1. ARIMIDEX ® (anastrozole) in the Treatment of Early Breast Cancer

2. 1. American Cancer Society. Cancer Facts and Figures 2005; 2. Morrow M et al. Oncology. 1997;11: 877-886. With permission of ONCOLOGY, Melville, NY. US Breast Cancer Statistics n~211,240 women will develop invasive breast cancer in 2005 1 n~40,410 women will die of breast cancer in 2005 1 nFive-year survival rate by stage 2 : –In situ 95% to 99% –Stage I 90% to 94% –Stage II 68% to 86% –Stage III42% to 55% –Stage IV15% to 18%

3. Treatment Options for Early Breast Cancer National Cancer Institute. Breast Cancer (PDQ ® ): Treatment 2004. www.nci.nih.gov/cancertopics/pdq/treatment/breast/healthprofessional. Surgery to remove tumor Radiation therapy Adjuvant therapy Hormonal therapy ChemotherapyChemotherapy

4. Estrogen Production in Premenopausal and Postmenopausal Patients Hypothalamus Gonadotropins (FSH + LH) Ovary Estrogens Progesterone Prolactin Growth Hormone Pituitary gland Adrenal gland Progesterone Androgens Estrogens Corticosteroids Adrenocorticotropic hormone (ACTH) PremenopausalPremenopausal Premenopausal and Postmenopausal Postmenopausal FSH=follicle-stimulating hormone; LH=luteinizing hormone.

5. Hormone Receptor Status: Relationship to Menopausal Status Menopausal Status Receptor Status (%) ER+/PgR+ER+/PgR-ER-/PgR+ER-/PgR- Pre (n=488) 45121528 Post (n=826) 6315517 ER=estrogen receptor; PgR=progesterone receptor. Bland KI et al. Surg Forum. 1981;32:410-412.

6. Hormonal Therapies for Postmenopausal Women With Hormone Receptor-Positive Early Breast Cancer Therapy Mechanism of Action Antiestrogens (eg, tamoxifen) Compete with endogenous estrogen for binding sites on estrogen receptors Aromatase inhibitors (eg, ARIMIDEX ® [anastrozole]) Inhibit conversion of androgens to estrogens EBCTCG. Lancet. 1992;339:1-15;71-85; ARIMIDEX ® (anastrozole) full Prescribing Information; AstraZeneca Pharmaceuticals LP, Wilmington, DE.

7. Aromatase Inhibition nThe aromatase enzyme selectively catalyzes only the production of estrogens (not other steroid hormones) nTypes of aromatase inhibitors –Selective vs nonselective –Competitive vs noncompetitive (irreversible)

8. Selective vs Nonselective Aromatase Inhibition Federman DD. The Adrenal. In: Dale DC, Federman DD, eds. Scientific American  Medicine. New York, NY: Scientific American Inc.; 1997. Multiple steps involving cytochrome P450 enzymes and production of steroid intermediates Cortisol AndrostenedioneAldosterone Testosterone EstroneEstradiol Selective inhibitors Nonselective inhibitors Cholesterol AromataseAromatase

9. Noncompetitive vs Competitive Aromatase Inhibitors Noncompetitive (“suicide”) nSteroidal nDaily administration nCovalent bond irreversibly inactivates enzyme nEnzyme activity is restored by new enzyme synthesis nPartial lack of cross- resistance with nonsteroidal inhibitors Competitive nNonsteroidal or steroidal nDaily administration nReversibly binds to the active enzyme binding site nEnzyme binding depends on relative concentrations and affinities of inhibitor and substrate Brodie AMH. Pharmacol Ther. 1993;60:501-515; Geisler J et al. Eur J Cancer. 1996;32A:789-792; Murray R, Pitt P. Breast Cancer Res Treat. 1995;35:249-253; Lønning PE et al. J Clin Oncol. 2000;18:2234-2244.

