Olaparib not cost-effective as maintenance therapy for platinum-sensitive, BRCA1/2 germline-mutated metastatic pancreatic cancer.

OBJECTIVE: To assess the cost-effectiveness and budget impact of olaparib as a maintenance therapy in platinum-responsive, metastatic pancreatic cancer patients harboring a germline BRCA1/2 mutation, using the Swiss context as a model. METHODS: Based on data from the POLO trial, published literature and local cost data, we developed a partitioned survival model of olaparib maintenance including full costs for BRCA1/2 germline testing compared to FOLFIRI maintenance chemotherapy and watch-and-wait. We calculated the incremental cost-effectiveness ratio (ICER) for the base case and several scenario analyses and estimated 5-year budget impact. RESULTS: Comparing olaparib with watch-and wait and maintenance chemotherapy resulted in incremental cost-effectiveness ratios of CHF 2,711,716 and CHF 2,217,083 per QALY gained, respectively. The 5-year costs for the olaparib strategy in Switzerland would be CHF 22.4 million, of which CHF 11.4 million would be accounted for by germline BRCA1/2 screening of the potentially eligible population. This would amount to a budget impact of CHF 15.4 million (USD 16.9 million) versus watch-and-wait. CONCLUSIONS: Olaparib is not a cost-effective maintenance treatment option. Companion diagnostics are an equally important cost driver as the drug itself.

A Randomized Trial of Two Remote Health Care Delivery Models on the Uptake of Genetic Testing and Impact on Patient-Reported Psychological Outcomes in Families With Pancreatic Cancer: The Genetic Education, Risk Assessment, and Testing (GENERATE) Study.

BACKGROUND & AIMS: Genetic testing uptake for cancer susceptibility in family members of patients with cancer is suboptimal. Among relatives of patients with pancreatic ductal adenocarcinoma (PDAC), The GENetic Education, Risk Assessment, and TEsting (GENERATE) study evaluated 2 online genetic education/testing delivery models and their impact on patient-reported psychological outcomes. METHODS: Eligible participants had ≥1 first-degree relative with PDAC, or ≥1 first-/second-degree relative with PDAC with a known pathogenic germline variant in 1 of 13 PDAC predisposition genes. Participants were randomized by family, between May 8, 2019, and June 1, 2021. Arm 1 participants underwent a remote interactive telemedicine session and online genetic education. Arm 2 participants were offered online genetic education only. All participants were offered germline testing. The primary outcome was genetic testing uptake, compared by permutation tests and mixed-effects logistic regression models. We hypothesized that Arm 1 participants would have a higher genetic testing uptake than Arm 2. Validated surveys were administered to assess patient-reported anxiety, depression, and cancer worry at baseline and 3 months postintervention. RESULTS: A total of 424 families were randomized, including 601 participants (n = 296 Arm 1; n = 305 Arm 2), 90% of whom completed genetic testing (Arm 1 [87%]; Arm 2 [93%], P = .014). Arm 1 participants were significantly less likely to complete genetic testing compared with Arm 2 participants (adjusted ratio [Arm1/Arm2] 0.90, 95% confidence interval 0.78-0.98). Among participants who completed patient-reported psychological outcomes questionnaires (Arm 1 [n = 194]; Arm 2 [n = 206]), the intervention did not affect mean anxiety, depression, or cancer worry scores. CONCLUSIONS: Remote genetic education and testing can be a successful and complementary option for delivering genetics care. (Clinicaltrials.gov, number NCT03762590).

CKS1B as a potential target for prognostic assessment and intervention in pancreatic cancer and its role in abnormal proliferation and cellular phenotype through mediation of cell cycle signaling pathways.

