Early Detection of Pancreatic Cancer—How?

World Pancreatic Cancer Day is being held on November 13. It is estimated that 367,000 new cases of pancreatic cancer will be diagnosed worldwide in 2015 and the dismal survival rate means that only 2–10% of patients will be alive 5 years after diagnosis.

Globally, pancreatic cancer is the seventh most common cause of cancer-related death, and while death rates for many cancers are dropping, the death rate for pancreatic cancer is rising in Europe and the United States.¹

The mortality of pancreatic cancer may, at least in part, be explained by the fact that early diagnosis is challenging. However, advances in the development of various biomarkers appear to hold promise for future screening of high-risk individuals, which—according to Cancer Research UK—includes patients with hereditary pancreatitis, a high incidence of pancreatic cancer in their family or a family history of at least one person with pancreatic cancer plus a linked cancer syndrome (e.g. a BRCA2 mutation).²

It has been reported that levels of serum cancer antigen 19-9 (CA19-9) are elevated in approximately 80% of patients with pancreatic cancer,³ and CA19-9 has been useful for therapeutic monitoring and early detection of recurrent disease after treatment in patients with known pancreatic cancer.⁴ However, CA19-9 is not a specific biomarker for pancreatic cancer. Moreover, patients who are negative for Lewis antigen a or b (approximately 10% of patients with pancreatic cancer) are unable to synthesize CA19-9. Although measurement of serum CA 19-9 levels is useful in patients with known pancreatic cancer, the use of this biomarker as a screening tool has yielded disappointing results.⁴

In addition to genetic alterations, dysregulation of specific epigenetic mechanisms is critical to tumour development. Comparing patients who have pancreatic cancer with healthy individuals and patients with chronic pancreatitis, Schultz et al. described differences in microRNA expression in whole blood with a view to identifying microRNA panels (classifiers) for diagnosing pancreatic cancer.³ microRNAs—non-coding 17–25-nucleotide-long RNAs that regulate gene expression—play important roles in tumour development and metastasis, and several have been described as specific to pancreatic cancer. Schultz and colleagues validated microRNA panels against CA19-9 sero-status and disease, and identified two panels for diagnosing pancreatic cancer using combinations of four and ten microRNAs in whole blood, respectively. The investigators call for further studies that could validate the use of these biomarkers as a screening tool for early-stage pancreatic cancer detection. More on the role of microRNAs in pancreatic tumour growth and progression can be found in a paper by Frampton and colleagues that was published in The Lancet in February 2015.⁵

Even more recently, in an article in Nature, Melo and colleagues⁶ suggested the use of a proteoglycan molecule (glypican-1 [GPC1]) anchored in the membrane of extracellular vesicles—exosomes—circulating in the bloodstream as a cancer biomarker. In particular, the team claimed that detection of GPC1⁺ exosomes in the blood could distinguish patients with early-stage and late-stage pancreatic cancer from patients with benign pancreatic disease and healthy individuals. The assay appeared more reliable than that based on CA19-9 detection. Compared with healthy donors, serum CA19-9 levels were increased in patients with cancer, but CA19-9 levels were also significantly increased in the serum of patients with benign pancreatic disease. Moreover, CA19-9 levels failed to distinguish patients with pancreatic cancer precursor lesions from healthy donors. An expanded interpretation of this important study, including a discussion of semantic issues, can be found in an accompanying News & Views article by Clotilde Théry.⁷

Apart from microRNAs, epigenetic features such as DNA methylation, satellite repeats and histone modifications might serve as biomarkers for early diagnosis of pancreatic cancer.⁸ Reviewing genes aberrantly methylated in pancreatic cancer, Henriksen and her team concluded that investigations into hypermethylated markers in cell-free DNA in plasma or serum are still limited by the availability of only a handful of small studies, which lack well-defined control groups, and that no single gene has been identified as a diagnostic marker.⁹

To read more about the many challenges related to identifying biomarkers for early diagnosis of pancreatic cancer, I recommend looking up a review by Jenkinson and colleagues.¹⁰ There are also a couple of interesting sessions from the recently concluded UEG Week 2015 in Barcelona that I’d like to highlight—all are available online. To learn more about ‘liquid biopsies’, including cell-free DNA, exosomes, and circulating tumour cells, you could look up the talk delivered by Aldo Scarpa, “Molecular diagnostics: From tissue biomarkers to liquid biopsies, single genes and panels”, which was part of the session “Pancreatic cancer: Where are we and what is the future?”¹¹ There’s also an update session on therapy, including talks on chemotherapy, surgical resection, preoperative and palliative treatment, and neoadjuvant and adjuvant treatment.¹² Finally, I would like to direct your attention to a talk that was given by Jean-Luc van Laethem, entitled “Pancreatic cancer in annual review”.¹³

Challenges aside, sensitive and specific biomarkers of early pancreatic cancer that can be obtained non-invasively appear critical to reducing the morbidity and mortality associated with pancreatic cancer. As we mark the 2015 World Pancreatic Cancer Day, we should set our hopes on it not being too long until one or more biomarkers prove valid for use in screening.

References

1. http://www.worldpancreaticcancerday.org/about/
2. http://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/pancreatic-cancer/risk-factors#heading-Eightteen
3. Schultz NA, Dehlendorff C, Jensen BV, et al. MicroRNA biomarkers in whole blood for detection of pancreatic cancer. JAMA 2015; 311: 392–404. http://jama.jamanetwork.com/article.aspx?articleid=1817797
4. Hidalgo M. Pancreatic cancer. N Eng J Med 2010; 362: 1605–1617. http://www.nejm.org/doi/full/10.1056/NEJMra0901557
5. Frampton AE, Castellano L, Colombo T. Integrated molecular analysis to investigate the role of microRNAs in pancreatic tumour growth and progression. Lancet 2015; 385 Suppl 1: S37. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)60352-X/abstract
6. Melo SA, Luecke LB, Kahlert C, et al. Glypican-1 identifies cancer exosomes and detects early pancreatic cancer. Nature 2015; 523: 177–182. http://www.nature.com/nature/journal/v523/n7559/full/nature14581.html
7. Théry C. Cancer: Diagnosis by extracellular vesicles. Nature 2015; 523: 161–162. http://www.nature.com/nature/journal/v523/n7559/full/nature14626.html
8. Fukushige S, Horii A. Road to early detection of pancreatic cancer: Attempts to utilize epigenetic biomarkers. Cancer Lett 2014; 342: 231–237. http://www.cancerletters.info/article/S0304-3835%2812%2900205-4/abstract
9. Henriksen SD, Madsen PH, Krarup H, et al. DNA hypermethylation as a blood-based marker for pancreatic cancer: A literature review. Pancreas 2015; 44: 1036–1045. http://journals.lww.com/pancreasjournal/Abstract/2015/10000/DNA_Hypermethylation_as_a_Blood_Based_Marker_for.5.aspx
10. Jenkinson C, Earl J, Ghaneh P, et al. Biomarkers for early diagnosis of pancreatic cancer. Expert Rev Gastroenterol Hepatol 2015; 9: 309—315. http://www.tandfonline.com/doi/full/10.1586/17474124.2015.965145
11. Pancreatic cancer: Where are we and what is the future? Session at UEG Week 2015. 
12. Therapy update: Pancreatic cancer Session at UEG Week 2015.
13. Pancreatic cancer in annual review Presentation by Jean-Luc van Laetham in the Pancreas: What’s new in 2015? Session at UEG Week 2015.