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Reliable Detection of Somatic Mutations for Pancreatic Cancer in Endoscopic Ultrasonography-Guided Fine Needle Aspirates with Next-Generation Sequencing: Implications from a Prospective Cohort Study

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Journal of Gastrointestinal Surgery Aims and scope

Abstract

Background or Purpose

Pancreatic ductal adenocarcinoma (PDAC) is commonly diagnosed by endoscopic ultrasound-guided fine needle aspiration (EUS-FNA). However, the diagnostic adequacy of EUS-FNA is often limited by low cellularity leading to inconclusive results. We aimed to investigate the feasibility and added utility of targeted next-generation sequencing (NGS) on PDAC EUS-FNAs.

Methods

EUS-FNAs were prospectively performed on 59 patients with suspected PDAC (2014-2017) at a high-volume center. FNAs were analyzed for the presence of somatic mutations using NGS to supplement cytopathologic evaluations and were compared to surgical specimens and circulating tumor DNA (ctDNA).

Results

Fifty-nine patients with suspected PDAC were evaluated, and 52 were diagnosed with PDAC on EUS-FNA. Four of the remaining seven patients had inconclusive EUS-FNAs and were ultimately diagnosed with PDAC after surgical resection. Of these 56 cases of PDAC, 48 (85.7%) and 18 (32.1%) harbored a KRAS and/or TP53 mutation on FNA NGS, respectively. Particularly, in the four inconclusive FNA PDAC diagnoses (false negatives), half harbored KRAS mutations on FNA. No KRAS/TP53 mutation was found in remaining three non-PDAC cases. All EUS-FNA detected KRAS mutations were detected in 16 patients that underwent primary tumor NGS (100% concordance), while 75% KRAS concordance was found between FNA and ctDNA NGS.

Conclusion

Targeted NGS can reliably detect KRAS mutations from EUS-FNA samples and exhibits high KRAS mutational concordance with primary tumor and ctDNA. This suggests targeted NGS of EUS-FNA samples may enable preoperative ctDNA prognostication using digital droplet PCR and supplement diagnoses in patients with inconclusive EUS-FNA.

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Funding

This work was supported by the grant from the Sol Goldman Pancreatic Cancer Research Grant (to JH).

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Author notes

  1. Joseph R. Habib, Yayun Zhu and Lingdi Yin contributed equally to this work.

Authors and Affiliations

  1. Department of Surgery, Johns Hopkins University School of Medicine, 600 N. Wolfe St, Baltimore, MD, 21287, USA

    Joseph R. Habib, Yayun Zhu, Lingdi Yin, Ammar A. Javed, Ding Ding, Jonathan Tenior, Michael Wright, Richard A Burkhart, William Burns, Christopher L. Wolfgang, Jun Yu & Jin He

  2. Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA

    Syed Z. Ali & Christopher L. Wolfgang

  3. Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA

    Richard A Burkhart, William Burns, Christopher L. Wolfgang & Jin He

  4. Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA

    Eunji Shin

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Contributions

Conception and design: JRH, YZ, LY, JY, and JH. Administrative support: RAB, WB, CLW, ES, JY, and JH. Provision of study materials: AAJ, DD, and JT. Collection and assembly of data: AAJ, DD, JT, MW, and SZA. Data analysis and interpretation: JRH, YZ, LY, JY, and JH. Manuscript writing: All authors. Final approval of manuscript: All authors. Obtained funding: JY and JH. Study supervision: JY and JH.

Corresponding authors

Correspondence to Jun Yu or Jin He.

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This study was approved by the Institutional Review Board (IRB) of the Johns Hopkins Hospital and informed consent was signed by all patients.

Conflict of Interest

 ES declares personal fees from Boston Scientific and Medtronic outside the submitted work.

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Supplementary Information

Figure S1.

EUS-FNA mutation profile in study population. (JPG 97 kb)

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Habib, J.R., Zhu, Y., Yin, L. et al. Reliable Detection of Somatic Mutations for Pancreatic Cancer in Endoscopic Ultrasonography-Guided Fine Needle Aspirates with Next-Generation Sequencing: Implications from a Prospective Cohort Study. J Gastrointest Surg 25, 3149–3159 (2021). https://doi.org/10.1007/s11605-021-05078-y

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