| 1. |
- Khomiak, Andrii, et al.
(författare)
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Recent Discoveries of Diagnostic, Prognostic and Predictive Biomarkers for Pancreatic Cancer
- 2020
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Ingår i: Cancers. - : MDPI. - 2072-6694. ; 12:11
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Forskningsöversikt (refereegranskat)abstract
- Simple Summary Biomarkers for cancer diagnosis, prognosis and prediction are important tools and an urgent need in precision medicine for pancreatic cancer. In recent years, many experimental and clinical studies aimed at identifying new biomarkers for pancreatic ductal adenocarcinoma. In the review, we summarized current investigations on using novel protein markers, cell-free DNA, metabolome compounds, immune and stroma signatures and microbiome compositions as biomarkers for pancreatic cancer. Our comprehensive overview shows that although there are new promising biomarkers, CA 19-9 remains currently the only regularly used and validated biomarker for pancreatic cancer in clinical routine. Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with a dismal prognosis that is frequently diagnosed at an advanced stage. Although less common than other malignant diseases, it currently ranks as the fourth most common cause of cancer-related death in the European Union with a five-year survival rate of below 9%. Surgical resection, followed by adjuvant chemotherapy, remains the only potentially curative treatment but only a minority of patients is diagnosed with locally resectable, non-metastatic disease. Patients with advanced disease are treated with chemotherapy but high rates of treatment resistance and unfavorable side-effect profiles of some of the used regimens remain major challenges. Biomarkers reflect pathophysiological or physiological processes linked to a disease and can be used as diagnostic, prognostic and predictive tools. Thus, accurate biomarkers can allow for better patient stratification and guide therapy choices. Currently, the only broadly used biomarker for PDAC, CA 19-9, has multiple limitations and the need for novel biomarkers is urgent. In this review, we highlight the current situation, recent discoveries and developments in the field of biomarkers of PDAC and their potential clinical applications.
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| 2. |
- Kordes, Maximilian
(författare)
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Diagnostic and predictive factors in pancreatic cancer : clinical and translational studies
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Aims: The aim of Study I was to assess the effectiveness of chemotherapy for patients with advanced pancreatic cancer in a real-world setting. Study II aimed to evaluate the utility of a clinical decision support system to identify precision oncology opportunities for pancreatic cancer. The aim of Study III was to identify the blood component most enriched with pancreatic cancer-derived circulating DNA; that of Study IV was to characterize long and short tumor-derived circulating DNA fragments. Methods: Study I is a single-institution retrospective cohort study of prospectively generated clinical data. We included a total of 595 patients and used univariate and multivariate models, including flexible parametric models to analyze overall survival and time to treatment failure according to different first-line chemotherapy regimens. Exploratory analyses included the adherence to different protocols, adverse events, and second-line chemotherapy. Study II is a prospective observational study of 39 patients with pancreatic cancer who were enrolled in the PePaCaKa-01 study. Archival tumor tissue was sequenced, and data was processed with the proprietary clinical decision support system MH Guide and results were evaluated by a study-specific molecular tumor board. Endpoints of the study were the frequency of successful generation of support system reports, the frequency of actionable molecular targets, and their evaluation by the tumor board. We performed a post-hoc analysis to determine the proportion of patients who received molecular informed therapies. Studies III– IV analyzed blood samples from a prospective cohort of patients with advanced pancreatic cancer. We systematically separated whole blood into red and white blood cells, platelets, apoptotic bodies, large and small extracellular vesicles, and soluble protein using differential centrifugation. We confirmed efficient