Intratumoural expression of dihydropyrimidine dehydrogenase is an independent prognostic factor in resected pancreatic ductal adenocarcinoma treated with adjuvant gemcitabine
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- Published online on: December 10, 2024 https://doi.org/10.3892/ol.2024.14845
- Article Number: 99
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Copyright: © Blomstrand et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
Introduction
Pancreatic ductal adenocarcinoma (PDAC) represents a challenging type of cancer with increasing mortality counts, projected to replace breast cancer as the third highest ranked cause of cancer-related deaths in Europe by 2025 (1). Historically, the outcome for patients with PDAC has been poor with almost no long-time survivors, yet recent data indicate a positive trend with 10-year survival (all stages combined) now climbing towards 10% (2).
One key factor for improved prognosis has been the introduction of adjuvant chemotherapy following curative intent resection in patients with disease limited to the locoregional area and who are in reasonably good performance status. Initially, 5-fluorouracil (5-FU) and folinic acid was mainstay treatment (3) however over the past 10–15 years protocols including gemcitabine single agent (Gem) (4), gemcitabine plus the 5-FU prodrug capecitabine (GemCape) (5), and 5-FU, leucovorin, irinotecan and oxaliplatin (FOLFIRINOX) (6) have largely replaced this standard. In addition, a combination of the 5-FU oral prodrug tegafur in combination with enzyme inhibitors gimeracil and oteracil (S-1) has evolved as a viable option mainly in Asian populations (7). Irrespective of the treatment regimen administered, benefit from chemotherapy is highly variable between patients and finding prognostic and treatment predictive markers to better guide therapeutic strategy has proven to be a goal yet to be accomplished.
Dihydropyrimidine dehydrogenase (DPD) is an enzyme encoded by the DPYD gene that is involved in the catabolism of thymine and uracil and is expressed in various tissues and cells of the body, including the liver, bone marrow and mononuclear cells of the blood, as well as in tumour tissue (8). In addition to its physiological function, DPD is also a key enzyme in the conversion of 5-FU into its pharmacologically inactive form dihydrofluorouracil (9). High expression of DPD mRNA and protein has been reported in several types of adenocarcinoma including those of the stomach, head and neck, and pancreas (10).
Germline variations of the DPYD gene are closely linked to severe toxicity to 5-FU and other pyrimidine analogues, and there is now a general recommendation to check all patients for such variants prior to starting treatment (11). Beside this, additional reports indicate that intratumoural expression of DPD (either due to germline or somatic mutations, epigenetic alterations, or post-transcriptional upregulation) is a marker for poor prognosis in various types of cancer as well as poor response to chemotherapeutic anti-metabolic drugs including 5-FU, capecitabine and S-1 when given alone or in combination with gemcitabine (12–17). In addition, in vitro and in vivo studies in urinary bladder cancer have implied DPD expression levels to interfere with sensitivity and resistance to gemcitabine (18).
The current study aimed to evaluate the potential prognostic impact of intratumoural DPD expression in a large real-world multi-centre cohort of patients with resected PDAC treated with adjuvant chemotherapy.
Materials and methods
TMA construction
A tissue microarray (TMA) with multiple biopsies of tumour tissue representing PDAC patients who underwent surgical resection between 1993–2019 in any of the Northern, Western, and Southeastern health care regions of Sweden, was constructed. The cohort from the Southeast region included all resected cases between 2009–2019 and has been described in detail in a previous publication (19).
