Tex.

    52. IES Bone Substudy: Changes in Bone Biomarkers SPEAKERS NOTES Withdrawal of tamoxifen and start of exemestane increased the rate of bone metabolism as indicated by increases in levels of circulating biochemical markers. Changes in the bone resorption marker, deoxypyridinole (DPD) were statistically significant between treatments.1 Changes in the bone formation marker, alkaline phosphatase (ALP) were statistically significant between treatments.1 Reference 1. Coleman RE, Banks LM, Girgis SI, et al. Skeletal effects of exemestane in the intergroup exemestane study (IES). Presented at: the San Antonio Breast Cancer Symposium; December 2005; San Antonio, Tex. SPEAKERS NOTES Withdrawal of tamoxifen and start of exemestane increased the rate of bone metabolism as indicated by increases in levels of circulating biochemical markers. Changes in the bone resorption marker, deoxypyridinole (DPD) were statistically significant between treatments.1 Changes in the bone formation marker, alkaline phosphatase (ALP) were statistically significant between treatments.1 Reference 1. Coleman RE, Banks LM, Girgis SI, et al. Skeletal effects of exemestane in the intergroup exemestane study (IES). Presented at: the San Antonio Breast Cancer Symposium; December 2005; San Antonio, Tex.

    53. Independent Exemestane Cost-Effectiveness Studies

    54. Definition of Quality Adjusted Life Year Quality Adjusted Life Year (QALY): A year of life adjusted for its quality. QALY example: A year in perfect health is considered equal to 1.0 QALY A year bedridden might have a value equal to 0.5 QALY SPEAKERS NOTES A Quality Adjusted Life Year (QALY) is defined as a year of life adjusted for its quality.1 For example: - A year in perfect health is considered equal to 1.0 QALY.1 - A year bedridden might have a value equal to 0.5 QALY.1 QALYs are designed to capture in a single summary measure the impacts of both quantity of life and quality of life.2 References Source: www.medterms.com. Torrance GW, Feeny D. Utilities and quality-adjusted life years. Int J Technol Assess Health Care. 1989;5(4):559-575. SPEAKERS NOTES A Quality Adjusted Life Year (QALY) is defined as a year of life adjusted for its quality.1 For example: - A year in perfect health is considered equal to 1.0 QALY.1 - A year bedridden might have a value equal to 0.5 QALY.1 QALYs are designed to capture in a single summary measure the impacts of both quantity of life and quality of life.2 References Source: www.medterms.com. Torrance GW, Feeny D. Utilities and quality-adjusted life years. Int J Technol Assess Health Care. 1989;5(4):559-575.