10. Aromatase Inhibitors*: Characteristics and Approved Indications AgentCompetitiveSteroidal EBC ABC Primary Adjuvant Extended Adjuvant Anastrozole (ARIMIDEX  ) YesNo– Letrozole (Femara  ) YesNo– Exemestane (Aromasin  ) NoYes–– Aminoglutethimide (Cytadren  ) YesNo–– =indicated ; – =not indicated. *Available in the United States. EBC=early breast cancer; ABC=advanced breast cancer.

11. ARIMIDEX ® (anastrozole) nPotent nonsteroidal inhibitor of aromatase nAchiral triazole derivative nSelective and competitive nOrally active nHalf-life = 50 hours nSteady state in 7 days nHepatic metabolism (85%) nAvailable in United States since 1996 nApproved dosage = 1 mg/day ARIMIDEX ® (anastrozole) full Prescribing Information; AstraZeneca Pharmaceuticals LP, Wilmington, DE. Anastrozole (C 17 H 19 N 5 ) CN CN N NN CH 3

12. Effect of ARIMIDEX ® (anastrozole) on Aromatase and Plasma Estrogens % Reduction (Mean) ARIMIDEX 1 mg (n=12) ARIMIDEX 10 mg (n=12) Aromatase96.798.1 Estradiol84.083.5 Estrone86.886.5 Estrone sulfate 93.595.7 The clinical relevance of these findings has not been fully evaluated. Geisler J et al. Br J Cancer. 1996;74:1286-1291.

13. Current Indications for ARIMIDEX ® (anastrozole) nPrimary adjuvant treatment of postmenopausal women with hormone receptor-positive early breast cancer based on an analysis of disease-free survival in patients treated for a median of 31 months. Further follow-up of study patients is required to determine long-term outcomes nFirst-line treatment of postmenopausal women with hormone receptor-positive or hormone receptor-unknown locally advanced or metastatic breast cancer nSecond-line treatment of advanced breast cancer in postmenopausal women with disease progression following tamoxifen therapy. Patients with ER-negative disease and patients who did not respond to previous tamoxifen therapy rarely responded to ARIMIDEX ARIMIDEX ® (anastrozole) full Prescribing Information; AstraZeneca Pharmaceuticals LP, Wilmington, DE.

14. The ATAC Trial nATAC – ARIMIDEX, Tamoxifen Alone or in Combination –One of the largest breast cancer treatment trials ever conducted (N=9366) involving 881 centers in 21 countries –First trial of adjuvant treatment of early operable breast cancer in postmenopausal women using a selective aromatase inhibitor –Indication in early breast cancer based on median of 31 months of treatment; median follow-up now extends to 68 months nDesigned to determine: 1.ARIMIDEX ® (anastrozole) at least as effective or more effective than tamoxifen 2.Safety for ARIMIDEX compared with tamoxifen 3.Safety and efficacy of the combination compared with tamoxifen

15. ATAC Trial: Design Postmenopausal women with operable invasive breast cancer (N=9366) Postmenopausal women with operable invasive breast cancer (N=9366) Surgery ± radiotherapy ± chemotherapy randomization 1:1:1 for 5 years Regular follow-up Primary trial endpoints n Disease-free survival n Safety/tolerability Primary trial endpoints n Disease-free survival n Safety/tolerability ARIMIDEX ® (anastrozole) 1 mg qd + Tamoxifen placebo ARIMIDEX 1 mg qd + Tamoxifen 20 mg qd Secondary trial endpoints n Incidence of contralateral breast cancer n Time to distant recurrence n Survival ARIMIDEX placebo + Tamoxifen 20 mg qd

16. ATAC Trial: Combination Arm nDiscontinued after initial analysis (median follow- up of 33 months) nRationale for discontinuation –No significant difference between tamoxifen and combination arm in efficacy or tolerability

17. ATAC Trial: Efficacy Endpoints Primary Endpoint Disease-free survival (Locoregional or distant recurrence, new primary breast cancer, or death from any cause [as a first event]) Secondary Endpoints Overall survival Distant disease-free survival Incidence of new (contralateral) breast cancers Hormone receptor-positive population was a protocol-defined subgroup. ARIMIDEX ® (anastrozole) full Prescribing Information; AstraZeneca Pharmaceuticals LP, Wilmington, DE.

