Leading the revolution in pancreatic cancerlols10外围官网
Pancreatic cancer is the 4th leading cause of cancer death in the western countries and the 7th leading cause globally, due to the complexities in its biology and management.1,2 In addition to this, it has one of the worst survival rates of all common cancers, with only 9% of patients with advanced (metastatic) disease surviving more than five years after diagnosis.2,3 Pancreatic ductal adenocarcinoma (PDAC) is the most common form of pancreatic cancer (accounting for 95% of cases4) compared with neuroendocrine tumours (PNETs) or islet cell tumours which are far less common.4lols10外围官网
PDAC is considered to be one of the most aggressive forms of cancer.5 Due to the diversity of genetic mutations and dense connective tissue that forms the pancreas, PDAC belongs to one of the most chemo-resistant cancers.1,6 PDAC has an extremely poor prognosis shown by a one-year survival rate of around 20% for all stages of the disease.7 To date, the causes of pancreatic cancer are not well understood, although certain risk factors such as smoking, diabetes, obesity and chronic pancreatitis have been identified.2lols10外围官网
The pancreas itself is a gland organ located in the abdomen near the liver. The pancreas plays a dual role in regulating bodily functions8:
- Endocrine system – here, the pancreas secretes hormones, including the blood sugar-regulating hormones insulin and glucagon
- Exocrine system – here, the pancreas secretes enzymes into the digestive tract through a duct into the duodenum
Pancreatic neuroendocrine tumours (PNETs), or islet cell tumours as they are commonly known, are a rare type of cancer that form in the endocrine cells.9 PNETs make up less than 2% of all pancreatic cancer cases and have a better prognosis compared to more common types of cancer.7lols10外围官网
Exocrine tumours account for 95% of pancreatic cancers and the most common type of exocrine tumour is PDAC.4 PDAC develops from the cells which line the ducts in the pancreas. These ducts carry the digestive juices, which contain enzymes, into the main pancreatic duct and then into the first part of the small intestine.4lols10外围官网
As this disease has the potential to spread quickly and symptoms often do not present until the later stages, more than 80% of pancreatic cancer patients are diagnosed when the disease has already spread to other organs in the body - for these patients the average survival is less than one year.10,11lols10外围官网
The reasons for the potentially quick spread of this disease are multi-factorial including the close proximity of major blood vessels in the pancreas which can be readily invaded by cancer cells, and non-specific symptoms.12 As these identifiers are elusive, this makes diagnosis extremely challenging, significantly reducing the chances of survival, making it a silent killerlols10外围官网
Historically, it’s been known that patients with advanced pancreatic cancer have faced poor outcomes due to the aggressive nature of the disease and limited treatment advancements compared to other tumour types, particularly lagging behind other common cancers with regards to precision therapy.13lols10外围官网
Although the current standard treatment for pancreatic cancer is surgery, approximately 20% of patients with advanced disease are eligible because by diagnosis the cancer has already spread.14 Other limited options for treatment include chemotherapy and radiotherapy, highlighting a critical unmet medical need for more effective treatment options.15 The high burden of symptoms in advanced pancreatic cancer presents further challenges, as symptoms can interfere with treatment impact and quality of life.16lols10外围官网
In PDAC, some tumour suppressor genes (which actively prevent the formation of cancer) are commonly mutated resulting in aggressive tumour growth.17 These genes, including BRCA1/2, PRSS1 and CDKN2A, are just some of the predictive biomarkers for metastatic pancreatic cancer, and have uses far beyond just diagnosis; improving potential treatment outcomes and helping to identify familial risk.18,19lols10外围官网
The BRCA1/2 genes form part of the DNA damage response (DDR), which includes various pathways that repair DNA damage. When the BRCA genes are mutated, this repair process is hindered, and the risk of developing cancer increases.20 Around 5-7% of pancreatic cancer patients are predicted to harbour a germline BRCA mutation which can act as a determinate feature in accessing appropriate treatment options.21lols10外围官网
Cancer cells have high levels of DNA damage, loss of one or more DNA repair pathways, and experience increased DNA replication stress. These properties can lead to cancer-specific DDR dependencies that can be exploited as potential therapeutic targets. By researching agents that can specifically target these dependencies, treatments may have the potential to be effective as they actively target a fundamental feature of cancer cells and turn this against itself, resulting in cancer cell death.22lols10外围官网
For more information on exploiting cancer specific DDR-dependencies click herelols10外围官网
1. Zeng et al. (2019). Chemoresistance in Pancreatic Cancer. International Journal of Molecular Sciences, 20, pp.4504.
2. Rawla et al. (2019). Epidemiology of Pancreatic Cancer: Global Trends, Etiology and Risk Factors. World Journal of Oncology, 10(1), pp.10-27.
