Leading the revolution in pancreatic cancer
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.4
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.2
Through dedicated research and development, we now feel there is cause for optimism when it comes to this often-fatal cancer. To understand why pancreatic cancer presents such an intricate and complex challenge, we must first understand the crucial role that the pancreas plays in regulating bodily functions.
The pancreas – bringing balance to the body
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 cancer is classified into two main groups in line with two systems where the pancreas plays a key role - tumours that form in the exocrine cells and tumours that form in the endocrine cells.
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.7
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.4
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.10,11
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 killer.
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.13
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.16
Pancreatic cancer – is it possible this difficult disease could be biomarker-driven?
We have already come so far in understanding what biomarker status means for cancers such as breast, prostate, ovarian, lung, gastric to name a few. With the emergence of genomic profiling technologies, and selective molecular targeted therapies, biomarkers have now been shown to play an increasingly important role in the clinical management of pancreatic cancer patients.
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.18,19
Targeted cancer therapies are drugs that interfere with specific molecules involved in cancer cell growth and survival. In order to understand how targeted treatments work, it’s important to understand the mechanisms at play in cancer cells.
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.21
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.22
For more information on exploiting cancer specific DDR-dependencies click here
The future for pancreatic cancer research and development
The prevalence of pancreatic cancer will continue to climb if we do not instigate further breakthroughs in diagnosis and treatment. Current strategies to improve treatment outcomes focus on early detection through screening and biomarker testing with more effective, targeted treatments.
BRCA-mutated metastatic pancreatic cancer is a devastating disease with critical unmet need but with ongoing innovation in genetic testing, biomarkers, potential targeted therapies and continuous research, we move one step closer in helping to change the prognosis for patients with difficult-to-treat cancers like pancreatic cancer. AstraZeneca is committed to driving this progression and we strongly believe that to increase the pace at which progress is made in pancreatic cancer survival, we must push forward as a community to help raise awareness of the unmet need and to activate change where we know improvements can be achieved.
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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