Prognostic impact of KRAS mutation in metastatic (met) pancreatic cancer patients (pts)

Abstract

Background: Pancreatic adenocarcinoma is the 4th leading cause of cancer-related death, with 80% of pts presenting with met disease at diagnosis and 5-year survival rates less than 10%. Activating KRAS mutations are found in more than 90% of cases and its prognostic impact is unknown. The aim of this study is to describe the frequency of KRAS mutations and correlate it with clinical outcomes in pts with met pancreatic cáncer. Methods: From January 2011 to December 2015, 92 metastatic pancreatic cancer pts were included in the molecular prescreening program of our centre. Archived tumour samples were analysed using mass spectrometry (Mass ARRAY, Sequenom, 20 cases) until June 2014 or next-generation sequencing (Amplicon, MiSeq, 72 cases) thereafter. All demographic, treatment and survival data were extracted retrospectively from electronic medical records. Results: Median age at diagnosis was 64 years (range 35-82). 56 pts (61%) were male, 37 pts (40%) were diagnosed with met disease, 58 pts (63%) had liver metastases. Prevalence of KRAS mutations was 89%, only 10 pts (11%) had KRAS wild type. The most common KRAS mutation was G12D (39 pts, 47%), followed by G12V (25 pts, 30%), G12R (2 pts, 13%) and Q61H (2 patients, 2%). A146V, G12A and G12C mutations were found in single cases. In the overall population, median survival after metastases diagnosis (SAM) was 16.1 months (CI95% 13.8-20.1). In KRAS mutated pts, median SAM, was 14.5 months, while in KRAS wild type pts median SAM was not reached (HR = 5.0 [CI95% 1.2-20.7], p = 0.01). The clonality of KRAS mutations (allele fractions adjusted for tumour purity) had no significant impact on TRD (p = 0.73). Progression-free survival (PFS) in 1st line chemotherapy was not different according to KRAS mutation status (5.3 months in KRAS mutated, 4.2 months in KRAS wild type, HR = 1.1 [CI95% 0.5-2.9], p = 0.77). Conclusions: With highly sensitive next-generation sequencing, KRAS mutations are found in close to 90% of met pancreatic cancer pts. The absence of KRAS mutations is associated with improved outcomes in the met setting ( prognostic marker), which is not explained by higher treatment benefit during 1st line chemotherapy (not a predictive marker).