Breast Cancer Patient Issues in Family Practice: An Interactive Session

1. Breast Cancer Patient Issuesin Family Practice:An Interactive Session

2. Acknowledgements Content Development Committee Sunil Verma, MD, MSEd, FRCPC Lisa Del Giudice, MSc, MD, CCFP Medical Oncologist, Staff Division of Medical Department of Family Medicine Oncology/Hematology Sunnybrook & Women's College Toronto Sunnybrook Regional Health Sciences Centre Cancer Centre Assistant Professor Assistant Professor, University of Toronto University of Toronto Toronto, Ontario Toronto, Ontario sunil.verma@sw.ca Novartis Pharma Canada Inc gratefully acknowledges the commitment and dedication of the Content Development Committee to the development of this program

3. Objectives • To recognize the risk of breast cancer recurrence and the common health problems faced by women with history of breast cancer • To review the requirements for complete follow-up care of women with history of breast cancer • To discuss the recent advances in the field of breast cancer, specifically in the arena of endocrine therapies • To describe the reasons for referrals back to the cancer centre for women with history of breast cancer

4. Breast Cancer • 2004 breast cancer rates from the National Cancer Institute of Canada • 21,200 new cases diagnosed in Canada • 5,200 deaths • Second leading cause of cancer death in women • Outcome is directly related to stage at diagnosis, eg, survival after 5 years* • Stage I disease 95% • Stage II disease 70%-85% • Stage III disease 50%-52% • Stage IV disease 17% National Cancer Institute of Canada/www.cancer.ca. Fisher et al. J Natl Cancer Inst Monographs 2001. *American Joint Committee on Cancer. Handbook for Staging of Cancer 1993.

5. 2004 Canadian Breast Cancer Incidence Rates Of the 21, 200 new cases • 16,700 (79%) were age ≥50 years • 11,000 (52%) were age ≥60 years www.cancer.ca

6. Mortality Rates in Patients With Breast Cancer Aged 50 to 69 Years 105 UK 90 60 USA Annual death rateper 100,000 women 45 75 30 15 0 1950 1960 1970 1980 2000 1990 Year Reprinted with permission from Elsevier Science. Lancet 2000.

7. Breast Cancer Presentation Early Breast Cancer Locally Advanced Breast Cancer Metastatic Breast Cancer

8. Early Breast Cancer Treatment Schema SURGERY Adjuvant Chemotherapy Adjuvant Radiation Adjuvant Endocrine

9. Early Breast Cancer Treatment Schema SURGERY Adjuvant Chemotherapy Adjuvant Radiation Adjuvant Endocrine Follow-Up

10. Case No. 1 • 45-year-old female patient • R breast lump originally diagnosed March 2004 • R breast lumpectomy and node dissection 6 weeks ago • Pathology • 2.5 cm size • Tumour Grade II/III • Estrogen receptor -ve/Progesterone receptor -ve (hormone receptor negative) • Lymph nodes 3/12 involved

11. Case No. 1 • What is her recurrence risk? • Without any further treatment? • With chemotherapy?

12. Prognostic Factors • In order for us to assess the recurrence risk we need to review certain prognostic factors • These prognostic factors include • Lymph node status • Tumour size • Tumour grade • Receptor status

13. Case No. 1: Recurrence Risk (10 yr)Benefit from Chemotherapy 58.7% 33.4% Percentage of patients (%) No additional therapy Chemotherapy

14. Case No. 1: Survival Benefit from Chemotherapy(Alive in 10 years) 70.1% 51.0% Percentage of patients (%) No additional therapy Chemotherapy

15. Case No. 1: Conclusion • Adjuvant chemotherapy results in • Lowering the recurrence risk, and • Improvement in survival • The patient in this case with early breast cancer should be considered for a medical oncology opinion for possible adjuvant chemotherapy

16. Exciting Advances in Breast Cancer Management • Chemotherapy • Molecular therapy • Endocrine therapy

17. Chemotherapy • Early breast cancer • Taxanes • Paclitaxel • Docetaxel • Dose-Dense • Every 2 weeks (compared to every 3 weeks of regular therapy) • Neoadjuvant

