Valorization

Authors

Cindy Canivet, Sophie Gourgou-Bourgade, Bertrand Napoléon, Laurent Palazzo, Nicolas Flori, Pierre Guibert, Guillaume Piessen, Dominique Farges-Bancel, Jean-François Seitz, Eric Assenat, Véronique Vendrely, Stéphanie Truant, Geoffroy Vanbiervliet, Philippe Berthelémy, Stéphane Garcia, Anne Gomez-Brouchet,Louis Buscail, Barbara Bournet and The BACAP Consortium

Background

The prognosis for pancreatic cancer remains poor despite diagnostic advances and treatments with new chemotherapeutic regimens. The five year survival rate remains below 3%. Consequently, there is an urgent need for new treatments to significantly improve the prognosis. In addition, there is a big gap in terms of the screening, early diagnosis and prevention of pancreatic cancer the incidence of which is increasing dramatically.

Methods

Design: the BACAP cohort is a prospective multicenter pancreatic cancer cohort (pancreatic ductal carcinoma) with clinical and multiple biological samples; Participating centers: 15 French academic and private hospitals; Study Population: any cytologically and/or histologically proven pancreatic carcinoma regardless of the stage (resectable, borderline, locally advanced or metastatic) or treatment (surgery, palliative chemotherapy, best supportive care). At least 1500 patients will be included. Clinical data collected include: disease presentation, epidemiological and social factors, baseline biology, radiology, endoscopic ultrasound, staging, pathology, treatments, follow-up (including biological and radiological), and survival. All these data are collected and stored through an e-observation system at a centralized data center. Biological samples and derived products (i.e. before any treatment): blood, saliva, endoscopic ultrasound-guided fine needle aspiration materials from the primary tumor, fine needle biopsy of metastases and surgically resected tissue. DNA and RNA are extracted from fine needle aspiration materials and are quantified and characterized for quality. Whole blood, plasma and serum are isolated from blood samples. Frozen tissues were specifically allocated to the cohort. All derived products and saliva are stored at − 80 °C. Main end-points: i) to centralize clinical data together with multiple biological samples that are harmonized in terms of sampling, the post sampling process and storage; ii) to identify new molecular markers for the diagnosis, prognosis and possibly the predictive response to pancreatic cancer surgery and or chemotherapy.

Discussion

The BACAP cohort is a unique prospective biological clinical database that provides the opportunity to identify correlations between the presence/expression of a broad panel of biomarkers (DNA, RNA, miRNA, proteins, etc.), epidemiological and social data, various clinical situations, various stages and the differentiation of the tumor, treatments and survival.

PMID : 30326968 ; Canivet et al. BMC Cancer (2018) 18:986

Authors

Corinne Frere, Barbara Bournet, Sophie Gourgou, Julien Fraisse, Cindy Canivet, Jean M. Connors, Louis Buscail and Dominique Farge and the BACAP Consortium

Background & aims

Pancreatic ductal adenocarcinoma (PDAC) is associated with the highest incidence of venous thromboembolism (VTE) of any cancer type. However, little is known about risk factors for VTE or its outcomes in patients with PDAC.

Method

We collected data from a prospective, observational study performed at multiple centers in France from May 2014 through November 2018 (the Base ClinicoBiologique de l’Adénocarcinome Pancréatique [BACAP] study) linked to a database of patients with a new diagnosis of PDAC of any stage. Data were collected from 731 patients at baseline and during clinical follow-up or in the event of symptoms. The primary endpoint was the onset of VTE during follow-up. The secondary endpoints were progression-free survival (PFS) and overall survival (OS) times.

Result

During a median followup of 19.3 months, 152 patients (20.79%) developed a VTE. The median time from PDAC diagnosis to the onset of VTE was 4.49 months. Cumulative incidence values of VTE were 8.07% (95% confidence interval [CI], 6.31–10.29) at 3 months and 19.21% (95% CI, 16.27–22.62) at 12 months. In multivariate analysis, PDAC primary tumor location (isthmus vs head: hazard ratio [HR], 2.06; 95% CI, 1.09–3.91; P ¼ .027) and stage (locally advanced vs resectable or borderline: HR, 1.66; 95% CI, 1.10–2.51, P ¼ .016; metastatic vs resectable or borderline: HR, 2.50; 95% CI, 1.64–3.79; P < .001) were independent risk Gastroenterology 2020;158:1346–1358 CLINICAL PANCREAS factors for the onset of VTE. Patients who developed VTE during follow-up had shorter times of PFS (HR, 1.74; 95% CI, 1.19–2.54; P ¼ .004) and OS (HR, 2.02; 95% CI, 1.57–2.60; P < .001).

