Endoscopic Strategies Broaden the Pancreatic Cancer Diagnostic and Treatment Paradigms

Tamas A. Gonda, MD

In pancreatic cancer, the role of the endoscopist continues to evolve as technologies like endoscopic ultrasound (EUS)–guided biopsies present clinicians with increasingly accurate information to characterize the tumor microenvironments of individual patients and determine effective targeted therapies, according to Tamas A. Gonda, MD, who spoke about personalized treatment in early pancreatic cancer during the 2023 City of Hope Advances and Innovations in Endoscopic Oncology and Multidisciplinary Gastrointestinal Cancer Care continuing medical education program. Additionally, Gonda emphasized that endoscopic practices in pancreatic cancer are expanding beyond predictive biopsies, as ablation strategies in clinical practice and under investigation may alter and improve the ways patients receive targeted therapies.¹

Gonda is an associate professor in the Department of Medicine at the NYU Grossman School of Medicine, as well as chief of Endoscopy at Tisch Hospital and director of the Pancreatic Disease Program at NYU Langone Health in New York.

The Role of EUS-Guided Biopsies in Determining Targeted Treatment Approaches

Recent advances in pancreatic cancer diagnosis and management signal future increases in personalized treatments that will likely be guided by germline testing technologies such as EUS-guided biopsies. The Pancan Know Your Tumor Initiative, which incorporated data from surgical resection specimens, metastatic pancreatic cancer biopsies, and endoscopic biopsies, showed that patients with pancreatic cancer with highly actionable biomarkers who received matched therapy had a median progression-free survival (PFS) of 4.1 months vs 1.9 months in those who received unmatched therapy (HR, 0.47; 95% CI, 0.24-0.94; P adj = .03).² Moreover, a randomized trial comparing EUS-guided fine needle aspiration (FNA) vs EUS flexible needle biopsy (FNB) for genomic profiling in pancreatic cancer showed mean DNA concentrations of 5.930 µg/mLvs 3.365 µg/mLwith FNB and FNA needles, respectively (P = .01), and overall higher specimen adequacy for genomic profiling, DNA yield, and histology yield with FNB vs FNA needles.³

“There are other tests that we can leverage that are coming,” Gonda remarked.¹

A study published in Gastroenterology in 2023 evaluated the ability of a transcriptomic-based tool to predict gemcitabine sensitivity in tumor biopsies from patients with advanced pancreatic adenocarcinoma.⁴ Findings from this transcriptomic analysis demonstrated that the gemcitabine sensitivity signature GemCore predicted response to gemcitabine-based therapies better than other prognostic markers, such as the RNA signature GemPred. Specifically, GemCore-positive patients had a median overall survival (OS) of 6.6 months (95% CI, 4.72-16.13) and a median PFS of 2.95 months (95% CI, 1.38-4.36) with gemcitabine, and GemCore-negative patients had a median OS of 2.1 months (95% CI, 1.64-3.48) and a median PFS of 0.36 months (95% CI, 0.00-1.34).

“This recent work shows that there is a significant ability to predict response to gemcitabine-based therapy, which is a core of this [pancreatic cancer treatment paradigm],” Gonda said of this study, which exclusively included tumor biopsies obtained through EUS FNA. “Single-cell transcriptomics can be done just as effectively from endoscopic biopsies as from resection biopsies. This is particularly remarkable because this is an analysis and a modality that relies on understanding the biology or the transcriptome in many different cell populations. Endoscopic biopsies allow you to understand the biology of these different cell populations…down to the different populations of immune cells and stromal cells.”¹

Additionally, Gonda and researchers at NYU Langone Health conducted a study using RNA sequencing of biopsy samples obtained by surgical resection, EUS, and interventional radiology to determine the efficacy of chemotherapy in patients with pancreatic adenocarcinoma. The investigators found that chemotherapy alters the pancreatic cancer tumor microenvironment regardless of tumor subtype. Notably, an evaluation of treatment-related checkpoint molecule expression in CD8+ T cells revealed high and broad expression of the inhibitory checkpoint molecule TIGIT.⁵

“[RNA sequencing of EUS-guided biopsies] has a significant ability to predict immunotherapy response in pancreatic cancer, which is a remarkable thing from purely a needle biopsy,” Gonda added. “Prognostic scores, transcriptomic analyses, and organoid-based treatments, especially if they can be done in a speedy manner to influence the first-line treatment of patients, [may be] something we will be doing in the near future.”¹

Future Treatment Directions With Ablative Approaches

When considering the role of the endoscopist in treating patients with pancreatic cancer, directly delivered therapies and ablation strategies may rise to the forefront of effective treatment modalities.

