DISCLAIMER

2. DISCLAIMER This slide deck in its original and unaltered format is a certified educational activity current as of October 2009. All materials contained herein reflect the views of the faculty, and not those of IMER, the CME provider, or the commercial supporter. These materials may discuss therapeutic products that have not been approved by the US Food and Drug Administration and off-label uses of approved products. Readers should not rely on this information as a substitute for professional medical advice, diagnosis, or treatment. The use of any information provided is solely at your own risk, and readers should verify the prescribing information and all data before treating patients or employing any therapeutic products described in this educational activity.

3. DISCLAIMER Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patients’ conditions and possible contraindications on dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.

4. Disclosure of Conflicts of InterestSandra M. Swain, MD Reported a financial interest/relationship or affiliation in the form of: Consultant, ImClone Systems Incorporated, Genentech BioOncology (and OSI Oncology), Abraxis Oncology; Contracted Research, Bristol-Myers Squibb Company, Genentech BioOncology (and OSI Oncology); Other, (Travel Expenses) sanofi-aventis U.S.

5. Community Oncology Clinical Debates in Breast Cancer

6. Case Study 1 51-year-old perimenopausal woman Presents following diagnosis of EBC  She has a 2.2 cm ER+/PgR+, HER2- negative tumor (by FISH) 1 positive axillary lymph node No other evidence of metastatic disease by  staging evaluation

7. Case Study 1 (cont.) In addition to endocrine therapy with  tamoxifen which of the following systemic  adjuvant therapies would you recommend? FEC x 6 TC x 4 (docetaxel) Dose dense AC x 4 followed by T x 4 (paclitaxel) TAC x 6 (docetaxel) 

8. Absolute Risk Reductions With Polychemotherapy During First 10 Years of Follow-Up

9. Evolution of Chemotherapy in Node-Positive Disease

10. Key Questions: Agents, Schedules 1st generation trials: Do taxanes work? – After anthracyclines C 9344 NSABP B-28 NSAPB B-27 PACS 01 GEICAM 9906 2nd generation trials: How to optimize? – Instead of anthracyclines US Oncology 9735 Pending: CALGB 40101 – Agent: E 1199 – Schedule: E 1199, C 9741 – Sequence and dose: B-30, BCIRG 005

11. CALGB 9344/Intergroup 0148 (N = 3,121) Sequential paclitaxel improves outcome in node-positive primary breast cancer

12. BCIRG001 Study Median follow-up: 4.6 years

14. Testing Type and Schedule of Taxane:E1199: Adjuvant AC ? T Vs. D q3w Vs. q1w

15. E1199: Grade 3/4 Safety Results

16. E1199: Efficacy Results Primary comparison Paclitaxel vs. docetaxel: HR = 1.032; p = .61 Q3w vs q1w: HR 1.062; P = 0.33

17. Trial Design

18. DFS

19. DFS by Treatment and Age Group

20. DFS For HER2-Positive Status

21. DFS For HER2-Negative Status

22. OS by Treatment

24. Meta Analysis A meta analysis evaluated the effectiveness  of regimens with taxanes vs. regimens  without taxanes – Subgroup analysis revealed both taxanes (docetaxel and paclitaxel) improved OS and DFS OS: Docetaxel HR 0.76 (95% CI 0.67–0.86, p < .0001) OS: Paclitaxel HR 0.85 (95% CI 0.76–0.94, p < .001) DFS: Docetaxel HR 0.80 (95% CI 0.74–0.87, p < .00001) DFS: Paclitaxel HR 0.82 (95% CI 0.76–0.89, p < .00001) – Despite a slightly favorable HR for docetaxel, a direct  comparison is needed to confirm superior efficacy – No evidence provided to restrict adjuvant taxane use to  node-positive women

25. ASCO and SABCS

26. BCIRG 005

28. Hematologic and Non-Hematologic Events GCSF GCSF

30. NSABP B-30 (N = 5,351) Primary aims Will TAC x 4 increase OS and DFS compared to AC ? T? Is AT x 4 at least as efficacious as TAC x 4 AC ? T?