Conclusion

In an analysis of data from the BACAP study, we found that frequent and early onsets of VTE after diagnoses of PDAC are associated with significant decreases in times of PFS and OS. Studies are needed to determine whether primary prophylaxis of VTE in patients with PDAC will improve morbidity and mortality related to VTE. (ClinicalTrials.gov, Number: clinicaltrials.gov as number NCT02818829).

PMID : 31843588; Gastroenterology. 2020 Apr;158(5):1346-1358

Authors

David Piquemal , Roman Bruno , Barbara Bournet , Francois Ghiringhelli , Florian Noguier , Cindy Canivet , Aurélie Bertaut , Fabien Pierrat , Ludovic Evesque , Amelia Gamez , Jerome Cros , Emilie Rederstorff , Erwan Petit , Johan Adnet , Angélique Saint , Antoine Drouillard, Emmanuelle Kempf, Emilie Soularue, Julie Vincent, Isabelle Baumgaertner, Audrey Hennequin, Christophe Tournigand, Daniel Lopez Trabada Ataz, Leila Bengrine, Come Lepage, Sylvain Manfredi, Pauline Afchain, Isabelle Trouilloud, Alice Gagnaire, Noelle K LoConte, Jean-Baptiste Bachet

Background

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer, and chemotherapy is a key treatment for advanced PDAC. Gemcitabine chemotherapy is still an important component of treatment; however, there is no routine biomarker to predict its efficacy. Predictive tests may help clinicians to decide on the best first-line chemotherapy.

Methods

This study is a confirmatory study of a blood-based RNA signature, called the GemciTest. This test measures the expression levels of nine genes using real-time polymerase chain reaction (PCR) processes. Clinical validation was carried out, through a discovery and a validation phases, on 336 patients (mean 68.7 years; range, 37–88 years) for whom blood was collected from two prospective cohorts and two tumor biobanks. These cohorts included previously untreated advanced PDAC patients who received either a gemcitabine- or fluoropyrimidine-based regimen.

Results

Gemcitabine-based treated patients with a positive GemciTest (22.9%) had a significantly longer progression-free survival (PFS) [5.3 vs. 2.8 months; HR =0.53 (95% CI: 0.31–0.92); P=0.023] and OS [10.4 vs. 4.8 months; HR =0.49 (95% CI: 0.29–0.85); P=0.0091]. On the contrary, fluoropyrimidine-based treate patients showed no significant difference in PFS and OS using this blood signature.

Conclusions

The GemciTest demonstrated that a blood-based RNA signature has the potential to aid in personalized therapy for PDAC, leading to better survival rates for patients receiving a gemcitabine-based first-line treatment.
Keywords: Pancreatic cancer; predictive diagnosis; liquid biopsy; gemcitabine-based.

PMID : 37201091; J Gastrointest Oncol. 2023 Apr 29;14(2):997-1007

Authors

Thibault B, Ramos-Delgado F, Pons-Tostivint E, Therville N, Cintas C, Arcucci S, Cassant-Sourdy S, Reyes-Castellanos G, Tosolini M, Villard AV, Cayron C, Baer R, Bertrand-Michel J, Pagan D, Ferreira Da Mota D, Yan H, Falcomatà C, Muscari F, Bournet B, Delord JP, Aksoy E, Carrier A, Cordelier P, Saur D, Basset C, Guillermet-Guibert J.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) patients frequently suffer from undetected micro-metastatic disease. This clinical situation would greatly benefit from additional investigation. Therefore, we set out to identify key signalling events that drive metastatic evolution from the pancreas. We searched for a gene signature that discriminate localised PDAC from confirmed metastatic PDAC and devised a preclinical protocol using circulating cell-free DNA (cfDNA) as an early biomarker of micro-metastatic disease to validate the identification of key signalling events. An unbiased approach identified, amongst actionable markers of disease progression, the PI3K pathway and a distinctive PI3Ka activation signature as predictive of PDAC aggressiveness and prognosis.

