Commentary: Pancreatic cancer: is the worst to come?

The paper by Anne-Marie Bouvier et al. brings scientific confirmation to a clinical impression.1 What we know, say and write is that pancreatic ductal adenocarcinoma (PDAC) is the fifth leading cause of cancer-related death in Western countries.2 In a recent North American analysis on deaths, projection of the ‘top cancer killers’ has, due to demographic changes, placed pancreatic cancer as the second cause of death by cancer in 2030 after lung cancer.3 In addition, and as stated by Bouvier et al. in their manuscript, ‘very recent predictions suggest that the burden of pancreatic cancer is expected to rise over the next 15 years regardless of age and sex in European regions as well as in other regions defined according to the World Health Organization’.1,4 It is a fact that the prognosis remains poor despite advances in diagnosis using high resolution imaging such as endoscopic ultrasound with fine needle aspiration biopsy, and treatments with new regimens of chemotherapeutic protocols (gemcitabine, FOLFIRINOX and nab-paclitaxel).5–7 Indeed, a vast majority of patients (85%) are diagnosed with tumours and/or metastases already locally advanced, because they lack specific symptoms and early markers for this otherwise highly aggressive disease. For these patients, the overall survival has doubled in the past 15 years (median survival passed from 6 to 12 months), but the 5-year survival remains less than 3%.2,5–7 When considering different birth cohorts (i.e. from 1920 to 1950), the probability of developing or of dying from pancreatic cancer before age 75 has increased in France.1 One might think that this increasing incidence is due to increasing life expectancy and/or to improved diagnosis. However, the trends are real, the incidence of pancreatic cancer is increasing and the age at diagnosis will certainly decrease in the future. Even if the trends are not similar in some other countries of Europe, it is well established that pancreatic cancer incidence follows the industrialization of Western countries.1,2 Some pre-neoplastic lesions and predisposing diseases have been identified, such as intraductal papillary mucinous tumours of the pancreas, chronic pancreatitis (especially in its hereditary origin) or hereditary cancer syndromes (Peutz Jeghers, familial atypical multiple mole melanoma syndrome, familial pancreatic cancer syndrome, BRCA2 family history …) but, on the whole, they account for no more than 5% to 10% of pancreatic cancer cases. In other words, the follow-up of these lesions or patients as it is organized nowadays will not modify the prognosis of the pancreatic cancers that arise de novo in the vast majority of cases. In addition, there is no high-risk population that could benefit from screening. However, even if we could isolate this high-risk sub-group, there is as yet no specific tumour marker available for pancreatic ductal adenocarcinoma. Numerous case-control and cohort studies have been conducted and some risk factors have been inconsistently identified, such as tobacco, obesity, diabetes and exposure to toxic substances. A recent meta-analysis relying on more than 100 studies concluded that tobacco smoking (‘strong’ evidence) and Helicobacter pylori infection (‘moderate’ evidence) are the major risk factors associated with PDAC, with respective estimated population attributable fractions of 11–32% and 4–25%.8 The authors also identified that the major protective factors are history of allergy (‘strong’ evidence) and increasing fruit or folate intake (‘moderate’ evidence). The risk of PDAC appears to be greater in people with a high-energy diet and lower in those with a diet rich in fruits and vegetables.1,8,9 The authors estimated that ‘About two-thirds of the major risk factors associated with PDAC are potentially modifiable, affording a unique opportunity for preventing one of our deadliest cancers’.8 This optimistic conclusion required prospective studies incorporating various epidemiological risk factors, such as smoking, obesity, environmental factors and nutritional behaviours. Specifically, large and long-term prospective cohorts focusing on nutritional habits deserve special attention to support these hypotheses. Many efforts have been made during the past 20 years in order to ‘see light at the end of the tunnel’: large-scale molecular analysis and characterization of PDAC, a better selection of patients for surgery (differentiating ‘borderline’ tumour from non-resectable), an improvement of surgical resection with special attention to the resection margins of the tumour, new regimens of chemotherapy and targeted therapies and a better approach to best supportive care.10 On the whole, palliative and adjuvant chemotherapy have improved clinical status and overall survival.5–7 However, there is a great gap in terms of screening, early diagnosis and prevention. That might explain the unchanged high mortality from this disease, but not the increasing incidence. Something has happened during the past 50 years, but we do not know what in terms of environment, toxic exposure or nutritional behaviour. Certainly, more targeted studies are needed. Recently the French National Institute of Cancer (INCa) launched a proposal dedicated to PDAC (the PAIR programme for ‘Programme d’Actions Intégrées de Recherche’) which plans to provide financial support for studies that will combine multidisciplinary approaches, i.e. translational, clinical and epidemiological data. In parallel, the INCa is supporting the constitution of a large French national prospective biobank dedicated to PDAC, which includes clinical, epidemiological and social data linked to biological samples such as blood, serum, plasma, saliva and DNA and RNA from tumour cells (the BACAP project for ‘Base ClinicoBiologique de l’Adénocarcinome Pancréatique’—[http://www.chu-toulouse.fr/-bacap-project]—funded by INCa). We hope that all of these national initiatives will help to answer unresolved questions such as: why is there such an increase in the incidence of PDAC in France? What is the profile of PDAC patients in the third millennium? What are the potential new co-factors of an otherwise unknown and ancient deadly disease? Conflict of interest: None declared.