“Pancreatic cancer is a difficult environment to get systemic therapy to the epithelial cells. There’s a potential advantage for directly delivered therapy there. Local [disease] control is associated with a significant survival benefit…[Additionally], pancreatic cancer is not an immunogenic cancer, and perhaps ablative therapies and directly delivered therapies can increase the immunogenicity.”

The 3 non-chemical ablation strategies that are currently available in pancreatic cancer are microwave ablation, radiofrequency ablation (RFA), and irreversible electroporation. Of these, EUS-guided RFA is in clinical use, and EUS-guided microwave ablation awaits FDA approval.

EUS-guided ablation approaches are favorable compared with surgically or radiographically guided biopsies for several reasons, Gonda noted. They provide visibility of the pancreatic duct and adjacent vessels, allowing for less invasive access to the tumor. Additionally, EUS-guided ablation allows endoscopists to see the ablation effects in real time during the treatment and adjust their approaches based on their proximity to pancreatic structures. Furthermore, the option for repeat ablation opportunities increases the chances that a patient will achieve a complete response from this therapy.

An ongoing, single-arm, phase 1 study (NCT05723107) at NYU Langone Health is investigating the tolerability of chemotherapy plus EUS-RFA in patients with unresectable, nonmetastatic pancreatic ductal adenocarcinoma who are receiving palliative second- or third-line therapy. The primary end point of this study is the percentage of patients who complete the therapy with no grade 3/4 adverse effects, and secondary end points include disease-free survival and OS.⁶

“We’re beginning to have a significant effect on the treatment of pancreatic cancer both in our way of utilizing endoscopic biopsies and our ability to successfully profile tumors in various ways from endoscopic biopsies and potentially incorporating and studying endoscopic ablation as a way to treat pancreatic cancer,” Gonda concluded.

References

1. Gonda TA. Pancreatic cancer: the era of personalized treatment in early disease. Presented at: 2023 City of Hope Advances and Innovations in Endoscopic Oncology and Multidisciplinary Gastrointestinal Cancer Care continuing medical education program; April 15, 2023; Scottsdale, AZ.
2. Pishvaian MJ, Bender RJ, Halverson D, et al. Molecular profiling of patients with pancreatic cancer: initial results from the Know Your Tumor Initiative. Clin Cancer Res. 2018;24(20):5018-5027. doi:10.1158/1078-0432.CCR-18-0531
3. Kandel P, Nassar A, Gomez V, et al. Comparison of endoscopic ultrasound-guided fine-needle biopsy versus fine-needle aspiration for genomic profiling and DNA yield in pancreatic cancer: a randomized crossover trial. Endoscopy. 2021;53(4):376-382. doi:10.1055/a-1223-2171
4. Fraunhoffer N, Chanez B, Teyssedou C, et al. A transcriptomic-based tool to predict gemcitabine sensitivity in advanced pancreatic adenocarcinoma. Gastroenterology. 2023;164(3):476-480.e4. doi:10.1053/j.gastro.2022.11.035
5. Werba G, Weissinger D, Kawaler EA, et al. Single-cell RNA sequencing reveals the effects of chemotherapy on human pancreatic adenocarcinoma and its tumor microenvironment. Nat Commun. 2023;14(1):797. doi:10.1038/s41467-023-36296-4
6. EUS RFA for treatment of pancreatic ductal adenocarcinoma (PDAC). ClinicalTrials.gov. Updated April 18, 2023. Accessed April 20, 2023. https://clinicaltrials.gov/ct2/show/NCT05723107