    55. Overview of Cost-Effectiveness: Exemestane Below Range SPEAKERS NOTES The generally accepted range for cost-effectiveness is between US$50,000 - $100,000 per quality-adjusted life-year. Note: this figure varies by country, with each geographic region having set a local standard by which treatment costs are assessed. Cost-effectiveness analyses of switching from tamoxifen to exemestane versus continued tamoxifen have been conducted. These analyses found that the cost per QALY of switching to exemestane falls within the generally accepted range for cost-effective therapy. In Belgium, cost per quality adjusted life year (QALY) for TAM-EXE vs TAM at 10 years was 14,147 ($18,156 in USD as of May 31, 2006).1 In the US, the cost-effectiveness of switching to exemestane vs staying on tamoxifen on a cost per QALY basis is $15,300 for ER-positive patients.2 In the UK, exemestane provides improvements in QALYs with an incremental cost of 6,838 ($12,809 in USD as of May 31, 2006) per QALY compared with tamoxifen.3 In Canada, the cost-effectiveness ratio of switching to exemestane per QALY was $15,516.4 References Skedgel C, Rayson D, Dewar R, et al. Cost-utility of adjuvant hormonal options in postmenopausal women with breast cancer: A Belgian perspective. Presented at: the European Breast Cancer Conference; March 2006; Nice, France. Thompson D, Taylor DCA, Montoya EL, et al. Cost-effectiveness of switching to exemestane following two-to-three years of therapy with tamoxifen in postmenopausal women with primary breast cancer. Presented at: the San Antonio Breast Cancer Symposium; December 2005; San Antonio, Tex. Wordsworth S, Tabberer M, Lees M, et al. Exemestane in adjuvant treatment of early-stage breast cancer in postmenopausal women: a cost-effectiveness model. Presented at: the European Breast Cancer Conference; March 2006; Nice, France. Risebrough NA, Verma S, Trudeau M, et al. Economic evaluation of switching to exemestane at 2.5 years versus continuing tamoxifen as adjuvant therapy in early breast cancer: A Canadian perspective. Presented at: the San Antonio Breast Cancer Symposium; December 2005; San Antonio, Tex. SPEAKERS NOTES The generally accepted range for cost-effectiveness is between US$50,000 - $100,000 per quality-adjusted life-year. Note: this figure varies by country, with each geographic region having set a local standard by which treatment costs are assessed. Cost-effectiveness analyses of switching from tamoxifen to exemestane versus continued tamoxifen have been conducted. These analyses found that the cost per QALY of switching to exemestane falls within the generally accepted range for cost-effective therapy. In Belgium, cost per quality adjusted life year (QALY) for TAM-EXE vs TAM at 10 years was 14,147 ($18,156 in USD as of May 31, 2006).1 In the US, the cost-effectiveness of switching to exemestane vs staying on tamoxifen on a cost per QALY basis is $15,300 for ER-positive patients.2 In the UK, exemestane provides improvements in QALYs with an incremental cost of 6,838 ($12,809 in USD as of May 31, 2006) per QALY compared with tamoxifen.3 In Canada, the cost-effectiveness ratio of switching to exemestane per QALY was $15,516.4 References Skedgel C, Rayson D, Dewar R, et al. Cost-utility of adjuvant hormonal options in postmenopausal women with breast cancer: A Belgian perspective. Presented at: the European Breast Cancer Conference; March 2006; Nice, France. Thompson D, Taylor DCA, Montoya EL, et al. Cost-effectiveness of switching to exemestane following two-to-three years of therapy with tamoxifen in postmenopausal women with primary breast cancer. Presented at: the San Antonio Breast Cancer Symposium; December 2005; San Antonio, Tex. Wordsworth S, Tabberer M, Lees M, et al. Exemestane in adjuvant treatment of early-stage breast cancer in postmenopausal women: a cost-effectiveness model. Presented at: the European Breast Cancer Conference; March 2006; Nice, France. Risebrough NA, Verma S, Trudeau M, et al. Economic evaluation of switching to exemestane at 2.5 years versus continuing tamoxifen as adjuvant therapy in early breast cancer: A Canadian perspective. Presented at: the San Antonio Breast Cancer Symposium; December 2005; San Antonio, Tex.

    58. Goserelin vs Not: Recurrences

    59. Chemotherapy versus LHRH analogues in premenopausal breast cancer patients

    64. Adjuvant AI after chemotherapy induced amenorrhoea : results from an audit

    65. Adjuvant AI after chemotherapy induced amenorrhoea Most women older than age 40 treated with CT will develop permanent amenorrhoea But in a minority amenorrhoea may be temporary (0-11%) The incidence of recovery may be increased by AIs (27% in the report by Smith) Predicting which pts will have return of ovarian function is not possible (a single measurement of FSH, LH and E2 reflects function only that time point)

    66. Aromatase Inhibitors Adjuvant Trials

    67. AI Adjuvant Trials. Disease Free Survival

    68. Receptors Profile & Treatment Selection Hormonotherapy + Chemotherapy Tamoxifen and/or Aromatase Inhibitors

    70. Receptors Profile & Treatment Selection Hormonotherapy + Chemotherapy Tamoxifen and/or Aromatase Inhibitors

    72. Adjuvant Aromatase Inhibitors

    73. Adjuvant Aromatase Inhibitors

    74. Adjuvant Aromatase Inhibitors

    75. ABCSG 8 trial structure

    82. ATAC: recurrences* before 2.5 years (HR+ patients) In agreement with the 1998 EBCTCG overview of adjuvant tamoxifen trials, the endpoint of Time to Recurrence excludes death prior to recurrence There was a significantly greater benefit with respect to recurrence for the anastrozole group than for the tamoxifen group. As with disease-free survival, the absolute difference between treatment arms with respect to recurrence increased out beyond completion of treatment to 6 years.In agreement with the 1998 EBCTCG overview of adjuvant tamoxifen trials, the endpoint of Time to Recurrence excludes death prior to recurrence There was a significantly greater benefit with respect to recurrence for the anastrozole group than for the tamoxifen group. As with disease-free survival, the absolute difference between treatment arms with respect to recurrence increased out beyond completion of treatment to 6 years.

