Early Detection of Pancreatic Cancer Free

Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease with increasing incidence. PDAC is the third-leading cause of cancer death in Germany and is projected to become the second-leading cause of cancer-related deaths by 2030. The majority of PDACs are incurable at presentation. Since 2001, rates of PDACs have steadily increased by more than 1% annually, and this increase appears greater among younger individuals, especially women [1, 2]. Lifestyle factors play an important role. Tobacco smoking, excess body weight, type-2 diabetes, the metabolic syndrome and heavy alcohol use increase people’s risk for PDAC. On the contrary, smoking cessation, intentional weight loss by obese persons, remissions of either the metabolic syndrome or type 2 diabetes lower PDAC risk. Adults of all ages can lower their risks through regular exercise, no tobacco and only limited alcohol use, a normal body weight, and a healthy diet with less red meat or processed meat [3].

About 10–36 percent of PDACs are attributable to genetic causes, of which there are two categories: first, a small but clinically important proportion of PDACs is associated with mutations in known predisposition genes, even in patients who have apparently sporadic tumors. Hereditary PDACs can be due to germline mutations in CDKN2A, STK11, BRCA1, BRCA2, PALB2, ATM, MSH2, MSH6, MLH1, P53, and PRSS1. Second, familial pancreatic cancer which is defined as a family with a pair of affected first-degree blood relatives (FDBRs; parent-child or sibling pair) who do not meet criteria for a known PDAC-associated genetic predisposition syndrome. Surveillance is recommended to FDBRs of any PDAC patient belonging to a family of either category [4]; those FDBRs are considered high-risk individuals (HRIs). For early detection, endoscopic ultrasonography or nuclear magnetic resonance imaging is performed annually. Surveillance aims to identify early-stage invasive PDACs (T1N0M0) and preinvasive lesions (intraductal papillary mucinous neoplasms and pancreatic intraepithelial neoplasia [PanIN]) with high-grade neoplastic changes. Approximately 95% of PDACs arise from PanIN. Surveillance should only be considered in HRIs who are candidates for pancreas surgery. Surveillance of HRIs results in earlier PDAC diagnosis, more early-stage PDACs and a better 5-year survival. The Cancer of the Pancreas Screening (CAPS) programme has provided strong evidence for improved survival of PDAC patients, whose neoplasms were diagnosed by surveillance [5].

General population-based screening for average-risk people is not recommended because the average lifetime risk for developing PDAC is too low (approximately 1 in 60). Therefore, persons at increased risk for sporadic PDAC should be identified and targeted screening may be considered. Mucinous pancreatic cysts, including IPMNs and mucinous cystic neoplasms are believed to give rise to 5–15% of PDACs. Several guidelines on how to manage patients with pancreatic cysts or cystic pancreatic tumors are available [4].

New-onset diabetes (NOD) after age 50 (60) has been suggested as an early indicator of sporadic PDAC with estimated 3-year risk within the range of 0.25–1.0%. Recent studies have revealed more extensive, multisystem, and progressive metabolic perturbations starting months to years before PDAC diagnosis. This PDAC-associated metabolic dysregulation syndrome progressively causes disruption of glucose regulation, alterations in lipid metabolism, and skeletal muscle wasting typical of cancer cachexia syndrome [6]. In this issue, Salman Chan [7] describes several prediction models that have been developed to identify HRIs among NOD patients, with recent models achieving AUCs up to 0.91. When NOD after age 50 (60) is coupled with weight loss, the risk for underlying sporadic PDAC increases 10- to 25-fold, i.e., up to a level similar to that of a FDBR of a PDAC patient from a familial pancreatic cancer family. Therefore, the NICE institute in London recommends that NOD patients with concurrent weight loss who are 60 years of age or older should have radiological imaging for PDAC within a fortnight [8]. Unexplained acute pancreatitis after the age of 60 years has also been suggested as an early indicator of PDAC with a 4-year risk of 5–7%. In recent years, deep learning techniques have been applied to more precisely predict PDAC risk from disease trajectories. Cost-effectiveness analysis suggests early detection programmes become viable when 3-year PDAC incidence exceeds 2% and at least 25% of PDAC are detected at a localized stage [7].

Once HRIs of sporadic PDAC have been identified, the focus of targeted early detection strategies is on developing biomarker and imaging-based modalities that will assist in early PDAC detection in HRIs. Bengtsson et al. [9] review current approaches to early detection biomarker development. There are now more than 10 ongoing controlled prospective clinical trials evaluating the efficacy of various novel biomarkers for early PDAC detection [10]. Quite a few of those novel biomarkers are very promising. For the time being, CA 19-9 yet remains the only valid biomarker, whose use in PDAC management is evidence-based.

Small isoattenuating PDACs often remain undetected to the clinical radiologist, as they are imperceptible to the human eye. This is a major obstacle to early-stage PDAC detection. Early detection initiatives now apply artificial intelligence to overcome those inherent limitations of conventional radiologic assessment by leveraging radiomics and deep learning models to extract subtle imaging signatures of PDACs. Antony et al. [11] point out that artificial intelligence driven models have the ability to detect prediagnostic PDACs on computed tomography scans months to years before clinical presentation by identifying textural and structural changes in the pancreas. Furthermore, automated volumetric pancreas segmentation may enhance reproducibility and may facilitate the discovery of imaging biomarkers that are associated with early carcinogenesis.

Quite an ambitious goal is to diagnose pancreatic neoplasms at those early stages, when they are still restricted to the pancreatic ductal epithelium, known as high-grade PanIN (HGPanIN)/carcinoma in situ (CIS, stage 0). In this issue, Masataka Kikuyama [12] describes serial pancreatic juice cytologic examinations in HRIs, in particular in patients with radiologically detected focal pancreatic parenchymal atrophy, as a promising method for diagnosing very early (HGPanIN or CIS) pancreatic neoplasms. Focal pancreatic parenchymal atrophy patients are known to harbor either HGPanIN/CIS or invasive PDAC in up to 30–50% of cases. Furthermore, the approach of Masataka Kikuyama [12] allows to study novel PDAC biomarkers specifically in pancreatic juice and at stages, when they are detectable only in pancreatic juice.

Finally, Poppinga et al. [13] stress that surgical resection remains the only curative treatment option for early-stage PDAC. Important to note, surgical R0-resection of a small (<1 cm) PDAC (pT1 R0 pN0 pL0 pV0 Pn0 M0) can result in a 5-year survival of up to 80%. The curative treatment option underscores the role of early PDAC detection. PDAC surgery, however, is associated with significant morbidity and mortality. In order to reduce in-hospital morbidity and to avoid in-hospital mortality, surgery of early-stage PDAC has been centralized in several countries to few high-volume centers [14, 15].