Surgical and Oncological Outcomes After Preoperative FOLFIRINOX Chemotherapy in Resected Pancreatic Cancer : An International Multicenter Cohort Study

Background. Preoperative FOLFIRINOX chemotherapy is increasingly administered to patients with borderline resectable (BRPC) and locally advanced pancreatic cancer (LAPC) to improve overall survival (OS). Multicenter studies reporting on the impact from the number of preoperative cycles and the use of adjuvant chemotherapy in relation to outcomes in this setting are lacking. This study aimed to assess the outcome of pancreatectomy after preoperative FOLFIRINOX, including predictors of OS.Methods. This international multicenter retrospective cohort study included patients from 31 centers in 19 European countries and the United States undergoing pancreatectomy after preoperative FOLFIRINOX chemotherapy (2012-2016). The primary end point was OS from diagnosis. Survival was assessed using Kaplan-Meier analysis and Cox regression.Results. The study included 423 patients who underwent pancreatectomy after a median of six (IQR 5-8) preoperative cycles of FOLFIRINOX. Postoperative major morbidity occurred for 88 (20.8%) patients and 90-day mortality for 12 (2.8%) patients. An R0 resection was achieved for 243 (57.4%) patients, and 259 (61.2%) patients received adjuvant chemotherapy. The median OS was 38 months (95% confidence interval [CI] 34-42 months) for BRPC and 33 months (95% CI 27-45 months) for LAPC. Overall survival was significantly associated with R0 resection (hazard ratio [HR] 1.63; 95% CI 1.20-2.20) and tumor differentiation (HR 1.43; 95% CI 1.08-1.91). Neither the number of preoperative chemotherapy cycles nor the use adjuvant chemotherapy was associated with OS.Conclusions. This international multicenter study found that pancreatectomy after FOLFIRINOX chemotherapy is associated with favorable outcomes for patients with BRPC and those with LAPC. Future studies should confirm that the number of neoadjuvant cycles and the use adjuvant chemotherapy have no relation to OS after resection.Peer reviewe

Role of circulating tumor DNA in the management of patients with pancreatic adenocarcinoma

Les adénocarcinomes du pancréas représentent la 5ème cause de mortalité par cancer et l'espérance de vie à 5 ans est inférieure à 9%. Malgré les progrès récents des chimiothérapies, le pronostic global des patients n'a été que peu amélioré et il n'existe à ce jour aucun marqueur fiable de l'évolution tumorale. L'identification d'un biomarqueur sanguin pronostique comme l'ADN tumoral circulant (ADNtc) pourrait ainsi constituer une piste prometteuse. L'objectif de notre travail était d'évaluer la place de l'ADNtc dans la prise en charge des patients avec un adénocarcinome du pancréas. Nous avons mis en évidence d'une part la faisabilité de la détection de l'ADNtc, et d'autre part la valeur pronostique de ce biomarqueur, aux différents stades de la maladie, en survie globale comme en survie sans récidive. Ce travail a été possible dans un premier temps grâce à la maîtrise des techniques de séquençage et au développement d'un algorithme d'analyse. Dans un second temps, nous avons mis en évidence deux gènes hyperméthylés spécifiques de l'adénocarcinome du pancréas (HOXD8 et POU4F1) et mis au point le matériel nécessaire (sondes et amorces) pour la détection de ces séquences dans l'ADN extrait de plasma par ddPCR. Cette technique a fait l'objet d'un dépôt de brevet et a été validée sur les plasmas de patients métastatiques issus de deux essais contrôlés randomisés permettant de montrer la valeur pronostique de l'ADNtc méthylé, indépendante de toute chimiothérapie. Nos résultats plaident pour le développement en routine clinique de l'ADNtc comme marqueur pronostique dans la prise en charge des patients, quel que soit le stade de la maladie, ainsi que pour une stratification des patients selon le statut ADNtc dans les futurs essais cliniques.Pancreatic adenocarcinoma (PDAC) is the 5th leading cause of cancer mortality, with a 5-year survival rate of less than 9%. Despite recent progress in systemic treatments, patients' overall prognosis has only slightly improved, and there is as yet no reliable marker of tumor progression. Identifying a prognostic blood biomarker such as circulating tumor DNA (ctDNA) could be a promising lead. The objective of our work was to evaluate the role of ctDNA in the management of patients with PDAC. Therefore, using next generation sequencing with a large genes panel, we have demonstrated the feasibility of ctDNA detection and that ctDNA improve the prognostic staging of metastatic and locally advanced PDAC. Our work highlights that the detection and evaluation of the quantity of ctDNA appears suitable as an independent prognostic factor in stage III or IV PDAC, and a prognostic factor of recurrence in resected patients when detected after surgery. This work was initially possible thanks to the mastery of sequencing techniques and an analysis algorithm's development. In a second step, we identified two specific hypermethylated genes of PDAC (HOXD8 and POU4F1) and developed the technique for detecting these sequences in cell-free DNA extracted from plasma by ddPCR. This technique was granted by a patent application and validated on metastatic patients' plasmas from two randomized controlled trials demonstrating the independent prognostic value of methylated ctDNA. Our results argue for the routine clinical development of ctDNA as a prognostic marker in the management of patients at any stage of the disease and stratification of patients according to ctDNA status in further clinical trials

