The emerging role of lapatinib in HER2-positive breast cancer.
ABSTRACT In breast cancer, overexpression of HER2 is associated with an aggressive tumor phenotype and poor prognosis. Lapatinib has demonstrated benefit in combination with capecitabine in patients with HER2-positive locally advanced and metastatic breast cancer that has progressed after prior treatment with an anthracycline, a taxane, and trastuzumab. It has also demonstrated benefit with paclitaxel in patients with metastatic disease not previously treated with chemotherapy. This review discusses results from clinical trials suggesting an advantage with the use of lapatinib with other treatment modalities in the setting of metastatic and locally advanced disease.
- SourceAvailable from: Marta Cuadros[show abstract] [hide abstract]
ABSTRACT: The Her2/neu status is of great clinical value in breast tumor patients. Fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) techniques are the test of choice for many practicing pathologies. The main objective of this retrospective study was to investigate the relationship between Her2/neu breast cancer amplification and overexpression (DNA, mRNA and protein). To accomplish this goal, we evaluated Her2/neu mRNA expression by real-time quantitative RT-PCR, gene amplification by FISH and protein expression by IHC. An excellent correlation between FISH and IHC Her2/neu results was observed, confirming that protein levels were directly related to DNA amplification. Polysomy 17 was frequently found in tumors showing Her2/neu overexpression. However, we did not find any statistically significant correlation among DNA, mRNA and protein levels, suggesting that Her2/neu could be post-transcriptionally regulated. There was a highagreement between Her2/neu gene amplification and protein overexpression but not mRNA expression levels. Nevertheless, IHC3+ and FISH-positive tumors indicated higher expression levels of Her2/neu mRNA by RT-PCR than those observed in IHC and FISH-negative tumors. These findings question the relevance of quantitative RT-PCR in routine assessment of Her2/neu overexpression in human breast cancer in the clinical laboratory setting.Pathobiology 01/2010; 77(1):38-45. · 1.95 Impact Factor
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ABSTRACT: The treatment of metastasized urothelial cancer has been evolving in recent years. In particular, in the second-line setting after the failure of platinum-containing therapy, options are few and besides vinflunine, the recently approved standard in Europe, well-designed highly selective clinical trials may be possible alternatives for patients in this palliative situation. However, targeted therapy approaches have not achieved the same results in urothelial cancer as for instance in renal cell carcinoma. Many of the new targeted drugs have been investigated as single agents in phase II clinical trials without convincing oncologic outcome. This review aims to highlight the most relevant clinical studies examining targeted agents in the second-line setting of metastasized transitional carcinoma of the urothelium.Anti-cancer drugs 08/2012; 23(10):1003-15. · 2.23 Impact Factor
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ABSTRACT: Non-small cell lung cancers with activating mutations in the epidermal growth factor receptor (EGFR) are highly responsive to EGFR tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib. Such cancers are "addicted" to EGFR, and treatment with a TKI invariably leads to down-regulation of the PI3K-AKT-mTOR and MEK-ERK signaling pathways, resulting in apoptosis. Using a dual PI3K-mTOR inhibitor, NVP-BEZ235, we evaluated whether PI3K-mTOR inhibition alone induced apoptosis in these cancers. In contrast to HER2-amplified breast cancers, we found that PI3K-mTOR inhibition did not promote substantial apoptosis in the EGFR mutant lung cancers. However, blocking both PI3K-mTOR and MEK simultaneously led to apoptosis to similar levels as the EGFR TKIs, suggesting that down-regulation of these pathways may account for much of the apoptosis promoted by EGFR inhibition. In EGFR mutant lung cancers, down-regulation of both intracellular pathways converged on the BH3 family of proteins regulating apoptosis. PI3K inhibition led to down-regulation of Mcl-1, and MEK inhibition led to up-regulation of BIM. In fact, down-regulation of Mcl-1 by siRNA was sufficient to sensitize these cancers to single-agent MEK inhibitors. Surprisingly, an AKT inhibitor did not decrease Mcl-1 levels, and when combined with MEK inhibitors, failed to induce apoptosis. Importantly, we observed that the combination of PI3K-mTOR and MEK inhibitors effectively shrunk tumors in a transgenic and xenograft model of EGFR T790M-L858R cancers. These data indicate simultaneous inhibition of PI3K-mTOR and MEK signaling is an effective strategy for treating EGFR mutant lung cancers, including those with acquired resistance to EGFR TKIs.Proceedings of the National Academy of Sciences 10/2009; 106(46):19503-8. · 9.74 Impact Factor