1. Highlights in the Management of Breast Cancer Rome, May 25-26, 2007 CLINICAL CASE 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+++ PT2PN0M0

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

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

5. June 2006 (after 3 cycles of Trastuzumab) LVEF=52.5% 18% reduction in LVEF (asymptomatic patient) Continue Trastuzumab Therapy?

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

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?

9. Reintroduce Trastuzumab only when LVEF is adequately re-established (i.e. > 55%)?

10. Discontinue Trastuzumab definitively?

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

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

13. ADJUVANT TRASTUZUMAB TRIALS COMPARISON OF CARDIOTOXICITY RISKS

14. 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 After 4.5 months (median) of Trastuzumab therapy, the mean LVEF decreased to 0.43 ±0.16 … The mean LVEF pre-Trastuzumab was 0.61 ± 0.13 Observational study

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 Thus, reintroducing Trastuzumab may be appropriate for some individuals who previously have experienced Trastuzumab-related cardiac dysfunction  Standard therapy for LV dysfunction and CHF may hasten this recovery, allowing Trastuzumab to be reitroduced

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

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

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 March 2007: Ecocardiography LVEF=61.5%

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.