18. ATAC Trial: Patient Characteristics *Includes patients who were ER-positive or PgR-positive, or both positive; † includes patients with both ER-negative and PgR-negative receptor status; ‡ includes all other combinations of ER and PgR receptor status unknown. ARIMIDEX ® (anastrozole) full Prescribing Information; AstraZeneca Pharmaceuticals LP, Wilmington, DE. ARIMIDEX ® (anastrozole)(n=3125)Tamoxifen(n=3116)Combination(n=3125) Mean age (years) 64.164.164.3 Mean weight (kg) 70.871.171.3 Receptor status (%) Positive* Positive*83.583.183.8 Negative † Negative †7.48.07.0 Other ‡ Other ‡8.88.69.1

19. ATAC Trial: Patient Characteristics (cont’d) *Among patients with breast conservation, radiotherapy was administered to 95% of patients in the ARIMIDEX arm, 94.1% in the tamoxifen arm, and 94.5% in the tamoxifen + ARIMIDEX combination arm. ARIMIDEX ® (anastrozole) full Prescribing Information; AstraZeneca Pharmaceuticals LP, Wilmington, DE. Primary Treatment (%) ARIMIDEX ® (anastrozole) (n=3125)Tamoxifen(n=3116)Combination(n=3125) Mastectomy Mastectomy47.847.348.1 Breast conservation* Breast conservation*52.352.852 Axillary surgery Axillary surgery95.595.795.2 Radiotherapy Radiotherapy63.362.562 Chemotherapy Chemotherapy22.320.820.8 Prior tamoxifen Prior tamoxifen1.61.61.7

20. ATAC Trial: Table of First Events in ITT Population (Median Follow-up of 33 Months) ARIMIDEX ® (anastrozole) (n=3125)Tamoxifen(n=3116) Total first events 318379 Locoregional*6783 Distant157181 New contralateral primaries 1433 Contralateral (invasive) 930 Contralateral (DCIS) 53 Deaths from breast cancer † 41 Deaths for other reason ‡ 7681 DCIS=ductal carcinoma in situ. *Including new primary ipsilateral breast cancer (including DCIS), and recurrences at the chest wall, axillary, and other regional lymph nodes; † includes deaths due to breast cancer that were reported as first events without evidence of prior recurrence. Subsequent evaluation for 47-month follow-up identified documentation for recurrence prior to death or death from cause other than breast cancer in these patients; ‡ includes only deaths that were first events. ARIMIDEX ® (anastrozole) full Prescribing Information; AstraZeneca Pharmaceuticals LP, Wilmington, DE.

21. ATAC Trial: All Recurrence and Death Events in HR+ Population (Median Follow-up of 68 Months) ARIMIDEX ® (anastrozole) (n=2618)Tamoxifen(n=2598) Locoregional recurrence* 76101 Distant recurrence * 226265 Contralateral breast cancer 2654 Death from any cause 296301 * * Distant recurrence is defined as the time between randomization and the earliest occurrence of distant recurrence or death following a locoregional occurrence.

22. Howell A et al. Presentation at the 27th Annual San Antonio Breast Cancer Symposium; December 8-11, 2004; San Antonio, Tex. At risk: ARIMIDEX261825402448235522682014830 Tamoxifen 259825162398230421891932774 ATAC Trial: Disease-Free Survival in HR-Positive Subpopulation (Median Follow-up of 68 Months) Number of events: ARIMIDEX vs tamoxifen Hazard ratio 95% CI P HR+ ITT 424 vs 497 575 vs 651 0.83 0.87 0.73-0.94 0.78-0.97.005.01 Probability of a first event (HR-positive subgroup) Follow-up time (years) 0 5 10 15 20 25 0123456 Absolute difference: 1.6%2.6%2.5%3.3% Proportion with first event (%) ARIMIDEX ® Tamoxifen

