Uncovering Molecular Differences in Pancreatic Ductal Adenocarcinoma Tissues From Black and White Patients in the US

AACR Cancer Health Disparities 2023 PRESENTATION
Authors Emily A. Teslow, Ph.D., Minxuan Huang, Ph.D., Melissa Stoppler, M.D., Albert Levin, Ph.D., Ling Huang, Ph.D.

Background – Pancreatic cancer is the 3rd leading cause of cancer-related deaths in the US, with a 5-year survival rate of approximately 12%. The occurrence of new pancreatic cancer cases has continued to rise in the last two decades, with the highest incidence observed in the Black and African American (BAA) population. While socioeconomic and environmental factors may contribute to observed racial disparities in the occurrence of pancreatic cancer, it is unclear whether there are molecular differences in pancreatic tumors across racially and ethnically diverse populations. The goal of this study was to identify key molecular differences between BAA and White patients’ pancreatic tumors.

Methods – We analyzed 4620 de-identified records with a primary diagnosis of pancreatic ductal adenocarcinoma (PDAC) who underwent somatic NGS testing via a commercially available 595-648 gene DNA panel as well as whole transcriptome RNA-seq. Race was extracted from clinical records (e.g., order forms, patient records, etc.). Somatic mutations, microsatellite instability (MSI), and tumor mutational burden (TMB) were compared between White (n=3797) and BAA (n=452) samples by Chi-squared or Fisher’s Exact tests. False discovery rate (FDR) corrections were applied to pairwise comparisons.

Results – The combined cohort had a median age of 68 years and 88% of records had stage 3 or 4 disease at the time of diagnosis. We found that alterations in TP53 (70% vs 62%, q=0.014) and KMT2C (6.9% vs 2.3% q<0.001) were at significantly higher frequencies in BAA vs White samples. Weakly significant differences were observed in BAA vs White samples based on alterations in KRAS (79% vs 74%, p=0.02), RNF43 (6% vs 3.7% p=0.022), and GNAS (0.2% vs 1.6%, p=0.022), all of which had q-values of 0.14 after FDR correction. When stratifying by detailed alterations, KRAS G12R was significantly more frequent in BAA than White (14% vs 10%, q=0.037), and GNAS R201H was more frequent in White vs BAA (0.9% vs. 0%, q=0.056) samples. Finally, when assessing biomarkers associated with immunotherapy response in solid tumors, we found that neither the frequency of TMB-H (≥ 10 mut/MB) nor MSI-high status were significantly different between BAA and White samples. Interestingly, in the subset of 676 PDAC patients who had PD-L1 IHC performed previously, BAA samples had a higher frequency of PD-L1 positivity compared with White samples (20% vs 12%, p=0.039).

Conclusions – We assessed molecular differences between BAA and White patients’ tumors in the largest cohort of PDAC records reported to date. Our findings suggest that there are key molecular tumor characteristics which occur more frequently in BAA PDAC tumors. In particular, alterations in genes such as KMT2C, which were more frequent in our cohort of BAA tumors, are known contributors to pancreatic tumorigenesis and represent potential therapeutic targets. These findings highlight the importance of studying racially and ethnically diverse populations to better understand key molecular alterations.