Pharmacological or tumour-restricted genetic PI3Kaselective inhibition prevented macro-metastatic evolution by hindering tumoural cell migratory behaviour independently of genetic alterations. We found that PI3Ka inhibition altered the quantity and the species composition of the produced lipid second messenger PIP3, with a selective decrease of C36:2 PI-3,4,5-P3. Tumoural PI3Ka inactivation prevented the accumulation of protumoural CD206-positive macrophages in the tumour-adjacent tissue. Tumour cell-intrinsic PI3Ka promotes pro-metastatic features that could be pharmacologically targeted to delay macrometastatic evolution.

PMID : 34033220 ; EMBO Mol Med. 2021 Jul 7;13(7):e13502

Authors

Nicolle R, Blum Y, Duconseil P, Vanbrugghe C, Brandone N, Poizat F, Roques J, Bigonnet M, Gayet O, Rubis M, Elarouci N, Armenoult L, Ayadi M, de Reyniès A, Giovannini M, Grandval P, Garcia S, Canivet C, Cros J, Bournet B, Buscail L; BACAP Consortium; Moutardier V, Gilabert M, Iovanna J, Dusetti N

Background

A significant gap in pancreatic ductal adenocarcinoma (PDAC) patient’s care is the lack of molecular parameters characterizing tumours and allowing a personalized treatment.

Methods

Patient-derived xenografts (PDX) were obtained from 76 consecutive PDAC and classified according to their histology into five groups. A PDAC molecular gradient (PAMG) was constructed from PDX transcriptomes recapitulating the five histological groups along a continuous gradient. The prognostic and predictive value for PMAG was evaluated in: i/ two independent series (n = 598) of resected tumours; ii/ 60 advanced tumours obtained by diagnostic EUS-guided biopsy needle flushing and iii/ on 28 biopsies from mFOLFIRINOX treated metastatic tumours.

Findings

A unique transcriptomic signature (PAGM) was generated with significant and independent prognostic value. PAMG significantly improves the characterization of PDAC heterogeneity compared to non-overlapping classifications as validated in 4 independent series of tumours (e.g. 308 consecutive resected PDAC, uHR=0.321 95% CI [0.2070.5] and 60 locally-advanced or metastatic PDAC, uHR=0.308 95% CI [0.1130.836]). The PAMG signature is also associated with progression under mFOLFIRINOX treatment (Pearson correlation to tumour response: -0.67, p-value < 0.001).

Interpretation

PAMG unify all PDAC pre-existing classifications inducing a shift in the actual paradigm of binary classifications towards a better characterization in a gradient.

PMID : 32629389 ; EBioMedicine. 2020 Jul;57:102858

Authors

Bardol T, Dujon AM, Taly V, Dunyach-Remy C, Lavigne JP, Costa-Silva B, Kurma K, Eslami-S Z, Cayrefourcq L, Canivet C, Muscari F, Bournet B, Alix-Panabières C.

Background

Pancreatic cancer, predominantly characterized by ductal adenocarcinoma (PDAC) accounts for 90% of cases and is the fourth leading cause of cancer-related deaths globally. Its incidence is notably increasing. This poor prognosis is primarily due to late-stage diagnosis (approximately 70% to 80% of patients are diagnosed at an advanced stage), aggressive tumor biology, and low sensitivity to chemotherapy. Consequently, it is crucial to identify and develop a simple, feasible and reproducible blood-based signature (i.e., combination of biomarkers) for early detection of PDAC.

Methods

The PANLIPSY study is a multi-center, non-interventional prospective clinical trial designed to achiev early detection of PDAC with high specifcity and sensitivity, using a combinatorial approach in blood samples. These samples are collected from patients with resectable, borderline or locally advanced, and metastatic stage PDAC within the framework of the French Biological and Clinical Database for PDAC cohort (BACAP 2). All partners of the BACAP consortium are eligible to participate.

The study will include 215 PDAC patients, plus 25 patients with benign pancreatic conditions from the PAncreatic Disease Cohort of TOuLouse (PACTOL) cohort, and 115 healthy controls, totaling 355 individuals. Circulating biomarkers will be collected in a total volume of 50 mL of blood, divided into one CellSave tube (10 mL), two CELL-FREE DNA BCT® preservative tubes (18 mL), and fve EDTA tubes (22 mL in total). Samples preparation will adhere to the guidelines of the European Liquid Biopsy Society (ELBS).

