Abstract The molecular underpinnings of pancreatic ductal adenocarcinoma (PDAC) in Hispanic populations remains virtually unexplored, limiting our understanding of PDAC’s molecular landscape in this group. This gap hampers the development of tailored therapeutic approaches for these underserved communities. In this pioneering study, we present the largest comprehensive molecular profiling of PDAC in a Hispanic cohort to date, leveraging PDAC tumor samples from 197 Hispanic patients living in Puerto Rico (PRH) using either the CARIS Life Sciences 592 gene panel or whole exome sequencing covering the period of 2015-2023. The cohort comprised 102 primary tumors and 95 metastatic tumors. Data was provided by the Precision Oncology Alliance (POA) using the CARIS Life Sciences NGS platform. We estimated the prevalence of somatic mutations in the PRH PDAC tumors and compared these findings with data from Memorial Sloan Kettering Cancer Center (MSK), which utilized MSK-IMPACT Panel for their analysis. Additionally, we referenced data from the AACR Project Genomics Evidence Neoplasia Information Exchanges (GENIE). Our findings reveal a distinct mutational architecture in PRH PDAC tumors, marked by significantly elevated frequencies of actionable mutations in BRCA1/2, suggesting an expanded role for PARP inhibitors in this population. Elevated frequencies of mutations in CDKN2A and SMAD4 were noted in PRH tumors, indicating differing tumorigenic pathways across populations. Additionally, higher mutational frequency of RECQL4 and FAT3 in PRH tumors suggests a distinct mutational landscape not typically represented in non-Hispanic populations. These findings underscore the need for population-specific molecular profiling to uncover novel therapeutic targets. Expanding our knowledge of PDAC’s molecular underpinnings in this population will provide new insights into the genetic and epigenetic drivers of PDAC in Hispanics, potentially leading to the identification of novel therapeutic targets that can improve treatment outcomes and survival. Furthermore, this study not only elucidates key genomic alterations driving PDAC in Hispanic patients but also lays the groundwork for future translational efforts in other underserved communities. Citation Format: Veroushka Ballester, Ingrid Montes, Sol V. Pérez-Martir, Hilmaris Centeno-Girona, Julie Dutil. Actionable Mutational Landscape of Pancreatic Cancer in Puerto Rican Hispanics: Implications for Targeted Therapy abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85 (18Suppl₃): Abstract nr B043.
Ballester et al. (Sun,) studied this question.