Genomic Characteristics of a Rare Pancreatic Cancer Undifferentiated Sarcomatoid Carcinoma Subtype

Academic Background

Pancreatic Ductal Adenocarcinoma (PDAC) is one of the deadliest cancers, characterized by early invasion and metastasis. Undifferentiated Sarcomatoid Carcinoma (USC) is a particularly aggressive but rare subtype of PDAC, accounting for 2%-3% of all PDAC cases. The histological features of USC include a lack of glandular differentiation and the presence of stromal-like spindle cells. Due to its rarity, the genomic landscape and tumor microenvironment (TME) of USC are not well characterized, with existing information primarily derived from case reports and small cohort studies.

Some previous case reports suggest that immune checkpoint inhibitors might be effective in treating USC. In contrast, immunotherapy has shown poor results in PDAC treatment. However, a cohort study of six USC patients found a positive correlation between PD-L1 and Notch gene expression. In other cancer types, Notch expression is also correlated with clinical responses to immune checkpoint inhibition, suggesting a potential targeted treatment approach for USC.

Source of Study

This research paper is authored by Erik B. Faber, Harris B. Krause, Khalid Amin, Philip Walker, Peter J. Hosein, Anthony F. Shields, Heinz-Josef Lenz, Ajay Prakash, Sanjay Goel, Matthew Oberley, Giuseppe Malleo, Claudio Luchini, Justin Hwang, Vaia Florou, Ignacio Garrido-Laguna, and Emil Lou, from institutions such as University of Minnesota, Caris Life Sciences, University of Miami, Wayne State University, University of Southern California, University of Utah, among others. The paper was published on May 9, 2024, in the JCO Precision Oncology journal.

Research Process and Methods

Sample and Pathology Review

The study utilized 20 USC samples and 5,562 non-USC PDAC samples, submitted by Caris Life Sciences, with sampling from 2016 to 2022. These samples were reviewed centrally by certified gastrointestinal pathologists to confirm the diagnosis and used the Halo AP platform for histological evaluation. Tumors not meeting the USC diagnostic criteria were excluded, including cases with minor undifferentiated components.

Genomic Sequencing

For formalin-fixed, paraffin-embedded tumor samples, microdissection was conducted to enrich the tumor portions. Targeted sequencing of a 592-gene panel was performed using Illumina’s NextSeq platform, or Whole-Exome Sequencing (WES) using the same company’s technology. Sequencing depth covered an average of 500×, and data analysis was based on variant frequency and amplicon coverage to detect mutations.

Mutation Detection

Mutations were interpreted by certified molecular geneticists and classified according to the standards of the American College of Medical Genetics and Genomics. Pathogenic and Likely Pathogenic variants were counted as mutations, while Benign, Likely Benign variants, and Variants of Unknown Significance were excluded.

Tumor Microenvironment (TME) Analysis

RNA deconvolution analysis was performed using Quantiseq algorithm on RNA sequencing data to estimate the proportions of immune cells in the TME. Tumor Mutational Burden (TMB) and Microsatellite Instability (MSI) status were determined.

Research Results

Clinical and Mutation Characteristics

Among the 20 USC patients, the most common mutated genes were TP53 (95%), KRAS (84%), and CDKN2A (21%), highly mutated in non-USC PDAC as well. For KRAS mutations, G12D, G12V, and G12R accounted for 56%, 31%, and 13%, respectively. Notable differences included mutations in tumor suppressor genes such as MSH6 (11%), MLH3 (8%), and CTCF (5.3%).

Immune Checkpoint Markers and Therapeutic Targets

Compared to non-USC PDAC, USC tumors showed a significant increase in PD-L1 positive expression (63% vs. 16%, p < .001), along with an increase in neutrophils (8.99% vs. 5.55%, p = .005), dendritic cells (1.08% vs. 0.00%, q = 0.022), and immune checkpoint genes PDCD1LG2 (4.6% vs. 1.3%, q = 0.001), PDCD1 (2.0% vs. 0.8%, q = 0.060), and HAVCR2 (45.9% vs. 21.7%, q = 0.107). These results suggest further exploration of immune checkpoint inhibitors in USC tumors.

Discussion and Conclusion

This study represents the largest molecular analysis of USC tumors to date. While USC and non-USC PDACs are similar in major driver gene mutations, the significant increase in PD-L1 and PDCD1LG2 gene expression in USC tumors highlights the potential for immune-targeted therapies. Findings also indicate fewer B cells but more neutrophils and M2 macrophages in USC tumors, suggesting a more immunosuppressive TME.

Significance and Value

This study reveals the unique immunological characteristics of USC through detailed genomic analysis, suggesting the potential use of immune checkpoint inhibitors in treating this aggressive PDAC subtype. Despite the small number of clinical cases, the biomarkers and potential targets identified in the study provide a robust basis for future treatment strategies. Further research could include comparing outcomes of USC patients receiving immunotherapy with those not, and evaluating treatment efficacy differences between USC and non-USC PDAC patients.