OBJECTIVES: To investigate the role of cell cycle protein-dependent kinase regulatory subunit 1B (CKS1B) in driving the aggressive and rapid proliferation observed in pancreatic cancer. METHODS: A comprehensive analysis was carried out using raw mRNA information and data from 2 databases: the cancer genome atlas and gene expression omnibus. The differential expression of CKS1B at the mRNA and tissue levels in cancer and adjacent paracancerous tissues were assessed. Additionally, the relationship of CKS1B expression and overall survival (OS) rate was investigated using Kaplan-Meier survival curves. Potential molecular mechanisms by which CKS1B may influence the biological characteristics of pancreatic cancer were explored using resources available within the encyclopedia of RNA interactomes database. RESULTS: The CKS1B exhibited significant differential expression at the mRNA as well as protein levels. A correlation with statistical significance between CKS1B expression and N stage, age, and alcohol consumption was observed. Notably, high CKS1B expression was determined as a predictive factor for worse OS. Furthermore, the analysis revealed a potential synergistic role between CKS1B and the molecule PKMYT1, which could impact the ATR-Chk1-Cdc25 signaling pathway and disrupt the G2/M checkpoint within the cell cycle, ultimately promoting abnormal tumor proliferation. CONCLUSION: The CKS1B may serve as a novel potential prognostic factor in pancreatic cancer and is involved in the abnormal proliferation biology phenotype by mediating cell cycle signaling pathways.

Short-term serial circulating tumor DNA assessment predicts therapeutic efficacy for patients with advanced pancreatic cancer.

PURPOSE: We investigated the potential clinical utility of short-term serial KRAS-mutated circulating cell-free tumor DNA (ctDNA) assessment for predicting therapeutic response in patients undergoing first-line chemotherapy for advanced pancreatic cancer. METHODS: We collected 144 blood samples from 18 patients with locally advanced or metastatic cancer that were undergoing initial first-line chemotherapy of gemcitabine plus nab-paclitaxel (GEM plus nab-PTX). Analysis of KRAS-mutated ctDNA was quantified by digital droplet polymerase chain reaction (ddPCR) as mutant allele frequency (MAF). This study investigated pretreatment KRAS-mutated ctDNA status and ctDNA kinetics every few days (days 1, 3, 5 and 7) after initiation of chemotherapy and their potential as predictive indicators. RESULTS: Of the 18 enrolled patients, an increase in KRAS-mutated ctDNA MAF values from day 0-7 after initiation of chemotherapy was significantly associated with disease progression (P < 0.001). Meanwhile, positive pretreatment ctDNA status (MAF ≥ 0.02%) (P = 0.585) and carbohydrate antigen 19-9 (CA19-9) values above the median (P = 0.266) were not associated with disease progression. In univariate analysis, this short-term increase in ctDNA MAF values (day 0-7) was found to be associated with significantly shorter progression free survival (PFS) (hazard ration [HR], 24.234; range, (2.761-212.686); P = 0.0002). CONCLUSION: This short-term ctDNA kinetics assessment may provide predictive information to reflect real-time therapeutic response and lead to effective refinement of regimen in patients with advanced pancreatic cancer undergoing systemic chemotherapy.

The Use of Integrated Molecular Testing in the Assessment and Management of Pancreatic Cysts.

PURPOSE OF REVIEW: As abdominal imaging becomes more sensitive and regularly used, pancreatic cystic lesions (PCLs) are being diagnosed more frequently. A small but clinically significant minority of these lesions have a predisposition to either harbor malignancy or undergo malignant transformation. This review highlights the current state and performance of cystic fluid biomarkers and how they may be incorporated into management. RECENT FINDINGS: Among the major domains of molecular testing for PCLs, DNA based analyses have demonstrated the highest accuracy in identifying cyst type and have the most data to support their clinical use. However, epigenetic and protein biomarker based molecular assessments have emerged with the potential to complement DNA based approaches. In addition, recent studies have increasingly demonstrated the value associated with combinations of mutations and other biomarkers in identifying higher grade mucinous cystic lesions. We present the performance of individual biomarkers in cyst fluid analysis with an emphasis on an algorithmic approach to improve the accurate identification of both cyst type and risk of malignant transformation.

Olaparib versus Placebo in Maintenance Treatment of Germline BRCA-Mutated Metastatic Pancreatic Cancer: A Cost-Utility Analysis from the Canadian Public Payer's Perspective.

