Prognostic and predictive impact of next-generation sequencing in metastatic pancreatic ductal adenocarcinoma.

4170 Background: Outcomes in de novo metastatic pancreatic ductal adenocarcinoma (mPDAC) remain dismal, although considerable heterogeneity exists in responses to therapy and survival. With increased use of tumor-cell next-generation sequencing (NGS) in mPDAC, improved understanding of the prognostic and predictive value of genomic alterations is needed. Methods: Between 2019-2023, 949 PDAC patients (pts) underwent targeted NGS (Oncomine), of which 161 had de novo metastatic disease. Progression-free survival (PFS) after front-line therapy and overall survival (OS) were correlated with clinical parameters and genomic alterations. Long-term survival (LTS) was defined as OS in the top quartile. Results: In pts who underwent at least one dose of systemic therapy (80%, n=128), mPFS and mOS were 6.6 and 10.4 months. Pts who received 5-FU-based front-line therapy (97% received a triplet with oxaliplatin and irinotecan or liposomal irinotecan) had improved outcomes compared to pts who underwent gemcitabine-based therapy (89% gemcitabine/nab-paclitaxel [gem/nab-P]; mOS 13.2 vs 7.3 months, HR 0.66, 95% CI 0.45-0.97). Tumor mutational burden (TMB), pathogenic mutations in genes involved in cell-cycle regulation (CCR) and DNA damage response (DDR), and loss of SMAD4 were not associated with broad differences in PFS/OS. As expected, in pts treated with 5-FU/platinum, mutations in DDR genes were associated with LTS ( p = 0.04). KRAS mutational status was prognostic (Table; p = 0.02 for OS). Surprisingly, KRAS wild type (WT) pts had poorer PFS/OS compared to KRAS -mutated pts. However, 3/12 KRAS WT pts, all with Class II BRAF and TP53 loss-of-function (LOF) mutations, were unable to tolerate any systemic therapy. In 3 KRAS WT pts with LTS, 2 had mutations in DDR genes and TMB > 10 Mut/Mb, while 2 had mutations in CCR genes. Multivariate analysis confirmed improved LTS of pts harboring KRAS G12R compared to G12D (OR 0.22, 95% CI 0.07-0.72, p = 0.01). TP53 was mutated in 75% of pts (18% gain-of-function [GOF]). WT TP53 was associated with improved survival (mOS 10.7 vs 5.0 months, HR 0.60, 95% CI 0.43-0.84). Interestingly, in pts receiving gem +/- nab-P, LTS was lacking in those with TP53 GOF mutations but not LOF mutations ( p = 0.13), a trend not seen in pts receiving 5-FU/platinum. Conclusions: Herein we show novel prognostic and predictive significance of genomic alterations in mPDAC. Heterogeneity exists in KRAS WT pts with BRAF and TP53 mutations conferring poorer prognosis and DDR and CCR gene mutations associated with LTS. KRAS G12D is associated with worse outcomes compared to G12R while G12V is intermediate. Pts with TP53 GOF mutations may benefit from 5-FU/platinum upfront. KRAS mutational status, frequency, and survival. KRAS Status N % mPFS (months) mOS (months) WT 12 7.5 3.1 3.5 G12C 2 1.2 2.1 2.1 G12D 70 43.5 5.0 6.6 G12R 25 15.5 9.7 13.2 G12V 36 22.4 4.9 10.5 Q61H/R 14 8.7 4.3 5.6 Other 2 1.2 5.5 7.8