All available slides were reviewed for each case and paraffin blocks corresponding to slides with the highest proportion of tumour cells were selected for the TMA. The TMA was manufactured with the previous ESPAC3 material-based TMA as a template (15). Two 1 mm in diameter micro core biopsies were taken from tumour cell rich areas in two blocks from the primary tumour and one 1 mm in diameter core biopsy from a block with lymph node metastasis (if present), in total 4–5 cores per case with an automated TMA Master or TMA Grandmaster (3DHistech Kft., Budapest, Hungary). In a few cases where poor core quality was readily detected during biopsy transferral (e.g., due to half or broken biopsies), additional blocks were retrieved (if available) to reach the total micro biopsy number of 4–5. In 86 other cases tumour tissue was embedded in new paraffin blocks as tumour was only found in xl-blocks in the original case (not compatible with the TMA machine). The biopsies were arranged in a grid pattern in receiving paraffin blocks with micro biopsies containing control tissue (alternating benign liver, pancreatic, colonic, and renal tissue) arranged in a fence-like manner in the perimeter of the grid (Fig. 1). Receiving blocks were then mildly heated to melt the cores with surrounding paraffin and subsequently 3.5 µm sections were taken with a HM355S microtome (Thermo Fisher Scientific, Waltham MA, USA) and mounted on Cut frosted microscope slides (Epredia, Kalamazoo MI, USA). One section from each block was stained with haematoxylin-eosin (HE) for reference and validation of tumour cell content in the micro biopsies.
Immunohistochemical staining
One additional slide, sectioned at a thickness of 3.5 µm, was retrieved from all TMA blocks and baked for 1 h at 60°C. Deparaffinization and staining were performed in BOND III stainers (Leica) using heat-induced epitope retrieval (HIER) with Bond Epitope Retrieval Solution 2, effective heating time of 20 min at 100°C, and Bond Polymer Refine Detection Kit (all reagents supplied by Leica). The primary antibody (rabbit anti-DPD, Abcam ab 134922, Abcam, Cambridge, UK) was used at a dilution of 1:2,000, with EnVision FLEX Antibody Diluent (Dako) and incubated for 15 min at room temperature. The staining procedures were designed according to a previously validated and optimised protocol for immunohistochemical analysis of intratumoural DPD expression in paraffin embedded TMA biopsies of PDAC (15).
DPD staining intensity assessment
Staining intensity was evaluated and scored by HB and NE in an individual and blinded manner in four tiers 0–3, replicating the methods used in the previous work utilizing the ESPAC3 tissue material (15). If heterogeneous staining intensity was present, the predominant pattern was chosen. When the raters scored the same core differently, the case was discussed, and a consensus score was established.
Representative stained slides are displayed in Fig. 1. Following completion of scoring, the cores were deciphered and cases with less than two evaluable tumour cores (e.g., no tumour in the core, section lost during preparation, no tissue left in the TMA block etc.) were excluded from further analysis. For included cases a mean score was calculated based on all cores from the same case rounded to the nearest integer. Cases were then dichotomized into low (0–1) or high (2–3) expression.
Statistical analysis
All cases fulfilling the inclusion criteria were included in the statistical analyses that were performed with SPSS v29 (IBM, Armonk, USA) and R Statistical Software (v4.3.1; R Foundation for Statistical Computing, Vienna, Austria). P<0.05 was considered to indicate a statistically significant difference. If not else stated, descriptive statistics were reported as median and interquartile range for continuous variables and as frequencies and percentages for categorical values. Comparisons were made with Mann Whitney U or χ2-test and unpaired Student's t-test for categorical and continuous parameters, respectively. Cohen's κ was used to assess interrater variability concerning IHC scoring. Primary outcome was median overall survival (OS), defined as time from the date of surgery until death or censoring, whatever occurred first. Kaplan-Meier survival analysis was used to estimate survival times and the log-rank test was utilized to detecting significant differences between subgroups. Assuming proportional hazards, univariate Cox regression analysis was used to identify potentially prognostic factors. Spearman's rank correlation was used to determine covariation between selected variables. A subsequent multivariate Cox regression model, including factors with P<0.10 in the univariate analysis, was used to determine independent prognostic factors. To calculate median follow-up time, the reverse Kaplan-Meier method was used (20).
Results
A total of 2,323 tumour cores were transferred to the TMA blocks, representing the total cohort of 552 included cases of resected PDAC. Fifty-seven cases were excluded due to less than two evaluable tumour containing micro biopsies being available, leaving a total of 495 cases in the final cohort available for analysis (Fig. 2). DPD staining was performed, and staining intensity was scored by two independent assessors. The staining pattern was generally homogenous and clear, with excellent inter-rater concordance (Cohen's κ=0.81).
