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Driver gene alterations tied to poorer outcomes in pancreatic adenocarcinoma

Roshini Claire Anthony
06 Dec 2017

Individuals with alterations in the main driver genes for pancreatic adenocarcinoma have poorer survival outcomes following surgical resection, according to a recent study.

Researchers used next-generation sequencing and immunohistochemistry to assess the impact of alterations in four main driver genes (KRAS, CDKN2A, SMAD4, and TP53) on the survival outcomes of 356 patients (median age 67 years, 46.3 percent female) who had undergone surgical resection for pancreatic adenocarcinoma.

Compared with patients with KRAS wild-type tumours, patients with KRAS mutant tumours had poorer disease-free survival (DFS; median, 12.3 vs 16.2 months) and overall survival (OS; median, 20.3 vs 38.6 months), with a 5-year OS outcome of 13.0 and 30.2 percent for patients with KRAS mutant and wild-type tumours, respectively. The impact on survival was especially evident in patients with KRAS G12D-mutant tumours compared with KRAS G12D wild-type tumours (median, 9.5 vs 14.8 months [DFS] and 15.3 vs 24.8 months [OS]). [JAMA Oncol 2017;doi:10.1001/jamaoncol.2017.3420]

Patients with tumours without CDKN2A expression had both worse DFS and OS compared with patients with CDKN2A expression (median, 11.5 vs 14.8 months [DFS] and median, 19.7 vs 24.6 months [OS]).

Lack of SMAD4 expression had no effect on survival outcomes compared with intact SMAD4 expression (hazard ratio [HR], 1.18; p=0.25 and HR, 1.07; p=0.62 for DFS and OS, respectively), while alterations in the TP53 gene were associated with poorer DFS (HR, 1.33; p=0.04) but not OS (HR, 1.18; p=0.23) when compared with TP53 wild-type tumours.

A greater number of altered driver genes was associated with poorer outcomes where, compared with patients with 0–2 altered genes, those with four altered genes had poorer DFS (HR, 1.79; p=0.002) and OS (HR, 1.38; p=0.06). Five-year OS reduced with the number of altered genes (18.4, 14.1, and 8.2 percent of patients with 0–2, 3, and 4 altered genes, respectively).

“[This study shows that] identifying the pathogenic alterations in the four main driver genes of pancreatic adenocarcinoma informs patient outcomes,” said the researchers.

Survival outcomes in patients with pancreatic adenocarcinoma are still suboptimal despite receiving adjuvant treatment following surgical resection, said the researchers. Another increasingly common treatment strategy is the initiation of chemotherapy and radiotherapy prior to surgery in the attempt to detect patients for whom surgery would not be beneficial as well as to “initiate therapy against micrometastatic disease”.

“Understanding the molecular events that determine patient outcomes has the potential to improve treatment approaches for patients with this aggressive malignancy. In the future, molecular assessment of pancreatic cancer may help guide the use and components of perioperative treatment programmes,” they said. 

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