A unique fea- ture of the study is the AI-based comparison of these complementary liquid biopsy biomarkers Main end-points: i) to defne a liquid biopsy signature that includes the most relevant circulating biomarkers, ii) to vali date the multi-marker panel in an independent cohort of healthy controls and patients, with resectable PDAC, and iii to establish a unique liquid biopsy biobank for PDAC study.

Discussion

The PANLIPSY study is a unique prospective non-interventional clinical trial that brings together liquid biopsy experts. The aim is to develop a biological signature for the early detection of PDAC based on AI-assisted detection of circulating biomarkers in blood samples (CTCs, ctDNA, EVs, circulating immune system, circulating cell free nucleosomes, proteins, and microbiota).

PMID : 38853244 ; BMC Cancer. 2024 Jun 10;24(1):709

Authors

Maulat C, Canivet C, Touraine C, Gourgou S, Napoleon B, Palazzo L, Flori N, Piessen G, Guibert P, Truant S, Assenat E, Buscail L, Bournet B, Muscari F, The Bacap Consortium.

Abstract

Surgery remains the only curative treatment for pancreatic ductal adenocarcinoma (PDAC). Therefore, a predictive score for resectability on diagnosis is needed. A total of 814 patients were included between 2014 and 2017 from 15 centers included in the BACAP (the national Anatomo-Clinical Database on Pancreatic Adenocarcinoma) prospective cohort. Three groups were defined: resectable (Res), locally advanced (LA), and metastatic (Met). Variables were analyzed and a predictive score was devised. Of the 814 patients included, 703 could be evaluated: 164 Res, 266 LA, and 273 Met.

The median ages of the patients were 69, 71, and 69, respectively. The median survival times were 21, 15, and nine months, respectively. Six criteria were significantly associated with a lower probability of resectability in multivariate analysis: venous/arterial thrombosis (p = 0.017), performance status 1 (p = 0.032) or ≥ 2 (p = 0.010), pain (p = 0.003), weight loss ≥ 8% (p = 0.019), topography of the tumor (body/tail) (p = 0.005), and maximal tumor size 20–33 mm (p < 0.013) or >33 mm (p < 0.001).

The BACAP score was devised using these criteria with an accuracy of 81.17% and an area under the receive operating characteristic (ROC) curve of 0.82 (95% confidence interval (CI): 0.78; 0.86). The presence of pejorative criteria or a BACAP score < 50% indicates that further investigations and even neoadjuvant treatment might be warranted.

PMID : 32218346 ; Cancers (Basel). 2020 Mar 25;12(4):783

Authors

Nicolle R, Canivet C, Palazzo L, Napoléon B, Ayadi M, Pignolet C, Cros J, Gourgou S, Selves J, Torrisani J, Dusetti N, Cordelier P, Buscail L, Bournet B; BACAP Consortium.

Background

We apply endoscopic ultrasound-guided fine needle aspiration biopsy to cytopathologically diagnose and sample nucleic acids from primary tumours regardless of the disease stage.

Methods

397 patients with proven pancreatic adenocarcinoma were included and followed up in a multicentre prospective study. DNA and mRNA were extracted from materials of primary tumours obtained by endoscopic ultrasound-guided fine needle aspiration biopsy and analysed using targeted deep sequencing and RNAseq respectively.

Findings

The variant allele frequency of the KRAS mutation was used to evaluate the tumour cellularity, ranging from 15 to 20% in all cells, regardless of the tumour stage. The molecular profile of metastatic primary tumours significantly differed from other types of tumours, more frequently having TP53 mutations (p = 0.0002), less frequently having RNF43 mutations, and possessing more basal-like mRNA component (p = 0.001). Molecular markers associated with improved overall survival were: mutations in homologous recombination deficiency genes in patients who received first-line platinum-based chemotherapy (p = 0.025) and wild-type TP53 gene in patients with locally advanced tumours who received radio-chemotherapy (p = 0.01). The GemPred transcriptomic profile was associated with a significantly better overall survival in patients with locally advanced or metastatic pancreatic cancer who received a gemcitabine-based first-line treatment (p = 0.019).

Interpretation

The combination of genomic and transcriptomic analyses of primary pancreatic tumours enables us to distinguish metastatic tumours from other tumour types. Our molecular strategy may assist in predicting overall survival outcomes for platinum or gemcitabine-based chemotherapies, as well as radio-chemotherapy.

PMID : 39383608 ; EBioMedicine. 2024 Nov;109:105373