3. Tiriac et al. (2019). Organoid Models for Translational Pancreatic Cancer Research. Current Opinion in Genetics and Development, 54, pp.7–11.
4. Pancreatic Cancer UK. (2018). Types Of Pancreatic Cancer. Available at: https://www.pancreaticcancer.org.uk/资讯rmation-and-support/facts-关于-pancreatic-cancer/types-of-pancreatic-cancer/ [Accessed May 2020].
5. Guo et al. (2020). Preoperative detection of KRAS G12D mutation in ctDNA is a powerful predictor for early recurrence of resectable PDAC patients. British Journal of Cancer, 122, pp.857–867.
6. Adamska et al. (2017). Pancreatic Ductal Adenocarcinoma: Current and Evolving Therapies. International Journal of Molecular Sciences, 18(7), pp.1338.
7. Siddappa et al. (2019). Sa1375 – The Utility of Ca 19-9 in Patients Undergoing Eus for Pancreatic Ductal Adenocarcinoma: Single Center Experience Over 2 Decades. Gastroenterology, 156 (6)1, pp.331-332.
8. American Cancer Society. (2020). What is a pancreatic neuroendocrine tumor? Available at: https://www.cancer.org/cancer/pancreatic-neuroendocrine-tumor/关于/what-is-pnet.html. [Accessed May 2020].
9. Pancreatic Cancer Action. (2019) Pancreatic Neuroendocrine Tumours. Available at: https://pancreaticcanceraction.org/关于-pancreatic-cancer/what-is-pancreatic-cancer/pancreatic-neuroendocrine-tumours/ . [Accessed May 2020].
10. Kaur et al. (2012). Early diagnosis of pancreatic cancer: challenges and new Developments. Biomarkers In Medicine, 6(5), pp.597–612.
11. Azar et al. (2019). Treatment and survival rates of stage IV pancreatic cancer at VA hospitals: a nation-wide study. Journal of Gastrointestinal Oncology, 10(4), pp.703-711.
12. McGuigan et al. (2018). Pancreatic cancer: A review of clinical diagnosis, epidemiology, treatment and outcomes. World Journal of Gastroenterology. 24(43), pp.4846-4861.
13. Conroy et al. (2016). Current standards and new innovative approaches for treatment of pancreatic cancer. European Journal of Cancer, 57, pp.10-22.
14. Niesen et al. (2019). Surgical and local therapeutic concepts of oligometastatic pancreatic cancer in the era of effective chemotherapy. European Surgery. 51:153–164
15. Guidelines in Practice. (2016). Pancreatic cancer: GPs can help prognosis by identifying early signs. Guidelines in Practice. Available at: www.guidelinesinpractice.co.uk/cancer/pancreatic-cancer-gps-can-help-prognosis-by-identifying-early-signs/352855.文章 [Accessed May 2020].
16. White et al. (2019). Understanding Symptom Burden in Patients With Advanced Cancer Living in Rural Areas. Oncology Nurse Forum, 47(3), pp.305-317.
17. Grant et al. (2016) Molecular Pathogenesis of Pancreatic Cancer. Progress in Molecular Biology and Translational Science, 144, pp.241–275.
18. Ngamruengphong et al. (2016). Screening for Pancreatic Cancer. Surgical Clinics of North America, 96(6), pp.1223–1233.
19. Zhan et al. (2018). Germline Variants and Risk for Pancreatic Cancer: A Systematic Review and Emerging Concepts. Pancreas, 47(8), pp.924-936.
20. Stover et al. (2016). Biomarkers of Response and Resistance to DNA Repair Targeted Therapies. Clinical Cancer Research, 22(23).
21. Pishvaian et al. (2017). BRCA2 secondary mutation-mediated resistance to platinum and PARP inhibitor-based therapy in pancreatic cancer. British Journal of Cancer, 116, pp.1021–1026.
22. O’Connor (2015). Targeting The DNA Damage Response In Cancer. Molecular Cell, 60(4), pp.547-560.
Veeva ID: Z4-24277
Date of Preparation: 12/05/2020
Date of Expiry: 22/05/2022