23. ARIMIDEX % (n=3092) Tamoxifen % (n=3094) % (n=3094) Odds Ratio (A vs T) 95% CI P All fractures* 11.07.71.491.25-1.77<.0001 Fractures of Hip † Hip †1.21.01.200.74-1.93.5 Spine Spine1.50.91.681.04-2.71.03 Wrist/ Colles Wrist/ Colles2.32.01.150.81-1.61.4 All other sites ‡ All other sites ‡7.14.61.591.28-1.98<.0001 Musculoskeletal- disorders: Arthralgia 35.629.41.321.19-1.47<.0001 *Patients  1 fracture occurring before recurrence, including patients no longer on treatment; † the incidence of hip fracture was low and similar for ARIMIDEX and tamoxifen; ‡ patients may have had  1 fractures at different sites. ATAC Trialists’ Group. Lancet. 2005:365:60-62. ATAC Trial: Increased Incidence of Prespecified Adverse Events With ARIMIDEX ® (anastrozole) Compared With Tamoxifen (Median Treatment of 60 Months)

24. ATAC Trial: Decreased Incidence of Prespecified Adverse Events With ARIMIDEX ® (anastrozole) Compared With Tamoxifen (Median Treatment of 60 Months) ARIMIDEX % (n=3092) Tamoxifen % (n=3094) % (n=3094) Odds Ratio (A vs T) 95% CI P Hot flashes 35.740.90.80 0.73- 0.89 <00001 Vaginal bleeding 5.410.20.500.41-0.61<.0001 Vaginal discharge 3.513.20.240.19-0.30<.0001 Venous thromboembolic events 2.84.50.610.47-0.80.0004 Deep venous thromboembolic events Deep venous thromboembolic events1.62.40.640.45-0.93.02 Ischemic cerebrovascular events 2.02.80.700.50-0.97.03 Endometrial cancer* 0.20.80.290.11-0.80.02 *n=2229 for ARIMIDEX, n=2236 for tamoxifen, excluding patients with hysterectomy at baseline, recorded at any time. ATAC Trialists’ Group. Lancet. 2005:365:60-62.

25. ATAC Trial: Comparable Incidence of Prespecified Adverse Events With ARIMIDEX ® (anastrozole) Compared With Tamoxifen (Median Treatment of 60 Months) ARIMIDEX % (n=3092) Tamoxifen % (n=3094) % (n=3094) Odds Ratio (A vs T) 95% CI P Ischemic cardiovascular disease 4.13.41.230.95-1.60.1 Mood disturbances 19.317.91.100.97-1.25.2 Nausea and vomiting 12.712.41.030.88-1.19.7 Fatigue/tiredness18.617.61.070.94-1.22.3 Cataracts5.96.90.850.69-1.04.1 *Angina pectoris was reported more frequently in the ARIMIDEX-treated patients (2.3%) than in the tamoxifen-treated patients (1.6%). Comparable number of incidences of myocardial infarction (ARIMIDEX [1.2%]; tamoxifen, [1.1%]) and of cardiac-related mortality (ARIMIDEX [1.4%]; tamoxifen, [1.4%]) were reported. ATAC Trialists’ Group. Lancet. 2005:365:60-62; Data on File, DA-ARI-06, AstraZeneca Pharmaceuticals, LP.

26. Important Safety Information About ARIMIDEX ® (anastrozole) nAnalysis performed at a median treatment of 60 months nPatients receiving ARIMIDEX had a mean decrease in both lumbar spine and total hip bone mineral density (BMD) compared with baseline. Patients receiving tamoxifen had a mean increase in both lumbar spine and total hip BMD compared with baseline nMore patients receiving ARIMIDEX were reported to have an elevated serum cholesterol compared with patients receiving tamoxifen (9% vs 3.5%, respectively)

27. Other Important Safety Information nWomen must be postmenopausal to take ARIMIDEX ® (anastrozole). ARIMIDEX can cause fetal harm when administered to a pregnant woman nEstrogen-containing therapies should not be used with ARIMIDEX as they may diminish its pharmacologic action nTamoxifen should not be co-administered with ARIMIDEX