Adjuvant Pancreatic Cancer Management: Towards New Perspectives in 2021

International audienceAdjuvant chemotherapy is currently used in all patients with resected pancreatic cancer who are able to begin treatment within 3 months after surgery. Since the recent publication of the PRODIGE 24 trial results, modified FOLFIRINOX has become the standard-of-care in the non-Asian population with localized pancreatic adenocarcinoma following surgery. Nevertheless, there is still a risk of toxicity, and feasibility may be limited in heavily pre-treated patients. In more frail patients, gemcitabine-based chemotherapy remains a suitable option, for example gemcitabine or 5FU in monotherapy. In Asia, although S1-based chemotherapy is the standard of care it is not readily available outside Asia and data are lacking in non-Asiatic patients. In patients in whom resection is not initially possible, intensified schemes such as FOLFIRINOX or gemcitabine-nabpaclitaxel have been confirmed as options to enhance the response rate and resectability, promoting research in adjuvant therapy. In particular, should oncologists prescribe adjuvant treatment after a long sequence of chemotherapy +/- chemoradiotherapy and surgery? Should oncologists consider the response rate, the R0 resection rate alone, or the initial chemotherapy regimen? And finally, should they take into consideration the duration of the entire sequence, or the presence of limited toxicities of induction treatment? The aim of this review is to summarize adjuvant management of resected pancreatic cancer and to raise current and future concerns, especially the need for biomarkers and the best holistic care for patients

Circulating tumour DNA: a challenging innovation to develop "precision onco-surgery" in pancreatic adenocarcinoma

: Pancreatic ductal adenocarcinoma (PDAC) is predicted to become the third leading cause of cancer-related mortality within the next decade. Management of PDAC remains challenging with limited effective treatment options and a dismal long-term prognosis. Liquid biopsy and circulating biomarkers seem to be promising to improve the multidisciplinary approach in PDAC treatment. Circulating tumour DNA (ctDNA) is the most studied blood liquid biopsy analyte and can provide insight into the molecular profile and individual characteristics of the tumour in real-time and in advance of standard imaging modalities. This could pave the way for identifying new therapeutic targets and markers of tumour response to supplement diagnostic and provide enhanced stratified treatment. Although its specificity seems excellent, the current sensitivity of ctDNA remains a limitation for clinical use, especially in patients with a low tumour burden. Increasing evidence suggests that ctDNA is a pertinent candidate biomarker to assess minimal residual disease after surgery but also a strong independent prognostic biomarker. This review explores the current knowledge and recent developments in ctDNA as a screening, diagnostic, prognostic and predictive biomarker in the management of resectable PDAC but also technical and analytical challenges that must be overcome to move toward "precision onco-surgery.

Quel avenir pour l’ADN tumoral circulant ? État des lieux et perspectives dans les cancers colorectaux, pulmonaires non à petites cellules et pancréatiques

International audienceDix ans après la mise en évidence de la valeur prédictive du statut KRAS pour les anticorps anti- EGFR, d'autres gènes impliqués dans l'oncogenèse et les réponses thérapeutiques ont été identifiés et sont aujourd'hui systématiquement recherchés. Le diagnostic moléculaire nécessite souvent des gestes invasifs, parfois iatrogènes, et sont limités par des problèmes de faisabilité, de quantité et de qualité des prélèvements. L'identification de ces mutations à partir de biomarqueurs sanguins permettrait de réduire les coûts et les délais diagnostiques. L'ADN tumoral circulant (ADNtc) est l'un des biomarqueurs sanguins les plus prometteurs. Dans cette revue, nous rapportons et discutons les derniers résultats obtenus avec l'ADNtc dans le cancer colorectal, le cancer broncho-pulmonaire non à petites cellules et l'adénocarcinome du pancréas. Si les méthodes de mise en évidence apparaissent très hétérogènes, la concordance entre les mutations retrouvées dans la tumeur et celles identifiées dans le sang dépassent les 95 % de spécificité dans de nombreuses études. La sensibilité de détection est quant à elle fortement liée au stade tumoral des patients. La présence d'ADNtc apparaît comme un facteur pronostique de survie sans progression et de survie globale. Enfin, de récentes études ont montré que l'évolution du taux d'ADNtc au cours de traitements systémiques avait une valeur prédictive pour l'efficacité thérapeutique. Ces résultats permettent d'envisager l'utilisation de l'ADNtc dans le suivi des patients afin d'identifier des récidives ou progressions précoces

Plasma circulating tumor DNA in pancreatic adenocarcinoma for screening, diagnosis, prognosis, treatment and follow-up: A systematic review