    83. BIG 1-98: cumulative incidence of breast cancer relapse Patients in the letrozole group had significantly lower rate of relapse compared with patients who received tamoxifen. It is more appropriate to compare TTR between ATAC and BIG 1-98 as definitions were similar in the two trials and excluded non breast cancer deaths. When looking at the Kaplan-Meier plots for BIG 1-98 it is worth remembering that the number of patients at risk at 5 years (approximately 550 patient per arm) represents less than 15% of the overall population and is only around a quarter of that seen in ATAC (approximately 2000 per arm) at the same time point. Combined with a shorter follow-up this means that BIG 1-98 data are not as mature as ATAC. Patients in the letrozole group had significantly lower rate of relapse compared with patients who received tamoxifen. It is more appropriate to compare TTR between ATAC and BIG 1-98 as definitions were similar in the two trials and excluded non breast cancer deaths. When looking at the Kaplan-Meier plots for BIG 1-98 it is worth remembering that the number of patients at risk at 5 years (approximately 550 patient per arm) represents less than 15% of the overall population and is only around a quarter of that seen in ATAC (approximately 2000 per arm) at the same time point. Combined with a shorter follow-up this means that BIG 1-98 data are not as mature as ATAC.

    84. Key Points An indirect comparison of data from women aged >50 years with ER-positive, early breast cancer demonstrates that tamoxifen exhibited similar efficacy in both the ATAC trial and the EBCTCG overview This comparison reveals that the tamoxifen group in the ATAC trial is continuing to perform as expected in the adjuvant setting, and that the better outcome seen with anastrozole cannot be explained by a poor performance of tamoxifen; although it should be noted that no adjustment was made for the difference in the nodal status between the EBCTCG overview and ATAC trial The 4-year recurrence-free estimate in the hormone receptor-positive group of patients of the ATAC trial treated with tamoxifen (89.6%) was similar to the rate seen in the Early Breast Cancer Trialists Collaborative Group (EBCTCG) 1995 overview for tamoxifen (87.0%)1. In contrast, the 4-year recurrence-free rate in the hormone receptor-positive group of patients treated with anastrozole in the ATAC trial was 92.2%2 Reference 1. EBCTCG. Tamoxifen for early breast cancer: an overview of the randomised trials. Lancet 1998; 351: 1451-1467. 2. The ATAC Trialists Group. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial. Lancet 2002; 359: 2131-2139. Key Points An indirect comparison of data from women aged >50 years with ER-positive, early breast cancer demonstrates that tamoxifen exhibited similar efficacy in both the ATAC trial and the EBCTCG overview This comparison reveals that the tamoxifen group in the ATAC trial is continuing to perform as expected in the adjuvant setting, and that the better outcome seen with anastrozole cannot be explained by a poor performance of tamoxifen; although it should be noted that no adjustment was made for the difference in the nodal status between the EBCTCG overview and ATAC trial The 4-year recurrence-free estimate in the hormone receptor-positive group of patients of the ATAC trial treated with tamoxifen (89.6%) was similar to the rate seen in the Early Breast Cancer Trialists Collaborative Group (EBCTCG) 1995 overview for tamoxifen (87.0%)1. In contrast, the 4-year recurrence-free rate in the hormone receptor-positive group of patients treated with anastrozole in the ATAC trial was 92.2%2 Reference 1. EBCTCG. Tamoxifen for early breast cancer: an overview of the randomised trials. Lancet 1998; 351: 1451-1467. 2. The ATAC Trialists Group. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial. Lancet 2002; 359: 2131-2139.

    85. Key Points An indirect comparison of data from women aged >50 years with ER-positive, early breast cancer demonstrates that tamoxifen exhibited similar efficacy in both the ATAC trial and the EBCTCG overview This comparison reveals that the tamoxifen group in the ATAC trial is continuing to perform as expected in the adjuvant setting, and that the better outcome seen with anastrozole cannot be explained by a poor performance of tamoxifen; although it should be noted that no adjustment was made for the difference in the nodal status between the EBCTCG overview and ATAC trial The 4-year recurrence-free estimate in the hormone receptor-positive group of patients of the ATAC trial treated with tamoxifen (89.6%) was similar to the rate seen in the Early Breast Cancer Trialists Collaborative Group (EBCTCG) 1995 overview for tamoxifen (87.0%)1. In contrast, the 4-year recurrence-free rate in the hormone receptor-positive group of patients treated with anastrozole in the ATAC trial was 92.2%2 Reference 1. EBCTCG. Tamoxifen for early breast cancer: an overview of the randomised trials. Lancet 1998; 351: 1451-1467. 2. The ATAC Trialists Group. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial. Lancet 2002; 359: 2131-2139. Key Points An indirect comparison of data from women aged >50 years with ER-positive, early breast cancer demonstrates that tamoxifen exhibited similar efficacy in both the ATAC trial and the EBCTCG overview This comparison reveals that the tamoxifen group in the ATAC trial is continuing to perform as expected in the adjuvant setting, and that the better outcome seen with anastrozole cannot be explained by a poor performance of tamoxifen; although it should be noted that no adjustment was made for the difference in the nodal status between the EBCTCG overview and ATAC trial The 4-year recurrence-free estimate in the hormone receptor-positive group of patients of the ATAC trial treated with tamoxifen (89.6%) was similar to the rate seen in the Early Breast Cancer Trialists Collaborative Group (EBCTCG) 1995 overview for tamoxifen (87.0%)1. In contrast, the 4-year recurrence-free rate in the hormone receptor-positive group of patients treated with anastrozole in the ATAC trial was 92.2%2 Reference 1. EBCTCG. Tamoxifen for early breast cancer: an overview of the randomised trials. Lancet 1998; 351: 1451-1467. 2. The ATAC Trialists Group. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial. Lancet 2002; 359: 2131-2139.