Descriptives
Seventeen patients were diagnosed with PDAC of a specified histological subtype, whilst 478 cases were diagnosed with PDAC not otherwise specified (NOS). Descriptive patient characteristics are shown for the full cohort and stratified as per DPD intensity level in Table I. DPD levels were significantly associated with tumour differentiation grade and overall survival, with low levels generally being linked with better prognostic features (high tumour differentiation grade and longer overall survival).
 | Table I.Patient characteristics for the total cohort and when divided into subgroups per DPD staining intensity level. |
Overall survival
Median overall survival in the total cohort, including all patients who had and who had not received any adjuvant chemotherapy, was 19.6 months (95% CI 17.4–23.8, Table I).
Patients who did not receive adjuvant chemotherapy had a worse outcome than those who did, with a median overall survival of 11.6 months (95% CI 9.6–13.5) vs. 28.8 months (95% CI 25.0–32.6), P<0.001, log-rank test).
Further subgrouping of patients, according to the type of chemotherapy received, revealed overall survival estimates of 28.1 months (95% CI24.1–32.0) and 28.1 months (95% CI 15.0–41.2) for the most commonly utilized protocols Gem (n=239) and GemCape (n=39), respectively. The other subgroups, including FOLFIRINOX, gemcitabine with nab-paclitaxel (Gem/nab-P), and 5-FU single agent, were too small (n<11 for each individual regimen) to perform separate subanalyses on.
When categorising the patients according to the intratumoural DPD expression levels, high expression was associated with shorter survival in the total cohort of patients (log-rank P=0.0053). This impact was most prominent in the Gem treated population, with median OS of 30.3 months (95% CI 26.3–34.5) and 21.5 months (95% CI 17.4–27.7) in the DPD low and high expression subgroups, respectively (P=0.005). A similar yet not statistically significant trend was evident in the group of patients who did not receive any postoperative chemotherapy (P=0.056), whereas no difference was observed in the GemCape treated subgroup (P=0.960) (Fig. 3).
Univariate analyses of overall survival
Given the heterogenous nature of the main groups of patients (no chemotherapy, Gem, and GemCape), these were separately assessed with Cox regression analysis in terms of potential prognostic factors and overall survival.
In the untreated group of patients, TNM stage, R-status, year of surgery and tumour differentiation grade were all statistically significant prognostic parameters (Table II).
| Table II.Univariate and multivariate Cox regression analyses on all patients combined, and in the subgroups who received and who did not receive adjuvant chemotherapy. |
In the Gem treated group, DPD level, sex, R-status, and TNM stage were prognostic whereas no factors showed significant prognostic value in the GemCape group (Table III). When combining all patients treated with any type of chemotherapy, DPD-level, sex, R-status, and TNM stage were prognostic in terms of overall survival (Table II).
| Table III.Univariate and multivariate Cox regression analyses on patients treated with adjuvant Gem and GemCape. |
Multivariate analyses of overall survival
All factors that returned P<0.10 in the univariate regression analyses were included in the subsequent multivariate Cox regression analyses (Kaplan-Meier curves for these factors are seen in Fig. S1). As Spearman's rank correlation analysis revealed no association between the year of surgery variable and the dependent variable DPD expression level (rho 0.109, negligible correlation; data not shown), the year of surgery variable was excluded in the multivariate analysis.
In the group of patients who had not received any chemotherapy, differentiation grade and TNM stage were both statistically significant independent prognostic factors with regards to overall survival (Table II).
In the Gem treated group of patients, TNM stage and DPD expression levels were both independent parameters for survival (with P=0.018 and P=0.036, respectively), whereas sex was borderline significant (P=0.050, Table III). Amongst GemCape treated patients, neither DPD-expression nor any other factors were found statistically significant (Table III). Upon grouping all types of chemotherapy together, only sex was a statistically significant factor in terms of survival (Table II).