International audienceWhile no biomarker is currently recommended for the management of pancreatic adenocarcinoma (PA), circulating tumor DNA (ctDNA) seems promising but little is known on how it may help to manage our patients in the near future. This systematic review of literature was designed to explore the current knowledge on ctDNA as a screening, diagnostic, prognostic, predictive and theranostic biomarker in the management of PA. We retrieved 62 full-text articles, 3 meta-analyses, 2 clinical trials, 1 abstract and 13 ongoing trials. Results were categorized into sections about screening, diagnosis, prognosis and follow-up of localized and advanced PA together with possible theranostics applications. Although its specificity is excellent, the current sensitivity of ctDNA remains a limitation especially in patients without metastatic disease. Therefore, this biomarker cannot be currently used as a screening or diagnostic tool. Increasing evidence suggests that ctDNA is a relevant candidate biomarker to assess minimal residual disease after radical surgery, but also a strong independent biomarker linked to a poor prognosis in advanced PA. Some recent data also indicates that ctDNA is an attractive biomarker for longitudinal follow-up and possibly early treatment adaptation. Its role in tumor profiling in advanced disease to decide targeted treatments remains to be explored. Altogether, ctDNA appears to be a reliable prognostic tool. Though promising results have been reported, further studies are still needed to define exactly how ctDNA can help physicians in the screening, diagnosis and treatment, as PA is expected to become a major cause of cancer-related deaths in the forthcoming decade

Prognostic value of the early change in neutrophil-to-lymphocyte ratio in metastatic pancreatic adenocarcinoma

International audienceIn metastatic pancreatic adenocarcinoma, a high neutrophil-to-lymphocyte ratio (NLR) at diagnosis is a marker of poor prognosis. The prognostic role of baseline NLR and NLR change during first-line chemotherapy were determined. We conducted a retrospective study by using data from a single-center prospective cohort and a randomized open-label, multicenter, randomized trial. Two hundred and twelve patients were analyzed. Baseline NLR>5 was an independent marker of poor prognosis for overall survival (HR=2.01, 95% CI 1.33-3.05; P=0.001) and progression-free survival (PFS; HR=1.80, 95% CI 1.23-2.65; P=0.0026). According to NLR dynamics (n=172), patients with NLR≤5 on days 1 and 15 had a significantly better prognosis than those with NLR≤5 on day 1 and NLR>5 on day 15 (HR=2.23, 95% CI 1.18-4.21; P=0.013), NLR >5 on day 1 and NLR ≤5 on day 15 (HR=3.25, 95% CI 1.86-5.68; P5 on days 1 and 15 (HR=3.37, 95% CI 1.93-5.90; P6 months; group effect: P5 had circulating tumor DNA. This study confirmed the independent prognostic value of baseline NLR >5 in metastatic pancreatic cancer. The change in NLR early during chemotherapy was also a prognostic indicator in patients with NLR ≤5

Circulating tumor DNA: a help to guide therapeutic strategy in patients with borderline and locally advanced pancreatic adenocarcinoma?

International audienceBackground: prognostic biomarkers could be useful to better select patients with borderline resectable (BR) or locally advanced (LA) pancreatic adenocarcinoma (PA) for chemoradiotherapy (CRT) and/or secondary resection.Aims: The main objective of this work was to study characteristics, received treatments and prognostic of patients with BR or LA PA according to their baseline circulating tumor DNA status and, for secondary objective, neutrophil-to-lymphocyte Ratio (NLR).Methods: ctDNA status at baseline was determined using Next Generation Sequencing in a consecutive monocentric cohort of patients with a BR or LA PA.Results: 69 patients were included, 31 with BR PA and 38 with LA PA. 14 (20.3%) patients had baseline positive ctDNA. Five (7.8%) patients had NLR> 5. Patients with positive ctDNA had 3.7 months shorter progression free survival (p = 0.006). Patients with positive ctDNA had earlier progression after the beginning of CRT (4.4 vs 7.1 months; p = 0.068) and shorter relapse free survival after secondary resection (9.2 vs 22.9 months; p = 0.016).Conclusions: positive ctDNA at baseline was associated with a worse prognosis in patients with BR or LA PA. These data are exploratory and must be confirmed in further prospective trials

Spectral slope variations for OSIRIS-REx target Asteroid (101955) Bennu: Possible evidence for a fine-grained regolith equatorial ridge

Ongoing spectroscopic reconnaissance of the OSIRIS-REx target Asteroid (101955) Bennu was performed in July 2011 and May 2012. Near-infrared spectra taken during these apparitions display slightly more positive ("redder") spectral slopes than most previously reported measurements. While observational systematic effects can produce such slope changes, and these effects cannot be ruled out, we entertain the hypothesis that the measurements are correct. Under this assumption, we present laboratory measurements investigating a plausible explanation that positive spectral slopes indicate a finer grain size for the most directly observed sub-Earth region on the asteroid. In all cases, the positive spectral slopes correspond to sub-Earth latitudes nearest to the equatorial ridge of Bennu. If confirmed by OSIRIS-REx in situ observations, one possible physical implication is that if the equatorial ridge is created by regolith migration during episodes of rapid rotation, that migration is most strongly dominated by finer grain material. Alternatively, after formation of the ridge (by regolith of any size distribution), larger-sized equatorial material may be more subject to loss due to centrifugal acceleration relative to finer grain material, where cohesive forces can preferentially retain the finest fraction (Rozitis, B., Maclennan, E., Emery, J.P. [2014]. Nature 512, 174-176)