Pancreatic cancer has an annual incidence of 2/10,000 in Canada, with a one-year mortality rate greater than 80%. In the absence of a cost-effectiveness analysis in Canada, this study's objective was to assess the cost-effectiveness of olaparib versus a placebo in adult patients with deleterious or suspected deleterious BRCA metastatic pancreatic adenocarcinoma, who did not show any progression for at least 16 weeks with first-line platinum-based chemotherapy. A partitioned survival model with a 5-year time horizon was adopted to estimate the costs and effectiveness. All of the costs were extracted from the public payer's available resources, effectiveness data were obtained from the POLO trial, and Canadian studies were used for utility inputs. Probabilistic sensitivity analyses and scenario analyses were performed. The total costs of olaparib and the placebo over five years were CAD 179,477 and CAD 68,569, with overall quality-adjusted life-years (QALYs) of 1.70 and 1.36, respectively. The incremental cost-effectiveness ratio (ICER) of the olaparib group compared with the placebo was CAD 329,517 per QALY. With a commonly cited willingness to pay (WTP) threshold of CAD 50,000 per QALY, the drug does not achieve acceptable cost-effectiveness mainly due to the high price of the medication and insufficient impact on the overall survival of patients with metastatic pancreatic cancer.

Circulating tumor DNA in molecular assessment feasibly predicts early progression of pancreatic cancer that cannot be identified via initial imaging.

Molecular assessment using circulating tumor DNA (ctDNA) has not been well-defined. We recruited 61 pancreatic cancer (PC) patients who underwent initial computed tomography (CT) imaging study during first-line chemotherapy. Initial molecular assessment was performed using droplet digital PCR and defined as the change in KRAS-mutated ctDNA before and after treatments, which was classified into five categories: mNT, molecular negative; mCR, complete response; mPR, partial response; mSD, stable disease; mPD, progressive disease. Of 61 patients, 14 diagnosed with PD after initial CT imaging showed significantly worse therapeutic outcomes than 47 patients with disease control. In these 47 patients, initial molecular assessment exhibited significant differences in therapeutic outcomes between patients with and without ctDNA (mPD + mSD vs. mCR + mNT; 13.2 M vs. 21.7 M, P = 0.0029) but no difference between those with mPD and mSD + mCR + mNT, suggesting that the presence of ctDNA had more impact on the therapeutic outcomes than change in its number. Multivariate analysis revealed that it was the only independent prognostic factor (P = 0.0405). The presence of ctDNA in initial molecular assessment predicted early tumor progression and identified PC patients more likely to benefit from chemotherapy.

Cost-effectiveness of pancreas surveillance: The CDKN2A-p16-Leiden cohort.

BACKGROUND: CDKN2A-p16-Leiden mutation carriers have a high lifetime risk of developing pancreatic ductal adenocarcinoma (PDAC), with very poor survival. Surveillance may improve prognosis. OBJECTIVE: To assess the cost-effectiveness of surveillance, as compared to no surveillance. METHODS: In 2000, a surveillance program was initiated at Leiden University Medical Center with annual MRI and optional endoscopic ultrasound. Data were collected on the resection rate of screen-detected tumors and on survival. The Kaplan-Meier method and a parametric cure model were used to analyze and compare survival. Based on the surveillance and survival data from the screening program, a state-transition model was constructed to estimate lifelong outcomes. RESULTS: A total of 347 mutation carriers participated in the surveillance program. PDAC was detected in 31 patients (8.9%) and the tumor could be resected in 22 patients (71.0%). Long-term cure among patients with resected PDAC was estimated at 47.1% (p < 0.001). The surveillance program was estimated to reduce mortality from PDAC by 12.1% and increase average life expectancy by 2.10 years. Lifelong costs increased by €13,900 per patient, with a cost-utility ratio of €14,000 per quality-adjusted life year gained. For annual surveillance to have an acceptable cost-effectiveness in other settings, lifetime PDAC risk needs to be 10% or higher. CONCLUSION: The tumor could be resected in most patients with a screen-detected PDAC. These patients had considerably better survival and as a result annual surveillance was found to be cost-effective.

Role of Up-Regulated Transmembrane Channel-Like Protein 5 in Pancreatic Adenocarcinoma.

