This study is based upon the following points:
1. Resistance to trastuzumab, either primary or secondary, is a clinically relevant issue.
2. PI3K/AKT activation, due to loss of expression/function of PTEN and/or activating
mutations of PIK3CA, is a mechanism of resistance with clinical relevance in breast
cancer. Such activation can be detected by:
- IHC evaluation of PTEN protein expression
- genotyping of PIK3CA exon 9 and 20
- IHC evaluation of phospho-AKT expression
3. BKM120 is an effective PI3K inhibitor. BKM120 and anti-HER2 therapy may have a
synergistic antitumor activity in preclinical model of HER2+ breast cancer.
4. Lapatinib is an effective anti-HER2 therapy in trastuzumab-resistant disease.
5. For the evaluation of novel targeted therapies, selecting a patient population enriched
for activation of the target to be modulated should allow to maximize the differences in
clinical outcome that are expected in the experimental arm, and thus to minimize the
patient number to include.
6. We propose to test in a phase I/II study the combination of lapatinib and BKM120 in
trastuzumab-resistant HER2+ MBC patients, enriched for activation of PI3K/AKT as
detected by loss of expression of PTEN (IHC), and/or mutation of PIK3CA and/or
overexpression of phospho-AKT (IHC). Only for phase II patients, mutational status will
be an inclusion criteria. For phase I patients molecular status will be a retrospective