Whole-exome tumor sequencing study in patients with biliary cancer with a response to MEK inhibitors.

Abstract

253 Background: We conducted a phase-II study with selumetinib (AZD6244), a small molecule inhibitor of MEK1/2, in advanced biliary tract cancers (BTC). The observed preliminary activity was confirmed with another MEK inhibitor (MEK162) that was tested in a similar patient population. To assess for tumor-specific genetic variants that mediate sensitivity to MEK inhibition in BTC, we performed whole-exome sequencing in patients with an objective response including a complete response to selumetinib. Methods: Normal and tumor DNA from available formalin-fixed paraffin-embedded tissue from biopsies of primary or metastatic tumor from two patients who experienced an objective response underwent whole-exome sequencing. Raw sequence reads were processed with GATK workflow and tumor-specific variants were identified using MuTect and VarScan 2. Following, we assessed the functional consequences of the variants. Copy number changes and potential gene fusion events were also screened. We compared the findings to assess for any commonality between the two samples. Ingenuity Pathway Analysis was used to assess whether the identified somatic variants were intrinsic to the MAPK pathway. Results: 1169 and 628 tumor-specific variants were identified in the two tumor samples. Further analysis demonstrated a similar number of functional and novel variants between the two samples, which were 60 and 53, respectively. No common variants or detectable fusion events were observed between the two samples. Copy number changes were found in chromosomes 1, 5, 6, 9, 10, 12, 17, 20, 21 and 22 in sample one, and in chromosome 11 and 12 on sample two with no common findings. Several variants in genes associated with ERK signaling were present in each tumor sample. Conclusions: Although no common tumor-specific somatic changes of significance several genes associated with ERK signaling were identified in the patients with an objective response. Confirmatory studies investigating the role of the identified genes need to be further investigated.