10th September, 2019. Dr Chee L Khoo
Let’s face it. We all dread the diagnosis of pancreatic cancer in any of our patients. There aren’t too many red flags that we can rely on to warn us that something is not right with this deep seated abdominal organ. Many of the symptoms are either subtle or non-specific like nausea, intermittent epigastric pain, nausea, weight loss, loss of appetite or back pain. Pancreatic cancer is pretty much a universally fatal disease where the number diagnosed equal the number of deaths. Would it make sense then to screen for pancreatic cancer?
The US Preventative Services Task Force (UKPSTF) recently recommends against screening for pancreatic ductal adenocarcinoma (PDAC) in asymptomatic adults (1). PDAC is relatively rare with an incidence of ~12 per 100,000 in the average risk population. PDAC unfortunately progress rapidly, leaving us with only a small window of opportunity for early detection (2). Nonetheless, there are a few things we need to do if we were to improve on those grim statistics:
Identification of at-risk groups
If we can detect and treat pre-cancerous lesions that give rise to invasive pancreatic ductal adenocarcinoma, we may be able to prevent some patients from ever developing invasive cancer. Further, some of the immuno-therapy may work better if targeted at earlier lesions (see below).
Although PDAC is relatively rare, populations with a significantly increased risk can now be identified and their risk quantified (3). Germline variants such as BRCA2, BRCA1, p16/CDKN2A, PALB2, STK11, ATM, PRSS1, and the DNA mismatch repair genes (4,5) have been found to increase the risk of pancreatic cancer.
Intraductal papillary mucinous neoplasms (see below) have been reported in patients with Peutz–Jeghers syndrome and McCune–Albright syndrome and in patients with familial adenomatous polyposis (6-9). Some studies have suggested that BD-IPMNs and BD-IPMN–associated cancers may be particularly common among patients with a history of a first-degree family member with PDAC.
A number of precursor lesions like pancreatic intraepithelial neoplasia, intraductal papillary mucinous neoplasms and mucinous cystic neoplasms are increasingly being detected on CT and MRI scans. Up to 15% of PDACs are thought to arise from mucinous pancreatic cysts which include intraductal papillary mucinous neoplasms (IPMNs) and mucinous cystic neoplasms (MCNs) (10).
IPMNs can be further categorised into either branched duct IPMN (BD-IPMN), main duct IPMN (MD-IPMN) or mixed type IPMN (MT-IPMN). PDAC is reported in 11%–80% of MD-IPMNs and 20%–65% of MT-IPMNs while BD-IPMN is documented in 1%–36% of surgical resections.
Approximately half of all pancreatic cysts are BD-IPMN. Advanced age, chronic pancreatitis, diabetes and insulin use are risk factors for PDAC in these patients. Longstanding type 2 DM is a modest risk factor for PDAC, New onset diabetes is a manifestation and harbinger of PDAC. New-onset diabetes mellitus in an elderly person significantly increases the likelihood that the person will be diagnosed as having pancreatic cancer.
We are already picking up IPMNs with CT scans although MRI or magnetic resonance cholangio-pancreatography (MRCP) is considered by many as the standard modality for diagnosing a BD-IPMN. Endoscopic ultrasound (EUS) can be useful for cases in which a diagnosis of a BD-IPMN is uncertain, a BD-IPMN that has worrisome features by CT/MRI, verification of malignancy in high-risk individuals and the identification of concomitant carcinomas with a sensitivity of up to 88%. The true utility of EUS is enhanced when coupled with fine-needle aspiration of pancreatic cyst fluid (PCF) that can be used for biochemical, cytologic, and DNA analyses.
Pancreatic cyst fluid analysis
High concentrations of carcinoembryonic antigen (CEA) (>192 ng/mL) within PCF are reflective of a mucinous pancreatic cyst with a 57%–79% sensitivity. However, sufficient PCF is not always available for CEA testing. Next-generation sequencing (NGS) has emerged as an adjunct to the evaluation of PCF. DNA shed from the exfoliated epithelium cells into the PCF can be analysed for an increasingly wide range of genomic alterations. Several other genetic, epigenetic, proteomic, and carbohydrate-based PCF biomarkers that are currently being validated for clinical use.
However, the majority of these biomarkers have not been rigorous validated. The Pancreatic Cyst Biomarker Validation Study is an ongoing double-blinded PCF biomarker study seeking to explore the role of these biomarkers (11).
Consensus and evidence-based guidelines for pancreatic cysts and, specifically, BD-IPMNs have been developed by several medical societies (3). Although the surveillance strategies for BD-IPMNs differ among these guidelines, they all agree that the risk of malignancy should be weighed against life expectancy and comorbidities. Despite the development of guidelines for the management of BD-IPMNs, it is still challenging to determine which BD-IPMNs harbour PDAC and even more difficult to determine which BD-IPMNs will undergo malignant transformation within the patient’s lifetime.
