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Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal, and molecularly diverse malignancies, with few therapeutic options. We have used next generation sequencing to define the molecular features of PDAC. Repurposing of therapeutics that target specific molecular mechanisms in different disease types offers considerable potential for rapid improvements in outcome. Herceptin®, a monoclonal antibody targeting HER2 has been successfully used to treat HER2-amplified breast cancer, and has recently been repurposed for gastric cancer; the incidence of HER2-amplified PDAC is poorly understood.
Through a combination of whole exome, whole genome, copy number and microarray analysis, we identified 1/99 PDAC tumours with a ~1MB high-level amplification, affecting HER2, resulting in high mRNA and protein expression. From an archival cohort of 369 PDAC tissues, and using IHC and SISH, we identified 10 patients (2.1%) with high-level HER2-amplification, and defined standardized guidelines for identifying HER2-amplified PDAC.
Strikingly, the distribution of metastatic sites in HER2 amplified PDAC showed strong preference to brain and lung, over the normal pattern of liver (P<5E-7; relative to non-HER2-amplified PDAC), similar to that observed in HER2-amplified breast cancer.
The substantial molecular heterogeneity of PDAC implies that with an incidence of 2.1%, HER2-amplification potentially represents a valuable therapeutic target. Since collecting these data, we observed a significant response to Herceptin therapy in a patient with HER2-amplified PDAC. We have established the IMPACT clinical trial to assess the efficacy of three genotype-guided therapies in PDAC, including Herceptin.
Authors: Mark J Cowley, Angela Chou, Nicola Waddell, David K Chang, Jiamin Wu, Mark Pinese, Lorraine Chantrill, Amber L Johns, Katia Nones, Ann-
Marie Patch, Sean M Grimmond, Andrew V Biankin