Key result
Combination therapy with trastuzumab and pertuzumab resulted in significantly greater tumour growth inhibition and a larger number of differentially expressed genes compared to either agent alone in ovarian cancer xenografts.
p-value: p=<0.05
Combination therapy with trastuzumab and pertuzumab in ovarian cancer xenografts induces a broader molecular response and greater tumor growth inhibition than either agent alone.
Supports preclinical rationale for dual HER2 blockade in ovarian cancer; leaves open clinical translation pending human trials.
BACKGROUND: Trastuzumab and pertuzumab target the Human Epidermal growth factor Receptor 2 (HER2). Combination therapy has been shown to provide enhanced antitumour activity; however, the downstream signalling to explain how these drugs mediate their response is not clearly understood. METHODS: Transcriptome profiling was performed after 4 days of trastuzumab, pertuzumab and combination treatment in human ovarian cancer in vivo. Signalling pathways identified were validated and investigated in primary ovarian xenografts at the protein level and across a timeseries. RESULTS: A greater number and variety of genes were differentially expressed by the combination of antibody therapies compared with either treatment alone. Protein levels of cyclin-dependent kinase inhibitors p21 and p27 were increased in response to both agents and further by the combination; pERK signalling was inhibited by all treatments; but only pertuzumab inhibited pAkt signalling. The expression of proliferation, apoptosis, cell division and cell-cycle markers was distinct in a panel of primary ovarian cancer xenografts, suggesting the heterogeneity of response in ovarian cancer and a need to establish predictive biomarkers. CONCLUSION: This first comprehensive study of the molecular response to trastuzumab, pertuzumab and combined therapy in vivo highlights both common and distinct downstream effects to agents used alone or in combination, suggesting that complementary pathways may be involved.
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Sims et al. (2012) studied Ovarian cancer. Trastuzumab and pertuzumab combination therapy vs. Trastuzumab alone, pertuzumab alone, or untreated control was evaluated on Tumour volume reduction and differential gene expression (p=<0.05). Combination therapy with trastuzumab and pertuzumab resulted in significantly greater tumour growth inhibition and a larger number of differentially expressed genes compared to either agent alone in ovarian cancer xenografts.
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