Discussion
Over the past 20 years, adjuvant chemotherapy has evolved as mainstay treatment in patients who have undergone curative intent resection of pancreatic adenocarcinoma. Despite significant therapeutic improvement, the prognosis remains poor, and there are still patient groups that do not benefit from the chemotherapy given. There are currently few, if any, treatment predictive molecular biomarkers that tell us who will be at high vs. low risk for recurrent disease and who will have good outcomes following adjuvant treatment.
With newer and more intense multi-drug regimens at hand, the need for prognostic profiling of the tumour, that may indicate what type of patient that will need more intense treatments and follow up, has become imminent.
Previous studies on DPD expression in various types of cancer including colorectal and pancreatic adenocarcinomas have indicated a potential prognostic and/or predictive value in patients treated with 5-FU or other fluoropyrimidines alone or in combination with Gem (12–17). In addition, DPD has been implied as a molecular marker for response to Gem in urinary bladder cancer cell lines and tumours (18).
The present study focused on the potential value of intratumoural DPD expression levels in a large cohort of patients with PDAC who underwent curative intent surgery over a period of 26 years (1993–2019) and covering three major catchment areas of Sweden.
As expected, outcomes were very poor amongst patients who did not receive any type of adjuvant chemotherapy. This was not surprising and is at least partly likely to be explained by selection bias in terms of patients with poor performance status and/or severe complications following the surgical resection being less likely to be fit for chemotherapy and, notably, the survival in this group was closely mirroring the observation arm of the ESPAC-1 trial (3). In addition, early relapses, preceding the window of starting adjuvant chemotherapy, may have contributed to the dismal outcome in this type of patients. Independent prognostic factors (following multivariate regression analysis) in patients who did not receive adjuvant chemotherapy were differentiation grade and TNM stage.
Amongst patients who did receive adjuvant chemotherapy, median overall survival was 28.8 months, which is in line with outcomes reported in the literature (3–6). There was no numerical difference between the two most common chemotherapy regimens utilised (Gem and GemCape) as median overall survival was 28.1 months in both groups. It should however be noted that the Gem group made up the vast majority of the population treated with chemotherapy (n=239, 75% of those who received any type of chemotherapy) whereas just 39 patients (14%) received GemCape. Therefore, selection bias cannot be excluded and any inter-group comparisons should be made with greatest caution.
Independent prognostic factors remaining statistically significant following multivariate Cox regression analysis included TNM stage and DPD expression status in the Gem group, whereas no factors appeared statistically significant in the GemCape group of patients. Again, the relatively small number of subjects in the latter (meaning a low power to detect any significant findings) should prompt careful interpretation.
As other types of chemotherapy including 5-FU with folinic acid, FOLFIRINOX, and gemcitabine plus nab-paclitaxel were only sporadically given in this cohort (n<11 in each treatment group), no meaningful analyses of prognostic factors including DPD-high vs. low were possible to do within these subgroups.
The results of this study cannot be directly compared with previous results on intratumoural DPD expression in patients of the ESPAC3 randomised controlled trial (15), as this was a real world cohort where no strict inclusion or exclusion criteria nor any randomisation to various treatments were applied. In the ESPAC3 trial population, DPD appeared as an independent prognostic marker in the 5-FU treated arm of patients but not in the Gem arm (although a non-significant numerical difference was still evident). On the other hand, the Kondo study (16) on patients receiving a combination of S-1 and gemcitabine revealed that DPD was an independent prognostic marker, with high expression being linked with worse prognosis.