32. NSABP B-30: DFS According to Subgroups

33. Questions Addressed in Adjuvant Clinical Trials (HER2-Normal)

34. Case Study 1 (cont.) 51-year-old perimenopausal woman Presents following diagnosis of EBC  She has a 2.2 cm ER+/PgR+, HER2- negative tumor (by FISH) 1 positive axillary lymph node No other evidence of metastatic disease by  staging evaluation

35. Case Study 1 (cont.) In addition to endocrine therapy with  tamoxifen which of the following systemic  adjuvant therapies would you recommend? FEC x 6 TC x 4 (docetaxel) Dose dense AC x 4 followed by T x 4 (paclitaxel) TAC x 6 (docetaxel) 

36. Case Study 2 42-year-old premenopausal woman detected a lump in right breast An evaluation by her primary physician confirmed the presence of the lump in the right breast with no palpable axillary nodes A mammogram confirmed the presence of ~ 3.5 cm spiculated mass A core biopsy confirmed a grade 3, HER2-positive, ER/PR negative infiltrating breast cancer

37. Case Study 2 (cont.) The patient’s past medical history was unremarkable except for mild hypertension  The patient proceeded to a lumpectomy and sentinel lymph node biopsy which confirmed a 3.0 cm infiltrating ductal carcinoma and 2/3 nodes were positive An axillary dissection revealed no additional positive lymph nodes An echocardiogram reveals an EF of 52% A bone scan and CT scans of the chest, abdomen and pelvis show no evidence of metastatic disease

38. Case Study 2 (cont.) The patient had an uneventful recovery and presents for a discussion of adjuvant therapy  In addition to adjuvant radiation therapy to the breast, you would recommend the following adjuvant systemic therapy AC followed by T (paclitaxel) with concurrent trastuzumab (with paclitaxel) for a total of 1 year AC followed by T (paclitaxel) with trastuzumab to start at the completion of paclitaxel for a duration of 1 year TCH (docetaxel, carboplatin, trastuzumab) with trastuzumab to continue for 1 year AC followed by trastuzumab for 2 years

39. Cardiac Complications of Systemic Therapy Individual modalities and combinations may act  independently or synergistically Cardiac irradiation combined with anthracyclines produces additive or supra-additive toxicity Damage from cancer treatment can affect all cardiac structures The heart may also incur subclinical damage, allowing later insult or sequential stress to trigger cardiac dysfunction There are several important cardiac complications of chemotherapy. First, nonsurgical cancer therapies can damage the heart in a variety of ways. Individual therapeutic modalities and combinations may act independently or synergistically. For example, cardiac irradiation combined with anthracyclines produces additive or superadditive cardiotoxicity. Damage from cancer treatments can affect all cardiac structures including the pericardium, myocardium, and valves. The heart may also incur subclinical damage, allowing later insults—called sequential stresses—to trigger cardiac dysfunction. Cardiac damage may occur via different mechanisms and can have different clinical implications depending on the treatment modality and the extent of irreversible structural change.There are several important cardiac complications of chemotherapy. First, nonsurgical cancer therapies can damage the heart in a variety of ways. Individual therapeutic modalities and combinations may act independently or synergistically. For example, cardiac irradiation combined with anthracyclines produces additive or superadditive cardiotoxicity. Damage from cancer treatments can affect all cardiac structures including the pericardium, myocardium, and valves. The heart may also incur subclinical damage, allowing later insults—called sequential stresses—to trigger cardiac dysfunction. Cardiac damage may occur via different mechanisms and can have different clinical implications depending on the treatment modality and the extent of irreversible structural change.

40. What Anticancer Drugs Can Do to the Heart and Circulatory System Cause cardiac depression Cause ischemia Cause dysrhythmia Cause hypotension with or without vascular collapse

41. Anthracyclines Cardiotoxic effects may manifest during early, late, or  posttreatment Early toxicity uncommon Chronic, potentially irreversible doxorubicin-associated  myopathy is a great concern Cardiomyopathy risk relative to cumulative dose Damage starts with the first administration Seldom noted at low cumulative dosages because of cardiac reserves Clinical expression low (< 5%) when dose < 400 mg/m2 Clinical expression becomes greater as dose surpasses 450 mg/m2 Cardiotoxic effects of anthracyclines may manifest early, late, or well after treatment. Early toxicity is uncommon and usually presents with nonspecific electrocardiographic changes or, sometimes, myopericarditis. Of greater concern is the chronic, potentially irreversible myopathy associated with doxorubicin. Importantly, cardiomyopathy risk clearly correlates with a cumulative dose. We now know that cardiac damage may start with the first administration of an anthracycline but is seldom noticed that early because the heart has tremendous reserves. Clinical expression of cardiomyopathy at low doses is relatively low—in fact, less than 5% when the doses remain below 400 mg/m2. The clinical expression becomes greater as the dose surpasses 450 mg/m2.Cardiotoxic effects of anthracyclines may manifest early, late, or well after treatment. Early toxicity is uncommon and usually presents with nonspecific electrocardiographic changes or, sometimes, myopericarditis. Of greater concern is the chronic, potentially irreversible myopathy associated with doxorubicin. Importantly, cardiomyopathy risk clearly correlates with a cumulative dose. We now know that cardiac damage may start with the first administration of an anthracycline but is seldom noticed that early because the heart has tremendous reserves. Clinical expression of cardiomyopathy at low doses is relatively low—in fact, less than 5% when the doses remain below 400 mg/m2. The clinical expression becomes greater as the dose surpasses 450 mg/m2.

