Intratumoural expression of dihydropyrimidine dehydrogenase is an independent prognostic factor in resected pancreatic ductal adenocarcinoma treated with adjuvant gemcitabine

Hakon Blomstrand; Malin Bodarve; Fredrik Groth; Peter Naredi; Malin Sund; Caroline Vilhav; Henrik Green; Bergthor Björnsson; Daniel Öhlund; Stina Lindblad; Oskar Franklin; Nils O Elander

doi:10.3892/ol.2024.14845

Intratumoural expression of dihydropyrimidine dehydrogenase is an independent prognostic factor in resected pancreatic ductal adenocarcinoma treated with adjuvant gemcitabine

Oncol Lett. 2024 Dec 10;29(2):99. doi: 10.3892/ol.2024.14845. eCollection 2025 Feb.

Authors

Hakon Blomstrand^{1

2}, Malin Bodarve², Fredrik Groth², Peter Naredi³, Malin Sund^{4

5}, Caroline Vilhav³, Henrik Green^{6

7}, Bergthor Björnsson^{1

8}, Daniel Öhlund⁹, Stina Lindblad⁹, Oskar Franklin^{4

10}, Nils O Elander^{1

11}

Affiliations

¹ Division of Surgery, Orthopaedics and Oncology, Department of Biomedical and Clinical Sciences, Linköping University, SE-58185 Linköping, Sweden.
² Department of Clinical Pathology, Linköping University Hospital, SE-58185 Linköping, Sweden.
³ Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, SE-40530 Gothenburg, Sweden.
⁴ Department of Diagnostics and Intervention, Umeå University, SE-90187 Umeå, Sweden.
⁵ Department of Surgery, University of Helsinki and Helsinki University Hospital, 00014 Helsinki, Finland.
⁶ Division of Clinical Chemistry and Pharmacology, Department of Biomedical and Clinical Sciences, Linköping University, SE-58185 Linköping, Sweden.
⁷ Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping University, SE-58185 Linköping, Sweden.
⁸ Department of Surgery, Linköping University Hospital, SE-58185 Linköping, Sweden.
⁹ Department of Diagnostics and Intervention, and Wallenberg Centre for Molecular Medicine, Umeå University, SE-90187 Umeå, Sweden.
¹⁰ Division of Surgical Oncology, Department of Surgery, University of Colorado School of Medicine, Aurora, CO 80045, USA.
¹¹ Clatterbridge Cancer Centre NHS Foundation Trust, Liverpool L7 8YA, United Kingdom.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is associated with a poor prognosis, and biomarkers to guide treatment decisions in PDAC are generally lacking. Intratumoural expression of dihydropyrimidine dehydrogenase (DPD) is a potential prognostic parameter in patients with PDAC undergoing surgical resection and postoperative chemotherapy. In the present study, DPD was analysed by immunohistochemistry of a tissue microarray platform including a real-world cohort of 495 patients with PDAC who had undergone resection with curative intent at any of three tertiary centres, including Northern, Western and Southeastern regions of Sweden, between 1993 and 2019. DPD level (high/low) was analysed and overall survival associations were assessed in treatment subgroups using a multivariate Cox regression model accounting for potential confounders. In patients who had not received adjuvant chemotherapy (n=182), the median overall survival time was 11.6 months (95% CI 9.6-13.5), compared with 28.8 months (25.0-32.6) among those who had (n=313; log-rank P<0.001). The most common type of chemotherapy was gemcitabine single agent (Gem, n=239) followed by gemcitabine plus capecitabine (GemCape, n=39). Tumour-Node-Metastasis (TNM) stage and DPD expression were statistically significant prognostic parameters in the Gem group (HR 1.19, 95% CI 1.01-1.41, P=0.036), with high expression of DPD linked with worse survival. In addition, tumour grade and TNM stage were statistically significant prognostic factors in the group that did not receive any chemotherapy (P≤0.001). No statistically significant parameters were identified in the GemCape group. Taken together, intratumoural expression of DPD may be considered a prognostic marker for patients with PDAC treated with adjuvant gemcitabine following surgical resection, with low expression levels predicting better survival. Further studies in larger cohorts of patients receiving multi-drug or non-gemcitabine based regimens are warranted.

Keywords: adjuvant chemotherapy; dihydropyrimidine dehydrogenase; gemcitabine; pancreatic cancer; pancreatic ductal carcinoma; prognosis; prognostic factors.

Grants and funding

This work was supported by the non-profit funding bodies FORSS (grant no. 941207), CKOC and Region Östergötland (grant nos. RÖ-962449, RÖ-935580, RÖ-962548, RÖ-937640, RÖ-990631, RÖ-975579 and RÖ-978701). HB received funding from Lion's Research Fund, Linköping. Oskar Franklin received funding from The Royal Swedish Academy of Sciences (PE Lindahl Foundation; grant nos. LM2021-0010 and LM2023-0012), The Swedish Society of Medicine (grant no. SLS-960379), Region Västerbotten in Umeå, Sweden (grant no. RV 967602), The Sjöberg Foundation, Cancerforskningsfonden i Norrland (grant no. LP 23-2337), Bengt Ihre Foundation (grant nos. SLS-960529 and SLS-986656) and Bengt Ihre Research Fellowship Grant. Daniel Öhlund received funding from the Cancer Research Foundation in Northern Sweden (grant nos. AMP23-1104 and LP 24-2377), the Swedish Cancer Society (grant no. 23 2707 Pj), The Swedish Research Council (grant no. 2022-00855), Region Västerbotten (grant no. RV-978812), the Knut and Alice Wallenberg Foundation, and the Marianne and Marcus Wallenberg Foundation (grant no. MMW 2020.0189). Malin Sund received funding from the Swedish Research Council (grant no. 2019-01690), the Swedish Cancer Society (grant no. 19 0273), Västerbotten Region (grant nos. RV-583411, RV-549731, RV-583411 and RV-841551), the Sigrid Juselius Foundation (grant no. 8166), Finska Läkaresällskapet, Medicinska Understödsföreningen Liv och Hälsa, the Sjöberg Foundation and VTR funding from Helsinki University Hospital (grant no. TYH2022329). None of the funding bodies participated in the design, conceptualization, data collection, analysis, interpretation of data, or writing of the manuscript of this study.