1. Breast Cancer Patient Issues in 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 TorontoToronto, 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. 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. 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 disease95% –Stage II disease 70%-85% –Stage III disease50%-52% –Stage IV disease 17%

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 0 Year 105 90 75 60 45 30 15 1950196019701980 1990 2000 Annual death rate per 100,000 women UK USA 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 Follow-Up Adjuvant Chemotherapy Adjuvant Radiation Adjuvant Endocrine

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) 51.0% 70.1% 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 SURGERY Neo-Adjuvant Chemotherapy 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 Reprinted from The Lancet, vol 351, Early Breast Cancer Trialists Collaborative Group, 1451, 1998, with permission from Elsevier Science. Years 100 % Recurrence-free 90 80 60 40 20 0 510+0 Node -ve: 14.9% SD 1.4: 2P<0.00001 Node +ve: 15.2% SD 2.5: 2P<0.00001 Node -ve Node +ve 87.4 79.2 74.9 75.6 64.3 59.7 58.3 44.5 70 50 30 10 Absolute Recurrence Reduction Tamoxifen (~5 y) Placebo Tamoxifen (~5 y) Recurrence as First Event

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 Type 1 (Steroidal Inactivator) Type 2 (Nonsteroidal Inhibitor) Exemestane (Aromasin) Anastrozole (Arimidex) Letrozole (Femara)

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

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

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 RANDOMIZATIONRANDOMIZATIONRANDOMIZATIONRANDOMIZATION Postmenopausal women Early ER + breast cancer Disease free after adjuvant tamoxifen 20 mg po qd × 2-3 years 2-3 years tamoxifen 20 mg po qd 2-3 years exemestane 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 (contd) The optimal choice of therapy is dependent on –Patients 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. RecurrencesBreast Cancer Deaths More Than Half of Breast Cancer Recurrences and Deaths Occur Post-Tamoxifen Adapted with permission. Early Breast Cancer Trialists Collaborative Group Meeting, 2000. Years 85.2 76.1 68.2 73.7 62.7 54.9 68% 55% 0 20 40 60 80 100 051015 Tamoxifen Control 15%17% 0 20 40 60 80 100 051015 73% 64% 80.9 73.0 87.8 73.2 64.0 Years Tamoxifen Control 9%18% 91.4 % of patients

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. NSABP B-14 Fisher et al. J Natl Cancer Inst 2001. DFS 100 90 80 70 60 50 % of patients 05 Placebo Tamoxifen Years 7 OS 05 Years 100 90 80 70 60 50 7 % of patients Placebo Tamoxifen Tamoxifen demonstrated higher rates of endometrial cancer, ischemic heart disease, and cerebrovascular disease. 82% 78% 94% 91% P=0.03 P=0.07 1246313246 No benefit of extending tamoxifen beyond 5 years of therapy

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

50. Extended adjuvant letrozole Adjuvant tamoxifen Rationale for the MA.17 Extended Adjuvant Trial 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 Goss et al. N Engl J Med 2003.

51. Trial Design of MA.17 Goss et al. N Engl J Med 2003. Randomization (All patients disease-free) Tamoxifen Placebo qd Letrozole 2.5 mg qd Approx. 5 years adjuvant5 years extended adjuvant 0–3 months n=2575 n=2582

52. Letrozole (MA.17) Efficacy Letrozole was superior to placebo –DFS (Disease Free Survival) –Distant DFS –Overall Survival difference in Lymph Node positive patients only

53. P=0.04 Node-Positive Node-Negative P=0.24 Overall Survival MA.17 0 20 40 60 80 100 Time from randomization (months) 0 1292 1276 10 1265 1250 20 972 964 30 572 571 40 275 283 50 93 60 3 5 0 20 40 60 80 100 Time from randomization (months) Femara Placebo 0 1171 1189 10 1144 1157 20 875 877 30 508 500 40 255 243 50 81 75 60 3 3 Percent LetrozolePlacebo Percent LetrozolePlacebo No. at Risk Adapted from Goss. ASCO 2004. While OS was not improved in node-negative patients, a similar reduction in local recurrences, new primaries, and distant recurrences occurred as in the node-positive patients

54. Letrozole (MA.17) Toxicity Letrozole compared to placebo Letrozole therapy associated with –Hot flashes –Vaginal bleeding/discharge –Osteoporosis Adapted from Goss. ASCO 2004.

55. Case No. 4: Summary Patients such as in this case, who have completed 5 years of therapy on tamoxifen, should –Be referred back to the cancer centre The medical oncologist will discuss extended therapy for these patients This discussion may involve –Recurrence risk –Patients co-morbidities –Patient preference

56. Summary: Use of Aromatase Inhibitors Aromatase inhibitors in adjuvant setting –Literature specific for post-menopausal women –Effective in preventing recurrence, reduction in distant metastasis and new contralateral breast cancer –Effective as first-line adjuvant, sequence, and extended therapy –Overall survival improvement seen only in node- positive patients with 5 years of letrozole in the extended setting –Long-term safety data remains to be studied

57. Best Adjuvant Strategy: Remains to be Seen Aromatase inhibitors –As neoadjuvant? –After 2-3 yrs of tamoxifen? –after 5 yrs of tamoxifen? –after 5 yrs of AI therapy? –Duration of AI therapy? –Only for high-risk breast cancer?

58. Follow-Up of Patients with History of Breast Cancer

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

60. Case No. 5 54-year-old female patient Dx with early stage breast cancer 2 years ago Received chemotherapy with an anthracycline- containing regimen (CEF) –Cyclophosphamide –Epirubicin –Fluorouracil

61. Case No. 5 What is the role of family physicians (FPs) in following these patients? Why is it important to follow patients with previous history of breast cancer? What are the requirements for appropriate follow-up?