    87. ER+/PR- breast cancer: biologic characteristics

    88. Response by PgR Allred expression category

    94. HER-2 in HR+: prognosis and hormone-resistance

    99. BIG 1-98 DFS by Central Pathological Assessment

    100. IES : subgroups Un aspetto particolarmente apprezzabile per lo studio IES costituito dalla coerenza dei risultati per i vari sottogruppi considerati: in altre parole limpatto favorevole di Exemestane rispetto a Tamoxifen si manifesta per i vari profili prognostici individuati.Un aspetto particolarmente apprezzabile per lo studio IES costituito dalla coerenza dei risultati per i vari sottogruppi considerati: in altre parole limpatto favorevole di Exemestane rispetto a Tamoxifen si manifesta per i vari profili prognostici individuati.

    103. Effects of estrogens in different organ systems Influence on mood Neuroprotection Reduction of intraocular pressure Amelioration of skin aging Maintenance of Bone Density Arterial Vasodilation Cardioprotection Growth and proliferation of breast tissue; risk factors for breast cancer Increase production livel proteins such as coagulation factors and hepatic lipoprotein receptors Putative reduction in risk of colon cancer Growth and differentiation of and water retention in primary sex organs; risk factor for endometrial cancer

    104. Cognitive Function in HRT trials During a mean follow-up of 5.4 years 3MSE scores were lower for ERT than for placebo (risk of having a 10 unit decrease in 3MSE scores = 1.47) Pooled data of ERT and ERPT show an increase risk for dementia and Mild Cognitive Impairment

    106. AIs versus Placebo: Letrozole in Tam pretreated patients

    107. Letrozole vs Placebo (MA-17)

    108. Letrozole vs Placebo (MA-17)

    109. Letrozole vs Placebo (MA-17)

    110. Cholesterol levels in MA.17

    112. MA.17: Ischemic cardiovascular disease

    113. Letrozole vs Placebo (MA-17)

    115. AIs versus Placebo: Exemestane

    116. Exemestane vs placebo: BMD & lipids results Annual rate of BMD loss was significantly p <0.05) higher in the femoral neck and not in the lumbar spine Increase of bone resorption and formation markers; return to baseline within 6 months Modest reduction of HDL-cholelesterol (p<0.001) and Apolipoprotein A1 (p= 0.004) No effect on other lipid parameters, homocysteine levels or coagulation parameters

    117. AIs versus Tamoxifen

    118. Arthritis/Arthralgias

    119. Joint Symptoms

    120. Gynecological Problems

    121. Gynecological issues with Tam Higher incidence of endometrial cancer Related to duration (OR 1.9 for 2-4 years of Tam) Related to time since last use known Poorer prognosis endometrial cancer? Higher incidence of vaginal bleeding Greater endometrial thickness (lower sensitivity, specificity and PPV)

    122. Endometrial events : Tamoxifen vs Aromatase Inhibitor

    124. Hypercholesterolemia reported in adjuvant AI trials BIG 1-98 trial and ATAC differ in their methods of collecting lipid data. According to the protocol in BIG 1-98, cholesterol levels were systematically collected in the case report forms every 6 months. In contrast, such information was collected irregularly in the ATAC trial because the visit forms did not specially request this information and it was only reported under any other relevant medical history. Furthermore it should be noted, that unlike with BIG 1-98, events occurring after treatment discontinuation were not reported.BIG 1-98 trial and ATAC differ in their methods of collecting lipid data. According to the protocol in BIG 1-98, cholesterol levels were systematically collected in the case report forms every 6 months. In contrast, such information was collected irregularly in the ATAC trial because the visit forms did not specially request this information and it was only reported under any other relevant medical history. Furthermore it should be noted, that unlike with BIG 1-98, events occurring after treatment discontinuation were not reported.

