Highlights in the Management of Breast Cancer Rome, May 25-26, 2007

1. Highlights in the Management of Breast Cancer Rome, May 25-26, 2007 CLINICALCASE Dott.ssa Simona Gildetti Cattedra di Oncologia Medica Università “G. D’Annunzio” Chieti-Pescara Direttore: Prof. Stefano Iacobelli

2. 48 years old, female, pre-menopausal • No comorbility September 2005: Left breast lumpectomy + axillary dissection Ductal infiltrating carcinoma, 2.4 cm, G3 ER=0% PR=0% HER2+++ PT2 PN0 M0

3. ADJUVANT TREATMENT Cardiac evaluation at baseline Ecocardiography LVEF=66.3% October 2005 – February 2006: FEC100 q21 6 cycles

4. ADJUVANT TREATMENT (2) Radiotherapy (March 2006) April 2006: Cardiac evaluation pre-Trastuzumab Ecocardiography: LVEF=64% Trastuzumab 6 mg/kg (8 mg/kg loading dose) q21 x 1 year

5. June 2006(after 3 cycles of Trastuzumab) LVEF=52.5% 18% reduction in LVEF (asymptomatic patient) Continue Trastuzumab Therapy? YES NO

6. Herceptin Temporally Discontinued July 2006 (after 4 weeks of suspension) LVEF=64.5% Reintroduction of Trastuzumab Therapy Cardiac function closely evaluated

7. August 2006 (after two other cycles of T): LVEF=50% 22% reduction (asymptomatic patient) What is the more appropriate management?

8. Continue Trastuzumab Therapy? YES NO

9. Reintroduce Trastuzumab only when LVEF is adequately re-established (i.e. > 55%)? YES NO

10. Discontinue Trastuzumab definitively? YES NO

11. Pooling of NSABP-B31 NCCTG N9831 N=3351 Med f-up=2y Four major adjuvant trials have shown that Trastuzumab reduces the risk of recurrence No Trast FinHER BCIRG006 HERA HR N=3222 Med f-up= 1,5y N=3387 Med f-up=1y TH or VH FEC TCH ChemoH ACTH ACP H 0.61 0.54 0.49 0.48 0.46 T=docetaxel C=cisplatin or carboplatin P=paclitaxel Chemo= mostly anthracyclines Timing of Trastuzumab initiation Upfront After 4 months After 8 months

12. The incidence of severe Trastuzumab cardiac related events in adjuvant trials remains within acceptable levels Summary of cardiac safety with Trastuzumab in early breast cancer Baselga et al, The Oncologist 2006;11 (suppl 1)

13. ADJUVANT TRASTUZUMAB TRIALS COMPARISON OF CARDIOTOXICITY RISKS

14. Observational study Over a 4-year period, 38 patients with HER2/neu-positive breast cancer, who have received anthracycline before Trastuzumab therapy, were referred for suspected Trastuzumab-related cardiotoxicity The mean LVEF pre-Trastuzumab was 0.61 ± 0.13 After 4.5 months (median) of Trastuzumab therapy, the mean LVEF decreased to 0.43 ±0.16 …

15. …after withdrawal of Trastuzumab, the LVEF increased to 0.56 ± 0.11, with a mean time to recovery of 1.5 months The median duration of reintroduced Trastuzumab therapy was 8.4 months Michael S. Ewer; J Clin Oncol 23; 2005

16. In summary… • The Trastuzumab-related cardiotoxicity in patients with HER2+ breast cancer seems to be largely reversible when trastuzumab is withdrawn • Standard therapy for LV dysfunction and CHF may hasten this recovery, allowing Trastuzumab to be reitroduced Thus, reintroducing Trastuzumab may be appropriate for some individuals who previously have experienced Trastuzumab-related cardiac dysfunction

17. Cardiac safety guidelines for the adjuvant use of Trastuzumab [Herceptin] in HER2-positive early breast cancer Ewer MS.; St. Gallen Conference, 2007 Management of asymptomatic decreases in LVEF during adjuvant Trastuzumab ?

18. Cardiac safety guidelines for the adjuvant use of Trastuzumab [Herceptin] in HER2-positive early breast cancer Management of symptomatic cardiac events during adjuvant Trastzumab ? Ewer MS.; St. Gallen Conference, 2007

19. August 2006 Trastuzumab has been definitively discontinued after the second reduction of LVEF Patient has been reviewed by a cardiologist: No therapy for heart failure Patient in follow-up LVEF=61.5% March 2007: Ecocardiography

20. Further follow-up of the adjuvant trials will increase our knowledge of the nature and reversibility of cardiac events associated with Trastuzumab use. These data will help to clarify the risk/benefit ratio on an individual patient.