Genomic and outcome analysis of recurrent versus de novo metastatic pancreatic ductal adenocarcinoma (PDAC) receiving systemic therapy: Results from the Australian MoST and CaSP screening programs.

4120 Background: The genomic and prognostic characteristics of recurrent (R, from curative surgery) v de novo (D) presentation in metastatic PDAC patients (pt) requiring systemic therapy (rx) remain underexplored. We examined the difference in genomic alterations (alts), overall survival (OS), and outcome to matched rx according to disease presentation (DP). Methods: The PDAC cohorts from the Australian Molecular Screening and Therapeutics (MoST) and Cancer Screening Programs (CaSP) completed sequencing from 2016 to July 2024 were analysed; archival tissue was sequenced using genomic profiling platforms (mainly TSO500 and FoundationOne CDx). Frequencies of genomic alts were compared between R and D groups; significance was assessed using Chi-square tests with the Benjamini-Hochberg method (q < 0.05). OS was calculated from the start of initial rx using Kaplan-Meier method, with hazard ratios (HR) from Cox regression used for comparison. OS outcomes were stratified by matched versus unmatched rx in pts harbouring genomic alts within clinically actionable Tier 1-3 categories per TOPOGRAPH knowledge base criteria. Results: 949 pts with PDAC with valid genomic results across both programs were included. The KRAS alts were numerically more frequent in D (n = 434/491, 88%, p = 0.02) than R (n = 380/458, 82%) groups. Both CDKN2A and SMAD4 alts were enriched in the D group ( CDKN2A , D: 248, 51% v R: 157, 34%; SMAD4 , D: 139, 29% v R: 85, 19%, p < 0.001 both). Among the 821 pts who started systemic rx, those with R PDAC (n = 411) showed longer median OS compared to those with D PDAC (n = 410, 18.9 v 13.0 months, mo; HR 0.59, 95% CI 0.49-0.69, p < 0.001). Genomic CDKN2A alts were associated with worse OS (median 13.4 v 16.5 mo, HR 1.34, 95% CI 1.14-1.58); most favourable prognosis was seen in 267 pts with CDKN2A wildtype in the R group (median 22.1 mo, 95% CI 17.4-25.9). After adjusting for both CDKN2A and SMAD4 alts, R group remained associated with a lower risk of death than D group (HR 0.61, 95% CI: 0.51-0.72, p < 0.001). Pts who received active matched rx (n = 23) showed longer OS than those who received unmatched rx (n = 314) in both D (30.1 v unmatched 14.0 mo) and R groups (34.6 v 24.1 mo). The prevalence of specific KRAS mutations showed no significant differences between D and R groups, including G12D (D: 192, 39% v R: 167, 36%, p = 0.44), G12V (D: 126, 26% v R: 113, 25%, p = 0.78), G12R (D: 59, 12% v R: 50, 11%, p = 0.67), G12C (D: 6, 1% v R: 10, 2%, p = 0.37), and Q61 mutations (D: 37, 8% v R: 26, 6%, p = 0.31). There were no differences in alts in TP53 , ARID1A, BRCA1/2, or other DNA repair pathway genes. Conclusions: Genomic and prognostic differences were seen in metastatic PDAC according to presentation, with CDKN2A alts enriched in de novo cases and associated with poor OS, emphasising the need to consider stratification of DP in trials and observational studies.