BACKGROUND: Pancreatic adenocarcinoma (PAAD) is a malignant tumor responsible for a heavy disease burden. Previously, only one pan-cancer study of Transmembrane channel-like protein 5 (TMC5) showed that TMC5 was highly expressed in PAAD, but the results lacked comprehensive verification, and the mechanism of TMC5 in PAAD was still unclear. METHODS: For exploring the expression and clinical value of TMC5 in PAAD better, we adopted a comprehensive evaluation method, using internal immunohistochemistry (IHC) data combined with microarray and RNA-sequencing data collected from public databases. The single cell RNA-sequencing (scRNA-seq) data were exploited to explore the TMC5 expression in cell populations and intercellular communication. The potential mechanism of TMC5 in PAAD was analyzed from the aspects of immune infiltration, transcriptional regulation, function and pathway enrichment. RESULTS: Our IHC data includes 148 PAAD samples and 19 non-PAAD samples, along with the available microarray and RNA-sequencing data (1166 PAAD samples, 704 non-PAAD samples). The comprehensive evaluation results showed that TMC5 was evidently up-regulated in PAAD (SMD = 1.17). Further analysis showed that TMC5 was over-expressed in cancerous epithelial cells. Furthermore, TMC5 was up-regulated in more advanced tumor T and N stages. Interestingly, we found that STAT3 as an immune marker of Th17 cells was not only positively correlated with TMC5 and up-regulated in PAAD tissues, but also the major predicted TMC5 transcription regulator. Moreover, STAT3 was involved in cancer pathway of PAAD. CONCLUSION: Up-regulated TMC5 indicates advanced tumor stage in PAAD patients, and its role in promoting PAAD development may be regulated by STAT3.

Model-based screening for pancreatic cancer in Sweden.

BACKGROUND: Detecting pancreatic cancer at an earlier stage may contribute to an increased survival. Patients with stage I pancreatic cancer have a 5-year survival rate of 36%, while stage IV patients have a 5-year survival rate of 1% in Sweden. Research into novel blood-based biomarkers for pancreatic cancer is highly intensive and innovative, but has yet to result in any routine screening test. The aim of this study was to evaluate the specificity and sensitivity of a hypothetical blood test for pancreatic cancer used for screening purposes and the economic aspects of testing. METHOD: A model of a screening test was created, with varying specificity and sensitivity both set at 80%, 85%, 90%, 95% or 99% and applied to selected risk groups. Excessive costs of false positive screening outcomes, QALYs, ICERs and total costs were calculated. RESULTS: Individuals with family history and genetic mutations associated with pancreatic cancer, new-onset diabetes ≥50 years of age and early symptoms had the highest positive predictive values and ICERs beneath the willingness-to-pay-level of EUR 100,000/QALY. Screening of the general population and smokers resulted in a high rate of false positive cases and extensive extra costs. CONCLUSIONS: General screening for pancreatic cancer is not cost-effective, while screening of certain high-risk groups may be economically justified given the availability of a high-performing blood-based test.

Cost-effectiveness of MicroRNA for Pancreatic Cancer Screening in Patients With Diabetes.

OBJECTIVES: The study aimed to assess the cost-effectiveness of microRNA compared with carbohydrate antigen 19-9, abdominal ultrasound, magnetic resonance imaging, endoscopic ultrasound, computed tomography, positron emission tomography, and no screening for pancreatic cancer (PC) screening in patients with diabetes. METHODS: We developed a state-transition model from a health care payer perspective and a lifetime horizon. We targeted 3 hypothetical cohorts of patients with long-standing type 2 diabetes (LSD), new-onset diabetes (NOD), and LSD having intraductal papillary mucinous neoplasm (IPMN), aged 40, 50, 60, and 70 years. The main outcomes were costs, quality-adjusted life-years, life expectancy life-years, incremental cost-effectiveness ratios, and deaths from PC. RESULTS: In the base-case analysis, abdominal ultrasound in patients with LSD and microRNA in patients with NOD and LSD having IPMN were the most cost-effective for all age groups. Cost-effectiveness was sensitive to PC incidence and the cost of microRNA. Probabilistic sensitivity analysis showed that microRNA was 42% to 54% cost-effective for NOD and 76% to 78% cost-effective for LSD having IPMN at a willingness-to-pay level of US $100,000 per quality-adjusted life-year gained. MicroRNA prevented 30,641 PC deaths in diabetic patients compared with no screening. CONCLUSIONS: In patients with NOD and LSD having IPMN, microRNA-based PC screening is cost-effective and recommended for early PC detection.