separation with protein assays (Western blotting and multiplex bead-based extracellular vesicle flow cytometry), nanoparticle tracking analysis and transmission electron microscopy, and extracted DNA from all components. We used digital PCR to quantify the abundance of KRASmut DNA, a hallmark of pancreatic cancerderived DNA. In Study IV we additionally used automated electrophoresis to quantify the lengths of circulating DNA fragments and ligation-based sequencing library preparation and tagmentation to selectively target short and long DNA fragments, respectively. Results: In Study I, we observed similar overall survival for gemcitabine/capecitabine, gemcitabine/nab-paclitaxel, and FOLFIRINOX (including modified regimens) compared to gemcitabine. Combinations of 5-fluorouracil/oxaliplatin and best supportive care were associated with poorer outcomes. Models adjusting for other demographic and clinical variables showed a survival benefit for gemcitabine-combinations and FOLFIRINOX. Exploratory analyses revealed differences in protocol adherence across different treatments, a relatively low frequency of AEs, and a difference between different sequences of first- and second-line therapy. In Study II, a CDSS report was generated for 31/39 patients, 28/31 reports were evaluated at the study-specific molecular tumor board The clinical decision support system made 80 individual recommendations to use molecularly informed therapies based on 61 genomic variants. In 21/28 cases, the tumor board classified at least one molecularly informed therapy as a potential clinical option. The post-hoc analysis revealed that six patients received molecularly informed treatment in routine care. In Study III, KRASmut DNA had the highest concentrations in the soluble protein and small vesicles blood fractions at late stages of PDAC. At early stages, it was highest in large and small extracellular vesicles. Small extracellular vesicles also contained the highest ratio of the concentrations of mutant : wild type KRAS DNA at this stage. In Study IV, blood from PDAC patients had significantly higher concentrations of short cell-free DNA in the soluble protein fraction than that of healthy individuals. The mutant allele frequency of KRASmut was highest in this blood component. Long genomic DNA fragments were most reliably measured in association with apoptotic bodies but KRASmut genomic DNA occurred in all assessed blood fractions. Conclusions: Chemotherapy in clinical routine use can result in outcomes that reflect relevant randomized controlled trials and gemcitabine-based regimens are highly effective this setting. Differences between different treatments might be related to how they are applied (Study I). The clinical decision support system MH Guide could identify clinically relevant opportunities for molecularly informed treatments of advanced pancreatic cancer (Study II). At early stages of pancreatic cancer, tumor-derived DNA is mostly associated with small extracellular vesicles; in more advanced disease it is mainly a feature of the soluble protein fraction (Study III). Short DNA fragments in this fraction are a more robust source of tumorderived DNA than longer genomic DNA fragments (Study IV).
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| 3. |
- Labori, Knut Jørgen, et al.
(författare)
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Neoadjuvant FOLFIRINOX versus upfront surgery for resectable pancreatic head cancer (NORPACT-1) : a multicentre, randomised, phase 2 trial
- 2024
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Ingår i: The Lancet Gastroenterology & Hepatology. - : The Lancet Group. - 2468-1253. ; 9:3, s. 205-217
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundIn patients undergoing resection for pancreatic cancer, adjuvant modified fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) improves overall survival compared with alternative chemotherapy regimens. We aimed to compare the efficacy and safety of neoadjuvant FOLFIRINOX with the standard strategy of upfront surgery in patients with resectable pancreatic ductal adenocarcinoma.MethodsNORPACT-1 was a multicentre, randomised, phase 2 trial done in 12 hospitals in Denmark, Finland, Norway, and Sweden. Eligible patients were aged 18 years or older, with a WHO performance status of 0 or 1, and had a resectable tumour of the pancreatic head radiologically strongly suspected to be pancreatic adenocarcinoma. Participants were randomly assigned (3:2 before October, 2018, and 1:1 after) to the neoadjuvant