Existing risk scores appear insufficient to assess the individual survival risk of patients with advanced pancreatic ductal adenocarcinoma (PDAC) and do not take advantage of the variety of ...parameters that are collected during clinical care.
In this retrospective study, we built a random survival forest model from clinical data of 203 patients with advanced PDAC. The parameters were assessed before initiation of systemic treatment and included age, CA19-9, C-reactive protein, metastatic status, neutrophil-to-lymphocyte ratio and total serum protein level. Separate models including imaging and molecular parameters were built for subgroups.
Over the entire cohort, a model based on clinical parameters achieved a c-index of 0.71. Our approach outperformed the American Joint Committee on Cancer (AJCC) staging system and the modified Glasgow Prognostic Score (mGPS) in the identification of high- and low-risk subgroups. Inclusion of the KRAS p.G12D mutational status could further improve the prediction, whereas radiomics data of the primary tumor only showed little benefit. In an external validation cohort of PDAC patients with liver metastases, our model achieved a c-index of 0.67 (mGPS: 0.59).
The combination of multimodal data and machine-learning algorithms holds potential for personalized prognostication in advanced PDAC already at diagnosis.
•We developed a machine-learning-based prediction model that outperforms the AJCC staging system and mGPS.•Applying our model to an external validation cohort demonstrates generalizability.•Explainable machine learning enables to understand the decision making of our model and identifies relevant parameters.•Combining clinical, imaging and genetic data holds potential for personalized prognostication in advanced PDAC.
Pancreatic cancer has a dismal prognosis. One reason is resistance to cytotoxic drugs. Molecularly matched therapies might overcome this resistance but the best approach to identify those patients ...who may benefit is unknown. Therefore, we sought to evaluate a molecularly guided treatment approach.
We retrospectively analyzed the clinical outcome and mutational status of patients with pancreatic cancer who received molecular profiling at the West German Cancer Center Essen from 2016 to 2021. We carried out a 47-gene DNA next-generation sequencing (NGS) panel. Furthermore, we assessed microsatellite instability-high/deficient mismatch repair (MSI-H/dMMR) status and, sequentially and only in case of KRAS wild-type, gene fusions via RNA-based NGS. Patient data and treatment were retrieved from the electronic medical records.
Of 190 included patients, 171 had pancreatic ductal adenocarcinoma (90%). One hundred and three patients had stage IV pancreatic cancer at diagnosis (54%). MMR analysis in 94 patients (94/190, 49.5%) identified 3 patients with dMMR (3/94, 3.2%). Notably, we identified 32 patients with KRAS wild-type status (16.8%). To identify driver alterations in these patients, we conducted an RNA-based fusion assay on 13 assessable samples and identified 5 potentially actionable fusions (5/13, 38.5%). Overall, we identified 34 patients with potentially actionable alterations (34/190, 17.9%). Of these 34 patients, 10 patients (10/34, 29.4%) finally received at least one molecularly targeted treatment and 4 patients had an exceptional response (>9 months on treatment).
Here, we show that a small-sized gene panel can suffice to identify relevant therapeutic options for pancreatic cancer patients. Informally comparing with previous large-scale studies, this approach yields a similar detection rate of actionable targets. We propose molecular sequencing of pancreatic cancer as standard of care to identify KRAS wild-type and rare molecular subsets for targeted treatment strategies.
•Combining a 47-gene NGS panel and a gene fusion panel may yield similar results as broader NGS panels in pancreatic cancer.•In case of KRAS wild-type, the RNA-based fusion assay found an actionable fusion in 38.5%.•Targeted therapy of pancreatic cancer patients can yield exceptional responses of >9 months on treatment.
Purpose
Despite recent advances in clinical imaging modalities, differentiation of pancreatic masses remains difficult. Here, we tested the diagnostic accuracy of molecular-based imaging including ...3′-deoxy-3′-
18
Ffluorothymidine (FLT) positron emission tomography (PET) and
18
Ffluorodeoxyglucose (FDG) PET/CT in patients with suspected pancreatic masses scheduled to undergo surgery.
Methods
A total of 46 patients with pancreatic tumours suspicious for malignancy and scheduled for resective surgery were recruited prospectively. In 41 patients, FLT PET and FDG PET/CT scans were performed. A diagnostic CT performed on a routine basis was available in 31 patients. FLT PET and FDG PET/CT emission images were acquired according to standard protocols. Tracer uptake in the tumour FDG and FLT standardized uptake value (SUV) was quantified by the region of interest (ROI) technique. For FDG PET/CT analysis, correct ROI placement was ensured via side-by-side reading of corresponding CT images.
Results
Of 41 patients, 33 had malignancy, whereas 8 patients had benign disease. Visual analysis of FDG and FLT PET resulted in sensitivity values of 91% (30/33) and 70% (23/33), respectively. Corresponding specificities were 50% (4/8) for FDG PET and 75% (6/8) for FLT PET. In the subgroup of patients with contrast-enhanced CT (
n
= 31), sensitivities were 96% (PET/CT), 88% (CT alone), 92% (FDG PET) and 72% (FLT PET), respectively. Mean FLT uptake in all malignant tumours was 3.0 (range SUV
max
1.1–6.5; mean FDG SUV
max
7.9, range 3.3–17.8;
p
< 0.001).