Better non-surgical treatment
For patients with resectable PDAC, traditional management is comprised of surgical resection followed by adjuvant therapy, although the role of neoadjuvant chemotherapy is being evaluated. Targeted and immunotherapies in numerous clinical trials have so far failed to improve overall survivals (OS). A primary reason for resistance likely lies in the highly immunosuppressive tumour micro-environment and stroma, along with low neo-antigen burden, both of which inhibit infiltration and recognition by effector T cells (12,13). In other words, PDAC is generally a “non-immunogenic” tumour that is resistant to immune recognition and killing.
Immune checkpoints enable self-tolerance and prevent autoimmunity under normal physiological conditions but they often become co-opted by tumours to prevent the immune system from mounting effective anti-tumour responses. Immune checkpoint inhibitors (ICI) have been beneficial in melanoma, renal cell carcinoma, lung and bladder cancers but have shown limited success in patients with PDAC.
One of the strategies being explored is to improve response to ICIs by making the PDAC tumour cells more immunogenic. To “infect” the PDAC tumour cells, whole cell, bacterial-based and yeast based vaccines are being developed (14). Immunotherapy is likely most effective when given closer in time to tumour initiation, when immune suppressive mechanisms are fewer and easier to bypass. Many promising combination therapies remain to be explored in ongoing and upcoming clinical trials.
Thus, if we can identify patients who are at high risk in developing PDAC, we can detect these cancers early so that our immunotherapy can have a better chance to work.
- US Preventive Services Task Force. Screening for pancreatic cancer: US Preventive Services Task Force reaffirmation recommendation statement [published online August 6, 2019]. JAMA. doi:10.1001/jama.2019.10232
- Yu J, Blackford AL, Dal Molin M,Wolfgang CL, Goggins M. Time to progression of pancreatic ductal adenocarcinoma from low-to-high tumour stages. Gut. 2015;64(11):1783-1789. doi:10.1136/gutjnl-2014-308653
- Singhi A, Koay E, Chari S, Maitra A. Early Detection of Pancreatic Cancer: Opportunities and Challenges. Gastroenterology 2019;156:2024–2040
- Roberts NJ, Norris AL, Petersen GM, et al. Whole genome sequencing defines the genetic heterogeneity of familial pancreatic cancer. Cancer Discov. 2016;6(2):166-175. doi:10.1158/2159-8290.CD-15-0402
- Hu C, Hart SN, Polley EC, et al. Association between inherited germline mutations in cancer predisposition genes and risk of pancreatic cancer. JAMA. 2018;319(23):2401-2409. doi:10.1001/jama.2018.6228
- Chetty R, Salahshor S, Bapat B, et al. Intraductal papillary mucinous neoplasm of the pancreas in a patient with attenuated familial adenomatous polyposis. J Clin Pathol 2005;58:97–101.
- Maire F, Hammel P, Terris B, et al. Intraductal papillary and mucinous pancreatic tumour: a new extracolonic tumour in familial adenomatous polyposis. Gut 2002; 51:446–449.
- Sato N, Rosty C, Jansen M, et al. STK11/LKB1 Peutz-Jeghers gene inactivation in intraductal papillarymucinous neoplasms of the pancreas. Am J Pathol 2001;159:2017–2022.
- Parvanescu A, Cros J, Ronot M, et al. Lessons from McCune-Albright syndrome-associated intraductal papillary mucinous neoplasms: GNAS-activating mutations in pancreatic carcinogenesis. JAMA Surg 2014; 149:858–862.
- Shi C, Hruban RH. Intraductal papillary mucinous neoplasm. Hum Pathol 2012;43:1–16.
- Singhi AD, Feng Z, Goggins M, et al. Pancreatic cyst biomarker validation study. Early Detection Research Network: National Cancer Institute. https://edrn.nci.nih.gov/protocols/428-pancreatic-cyst-biomarker-validationstudy.
- Laheru D, Jaffee EM. Immunotherapy for pancreatic cancer – science driving clinical progress. Nat Rev Cancer. 2005;5(6):459–67.
- Zheng L, Xue J, Jaffee EM, Habtezion A. Role of immune cells and immune-based therapies in pancreatitis and pancreatic ductal adenocarcinoma. Gastroenterology. 2013;144(6):1230–40.
- Wu AA, Jaffee E, Lee V. Current status of immunotherapies for treating pancreatic cancer. Curr Oncol Rep. 2019;21(7):60. doi:10.1007/s11912-019-0811-5