Whereas the present results indicate that DPD is an independent predictor of the outcome in PDAC patients treated with postoperative Gem, the cohort studied here cannot be used to answer whether guidance to any of the more intense multi-drug protocols with GemCape (5), Gemcitabine and Nab-paclitaxel (21), or FOLFIRINOX (6) would have been beneficial for patients with high expression of DPD. Although 39 patients in the present population were treated with GemCape, and no statistically significant factors were evident in the multivariate regression model, statistical power would not be sufficient to rule out any impact of DPD (or any of the other potentially prognostic markers) in this or any of the even smaller subgroups. In addition, it would be most relevant for a future prospective trial to explore whether the addition of a DPD inhibitor such as gimeracil, one of three active substances in the S-1 combination, might be able to override the negative impact of high levels of DPD in the tumour. In theory, such a Gem plus gimeracil combination might be particularly valuable in patients with high expression of DPD in their tumour.
The weaknesses of this study are mainly inherent to the retrospective study design, and as there was no randomisation to various treatment arms any inter-arm differences observed should be interpreted with caution. Selection of treatment is likely to have been affected by background patient factors and comorbidity status as well as postoperative recovery and occurrence of complications. During the studied period, the predominant adjuvant protocol was Gem, with a smaller proportion of patients being subjected to the more recent multi-drug regimens that are now available and generally recommended.
The main strengths include the long term and comprehensive multi-centre real-world approach, meaning that a large number of patients with PDAC undergoing curative intent resection in three major health care regions were included. Detailed clinical information was available and follow up time was sufficient to yield robust data on overall survival. To our knowledge, this is the largest real-world cohort of patients with resected PDAC treated with gemcitabine where DPD has been explored as a prognostic marker.
Future studies should focus on exploring the value of intratumoural DPD expression levels in patients undergoing adjuvant chemotherapy with contemporary multi-drug regimens, as well as exploring other potential enzymes and transport proteins involved in the metabolism and turnover of nucleic acids hence playing a potential role for sensitivity to-anti pyrimidine chemotherapeutics. Such candidate biomarkers include (but would not be limited to) thymidylate synthase, orotate phosphoribosyl transferase, cytidine deaminase, human equilibrative nucleoside transporter-1, and intratumoural human antigen all known to be involved in the turnover of antimetabolic chemotherapeutics (15,16,22–25). In addition, preclinical research will be necessary to dissect the mechanisms by which DPD and other metabolic enzymes affect the sensitivity to 5-FU, gemcitabine and other compounds.
Ideally, individual or panels of predictive biomarkers should be identified and explored as treatment guiding tools in a prospective trial setting, to establish algorithms for optimal adjuvant treatment strategies and drug(s) of choice in patients with localised PDAC undergoing surgical resection.
In conclusion, intratumoural DPD expression is an independent prognostic factor in patients with PDAC undergoing surgical resection followed by adjuvant gemcitabine. Additional studies of DPD as a potential predictive biomarker in cohorts of PDAC patients treated with gemcitabine and non-gemcitabine based multi-drug chemotherapy protocols are warranted.
Supplementary Material
Supporting Data
Acknowledgements
The authors would like to thank Ms. Lisa Kölhed and Ms. Liza Haglund (laboratory technicians, Department of Pathology, Linköping University Hospital, Sweden) who remoulded the paraffin blocks for this study, Dr Mats Fredrikson (Linköping University, Sweden) for statistical advice, and the late Dr Alkwin Wanders (Aalborg University Hospital, Denmark) who played a key role in the early work-up of this study.
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.
Availability of data and materials
The data generated in this study are available at reasonable request to the corresponding author.
Authors' contributions
Conceptualisation and design were performed by HB, PN, MS, CV, HG, BB, DÖ, SL, OF and NOE. HB, MB, FG, PN, MS, CV, DÖ, SL and OF constructed the TMA. HB, MB and FG were responsible for tissue management and preparation. Staining was performed by MB and FG, scoring by HB and NOE. Data analysis was conducted by HB, HG, BB, DÖ, SL, OF and NE. HB and NOE drafted the manuscript. HB and NOE confirm the authenticity of all the raw data. All authors contributed to, and read and approved the final version of the manuscript.
Ethics approval and consent to participate
This study was performed according to The Declaration of Helsinki and was approved by the Swedish Ethics Review Board (approval number 2020-01511). Due to the retrospective non-interventional nature of the study, the review board waived the need for informed consent.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
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