62. Role of Family Physician FPs remain the primary care givers for most of these patients FPs may provide follow-up as –Sole provider of care –In conjunction with the cancer centre

63. Who Should Do the Follow-up? Ontario Study –Randomized breast cancer follow-up to Cancer centres Family physicians Results –No difference in patient outcome Serious clinical events Grunfeld et al. PASCO 2004.

64. Why Follow Patients? Follow-up may help –Provide adequate psychosocial support and counseling –Detect recurrent and metastatic disease –Detect other malignancies –Monitor toxicities related to current or previous treatment

65. Canadian Steering Committee Goals of Follow-Up Three major objectives of follow-up care –Support and counseling –Detection of disease relapse locally and distant –Surveillance for second malignancies

66. Frequency of Follow-Up Bari Consensus Conference (1995) recommendations –Visits every 3 months for the first 2 years, then –Every 6 months for the next 3 years, then –Annually thereafter

67. Available Guidelines Canadian Steering Committee on Clinical Practice Guidelines (Canadian Task Force) American Society of Clinical Oncology (ASCO) Canadian Steering Committee on Clinical Practice Guidelines. CMAJ 1999. American Society of Clinical Oncology. JCO 1998.

68. Summary of Guidelines History and physical –Every 3-6 months first 3 yrs after primary therapy –Then q 6 months for 2 yrs –Then annually Annual mammogram Encourage monthly BSE Educate re: recurrence symptoms Regular pelvic exams Canadian Steering Committee on Clinical Practice Guidelines. CMAJ 1999. American Society of Clinical Oncology. JCO 1998.

69. Summary of Guidelines Do Not Do Routinely CBC, renal function tests, liver function tests, albumin, protein, calcium Chest X-ray Bone scan Liver ultrasound CT Tumour markers: CEA, CA 15-3 Canadian Steering Committee on Clinical Practice Guidelines. CMAJ 1999. American Society of Clinical Oncology. JCO 1998.

70. Follow-up for Breast Cancer Patients On Endocrine Therapies Bloodwork –No need for routine blood work Bone mineral density (BMD) –Of particular importance for patients on aromatase inhibitors Recommend baseline, then annually

71. Follow-up for Breast Cancer Patients On Endocrine Therapies (contd) Ophthalmologic evaluation –Symptom driven –If previous history – annual exam No role for other routine investigations –Including pelvic or abdominal U/S, Doppler, etc.

72. Common Health Issues Among Breast Cancer Patients

73. Common Health Issues Cardiac toxicity Osteoporosis Early menopause Secondary cancers

74. Case No. 5 (contd) Patient now has increasing SOB with exertion –What other features on history and physical examination are important? –What investigations are critical to help us with the diagnosis?

75. Cardiac Toxicity – Chemotherapy Related Anthracyclines –Daunorubicin, doxorubicin, idarubicin, epirubicin, and mitoxantrone Toxicity effects –Acute (during administration) Arrythmias, pericarditis-myocarditis –Early (Several days to mos following) CHF, with peak at 3 mos after last dose –Late (years to decades following) CHF may develop up to 10-12 yrs after last anthracyline dose

76. Cardiac Toxicity – Anthracyclines Risk factors for the development of anthracycline cardiac toxicity –Cumulative dose – strongest risk factor –Age –Prior irradiation –Concomitant administration of other agents –Previous history of cardiac disease

77. Cardiac Toxicity – Other Therapies Aromatase inhibitors –Long-term cardiac toxicity remains to be studied with these agents Herceptin

78. Osteoporosis Hormone-dependent osteoporosis –Early menopause –Chemotherapy-induced premature ovarian failure –Endocrine treatment Hormone-independent osteoporosis –Direct effect of chemotherapy –History of breast cancer

79. Management of Osteoporosis for Patients on Aromatase Inhibitors Surveillance –Annual BMD –Height measurements If needed: T + L Spine X-rays –Risk factor assessment Therapy –Bone hygiene Calcium 1500 mg/d + Vitamin D 800 I.U. supplement –Bisphosphonate therapy Early initiation of bisphosphonate therapy if »BMD t score <2.5 »Progressive bone loss Hillner et al. JCO 2003.

80. Early Menopause Fertility issues Menopausal symptoms –Treatment related –Non-treatment related Osteoporosis (previously discussed)

81. Secondary Cancers Incident case Breast cancer –New primary cancer Risk about 1% per year –Recurrence Local Metastatic Other cancers Treatment independent Secondary to treatment –Chemotherapy –Radiation –Endocrine

82. Other Concerns Lymphoedema –Referrals to supportive care services Family members –Screening for breast cancer –Screening for other cancers –Genetic assessment

83. Case No. 5 (contd) Patient now presents with back pain over the last 4 months Pain located in lower thoracic/upper lumbar area

84. Case No. 5 (contd) When should the FP refer the patient back to the cancer centre? What are some concerning symptoms associated with back pain? What are the common sites of distant metastasis? How should we investigate?

85. When Should FPs Refer Patients to Cancer Centre? Cancer related –New breast lump or local lymphadenopathy New primary breast cancer Cancer recurrence –Concerning distant symptoms –Secondary cancers

86. When Should FPs Specifically Consult Medical Oncology? Treatment related –New endocrine treatment for follow-up population –Toxicities –Patient driven

87. Early Breast Cancer Role of Family Physicians SURGERY Adjuvant Chemotherapy Adjuvant Radiation Adjuvant Endocrine Follow-Up Family physicians

88. Conclusions There have been some key advances in the management of breast cancer in the last few years Regular and appropriate follow-up care is essential for patients with history of breast cancer

89. Conclusions Family physicians play an integral role in the management of these patients It is important to refer patients to cancer centre –To evaluate any specific concerns, or –To review if they are suitable candidates for new therapies