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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. OUTLINE. Introduction Mechanism of resistance to HER2 therapy
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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
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
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
Potential mechanisms of action of trastuzumab Burstein HJ et al, N Engl J Med, 2005
Anti-HER 2 drugs in late-stage clinical development or already approved for clinical practice Puglisi et al, Drugs 2012
New drugs targeting downstream HER2-pathways in early stage clinical development Puglisi et al, Drugs 2012
Ongoing trial of non HER-2 targeted agents PI3K pathway Sharial et al, Ann Oncol 2012
Phase I/II study X2107: BKM120 plus trastuzumab in HER2 positive trastuzumab resistant BC
Phase I/II trials with everolimus plus trastuzumab Sharial M. et al Ann Oncol 2012
Phase III trial: BOLERO-1 (advanced breast cancer, first line) Available at: http://www.clinicaltrials.gov/ct2/show/NCT00876395. Accessed April 1, 2013.
Phase III trial: BOLERO-3 (advanced breast cancer, pretreated) Available at: http://www.clinicaltrials.gov/ct2/show/NCT01007942. Accessed April 1, 2013
Investigation of the association between tumor PTEN protein expression and Disease Free Survival 1802 patients
Results Benefit of adjuvant trastuzumab is indipendent of PTEN status Perez EA et al, J Clin Oncol 2013
CLEOPATRA: biomarker analysis Baselga J et al, SABCS 2012
Biomarker analyses: exploration of predictive effects HER2 IS THE ONLY MARKER FOR SELECTING PATIENTS FOR HER2-TARGETED THERAPY
Biomarker analyses: exploration of prognostic effects Baselga J et al, SABCS 2012
Biomarker analyses: exploration of prognostic effects Baselga J et al, SABCS 2012
Biomarker analyses: exploration of prognostic effects Shorter median PFS observed with mutated PIK3CA while treatment effect is maintained Baselga J et al, SABCS 2012
NeoSphere: main results Gianni L. et al, Lancet Oncol 2011
Definition of immune related metagenes Gianni L et al, SABCS 2012
Selection of immune biomarkers based on their expected biological relevance Gianni L et al, SABCS 2012
Results: multivariate analysis Gianni L et al, SABCS 2012
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?
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