Cohort profile and heritability assessment of familial pancreatic cancer: a nation-wide study.

BACKGROUND: Familial Pancreatic Cancer (FPC) is responsible for up to 10% of all cases of pancreatic ductal adenocarcinoma (PDAC). Individuals predisposed for FPC have an estimated lifetime risk of 16-39% of developing PDAC. While heritability of PDAC has been estimated to be 36% in a Nordic twin study, no heritability estimate specific on FPC has been reported. METHODS: A national cohort of Danish families with predisposition for FPC is currently included in a screening program for PDAC at Odense University Hospital. Family members included in the screening program were interviewed for pedigree data including: cases of PDAC among first-degree relatives (FDRs) and number of affected/unaffected siblings. Heritability for FPC in the predisposed families was assessed by doubling the estimated intra-class correlation coefficient (ICC) from a random intercept logistic model fitted to data on FDRs. RESULTS: Among families with predisposition for FPC, 83 cases of PDAC were identified. The median age at diagnosis of PDAC was 66 years, and median time from diagnosis to death was 7.6 months. A total of 359 individuals were found as unaffected FDRs of the 83 PDAC cases. The retrieved FDRs included a total of 247 individuals in sibship and 317 individuals in parent-offspring relatedness. We estimated an ICC of 0.25, corresponding to a narrow sense additive heritability estimate of 0.51 in the FPC family cohort. CONCLUSION: We have established a nation-wide cohort of FPC families to facilitate clinical and genetic studies on FPC. The estimated heritability of 51% prominently underlines a strong genetic background of FPC.

Molecular analysis of cyst fluids improves the diagnostic accuracy of pre-operative assessment of pancreatic cystic lesions.

Pancreatic cystic lesions (PCL) are increasingly diagnosed. Endoscopic ultrasound fine-needle aspiration (EUS-FNA) cytology is often used for diagnostic confirmation but can be inconclusive. In this study, the role of molecular analyses in the pre-operative diagnostics of PCL is evaluated. Targeted Next Generation Sequencing (NGS) applied on cytology smears was retrospectively evaluated in a cohort of 37 resected PCL. Usefulness of NGS on fresh cyst fluids was tested in a prospective cohort of patients with newly diagnosed PCL (n = 71). In the retrospective cohort, cytology plus NGS displayed higher sensitivity (94.1% vs. 87.1%) and specificity (100% vs. 50%) than cytology alone for the detection of mucinous neoplasms. In the prospective cohort, sensitivity and specificity of conventional cytology alone were 54.2% and 100% for the detection of mucinous neoplasia and 50.0% and 100% for the detection of high-grade dysplasia, respectively. Adding NGS, all lesions which underwent histopathologic verification (12/71, 17%) could be classified without false positive or false negative results regarding the detection of mucinous neoplasm so far. NGS analysis of cfDNA in PCL fluids is feasible and can increase diagnostic accuracy in the detection of mucinous neoplasms compared to cytology alone. However, algorithms for the detection of high-risk lesions need further improvement.

A multilayered post-GWAS assessment on genetic susceptibility to pancreatic cancer.

BACKGROUND: Pancreatic cancer (PC) is a complex disease in which both non-genetic and genetic factors interplay. To date, 40 GWAS hits have been associated with PC risk in individuals of European descent, explaining 4.1% of the phenotypic variance. METHODS: We complemented a new conventional PC GWAS (1D) with genome spatial autocorrelation analysis (2D) permitting to prioritize low frequency variants not detected by GWAS. These were further expanded via Hi-C map (3D) interactions to gain additional insight into the inherited basis of PC. In silico functional analysis of public genomic information allowed prioritization of potentially relevant candidate variants. RESULTS: We identified several new variants located in genes for which there is experimental evidence of their implication in the biology and function of pancreatic acinar cells. Among them is a novel independent variant in NR5A2 (rs3790840) with a meta-analysis p value = 5.91E-06 in 1D approach and a Local Moran's Index (LMI) = 7.76 in 2D approach. We also identified a multi-hit region in CASC8-a lncRNA associated with pancreatic carcinogenesis-with a lowest p value = 6.91E-05. Importantly, two new PC loci were identified both by 2D and 3D approaches: SIAH3 (LMI = 18.24), CTRB2/BCAR1 (LMI = 6.03), in addition to a chromatin interacting region in XBP1-a major regulator of the ER stress and unfolded protein responses in acinar cells-identified by 3D; all of them with a strong in silico functional support. CONCLUSIONS: This multi-step strategy, combined with an in-depth in silico functional analysis, offers a comprehensive approach to advance the study of PC genetic susceptibility and could be applied to other diseases.

Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology.

The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic focus primarily on assessment of pathogenic or likely pathogenic variants associated with increased risk of breast, ovarian, and pancreatic cancer and recommended approaches to genetic testing/counseling and management strategies in individuals with these pathogenic or likely pathogenic variants. This manuscript focuses on cancer risk and risk management for BRCA-related breast/ovarian cancer syndrome and Li-Fraumeni syndrome. Carriers of a BRCA1/2 pathogenic or likely pathogenic variant have an excessive risk for both breast and ovarian cancer that warrants consideration of more intensive screening and preventive strategies. There is also evidence that risks of prostate cancer and pancreatic cancer are elevated in these carriers. Li-Fraumeni syndrome is a highly penetrant cancer syndrome associated with a high lifetime risk for cancer, including soft tissue sarcomas, osteosarcomas, premenopausal breast cancer, colon cancer, gastric cancer, adrenocortical carcinoma, and brain tumors.

Cost-effectiveness analysis of universal germline testing for patients with pancreatic cancer.

BACKGROUND: Historically, germline testing of patients with pancreatic cancer was performed selectively in patients with a strong family history of cancer. Current guidelines recommend universal testing because some patients may have actionable germline pathogenic variants without family history. METHODS: We conducted a cost-effectiveness analysis using a decision-tree model to compare universal versus selective testing strategies for patients with pancreatic cancer. Costs, probabilities, and overall survival were estimated from the published literature and institutional data. One-way and probabilistic sensitivity analyses explored model uncertainty. RESULTS: Universal germline genetic testing had an incremental cost of $310 with an increase of 0.003 life-years. The incremental cost-effectiveness ratio was $121,924/life-years. Parameters which were most impactful (sensitivity analysis) included the median overall survival of patients with advanced disease treated with personalized therapy, cost of personalized therapy for advanced disease, and the probability of receiving personalized therapy in advanced disease. A strategy of selective testing was more cost-effective in 59% of iterations when the willingness-to-pay threshold was set to $100,000/life-years. CONCLUSION: Our model suggested that selective germline testing of patients with newly diagnosed pancreatic cancer is more cost-effective than universal testing. Additional research is needed to explore the impact of cascade testing of relatives on cost-effectiveness.

Improved Assessment of Response Status in Patients with Pancreatic Cancer Treated with Neoadjuvant Therapy using Somatic Mutations and Liquid Biopsy Analysis.

PURPOSE: To evaluate somatic mutations, circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) in patients with Pancreatic ductal adenocarcinoma (PDAC) with pathologic complete response (pCR) to neoadjuvant therapy (NAT) and find their associations with outcome. EXPERIMENTAL DESIGN: Thirty-six patients with PDAC with pCR were identified from 2009 to 2017. Macrodissection was performed on resected specimens to isolate DNA from 332 regions of interest including fibrosis, normal duct, normal parenchyma, and undefined ductal cells (UDCs). Cell-free DNA and CTCs were also extracted. Next-generation sequencing was used to detect mutations of KRAS, CDKN2A, SMAD4, TP53, GNAS, and BRAF. RESULTS: KRAS mutation was detected in UDCs and fibrosis while SMAD4, TP53, and GNAS were only seen in UDCs. Patients with TP53 mutation showed relatively worse overall survival (HR, 3.596, 95% CI, 0.855-15.130; P = 0.081). Five patients available for CTCs data were all positive for CTCs and seven of 16 patients with pCR were detected with ctDNA at surgery. We proposed a new concept of regression assessment combining genomic analysis of resected specimens and liquid biopsy data for PDAC, namely, molecular complete response (mCR). Three of six patients with mCR recurred as compared with six in 15 non-mCR patients. Seven of 15 non-mCR patients died during follow-up, while there was only one in six patients with mCR. CONCLUSIONS: This study first reports that somatic mutations, CTCs, and ctDNA existed even in patients with PDAC with pCR to NAT, which could possibly predict early recurrence and reduced survival. The current regression evaluation system of PDAC needs to be reassessed at a molecular level.

