Synthetic lethality targets in pancreatic ductal adenocarcinoma: prevalence and limitations of liquid biopsy detection in a minority-serving cancer center

Aims Synthetic lethality (SL) exploits genetic vulnerabilities in cancer cells, offering therapeutic opportunities beyond conventional targets. While BRCA/poly(ADP-ribose) polymerase (PARP) inhibition is FDA-approved for pancreatic ductal adenocarcinoma (PDAC), the prevalence of other actionable SL targets remains poorly characterized.Patients and methods We retrospectively analyzed 260 PDAC patients at the University of New Mexico Comprehensive Cancer Center (2017–2022); 74 underwent somatic sequencing (54 tissue, 17 liquid biopsy) and 117 underwent germline testing. The cohort included 11% Native American patients. We characterized eight SL gene targets and compared mutation detection between biopsy methods.Results TP53 mutations were identified in 73% of patients and CDKN2A was the most prevalent SL target (46%), followed by SMAD4 (24%), MTAP (15%), and ARID1A (14%). Liquid biopsy significantly underdetected key alterations: KRAS detection decreased from 93% (tissue) to 47% (liquid, p < 0.001) and SMAD4 from 33% to 0% (p = 0.004). Native American patients showed significantly lower TP53 mutations than White patients (38% vs 79%, p = 0.023).Conclusions Multiple SL targets beyond BRCA exist in PDAC. Liquid biopsy inadequately detects critical alterations, particularly deletions. Native American patients demonstrated preliminary molecular differences warranting validation in larger studies. Tissue-based molecular profiling will be essential for comprehensive patient selection as SL-targeted therapies advance.