Although pancreatic cancer is viewed to be uniformly aggressive, there is considerable heterogeneity in treatment responses among patients. Some patients show durable responses that last for months to a year or more, whereas others do not respond at all with shockingly rapid death. This variability reflects underlying disease heterogeneity, which is thought to arise from non-genetic mechanisms, because nearly all tumours pass through the same mutational path: KRAS>CDKN2A>TP53>SMAD4. However, our comprehensive molecular analysis of more than 300 patients has uncovered that treatment response and survival have a genetic basis. Although more than 90% of patients have mutation in KRAS, a quarter of metastatic patients showed amplification of the mutant allele that creates major DNA copy number imbalances of this mutation. Tumours from these patients with metastatic disease have major copy number imbalances in mutant KRAS, are highly chemoresistant and harbour an aggressive ‘basal-like’ transcriptional phenotype. Alternatively, patients with minor KRAS imbalances, or balanced tumours, respond better to chemotherapy and show a less aggressive ‘classical’ molecular phenotype. Identifying a genomic aberration that can stratify treatment response in metastatic patients is crucial to finding the mechanisms that drive treatment resistance. At the moment, our findings remain an association.

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