FOLFIRINOX group or upfront surgery group. Patients in the neoadjuvant FOLFIRINOX group received four neoadjuvant cycles of FOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, leucovorin 400 mg/m2, and fluorouracil 400 mg/m2 bolus then 2400 mg/m2 over 46 h on day 1 of each 14-day cycle), followed by surgery and adjuvant chemotherapy. Patients in the upfront surgery group underwent surgery and then received adjuvant chemotherapy. Initially, adjuvant chemotherapy was gemcitabine plus capecitabine (gemcitabine 1000 mg/m2 over 30 min on days 1, 8, and 15 of each 28-day cycle and capecitabine 830 mg/m2 twice daily for 3 weeks with 1 week of rest in each 28-day cycle; four cycles in the neoadjuvant FOLFIRINOX group, six cycles in the upfront surgery group). A protocol amendment was subsequently made to permit use of adjuvant modified FOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 150 mg/m2, leucovorin 400 mg/m2, and fluorouracil 2400 mg/m2 over 46 h on day 1 of each 14-day cycle; eight cycles in the neoadjuvant FOLFIRINOX group, 12 cycles in the upfront surgery group). Randomisation was performed with a computerised algorithm that stratified for each participating centre and used a concealed block size of two to six. Patients, investigators, and study team members were not masked to treatment allocation. The primary endpoint was overall survival at 18 months. Analyses were done in the intention-to-treat (ITT) and per-protocol populations. Safety was assessed in all patients who were randomly assigned and received at least one cycle of neoadjuvant or adjuvant therapy. This trial is registered with ClinicalTrials.gov, NCT02919787, and EudraCT, 2015-001635-21, and is ongoing.FindingsBetween Feb 8, 2017, and April 21, 2021, 77 patients were randomly assigned to receive neoadjuvant FOLFIRINOX and 63 to undergo upfront surgery. All patients were included in the ITT analysis. For the per-protocol analysis, 17 (22%) patients were excluded from the neoadjuvant FOLFIRINOX group (ten did not receive neoadjuvant therapy, four did not have pancreatic ductal adenocarcinoma, and three received another neoadjuvant regimen), and eight (13%) were excluded from the upfront surgery group (seven did not have pancreatic ductal adenocarcinoma and one did not undergo surgical exploration). 61 (79%) of 77 patients in the neoadjuvant FOLFIRINOX group received neoadjuvant therapy. The proportion of patients alive at 18 months by ITT was 60% (95% CI 49–71) in the neoadjuvant FOLFIRINOX group versus 73% (62–84) in the upfront surgery group (p=0·032), and median overall survival by ITT was 25·1 months (95% CI 17·2–34·9) versus 38·5 months (27·6–not reached; hazard ratio [HR] 1·52 [95% CI 1·00–2·33], log-rank p=0·050). The proportion of patients alive at 18 months in per-protocol analysis was 57% (95% CI 46–67) in the neoadjuvant FOLFIRINOX group versus 70% (55–83) in the upfront surgery group (p=0·14), and median overall survival in per-protocol population was 23·0 months (95% CI 16·2–34·9) versus 34·4 months (19·4–not reached; HR 1·46 [95% CI 0·99–2·17], log-rank p=0·058). In the safety population, 42 (58%) of 73 patients in the neoadjuvant FOLFIRINOX group and 19 (40%) of 47 patients in the upfront surgery group had at least one grade 3 or worse adverse event. 63 (82%) of 77 patients in the neoadjuvant group and 56 (89%) of 63 patients in the upfront surgery group had resection (p=0·24). One sudden death of unknown cause and one COVID-19-related death occurred after the first cycle of neoadjuvant FOLFIRINOX. Adjuvant chemotherapy was initiated in 51 (86%) of 59 patients with resected pancreatic ductal adenocarcinoma in the neoadjuvant FOLFIRINOX group and 44 (90%) of 49 patients with resected pancreatic ductal adenocarcinoma in the upfront surgery group (p=0·56). Adjuvant modified FOLFIRINOX was given to 13 (25%) patients in the neoadjuvant FOLFIRINOX group and 19 (43%) patients in the upfront surgery group. During adjuvant chemotherapy, neutropenia (11 [22%] patients in the neoadjuvant FOLFIRINOX group and five [11%] in the upfront surgery group) was the most common grade 3 or worse adverse event.InterpretationThis phase 2 trial did not show a survival benefit from neoadjuvant FOLFIRINOX in resectable pancreatic ductal adenocarcinoma compared with upfront surgery. Implementation of neoadjuvant FOLFIRINOX was challenging. Future trials on treatment sequencing in resectable pancreatic ductal adenocarcinoma should be biomarker driven.
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