ASA - Mutational Status of Driver Genes in Patients with Resected Pancreatic Ductal Adenocarcinoma Is Associated with Pathological Characteristics and Overall Survival

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Mutational Status of Driver Genes in Patients with Resected Pancreatic Ductal Adenocarcinoma Is Associated with Pathological Characteristics and Overall Survival
*Brady A. Campbell¹, *Marco Dal Molin¹, *Dario Solinas¹, *Julia Purchla¹, *Thomas McPhaul¹, *Swathikan Chidambaram¹, John Cameron¹, *Amanda L. Blackford², *Ralph H. Hruban³, *Christopher R. Shubert¹, *Kelly J. Lafaro¹, *Richard A. Burkhart¹, *William R. Burns¹, *Jin He¹
¹Surgery, Johns Hopkins University School of Medicine, Baltimore, MD; ²Oncology, Johns Hopkins University School of Medicine, Baltimore, MD; ³Pathology, Johns Hopkins University School of Medicine, Baltimore, MD

Objectives: The mutational landscape of pancreatic ductal adenocarcinoma (PDAC) is dominated by alterations in four driver genes: KRAS, TP53, SMAD4, CDKN2A. Whether the mutational status of driver genes is associated with clinical and pathologic outcomes in patients with localized PDAC remains unclear. We aimed to evaluate whether alterations in PDAC driver genes are associated with pathological characteristics and prognosis. Methods: We performed a single-institution, retrospective analysis of patients who underwent resection for PDAC between 2018-2022 and whose cancer was profiled using targeted next-generation DNA sequencing. Pathogenic or likely pathogenic alterations were analyzed, whereas variants of unknown significance were excluded. Associations between mutational status and clinical-pathological characteristics and overall survival were investigated using multivariable Cox proportional hazards model adjusting for age at surgery, gender, T stage, Clavien-Dindo complication score, and perioperative treatment. Results: In total, 508 patients were included; most received preoperative chemotherapy (n=402, 79.1%). KRAS was the most frequently mutated gene (456, 89.8%), followed by TP53 (292, 57.5%), SMAD4 (104, 20.3%), and CDKN2A (88, 17.3%). Median follow-up was 3.5 years. The presence of wild-type KRAS (KRAS-wt) was associated with lower T- (p<0.001) and N-stage (p=0.02) and lower rates of perineural invasion (p=0.04), when adjusting for receipt of preoperative chemotherapy. Mutations in TP53, SMAD4 or CDKN2A were not associated with higher T- or N-stage. Patients with TP53 mutations had higher rates of perineural invasion, compared with TP53-wt (p=0.01). The median overall survival (mOS) for the whole cohort was 2.5 years (2.1-2.9 95% CI). Patients with KRAS-wt had improved mOS compared to patients with KRAS mutations (HR 2.23, p=0.002). Patients with TP53 mutations had a shorter mOS than patients with TP53-wt (HR 1.59, p<0.001). No differences in survival were observed in patients with SMAD4 or CDKN2A mutant vs wild type. On multivariable analysis, N0 stage, anatomically resectable cancer, and absent lympho-vascular invasion were associated with improved mOS. Absence of any of the four main driver mutation genes was associated with significantly longer mOS than the presence of ?2 co-existing mutations. Co-occurrence of all four driver gene mutations was associated with worse mOS than the absence of mutations (HR 2.9, 1.3-6.5 95% CI, p<0.01). (Table 1) Conclusions: Knowledge of mutational status in KRAS, TP53, SMAD4 and CDKN2A provides prognostic information for patients undergoing resection for PDAC. Presence of KRAS-wt and TP53-wt was associated with improved pathological characteristics and mOS, regardless of preoperative therapy. Co-occurrence of two or more mutations in the four driver genes was associated with worse survival.
Table 1. The association of driver gene mutational status in patients with resected PDAC and mOS analyzed with a multivariable Cox proportional hazards model.

Variables	Median OS (years) (95% CI)	HR (95% CI)	p-value
KRAS Mutation Absent Present	- Not reached 2.31 (2.06, 2.7)	- Ref. 2.23 (1.33, 3.74)	- - 0.002
KRAS Mutation, type WT G12D G12R G12V Other	- Not reached 2.03 (1.68, 2.47) 2.88 (2.31, 6.55+) 2.38 (1.92, 3.4) 2.7 (1.78, 3.88)	- Ref. 2.82 (1.64, 4.84) 1.67 (0.92, 3.04) 1.93 (1.1, 3.37) 2.37 (1.27, 4.42)	- - <0.001 0.090 0.020 0.007
TP53 Mutation Absent Present	- 3.11 (2.22, 3.24) 2.13 (1.58, 2.88)	- Ref. 1.59 (1.23, 2.06)	- - <0.001
Number of Driver Mutations 0 1 2 3 4	- Not reached 2.97 (2.44, 6.55+) 2.06 (1.72, 2.67) 2.17 (1.75, 3.19) 2.04 (1.19, 6.55+)	- Ref. 1.68 (0.9, 3.14) 2.91 (1.6, 5.28) 2.59 (1.37, 4.9) 2.92 (1.31, 6.52)	- - 0.100 <0.001 0.003 0.009

HR = Hazard Ratio, Ref = Reference value, "-" = placeholder to ensure alignment

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