Conclusion
For differentiation of pancreatic tumours, FDG PET and FDG PET/CT showed a higher sensitivity but lower specificity than FLT PET. Interestingly, visual analysis of FLT PET led to two false-positive findings by misinterpreting physiological bowel uptake as pathological FLT uptake in the pancreas. Due to the limited number of patients, the clinical value of adding FLT PET to the diagnostic workup of pancreatic tumours remains to be determined.
Background: Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease still lacking effective therapeutic strategies. PDAC is initiated by oncogenic KRAS and relies on its downstream target ...Ras-related C3 botulinum toxin substrate 1 (RAC1). RAC1 is a therapeutic target in melanoma, leukemia and lymphoma. Here we investigate the therapeutic potential of RAC1 as a molecular target in PDAC. We used the small molecule inhibitor EHT1864 together with the standard therapeutic drug gemcitabine to inhibit RAC1 activity in endogenous genetically engineered mouse model of PDAC. Material and Methods: Two inhibitors of RAC1 activation. EHT1864 (EHT) and NSC2376 (NSC) were used alone and in combination with gemcitabine to assess cell proliferation using murine and human PDAC cell lines. Inhibition of RAC1 activity was verified using pull down assay in vitro and in vivo. A cohort of Ptf1awt/cre;Kraswt/LSL-KrasG12D;p53fl/fl (CKP) mice (NNaCI = 16, NGem = 20, NEHT+Gem = 12) was enrolled in this study when harboring a tumor of (300 mm3) measured by T2-weighted MRI sequence (Philips Achieva 1.5T). CKP mice either received a single therapy of gemcitabine (Gem) or mock (NaCI) {120mg/kg by intraperitoneal (i.p.) injection, 4 doses at days 0, 3, 7 and 10) or combinatorial treatment of gemcitabine (100mg/kg i.p. twice a week) together with EHT1864 (EHT+Gem) (80 mg/kg subcutaneously daily) over 3 weeks. Results: EHT1864 inhibited tumor cell growth of murine PDAC cell lines six times better than NSC2376 (IC50EHT =25µM, IC50NSC = 159µM). Both inhibitors acted additive with gemcitabine. Therefore a combination of EHT1864 and gemcitabine was chosen for treatment of CKP mice. This regiment led to a reduced overall tumor load (mean relative volume change: VNaCI = 51±40%; VGem=44±63%; VGem+EHT = 26±27%) and to a significant survival benefit compared to mock treated group (median survival: MSNaci = 23 days, MSGem+EHT = 31 days. P = 0.04), however not in comparison to gemcitabine treated cochort (MSGem = 21 days, P = 0.26). Moreover, mice treated with the combination of EHT1864 and gemcitabine developed significantly less undifferentiated (e.g. sarcomatoid, mesenchymal-like) tumors compared to the control (8% in EHT1864/gemcitabine vs. 25% in each of the control groups). Notably, EHT1864 inhibited cell proliferation of both murine and human mesenchymal-like PDAC cell lines twice more effectively than it did in the epithelial ones (murine: IC50m=23µM, IC50e = 44µM, P = 0.002; human: IC50m = 22µM, IC50e = 46µM, P = 0.02). Conclusions: Activation of RAC1 is required for the proliferation of mesenchymal-like PDAC cells and could be used as a marker for stratification of targeted therapy of PDAC.
Pulmonary metastasis (M1-PUL) as first site of dissemination in pancreatic ductal adenocarcinoma (PDAC) is a rare event and may define a distinct biological subgroup.
Arbeitsgemeinschaft ...Internistische Onkologie-Young Medical Oncologists-Pankreas-0515 study (AIO-YMO-PAK-0515) was a retrospective German multicenter study investigating clinical and molecular characteristics of M1-PUL PDAC patients; 115 M1-PUL PDAC patients from 7 participating centers were included. Clinical characteristics and potential prognostic factors were defined within the M1-PUL cohort. Archival tumor samples were analyzed for Her2/neu, HNF1A and KRT81 expression. Additionally, messenger RNA (mRNA) expression analysis (using a 770-gene immune profiling panel) was carried out in the M1-PUL and in a control cohort (M1-ANY).
Median overall survival in the entire M1-PUL cohort was 20 months; the most favorable prognosis (median survival: 28 months) was observed in the subgroup of 66 PDAC patients with metachronous lung metastases after previous curative-intent surgery. The number of metastatic lesions, uni- or bilateral lung involvement as well as metastasectomy were identified as potential prognostic factors. Her2/neu expression and PDAC subtyping (by HNF1A and KRT81) did not differ between the M1-PUL and the M1-ANY cohort. mRNA expression analysis revealed significant differentially expressed genes between both cohorts: CD63 and LAMP1 were among the top 20 differentially expressed genes and were identified as potential mediators of organotropism and favorable survival outcome of M1-PUL patients.
M1-PUL represents a clinically favorable cohort in PDAC patients. Site of relapse might already be predetermined at the time of surgery and could potentially be predicted by gene expression profiling.
•The retrospective multicenter AIO-YMO-PAK-0515 study defines M1-PUL as a clinically favorable subgroup in PDAC.•The number of metastatic lesions, bilateral lung involvement and surgical metastasectomy may serve as prognostic factors.•Immune-related gene expression differs between patients with isolated pulmonary relapse versus other sites of relapse.
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