Among patients with pancreatic ductal adenocarcinoma who had undergone first-line therapy, longer survival was found to be associated with the presence of KRAS G12R mutations, but this survival benefit was attenuated by co-occurring PI3K alterations, according to the results of a retrospective study published in the The Oncologist.

“The KRAS/PI3K genomic profile could inform therapeutic vulnerabilities in patients with PDA [pancreatic ductal adenocarcinoma],” the researchers wrote.

The retrospective study included data from 126 patients with advanced pancreatic ductal adenocarcinoma who received first-line therapy and underwent tumor genomic sequencing between 2013 and 2020. 

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Patient and tumor characteristics were similar between the KRAS wild-type, KRAS G12R, and non-G12R mutation groups. The majority of patients (86.5%) had metastatic disease that was moderately or poorly differentiated or had no grade assigned. Most primary tumors were located within the head/uncinate process of the pancreas, followed by the body and tail. 

KRAS mutations occurred in 88% of patients. The most common variants were G12D among 38.7% of patients, G12V among 31.5%, and G12R among 20.7%. 

Overall survival was significantly longer among patients with a KRAS G12R mutation, with a median of 20.4 months compared with 14.3 months among patients without a G12R mutation (multivariate hazard ratio [HR], 0.55; 95% CI, 0.37-0.79; P =.0008). Progression-free survival was also longer among patients with a KRAS G12R mutation (multivariate HR, 0.58; 95% CI, 0.38-0.89; P =.0061).

A PI3K pathway mutation was identified among 11.9% of patients. Overall survival was similar among patients with or without a PI3K pathway mutation, except in the presence of a KRAS G12R mutation.

PI3K pathway mutations occurred among 26% of patients with a KRAS G12R mutation and among 8% of patients without a KRAS G12R mutation (P =.027) Approximately one-third of patients with a KRAS G12R mutation also had homologous recombination DNA defects, compared with 12.5% of patients without a G12R mutation (P =.025). 

Patients with both a KRAS G12R mutation and a PI3K pathway alteration had numerically shorter median overall survival than patients without a PI3K mutation — 19.4 months and 24.2 months, respectively — but this did not reach statistical significance (multivariate HR, 1.58; 95% CI, 0.81-3.18; P =.174). The co-occurrence of KRAS G12R and PI3K pathway mutations did not affect progression-free survival (multivariate HR, 0.78; 95% CI, 0.29-2.13; P =.620).

Other common co-occurring alterations were found in TP53, CDKN2A, SMAD4, and BRCA1/2 or PALB2. No differences in co-occurring mutations in these genes and KRAS were identified.

“The data demonstrate biologically and potentially therapeutically relevant differences among cancers with coexisting KRAS G12R and PI3K pathway alterations and support further investigation of a rational combination of targeted therapies aimed at cancers with specific KRAS variants,” the researchers concluded.

Disclosures: Some of the study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.


Diehl AC, Hannan LM, Zhen DB, et al. KRAS mutation variants and co-occurring PI3K pathway alterations impact survival for patients with pancreatic ductal adenocarcinomas. Oncologist. Published online September 17, 2022. doi:10.1093/oncolo/oyac179