28. Other Important Safety Information (cont’d) nAt a median treatment of 60 months, the most common side effects seen with ARIMIDEX ® (anastrozole) vs tamoxifen in the ATAC Trial include –Hot flashes (36% vs 41%) –Joint disorders (including arthritis, arthrosis, and arthralgia) (36% vs 29%) –Fatigue/asthenia (19% vs 18%) –Mood disturbances (19% vs 18%) –Pain (17% vs 16%) –Nausea and vomiting (13% vs 12%) –Pharyngitis (14% vs 14%) –Depression (13% vs 12%) –Fractures, including fractures of the spine, hip, and wrist (10% vs 7%)

29. Current Indications for NOLVADEX ® (tamoxifen citrate) nTreatment of node-positive breast cancer in postmenopausal women following total mastectomy or segmental mastectomy, axillary dissection, and breast irradiation nTreatment of axillary node-negative breast cancer in women following total mastectomy or segmental mastectomy, axillary dissection, and breast irradiation nNOLVADEX reduces the occurrence of contralateral breast cancer in patients receiving adjuvant therapy with NOLVADEX for breast cancer NOLVADEX ® (tamoxifen citrate) full Prescribing information, AstraZeneca Pharmaceuticals LP, Wilmington, DE

30. Important Safety Information About Tamoxifen nSerious and life-threatening events associated with NOLVADEX  (tamoxifen citrate) include uterine malignancies, stroke, and pulmonary emboli, some of which have been fatal. In clinical trials, uterine malignancies, including endometrial cancer and uterine sarcomas (see WARNINGS, Effects on the Uterus—Endometrial Cancer and Uterine Sarcoma, in full Prescribing Information), and venous thrombotic events, including pulmonary emboli, occurred 2 to 4 times more often with NOLVADEX than placebo, but each in less then 1% of women. Stroke, cataracts, and cataract surgery also occurred more often with NOLVADEX. The most frequently reported adverse reactions were hot flashes and vaginal discharge nWomen who are pregnant or plan to become pregnant should not take NOLVADEX. Women who have a history of deep vein thrombosis or pulmonary embolism or who currently use anticoagulants should not take NOLVADEX to reduce their risk of breast cancer (see CONTRAINDICATIONS section of full Prescribing Information)

31. Dosage and Duration of ARIMIDEX ® (anastrozole) Therapy nDosage: 1-mg tablet taken once a day nOptimal duration of adjuvant therapy is unknown

32. ATAC Trial: Efficacy Summary (Median Follow-up of 68 Months) nARIMIDEX ® (anastrozole) shows: –Significantly improved disease-free survival over tamoxifen –Significant reduction in the event rate in hormone receptor-positive patients (hazard ratio 0.83 [95% CI, 0.73-0.94], P=.005) –Significant reduction in the event rate seen in the overall population (hazard ratio 0.87 [95% CI, 0.78-0.97], P=.01) nThese study results are based on patients followed for a median of 68 months

33. ATAC Trial: Safety Summary (Median Treatment of 60 months) nARIMIDEX ® (anastrozole) showed increased incidence of: –Joint disorders (including arthritis, arthrosis, and arthralgia) –Fractures, including fractures of the spine, hip and wrist nARIMIDEX showed decreased incidence of: –Hot flashes –Vaginal bleeding and discharge –Venous thromboembolic events, including deep venous thromboembolic events –Ischemic cerebrovascular events –Endometrial cancer

34. Conclusions: in Early Breast Cancer nThe ASCO 2005 Technology Assessment recommends: –“Based on results from multiple large randomized trials, adjuvant therapy for postmenopausal women with hormone receptor- positive breast cancer should include an aromatase inhibitor in order to lower the risk of tumor recurrence” –“It is unknown if the three available drugs are interchangeable in clinical practice. In general, the Panel favors using the aromatase inhibitor that has been studied in the setting most closely approximating any individual patient’s clinical circumstances.”

35. Conclusions: ARIMIDEX ® (anastrozole) in Early Breast Cancer nIn the ATAC Trial, at a median follow-up of 68 months, ARIMIDEX significantly improved disease-free survival over tamoxifen in postmenopausal women with hormone receptor-positive early breast cancer nARIMIDEX is the first aromatase inhibitor approved as primary adjuvant therapy for early breast cancer in postmenopausal women with hormone receptor-positive disease