18. Neo-Adjuvant Chemotherapy Neo-Adjuvant Chemotherapy SURGERY Adjuvant Radiation Adjuvant Endocrine

19. Molecular Therapy

20. Advances in Endocrine Therapy:“A Revolution in the Treatment of Breast Cancer”

21. Case No. 2 • 64-year-old female patient • Recent dx of L sided breast cancer • Mastectomy and axillary nodal dissection (AND) • Pathology • Tumour Size 1.2 cm • Tumour Grade II/III • Estrogen receptor +ve/progesterone receptor +ve (hormone receptor +ve) • Lymph node negative (0/18)

22. Case No. 2 • What are the different treatment strategies available for this patient? • Tamoxifen for 5 years

23. Case No. 2 • What are the benefits of tamoxifen? • What are the toxicities related to tamoxifen?

24. Tamoxifen: Improvement in Disease-Free Survival Recurrence as First Event 100 Tamoxifen (~5 y) 87.4 90 79.2 Placebo 80 74.9 Tamoxifen (~5 y) Node -ve 70 75.6 64.3 Placebo 60 59.7 58.3 Node +ve 50 % Recurrence-free 40 44.5 30 Absolute Recurrence Reduction 20 Node -ve: 14.9% SD 1.4: 2P<0.00001 Node +ve: 15.2% SD 2.5: 2P<0.00001 10 0 0 5 10+ Years Reprinted from The Lancet, vol 351, Early Breast Cancer Trialists’ Collaborative Group, 1451, 1998,with permission from Elsevier Science.

25. Toxicity of Tamoxifen • Endometrial cancer • Venous thrombosis • Hot flashes • Vaginal dryness/bleeding

26. Case No. 2 • What are the different treatment strategies available for this patient? • Tamoxifen for 5 years • Aromatase inhibitor [AI] for 5 years • Tamoxifen for 2 -3 years followed by an AI to complete 5 years of treatment • Tamoxifen for 5 years followed by an AI for 5 years Winer et al. JCO 2005.

27. Case No. 2: Further Questions • What is the mechanism of action of aromatase inhibitors? • What are the different classes of aromatase inhibitors? • Is there any evidence that aromatase inhibitors • Are better than tamoxifen? • Can be used within the first 5 years in sequence with tamoxifen?

28. Mechanism of Action Smith et al. N Engl J Med 2004.

29. Classes of Aromatase Inhibitors

30. Tamoxifen vs. Aromatase Inhibitors in Early Breast CancerFirst Line ATAC Trial (Anastrozole) BIG 1-98 Trial (Letrozole)

31. Postmenopausal women with invasive breast cancer â Surgery  radiotherapy  chemotherapy â Randomization 1:1:1 for 5 years æ â å Anastrozole placebo+Tamoxifen 20mg od Anastrozole 1mg od+Tamoxifen placebo Anastrozole 1mg od+Tamoxifen 20mg od + â â â n=3125 n=3116 n=3125 ATAC (Anastrozole) ATAC Trialists’ Group. Lancet 2005.

32. ATAC Trial (Anastrozole): Efficacy • Anastrazole shown to be superior to tamoxifen • Improved Disease Free Survival (DFS) • Contralateral breast cancer • No difference in Overall Survival (OS)

33. BIG 1-98 Trial (Letrozole): Efficacy • Early results from this study show that • Letrozole is also superior to tamoxifen for • Disease Free Survival • Distant recurrences (Systemic Disease Free Survival)

34. Aromatase Inhibitor Toxicity • In favour of Aromatase Inhibitors • Endometrial cancer • Vaginal bleeding/discharge • Thromboembolic disease • In favour of tamoxifen • Arthralgias • Osteoporosis

35. Case No. 3 64-year-old female patient • Hx of L sided breast cancer • Original dx 2002 • Mastectomy and AND • Pathology • Tumour Size: 1.2 cm • Tumour Grade: II/III • ER +ve/PR +ve • Lymph node negative (0/18) • On tamoxifen since 2002

