Introduction: Pancreatic ductal adenocarcinoma (PDAC) is a devastating diagnosis with a five-year survival rate below 9%. Among various ethnic groups there are differing incidence and mortality rates that underpin a patient’s overall prognosis. Blacks have higher incidence and mortality rates and a worse prognosis compared to Whites. Conversely, Hispanic/Latino patients have the lowest recorded incidence and mortality rates. Though well recognized by experts, these discrepancies are poorly understood and unaccounted for by socioeconomic means. Therefore, we hypothesize that divergent biology drives the observed disparities in PDAC. Methods: Patients with PDAC that underwent surgery at our institution between 2010 and 2017 were included in this retrospective study. Surgical pathology reports were reviewed, and cases were matched by age, gender, and tumor grade. Psoas muscle indices (PMI) were measured from pre-operative CT scans. Baseline indices for respective ethnic groups were determined from healthy patients with non-oncologic pathology. Whole-exome sequencing was then performed on DNA from tumor and adjacent benign parenchyma. Results: Healthy Blacks have a significantly greater PMI than case-matched Whites (0.90 vs. 0.70, p < 0.005). Blacks and Whites with PDAC have a similar average pre-operative PMI (0.67 vs. 0.61, p = 0.3). However, when comparing pre-operative PMI to the baseline control PMI for the two racial groups, Blacks have a significantly greater percent decrease than Whites (29% vs. 14%, p < 0.05). By whole-exome sequencing, 22 new somatic mutations were identified in Black tumor samples compared to 7 new mutations in Whites. Among mutations exclusively present Blacks, ABCF1 and ANAPC1 were reported to be associated with chemoresponse and survival in colorectal and lung adenocarcinomas, respectively. Cytochrome p450 family member CYP2A7 mutations were associated with peritoneal metastasis. PHACTR4 mutations were associated with Stat3 signaling activation and IL-6 mediated phosphorylation in hepatocellular carcinoma. Lastly, Hispanic/Latino patients, while not part of our tumor molecular sequencing, more frequently sought surgical intervention for pre-malignant cystic pancreatic neoplasms when compared to Whites (28% vs. 7%, p < 0.05). Conclusion: Novel mutations and a strongly cachectic phenotype characterize Blacks with PDAC and may drive a particularly poor prognosis. While more research might define a molecular rationale for the better clinical outcomes in Latinos, Hispanic/Latino patients most frequently seek care for pre-malignant lesions. We conclude that recognizing the biological basis of cancer health disparities is essential for forming appropriate clinical decisions and defining specific therapeutic targets in ethnically diverse patients with PDAC.

Citation Format: Miles E Cameron, Patrick W Underwood, Michael U Maduka, Steven J Hughes, Andrea N Riner, Jennifer B Permuth, Andrew R Judge, Jose G Trevino. Divergent biology in ethnically diverse populations is central to health disparities in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr D106.