KRAS mutation in pancreatic ductal adenocarcinoma: Does it influence prognosis or stage of disease at presentation?.

Abstract

Background and Aim: Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer death in Australia and the world, and patients have a poor 5-year survival rate. Most patients present with unresectable disease at diagnosis. There is no clinically available biomarker to assess prognosis in patients with PDAC. However, KRAS mutation is present in more than 90% of PDAC cases. This study aimed to investigate the role of detecting the KRAS mutation and subtype in patients with PDAC to determine prognosis across all stages of disease. Method(s):We performed a retrospective cohort study to assess KRAS status in patients presenting with PDAC between 2016 and 2020. Tissue for genetic testing was obtained either by endoscopic ultrasound fine-needle aspiration (EUS-FNA) or from resection specimens. The presence of KRAS mutations was assessed by multiplex polymerase chain reaction (PCR) (STRIP assay), next-generation sequencing (NGS) (TSO-500 gene panel), or digital droplet PCR. We reviewed patient records to determine age, sex, date of diagnosis, date of death, National Comprehensive Cancer Network (NCCN) clinical stage for resectability, and type of treatment received (surgery, chemotherapy and/or radiotherapy without surgery, and supportive care only). Survival was measured from date of EUS-FNA or resection histological diagnosis until death or the end of the study period. Result(s): Of 206 patients presenting with PDAC, 184 with survival data were included (92 male; mean age, 68.9 +/- 11.3 years). Of these, 157 patients (85.3%) had a KRAS mutation and 27 (14.7%) had wild-type KRAS. The KRAS mutation was detected through EUS-FNA in 164 patients (89.1%) and through resection specimens in 20 (10.9%). There were 64 (34.8%) patients who had the G12D mutation subtype, 52 (28.3%) had G12V, 22 (12.0%) had G12R, nine (4.9%) had Q61H, four (2.2%) had G12C, two (1.1%) had G12A, two (1.1%) had G13D, and two (1.1%) had Q61R. The stage at diagnosis was operable in 26.6%, borderline resectable in 10.4%, locally advanced in 28.3%, and metastatic in 34.7%. There was no significant difference in survival between patients with KRAS mutation (median, 297 days) and those with wild-type KRAS (median, 420 days) (hazard ratio, 1.435; 95% CI, 0.4363-1.146; P = 0.6365). There was also no statistically significant correlation between KRAS mutation and clinical stage at diagnosis (P = 0.38). Conclusion(s): Although no statistically significant association was found between KRAS mutation, subtype, and prognosis, the Kaplan-Meier curves did suggest trends of association, with patients with wild-type KRAS appearing to have a longer survival. The KRAS mutation and subtype frequency rates were similar to those in existing literature. However, this is the first study to look at patients across all stages of disease, which provides a more representative cohort, as well as exploring for the first time a relationship between KRAS mutation and NCCN resectability stage at diagnosis. There is scope for further studies investigating this area.