Mutant KRAS and GATA6 Stratify Survival in Patients Treated with Chemotherapy for Pancreatic Adenocarcinoma: A Prospective Cohort Study

Overview

Journal Cancers (Basel)

Publisher MDPI

Specialty Oncology

Date 2025 Mar 13

PMID 40075743

Authors

Jung Won Chun

Dong-Eun Lee

Nayoung Han

SooBeen Heo

Hyeji Kim

Mi Rim Lee

Hyeong Min Park

Sung-Sik Han

Sang-Jae Park

Tae Hyun Kim

Woo Jin Lee

Yun-Hee Kim

Sun-Young Kong

Sang Myung Woo

Affiliations

Soon will be listed here.

Abstract

Background: Several pancreatic adenocarcinoma (PA) biomarkers beyond the traditional carbohydrate antigen (CA)19-9 have been identified but are lacking large-scale prospective validation. This prospective cohort study evaluated the prognostic impact of potential PA biomarkers.

Methods: We enrolled 238 of 288 patients with histologically proven PA. We assessed candidate biomarkers, including CA19-9, germline , and mutations, as well as mutant circulating tumor DNA (ctDNA) in blood samples. Additionally, we evaluated the expression of SLC29A1 (hENT1), DCK, CES2, and GATA6. We examined the association of candidate biomarkers with progression-free survival (PFS) and overall survival (OS).

Results: We analyzed biomarker efficacy in 200 (median age 65 years; 55% male) of the enrolled patients who received chemotherapy. A high mutant ctDNA concentration (hazard ratio [HR]: 1.508 and 95% confidence interval [CI]: 1.052-2.161 for PFS; HR: 1.796 and 95% CI: 1.203-2.681 for OS) and high CA19-9 level (HR: 1.647 and 95% CI: 1.177-2.306 for PFS; HR: 1.803 and 95% CI: 1.248-2.605 for OS) were associated with poor prognosis. High GATA6 RNA expression was linked to longer PFS (HR: 0.336 and 95% CI: 0.195-0.582) and OS (HR: 0.304 and 95% CI: 0.165-0.560).

Conclusions: Plasma mutant ctDNA concentrations and GATA6 expression could serve as significant prognostic biomarkers in patients with PA, potentially guiding therapeutic decisions and prognostication.

References

Farrell J, Elsaleh H, Garcia M, Lai R, Ammar A, Regine W . Human equilibrative nucleoside transporter 1 levels predict response to gemcitabine in patients with pancreatic cancer. Gastroenterology. 2008; 136(1):187-95. DOI: 10.1053/j.gastro.2008.09.067. View

Kim S, Park B, Seo J, Choi J, Choi J, Lee C . Carbohydrate antigen 19-9 elevation without evidence of malignant or pancreatobiliary diseases. Sci Rep. 2020; 10(1):8820. PMC: 7264353. DOI: 10.1038/s41598-020-65720-8. View

Guven D, Sahin T, Yildirim H, Aktepe O, Dizdar O, Yalcin S . A systematic review and meta-analysis of the association between circulating tumor DNA (ctDNA) and prognosis in pancreatic cancer. Crit Rev Oncol Hematol. 2021; 168:103528. DOI: 10.1016/j.critrevonc.2021.103528. View

Norton C, Shaw M, Rubnitz Z, Smith J, Soares H, Nevala-Plagemann C . KRAS Mutation Status and Treatment Outcomes in Patients With Metastatic Pancreatic Adenocarcinoma. JAMA Netw Open. 2025; 8(1):e2453588. PMC: 11707629. DOI: 10.1001/jamanetworkopen.2024.53588. View

OKane G, Grunwald B, Jang G, Masoomian M, Picardo S, Grant R . GATA6 Expression Distinguishes Classical and Basal-like Subtypes in Advanced Pancreatic Cancer. Clin Cancer Res. 2020; 26(18):4901-4910. DOI: 10.1158/1078-0432.CCR-19-3724. View

Murphy J, Wo J, Ryan D, Jiang W, Yeap B, Drapek L . Total Neoadjuvant Therapy With FOLFIRINOX Followed by Individualized Chemoradiotherapy for Borderline Resectable Pancreatic Adenocarcinoma: A Phase 2 Clinical Trial. JAMA Oncol. 2018; 4(7):963-969. PMC: 6145728. DOI: 10.1001/jamaoncol.2018.0329. View