42. CHF Vs. Cumulative Dose With Bolus Doxorubicin

43. Agents That Increase Anthracycline Cardiotoxicity Cyclophosphamide Cardiotoxic at high doses Increased cardiotoxicity when combined with doxorubicin Paclitaxel – May cause bradycardia, hypertension, or hypotension and increases the plasma concentration of doxorubicin Trastuzumab Causes an inherent but largely transient contractile dysfunction Increases expression of doxorubicin-induced cardiotoxicity as trastuzumab constitutes a sequential stress Several agents that increase anthracycline cardiotoxicity have been identified. First, cyclophosphamide, especially at high doses, can cause a cardiotoxic effect. Paclitaxel may cause bradycardia, hypertension, or hypotension and can increase the plasma concentration of doxorubicin. Trastuzumab causes inherent but largely transient contractile dysfunction. It may also increase doxorubicin-induced cardiotoxicity as trastuzumab constitutes a sequential stress.Several agents that increase anthracycline cardiotoxicity have been identified. First, cyclophosphamide, especially at high doses, can cause a cardiotoxic effect. Paclitaxel may cause bradycardia, hypertension, or hypotension and can increase the plasma concentration of doxorubicin. Trastuzumab causes inherent but largely transient contractile dysfunction. It may also increase doxorubicin-induced cardiotoxicity as trastuzumab constitutes a sequential stress.

44. Two Types of Treatment-Related Cardiac Dysfunction

45. Sequential Stress:Insult Added to Injury Cardiac injury (with anthracycline) Damage often subclinical Difficult to measure early because heart compensates Tools to measure are suboptimal We add an insult to this injury (trastuzumab) Dysfunction sometimes reaches the threshold Insult reversible (but prior damage generally not) Dysfunction usually resolves clinically (but in some cases damage may reach a threshold where it progresses)

46. What Is Probably Happening The greater the underlying injury (or the smaller the cardiac  reserves), the more likely the type II agent will augment the  type I injury While type II injury may be a temporary phenomenon  when taken independently, additional cellular death may  occur if the myocardial stress is sufficient This could explain why some patients, especially those  treated with anthracyclines prior to trastuzumab, may not  fully recover The clinical manifestations of both type I and type II  cardiotoxicity are the same, although the duration may be  quite different

47. Phenotypic Analysis of erbB2Knockout Mouse Myocardium Finally, the last slide puts the biologic mechanism together for why we are seeing this. Work done by Ken Chien, MD, when he was at the University of California, San Diego, showed these data. Dr. Chien a molecular cardiologist who was struck by the fact that there was this interaction between trastuzumab and anthracycline-based therapy in the clinical trials. He conducted a conditional knockout of the HER2 gene in murine species and found that, when one does a conditional knock out, the animal lives to adulthood and there does not appear to be any deleterious effects on the heart , as shown in the cross-section on the left-hand side of the picture. . However, on the right-hand side of the slide one sees what happens when the heart is stressed. In this instance, an outflow problem puts stress on the left ventricle and one immediately gets a significant dilated cardiomyopathy that is reminiscent of what is seen in the clinical picture of the worst cardiotoxicity with trastuzumab. It appears that the HER2 gene, when it is operating, provides a protective function for the heart muscle against stress. In the clinic, when adding trastuzumab to anthracycline, that likely defines and describes why this clinical phenomenon is happening. Thank you very much for your attention. Finally, the last slide puts the biologic mechanism together for why we are seeing this. Work done by Ken Chien, MD, when he was at the University of California, San Diego, showed these data. Dr. Chien a molecular cardiologist who was struck by the fact that there was this interaction between trastuzumab and anthracycline-based therapy in the clinical trials. He conducted a conditional knockout of the HER2 gene in murine species and found that, when one does a conditional knock out, the animal lives to adulthood and there does not appear to be any deleterious effects on the heart , as shown in the cross-section on the left-hand side of the picture. . However, on the right-hand side of the slide one sees what happens when the heart is stressed. In this instance, an outflow problem puts stress on the left ventricle and one immediately gets a significant dilated cardiomyopathy that is reminiscent of what is seen in the clinical picture of the worst cardiotoxicity with trastuzumab. It appears that the HER2 gene, when it is operating, provides a protective function for the heart muscle against stress. In the clinic, when adding trastuzumab to anthracycline, that likely defines and describes why this clinical phenomenon is happening. Thank you very much for your attention.

