Abstract 1543P
Background
Characterization of the genomic alterations in pancreatic ductal adenocarcinoma (PDAC) patients can draw a roadmap for precision medicine.
Methods
Comprehensive genomic profiling (CGP) was performed with a 509-gene next generation sequencing (NGS) panel on tumor tissues from a cohort of 339 Chinese PDAC patients. The clinical relevance of germline and somatic mutations, copy number alterations and fusions with a curated list of targetable genes for RAF/MEK/ERK inhibitors, CDK inhibitors, Platinum chemo/PARP inhibitors, PORCN inhibitors, RTK inhibitors, MTOR inhibitors, Bromodomain inhibitors, PI3K/AKT inhibitors, WNT signaling inhibitors, JAK inhibitors, MDM2 inhibitors and SF3b modulator were assessed.
Results
Excluding common mutations in KRAS or CDKN2A, genetic alterations in PDACs were mainly enriched in the Central carbon metabolism in cancer pathway, ErbB signaling pathway, FoxO signaling pathway and VEGF signaling pathway (P<0.0001). Genetic alterations with targeting potential were identified in 33% (112/339) of PDAC patients, and 9% (31/339) of the samples were found to be targetable for two or more types of inhibitors, suggesting a genotype-driven combination therapy opportunity. The top three actionable alterations were ATM (6%), RNF43 (4%) and PIK3CA (4%). Low-prevalence alterations in several genes tractable of other targeted therapies were also observed, including mutations in STK11, FBXW7, MYC, SF3B1, JAK1, JAK3 as well as high-level amplifications of MDM2. There were 9% (31/339) of PDACs harbored germline or somatic mutations in one of the DNA damage repair (DDR) genes BRCA1, BRCA2, ATM and PALB2. Excluding common events in TP53, the overall mutation rate of all eight DDR pathways was 24% (80/339), among which 6% (20/339) exhibited co-mutations in two or more DDR pathways, suggesting that these tumors may be more amenable to platinum-based chemotherapy or poly-(ADP-ribose) polymerase (PARP) inhibition.
Conclusions
We found that beyond KRAS and CDKN2A, 33% and 24% of PDACs may confer better phenotype in combination therapy and DDR-targeted treatment, respectively. These data supported the necessity of deep molecular profiling for PDACs, to identify targets of therapeutic potential.
Clinical trial identification
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
X. Li, H. Yuan, T. Ma: Full/Part-time employment: Genetron Health (Beijing) Technology, Co. Ltd. All authors have declared no conflicts of interest.