HIGHLIGHTS IN THE MANAGEMENT OF BREAST CANCER

1. HIGHLIGHTS IN THE MANAGEMENT OF BREAST CANCER “Locally advanced and metastatic disease Overcoming treatment resistance in HER2-positive breast cancer" Dott.ssa Poletto Elena AOU S.M. Misericordia, Udine

2. OUTLINE • Introduction • Mechanism of resistance to HER2 therapy • How to overcome treatment resistance: • New anti-HER2 drugs • New drugs targeting downstream HER2-pathways • New predictive and prognostic markers: • N9831 trial • CLEOPATRA trial • NeoSphere Trial

3. Introduction • Aproximately 15-20% of breast cancers overexpress HER2 • Trastuzumab has substantially improved outcomes in HER2-positive breast cancer • De novo and acquired resistance is observed and represents an important clinical challenge

4. Potential mechanisms of action of trastuzumab Burstein HJ et al, N Engl J Med, 2005

5. Mechanisms of resistance to HER2 therapy

6. Rexer BN, Artega CL; Crit Rev Oncog, 2012

7. How to overcome treatment resistance

8. Anti-HER 2 drugs in late-stage clinical development or already approved for clinical practice Puglisi et al, Drugs 2012

9. Main phase III trials with new HER2 targeted drugs

10. New drugs targeting downstream HER2-pathways in early stage clinical development Puglisi et al, Drugs 2012

11. Ongoing trial of non HER-2 targeted agents PI3K pathway Sharial et al, Ann Oncol 2012

12. mTOR and PI3K inhibitors

13. Phase I/II study X2107: BKM120 plus trastuzumab in HER2 positive trastuzumab resistant BC

14. Phase I/II trials with everolimus plus trastuzumab Sharial M. et al Ann Oncol 2012

15. Phase III trial: BOLERO-1 (advanced breast cancer, first line) Available at: http://www.clinicaltrials.gov/ct2/show/NCT00876395. Accessed April 1, 2013.

16. Phase III trial: BOLERO-3 (advanced breast cancer, pretreated) Available at: http://www.clinicaltrials.gov/ct2/show/NCT01007942. Accessed April 1, 2013

17. New predictive and prognostic biomarkers

18. N9831 and PTEN

19. Investigation of the association between tumor PTEN protein expression and Disease Free Survival 1802 patients

20. Results Benefit of adjuvant trastuzumab is indipendent of PTEN status Perez EA et al, J Clin Oncol 2013

21. CLEOPATRA

22. CLEOPATRA: biomarker analysis Baselga J et al, SABCS 2012

23. Biomarker analyses: exploration of predictive effects HER2 IS THE ONLY MARKER FOR SELECTING PATIENTS FOR HER2-TARGETED THERAPY

24. Biomarker analyses: exploration of prognostic effects Baselga J et al, SABCS 2012

25. Biomarker analyses: exploration of prognostic effects Baselga J et al, SABCS 2012

26. Biomarker analyses: exploration of prognostic effects Shorter median PFS observed with mutated PIK3CA while treatment effect is maintained Baselga J et al, SABCS 2012

27. NeoSphere and adaptive immune response

28. NeoSphere: study design

29. NeoSphere: main results Gianni L. et al, Lancet Oncol 2011

30. Definition of immune related metagenes Gianni L et al, SABCS 2012

31. Selection of immune biomarkers based on their expected biological relevance Gianni L et al, SABCS 2012

32. Results: multivariate analysis Gianni L et al, SABCS 2012

33. Summary results • Adaptive immune response seems to modulate benefit from HER2-targeted therapies • High PDL1 expression was strongly associated with residual disease in all arms of treatment • High pCR was associated with high expression of: • PD1 • STAT1 Rational for combining HER-2 targeted treatments with immune-modulating agents?

34. Conclusions • De novo and acquired resistance to trastuzumab represents a real clinical challenge • There are a great number of new anti-HER2 agents under investigation • Pertuzumab and T-DM1 have shown efficacy in limit or abrogate acquired resistance to primary anti-HER2 therapy • Translational research is critical in the development of novel biomarker predictive of clinical benefit with the new targeted agents in HER2 positive breast cancer