    125. Serum cholesterol levels in BIG 1-98 Median change (%) versus baseline

    126. Tamoxifen & Lipids

    128. Summary: Incidence of CVD in adjuvant AI trials

    130. Cardio-protective effect of tamoxifen Metanalysis 32 trials comparing tamoxifen against a control group (metastatic, adjuvant, and prevention settings) 12 reported on myocardial infarction death > 52,000 patients; 66% postmenopausal; mean age 54.8 yrs; mean treatment duration: 4.3 yrs; mean FU: 5.6 yrs Relative risk ratio for fatal MIs (tamoxifen / control): 0.62 (95% CI: 0.41-0.93) Risk ratio without the Scottish trial: 0.81 (95% CI: 0.48-1.37)

    131. Cardio-protective effect of tamoxifen Early Breast Cancer Trialists Collaborative Group experience at 15 yrs (Lancet 2005) ~ 66,000 women treated with tamoxifen Subset of ~15,000 women treated with 5 yrs tamoxifen versus control: 189 vs 169 vascular deaths (tamoxifen vs control, NS) Stroke: 54 vs 29 (p=0.07) Thromboembolic: 15 vs 8 (NS); Cardiac cause: 120 vs 132 (p=0.06)

    132. Bone Health

    133. AI and fractures

    134. Fracture risk over time: ATAC

    135. Fracture risk over time: ATAC

    136. ATAC bone-substudy No pt with normal bone became osteoporotic Slowing down of bone-loss in years 2-5 Correlation of bone markers and BMD decrease Patients at risk of bone loss should be identified and managed

    137. Quality of Life

    138. Quality of Life - Studies

    139. Quality of Life - Studies

    140. Quality of Life - Studies

    141. Counteracting the AIs negative effects

    142. ASCO Guidelines Farmaci che agiscono sulla struttura e mineralizzazione ossea Acido etidronico orale 0,400 g Nota 42 classe A parenterale 1,5 g Acido Clodronico orale 1,600 g A/C prenterale 1,500 g A/C Acido Pamidronico parenterale 60-90 mg H Acido Alendronico orale 10 mg NOTA 79 Acido Tiludronico orale 0,400 g Acido Ibandronico orale H parenterale 4 mg Acido Risedronico orale 5 mg A/C Nota 79 Acido Zoledronico parenterale 4 mg Nota 42; morbo di Paget Osseo per letidronato, mts osteolitiche o mieloma per il clodronato. Nota 79: profilassi secondaria in pregresse fratture osteoporotiche, profilassi primaria in pazienti in terapia steroidea da >3 mesicon pregressi collassi vertebrali o fratture.Farmaci che agiscono sulla struttura e mineralizzazione ossea Acido etidronico orale 0,400 g Nota 42 classe A parenterale 1,5 g Acido Clodronico orale 1,600 g A/C prenterale 1,500 g A/C Acido Pamidronico parenterale 60-90 mg H Acido Alendronico orale 10 mg NOTA 79 Acido Tiludronico orale 0,400 g Acido Ibandronico orale H parenterale 4 mg Acido Risedronico orale 5 mg A/C Nota 79 Acido Zoledronico parenterale 4 mg Nota 42; morbo di Paget Osseo per letidronato, mts osteolitiche o mieloma per il clodronato. Nota 79: profilassi secondaria in pregresse fratture osteoporotiche, profilassi primaria in pazienti in terapia steroidea da >3 mesicon pregressi collassi vertebrali o fratture.

    143. Patient base selection (not tumor profile): Tamoxifen to be excluded Tam res tumors (ER+PgR-, HER2+, DVT risk High metabolizers .

    144. Selection on the basis of patient (not tumor profile): Tamoxifen to be excluded Pre (peri) menopause Osteoporosis?? .

    145. Conclusions

    146. Conclusions Pts at risk of breast cancer relapse and death should receive the agent most effective and with the most manageable toxicity Tamoxifen cannot be considered for prevention or treatment of diseases of ageing women For osteopenia/osteoporosis: diet, physical activity, bisphosphonates For hypercholesterolemia: diet, physical activity, statins

    147. Relative and absolute risk reduction

    148. Relative and absolute risk reduction

    149. Relative and absolute risk reduction

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