F. Nusrat1, A. Nevler2, E. Gorgov2, O. Isesele1, A. Khanna1, W. Bowne2, C. Yeo2, A. Jain2, H. Lavu2 1Thomas Jefferson University, Sidney Kimmel Medical College, Philadelphia, PA, USA 2Thomas Jefferson University, Jefferson Pancreas, Biliary And Related Cancer Center, Philadelphia, PA, USA
Introduction:
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and therapy-resistant cancer, making it among the most lethal of all major cancers. PDAC has a distinct genomic profile, with somatic KRAS proto-oncogene mutations in 85% – 95% of PDAC cases. This study aimed to measure the prognostic impact of specific KRAS mutations in resected PDAC patients from a large, high-volume tertiary referral center.
Methods:
This retrospective study included a cohort of 315 evaluable PDAC patients who underwent curative-intent pancreatic resection at our institution between 2016 – 2021. Demographic, histologic, and oncologic outcome data were recorded. Metastatic and non-PDAC cases with perioperative mortality were excluded. Genetic data from surgical specimens were obtained from next-generation sequencing assays in mutation-prone regions of the KRAS gene on chromosome 12p, including the hotspot codons 12, 13, and 61.
Results:
There were 295 patients (93.7%) with at least one KRAS mutation, of which 8 patients (2.5%) had more than one mutation. By mutation subtype, the cohort included 129 KRAS G12D (41.0%), 46 KRAS G12R (14.6%), 96 KRAS G12V (30.5%), and 12 KRAS Q61H (3.8%) patients. The median overall survival (OS) of the cohort was 33.2 ± 3.1 months. Kaplan-Meier analysis revealed KRAS mutational status to be associated with significant variability in overall survival: wild-type KRAS (WT-KRAS) with a median OS of 68.5 months; G12R with a median OS of 41.9 ± 7.8 months; G12D/G12V and Q61H with a median OS of 29.9 ± 3.3 months and 29.3 ± 3.5 months, respectively. Cox regression analysis revealed worse survival with increased age and the presence of perineural and lymphovascular invasion (P < 0.05). Patients with either KRAS G12D or KRAS G12V were correlated with worse overall survival (HR 2.5, P = 0.041) compared to those with WT-KRAS, as shown in Figure 1. KRAS Q61H, while not significant, also trended toward conferring worse survival compared to WT-KRAS (HR 2.7, P = 0.114). KRAS G12R did not significantly differ in survival compared to WT-KRAS (HR 1.5, P = 0.476).
Conclusion:
In resected PDAC patients, KRAS G12D and KRAS G12V mutations were associated with worse overall survival compared to WT-KRAS, whereas KRAS G12R was not significantly different than WT-KRAS.