48. Effect of Trastuzumab on the Heart Trastuzumab-associated cardiac toxicity is postulated  to exacerbate prior anthracycline damage

49. Major Trastuzumab Adjuvant Trials

50. Number of Cardiac Deaths in the Adjuvant Trials (Trastuzumab Arms) NSABP B-31 0 cardiac deaths BCIRG 006 0 cardiac deaths HERA trial 0 cardiac deaths Intergroup trial 1 cardiac death FinHER trial 0 cardiac deaths

51. 3-Year DFS Adjuvant Trastuzumab Trials

52. 3-Year OS Adjuvant Trastuzumab Trials

53. Cardiac Safety

54. Patient Eligibility for Adjuvant Trastuzumab Trials HER2+ by FISH or +++ by IHC verified centrally (N9831) or by approved reference lab (B-31) Normal LVEF No past or active cardiac disease including History of myocardial infarction History of CHF Angina pectoris requiring medication Arrhythmia requiring medication Clinically significant valvular disease Uncontrolled hypertension Left ventricular hypertrophy Cardiomegaly on chest x-ray

55. Asymptomatic PatientsRules for Trastuzumab ContinuationBased on Serial LVEF Once the patients start Herceptin, they will be monitored at set intervals by MUGA scan. The above criteria must be followed for continuing or stopping Herceptin in patients who are asymptomatic. If a repeat MUGA scan is indicated, that MUGA scan must fall into one of the categories labeled “continue” (above) before the patient can proceed with further weekly Herceptin doses. Once the patients start Herceptin, they will be monitored at set intervals by MUGA scan. The above criteria must be followed for continuing or stopping Herceptin in patients who are asymptomatic. If a repeat MUGA scan is indicated, that MUGA scan must fall into one of the categories labeled “continue” (above) before the patient can proceed with further weekly Herceptin doses.

56. Cardiac Safety in EBC: Summary

57. N9831 Total Incidence of Cardiac Events

58. NSABP B-31: Potential Risk Factors for CHF However, the sequential use of trastuzumab following adjuvant anthracycline-based chemotherapy in the major trials was associated with some cardiac dysfunction.2-5 The recent 4-year update of the NSABP B-31 trial reported a 4-year cumulative incidence of cardiac events (New York Heart Association Class III or IV congestive heart failure [CHF] or cardiac-related death) of 3.9% in the trastuzumab-containing arm compared to 0.8% in the control arm (HR 5.1), which was essentially unchanged from that reported at a follow-up of 3 years (4.1% vs. 0.8%; HR 5.9), indicating no delayed trastuzumab-associated cardiotoxicity.7 In this update, the potential risk factors previously identified at the 3-year analysis that continued to be significantly correlated with trastuzumab-associated CHF included post-AC left ventricular ejection fraction (LVEF) (P < .0001) and baseline LVEF (P = .0002) (Table 1).7 Age at entry (P = .03) and treatment with hypertension medications (P = .03) were also still found to be correlated with trastuzumab-associated CHF. However, the sequential use of trastuzumab following adjuvant anthracycline-based chemotherapy in the major trials was associated with some cardiac dysfunction.2-5 The recent 4-year update of the NSABP B-31 trial reported a 4-year cumulative incidence of cardiac events (New York Heart Association Class III or IV congestive heart failure [CHF] or cardiac-related death) of 3.9% in the trastuzumab-containing arm compared to 0.8% in the control arm (HR 5.1), which was essentially unchanged from that reported at a follow-up of 3 years (4.1% vs. 0.8%; HR 5.9), indicating no delayed trastuzumab-associated cardiotoxicity.7 In this update, the potential risk factors previously identified at the 3-year analysis that continued to be significantly correlated with trastuzumab-associated CHF included post-AC left ventricular ejection fraction (LVEF) (P < .0001) and baseline LVEF (P = .0002) (Table 1).7 Age at entry (P = .03) and treatment with hypertension medications (P = .03) were also still found to be correlated with trastuzumab-associated CHF.

60. Results: Changes in LVEF From Baseline to Re-Treatment With Trastuzumab Reversibility: About 1,000 patients treated (38 cardiac events identified)

61. Clinical Outcomes in BCIRG 006 – 65- Month median Follow-up

62. Clinical Outcomes in BCIRG 006 at 5.4 years According to Topo II status