Next-generation sequencing and histological response assessment in peritoneal metastasis from pancreatic cancer treated with PIPAC.

BACKGROUND: Peritoneal metastasis from pancreatic cancer (PM-PC) may be treated with repeated pressurised intraperitoneal aerosol chemotherapy (PIPAC). Utility of next-generation sequencing (NGS) to detect cancer-related mutations in peritoneal quadrant biopsies (QBs) and peritoneal fluid (PF) after systemic and PIPAC treatment has not been evaluated. Around 90% of pancreatic cancers (PCs) harbour a KRAS mutation, making PC ideal for the evaluation of this aspect. AIMS: Evaluation of PM-PC in terms of (1) histological response to PIPAC using Peritoneal Regression Grading Score (PRGS), (2) clinical characteristics and (3) frequency of mutations in QBs and PF before and after PIPAC. METHODS: Peritoneal QBs and PF were obtained prior to each PIPAC. NGS for 22 cancer-related genes was performed on primary tumours, QBs and PFs. Response was assessed by the four-tiered PRGS. RESULTS: Sixteen patients treated with a median of three PIPAC procedures were included. The mean PRGS was reduced from 1.91 to 1.58 (p=0.02). Fifty-seven specimens (13 primary tumours, 2 metastatic lymph nodes, 16 PFs and 26 QB sets) were analysed with NGS. KRAS mutation was found in 14/16 patients (87.50%) and in QBs, primary tumours and PF in 8/12 (66.67%), 8/13 (61.53%) and 6/9 (66.67%). The median overall survival was 9.9 months (SE 1.5, 95% CI 4.9 to 13.9). CONCLUSION: PIPAC induces histological response in the majority of patients with PM-PC. KRAS mutation can be found in PM-PC after PIPAC at a frequency similar to the primaries. NGS may be used to detect predictive mutations in PM-PC of various origins, also when only post-PIPAC QBs or PFs are available.

An assessment of chromosomal alterations detected by fluorescence in situ hybridisation in pancreatobiliary tract malignancy.

BACKGROUND: Using fluorescence in situ hybridisation (FISH) to detect any gain of chromosomes 3, 7, or 17 and loss of the 9p21 locus has been proven to be sensitive in the diagnosis of pancreatobiliary tumors. However, both genetic and environmental factors contribute to the pathogenesis of pancreatobiliary tumors. Therefore, it is unknown whether this method is suitable for Chinese patients with pancreatobiliary tumors. This study aims to compare the sensitivity, specificity, predictive values and accuracy of cytology, ERCP/MRCP and FISH based on Chinese patients with pancreatobiliary tumors,and to analyze differences between brushing-based and formalin-fixed paraffin-embedded (FFPE)-based FISH. METHODS: A total of 66 brush cytology specimens obtained during ERCP were detected by FISH and cytology test respectively to compare the sensitivity, specificity, predictive values and accuracy. Besides, FFPE-based FISH was performed on 46 corresponding paraffin sections of pancreatobiliary tumors obtained by surgical resection. RESULTS: Our findings demonstrate that FISH greatly improves diagnostic sensitivity and negative predictive value compared to ERCP/MRCP and cytology without much reduction in specificity and positive predictive value. However, our results also indicate that FFPE-based FISH could not effectively identify the false-negative of brushing-based FISH. CONCLUSIONS: We believe that FISH can effectively distinguish true positive and false positive results of cytological or radiological suspicions of malignancy. However, FFPE-based FISH still does not precisely recognize the false-negative of brushing-based FISH. Both cytology-based and PPFE-based FISH had limitation in some specimens.