Sivapalan L, Kocher H, Ross-Adams H, Chelala C . Molecular profiling of ctDNA in pancreatic cancer: Opportunities and challenges for clinical application. Pancreatology. 2021; 21(2):363-378. PMC: 7994018. DOI: 10.1016/j.pan.2020.12.017. View

Wei T, Zhang Q, Li X, Su W, Li G, Ma T . Monitoring Tumor Burden in Response to FOLFIRINOX Chemotherapy Via Profiling Circulating Cell-Free DNA in Pancreatic Cancer. Mol Cancer Ther. 2018; 18(1):196-203. DOI: 10.1158/1535-7163.MCT-17-1298. View

Conroy T, Hammel P, Hebbar M, Abdelghani M, Wei A, Raoul J . FOLFIRINOX or Gemcitabine as Adjuvant Therapy for Pancreatic Cancer. N Engl J Med. 2018; 379(25):2395-2406. DOI: 10.1056/NEJMoa1809775. View

10.

. The global, regional, and national burden of pancreatic cancer and its attributable risk factors in 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet Gastroenterol Hepatol. 2019; 4(12):934-947. PMC: 7026711. DOI: 10.1016/S2468-1253(19)30347-4. View

11.

Miyasaka Y, Ohtsuka T, Kimura R, Matsuda R, Mori Y, Nakata K . Neoadjuvant Chemotherapy with Gemcitabine Plus Nab-Paclitaxel for Borderline Resectable Pancreatic Cancer Potentially Improves Survival and Facilitates Surgery. Ann Surg Oncol. 2019; 26(5):1528-1534. DOI: 10.1245/s10434-019-07309-8. View

12.

Pietrasz D, Pecuchet N, Garlan F, Didelot A, Dubreuil O, Doat S . Plasma Circulating Tumor DNA in Pancreatic Cancer Patients Is a Prognostic Marker. Clin Cancer Res. 2016; 23(1):116-123. DOI: 10.1158/1078-0432.CCR-16-0806. View

13.

Chan-Seng-Yue M, Kim J, Wilson G, Ng K, Figueroa E, OKane G . Transcription phenotypes of pancreatic cancer are driven by genomic events during tumor evolution. Nat Genet. 2020; 52(2):231-240. DOI: 10.1038/s41588-019-0566-9. View

14.

Duan K, Jang G, Grant R, Wilson J, Notta F, OKane G . The value of GATA6 immunohistochemistry and computer-assisted diagnosis to predict clinical outcome in advanced pancreatic cancer. Sci Rep. 2021; 11(1):14951. PMC: 8298486. DOI: 10.1038/s41598-021-94544-3. View

15.

Berger A, Garcia Jr M, Hoffman J, Regine W, Abrams R, Safran H . Postresection CA 19-9 predicts overall survival in patients with pancreatic cancer treated with adjuvant chemoradiation: a prospective validation by RTOG 9704. J Clin Oncol. 2008; 26(36):5918-22. PMC: 2645109. DOI: 10.1200/JCO.2008.18.6288. View

16.

Bailey P, Chang D, Nones K, Johns A, Patch A, Gingras M . Genomic analyses identify molecular subtypes of pancreatic cancer. Nature. 2016; 531(7592):47-52. DOI: 10.1038/nature16965. View

17.

Perkhofer L, Gout J, Roger E, Kude de Almeida F, Baptista Simoes C, Wiesmuller L . DNA damage repair as a target in pancreatic cancer: state-of-the-art and future perspectives. Gut. 2020; 70(3):606-617. PMC: 7873425. DOI: 10.1136/gutjnl-2019-319984. View

18.

Bankhead P, Loughrey M, Fernandez J, Dombrowski Y, McArt D, Dunne P . QuPath: Open source software for digital pathology image analysis. Sci Rep. 2017; 7(1):16878. PMC: 5715110. DOI: 10.1038/s41598-017-17204-5. View

19.

Huang J, Lok V, Ngai C, Zhang L, Yuan J, Lao X . Worldwide Burden of, Risk Factors for, and Trends in Pancreatic Cancer. Gastroenterology. 2020; 160(3):744-754. DOI: 10.1053/j.gastro.2020.10.007. View

20.

Ryu K, Park S, Chun J, Cho E, Choi J, Lee D . Prevalence and Risk Factors of Germline Pathogenic Variants in Pancreatic Ductal Adenocarcinoma. Cancer Res Treat. 2023; 55(4):1303-1312. PMC: 10582541. DOI: 10.4143/crt.2023.291. View