Why is pancreatic cancer so lethal?

By Yuki Agarwala

Pancreatic cancer is known to be one of the deadliest cancers in the world: in the UK, the survival rate is only 7.3% after 5 years, and drops to under 2% after 10 years (Pancreatic cancer, 2021). As the 10^th most common cancer in the UK, pancreatic cancer is not extremely common, but once it is diagnosed, the survival rate is not high. There has not been significant improvement in the survival rate in the UK, either. Why is this? What makes pancreatic cancer so difficult to diagnose and treat?

It is important to note that many patients are often misdiagnosed as having pancreatic cancer, even though they have other diseases such as neoplasms, which can be benign or malignant (cancerous) (NCI Dictionary, n.d.). This may have inflated the statistics on the survival rate of pancreatic cancer patients, and the actual rate could be even lower (Pancreatic cancer, 2021).

95% of pancreatic cancers, or malignant neoplasms, originate in the ducts and are known as pancreatic ductal adenocarcinomas (PDAC) (Cid-Arregui, 2015). Other malignant neoplasms include neuroendocrine tumors, which secrete hormones, and acinar carcinomas, which secrete digestive enzymes (Kleeff, 2016). The incidence of PDAC has been rising over the past few years. As a lethal disease, it is often only diagnosed in the late stages, during which radical resection or the surgical removal of the pancreas becomes extremely difficult. The genetic characteristics of the cancer means that it is very easy for the tumor to grow and metastasize. This involves important adaptations including cellular metabolism, signaling, and adhesion (Cid-Arregui, 2015). These tumors have also been determined to develop dense desmoplastic stromata which facilitate resistance to chemotherapy and radiation. While stromata are crucial for resistance to therapy, some cases of therapy-resistant tumors without stromata have also emerged. Studying these types of tumors will be key to understanding the function of stromata and how they can contribute to the treatment of pancreatic cancer (Hruban et al, 2019). Thus, the genetic makeup of pancreatic tumors, in conjunction with their ability to develop dense stromata, makes pancreatic cancer very difficult to treat. In fact, the 5-year survival rate for metastasized PDAC is a mere 2.3% in the US. The majority of deaths are caused by metastasis of the original tumor, or the presence of many primary tumors, and the lack of an effective early detection system for PDAC renders it the most lethal cancer (Cid-Arregui, 2015).

Pancreatic cancers are very difficult to detect in the early stages because the tumors often do not have any specific or sensitive markers. The early stages tend to be asymptomatic, and when the cancer becomes detectable, it has often already metastasized. The few patients who do survive the cancer have often had a surgical resection, but their 5-year survival rate is a modest 15-25% (Kleeff et al, 2016). Research has shown that cancers almost always arise from pre-existing neoplasms which remain in the noncancerous stage for years before becoming active and metastasizing to other parts of the body. This provides a large window for early diagnosis and cure of pancreatic cancer. Two well-known pancreatic cancer precursors – intraductal papillary mucinous neoplasms (IPMNs) and mucinous cystic neoplasms (MCNs) – can be detected on imaging and followed clinically for years as they do not rapidly progress into invasive cancers. If they do become invasive, this can often be identified on imaging. However, pancreatic intraepithelial neoplasia (PanIN), the third well-known pancreatic cancer precursor, is too small to detect via imaging and rapidly progress into invasive cancers. This makes early detection of these neoplasms very difficult (Hruban et al, 2019). 

It might be only natural to think that patients with small resectable pancreatic cancers would have a high survival rate. However, data have shown that among patients with small tumor sizes (<2cm) who had metastasis to the lymph nodes, more than 40% of patients died within 5 years (Egawa et al, 2004). This outcome is very different to small cancers in other diseases such as small (<2cm) node and hormone receptor-negative breast cancers which have an 88% 5-year survival rate. Thus, although late-stage detection of pancreatic cancer leads to its poor prognosis, early metastasis of the cancer is also responsible for its significantly lower survival rates (Hruban et al, 2019).

Scientists have found out that most pancreatic cancers are caused by activated Ras proteins, which are very difficult to target for drug development (Tempero, 2017). This is because most drugs are natural products or synthetic versions of these products. The only activated Ras inhibitors in nature compete with the ligand at the ligand-binding site of the cell surface receptor to reduce Ras efficiency or produce covalently modified Ras which are resistant to GTPase activating proteins. Since Ras are small enzymes, blocking active sites could reduce its biological function, but the phenotype of activated Ras is in itself is being caused by a loss of GTPase function. This makes it very difficult to attempt to restore Ras function via small molecules that target the active site of the enzyme (Mattingly, 2013). 

In terms of surgical procedures to remove the tumors, in stages I and II PDAC, the pancreas is usually resectable, but there is a large chance of the tumor metastasizing during or after surgery, leading to relapse. Recently, chemotherapy, chemoradiation, and many other therapies – together known as neoadjuvant therapy – have been provided to patients before surgery to shrink the tumors and make them resectable while also reducing the possibility of post-surgical metastasis.  While this has been shown to be more effective than other treatments, the survival rate for pancreatic cancer is still low due to difficulty in early diagnosis and cure of the cancer (Cid-Arregui, 2015).

Many factors contribute to the development of pancreatic cancer, including genetic predispositions and various risk factors. Much like other cancers, pancreatic cancer is not possible to resect at the late stage after it has already metastasized. However, it is unique in that it is very difficult to detect in the early stage due to a lack of symptoms and non-specificity of the markers on the cell. In addition, the rapid metastasis of even small tumors, and the challenges associated with targeting the activated Ras protein for drug development both contribute to the reduced possibility of curing the cancer. Further research into the origins of the cancer and the various factors that lead to the aggressiveness and poor prognosis of the cancer would be vital to reduce its lethality and thus improve survival rates.

References:

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2. NCI Dictionary of Cancer Terms (n.d). National Cancer Institute. Available from: https://www.cancer.gov/publications/dictionaries/cancer-terms/def/neoplasm [Accessed: 30 June 2021].
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