36. Case No. 3 • The different treatment strategies available for this patient are • Complete tamoxifen for 5 years • Tamoxifen for 2 years followed by exemestane (an AI) to complete 5 years of therapy • Tamoxifen for 5 years followed by letrozole (an AI) for another 5 years of therapy

37. Switching From Tamoxifen to Aromatase Inhibitors IES Trial (Exemestane)

38. IES Schema RANDOMIZATION • Postmenopausal women • Early ER+ breast cancer • Disease free after adjuvant tamoxifen • 20 mg po qd × • 2-3 years • 2-3 yearsexemestane20 mg po qd • 2-3 yearstamoxifen 20 mg po qd 5 years total therapy Coombes et al. N Engl J Med 2004.

39. IES Trial (Exemestane): Efficacy • Exemestane was superior to tamoxifen • Disease Free Survival (DFS) • Distant DFS • No difference in OS (Overall Survival)

40. IES Trial (Exemestane):Toxicity • In favour of exemestane • Vaginal bleeding/discharge • Endometrial cancer • Thromboembolic disease • In favour of tamoxifen • Arthralgia • Osteoporosis

41. Summary • Many options available for first-line treatment of hormone receptor positive early breast cancer • Tamoxifen for 5 years, or • Anastrozole (AI) for 5 years, or • Letrozole (AI) for 5 years, or • Tamoxifen for 2 years followed by exemestane (AI) to complete 5 years of therapy Winer et al. JCO 2005.

42. Summary (cont’d) • The optimal choice of therapy is dependent on • Patient’s underlying health • Tumour-related factors • Patient preference

43. Extending Endocrine Treatment Beyond Five Years of Therapy MA.17 Trial (Letrozole)

44. Case No. 4 63-year-old female patient • Hx of breast cancer, originally dx 5 years ago • L lumpectomy and AND • Pathology at that time: • Tumour Size 2.5 cm • Tumour Grade III/III • Estrogen receptor +ve/progesterone receptor -ve • Lymph node 2/14 +ve • Followed by chemotherapy and radiation tx • Received tamoxifen for 5 years • Completed tx 2 months ago

45. Case No. 4 • What is her risk of recurrence now after completing 5 years of therapy with tamoxifen? • Should we keep her on tamoxifen longer?

46. More Than Half of Breast Cancer Recurrences and Deaths Occur Post-Tamoxifen Recurrences Breast Cancer Deaths 15% 17% 9% 18% 100 100 91.4 85.2 80.9 76.1 80 80 73.0 87.8 68.2 73% 68% 73.7 73.2 64% 60 60 55% 62.7 64.0 % of patients % of patients 54.9 40 40 Tamoxifen Control Tamoxifen Control 20 20 0 0 0 5 10 15 0 5 10 15 Years Years Adapted with permission. Early Breast Cancer Trialists’ Collaborative Group Meeting, 2000.

47. Case No. 4: Recurrence Risk • In this case situation, on average, • 70% of patients will be alive and without disease at 5 years • There is still a 26% chance of relapse within next 5 years

48. DFS OS P=0.07 100 100 P=0.03 94% 90 90 91% 82% 80 80 % of patients % of patients 78% 70 70 Placebo Tamoxifen Placebo Tamoxifen 60 60 50 50 0 1 2 3 4 5 6 7 0 1 2 3 4 5 6 7 Years Years • Tamoxifen demonstrated higher rates of endometrial cancer, ischemicheart disease, and cerebrovascular disease. NSABP B-14 No benefit of extending tamoxifen beyond 5 years of therapy Fisher et al. J Natl Cancer Inst 2001.

49. Case No. 4 • Are there other therapeutic options available for this patient?

50. Rationale for the MA.17 Extended Adjuvant Trial Adjuvant tamoxifen • Lack of benefit when adjuvant tamoxifen treatment is extended beyond 5 years • Increasing risk for long-term adverse effects (thromboembolism, endometrial hyperplasia/cancer, hot flashes, vaginal/urinary symptoms) • Need to extend DFS/OS beyond adjuvant tamoxifen Extended adjuvant letrozole Goss et al. N Engl J Med 2003.