Silent but deadly: pancreatic cancer

When we think of cancer, lung and breast cancer often come to mind because of their prevalence and the extensive awareness efforts surrounding them. However, pancreatic cancer remains largely unnoticed, despite being a serious challenge with one of the highest mortality rates among all cancers and a rising incidence. Its propensity for late detection makes it far deadlier than many realise. As the number of cases continues to rise, it is crucial to spotlight this relentless disease, explore why it is so difficult to treat, and examine ongoing efforts to change its trajectory.

Types of pancreatic cancer

• Pancreatic Ductal Adenocarcinoma (PDAC)
  This is the most common type of pancreatic cancer, accounting for about 90% of cases. It originates in the lining of the pancreatic ducts - tiny channels that transport digestive enzymes from the pancreas to the small intestine - and is categorised as an exocrine tumour. 
• Acinar Cell Carcinoma
  This rare and exocrine form, making up roughly 1% of cases, arises from the cells that produce digestive enzymes. 
• Pancreatic Neuroendocrine Tumours (NETs)
  Although rare, NETs develop in the hormone-producing cells of the pancreas. These tumours tend to grow more slowly and their behaviour can vary significantly, based on the hormones they release. 

Alarming statistics! 

Pancreatic cancer is the seventh most common cause of cancer death worldwide, ranking fourth in Europe and third in Northern America for lethality among all cancers. Despite advances in surgical techniques and therapy regimens, the 5-year survival rate for pancreatic cancer remains the lowest of any cancer type at just 13% across all stages. Even for the small percentage of patients (15%) diagnosed with localised disease, the survival rate is only 44%. NETs have a younger median age of diagnosis and a better prognosis with a 5-year survival rate of 53% all stages combined. Nevertheless, mortality rates are projected to increase by 42% in Europe over the next 15 years. 

Key risk factors for pancreatic cancer 

Several modifiable risk factors are associated with pancreatic cancer, including cigarette smoking, obesity, diabetes, and alcohol intake. The prevalence of these risk factors is on the rise globally, leading to increased incidence rates. Inherited genetic factors also play a critical role, such as pathogenic variants in hereditary cancer genes, related to hereditary pancreatitis, and common variants identified through genome-wide studies. 

Genetic mutations in pancreatic cancer 

Pancreatic cancer often involves specific genetic mutations and molecular changes that drive its growth. These changes can be inherited or develop over a person’s lifetime due to environmental factors or random cellular errors. Key mutations include: 

• KRAS Mutation: found in over 90% of pancreatic adenocarcinomas. 
• TP53 Mutation: a tumour suppressor gene that helps prevent cancer by repairing damaged DNA. 
• CDKN2A Mutation: encodes a protein that regulates the cell cycle. 
• SMAD4 Mutation: involved in cell signalling pathways, present in about 50% of pancreatic cancers. 
• BRCA1 and BRCA2 Mutations: impact DNA repair. 

Symptoms and diagnosis 

Symptoms of pancreatic cancer are often vague and non-specific, which can include abdominal pain, jaundice, weight loss, and new onset or worsening of diabetes. Because of these non-specific symptoms, pancreatic cancer is often detected at advanced stages.  

Non-invasive biomarkers are limited and only carbohydrate antigen 19-9 (CA19-9) can be used for monitoring the treatment response and recurrence in patients diagnosed with PDAC, but due to limited sensitivity and specificity of CA19-9, it is inadequate for diagnosis. Therefore, computed tomography (CT) is the main diagnostic tool, supplemented by abdominal MRI when CT results are inconclusive. 

Current pancreatic cancer treatments 

Surgical resection is the only potentially curative treatment for pancreatic cancer. For patients who undergo curative surgery, adjuvant chemotherapy with mFOLFIRINOX has become the standard of care. Neoadjuvant therapy, being chemotherapy or chemoradiotherapy, as preoperative treatment for patients with resectable pancreatic cancer is a valid strategy that gains momentum. 

For up to 85% of patients with pancreatic cancer whose tumours are not surgically resectable at the diagnosis, therapeutic options are limited. In this case, chemotherapy, such as gemcitabine or mFOLFIRINOX, have been the first-line therapeutic drug for some decades. 

A combination of nanoliposomal irinotecan with a 5-FU-LV regimen consisting of fluorouracil and leucovorin, offers a second-line treatment option, but no standard third-line regimen can be recommended due to poor nutritional status and/or poor performance status of the patients at this stage. 

Tumours in patients with BRCA mutations (5%-7% ) respond better to treatment with DNA crosslinking agents such as platinum compounds and poly (ADP-ribose) polymerase (PARP) inhibitors. 

In rare cases, people with microsatellite instability (MSI) in their tumours can be treated with the immune checkpoint inhibitor pembrolizumab.  

Research challenges 

Given pancreatic high mortality and complexity, new insights and treatments are urgently needed:

• Early detection
  Surgery offers the best chance of controlling pancreatic cancer for a long time, yet most patients are diagnosed at later stages and are not eligible for surgery. Tests to diagnose pancreatic cancer in the earliest stages are crucial. 
• Tumour access
  Pancreatic tumours are surrounded by a dense tissue layer, called the stroma, making it difficult for the treatment to reach the tumour. Research to get treatment through the stroma could enhance therapeutic efficacy. 
• Targeted therapies
  Some cancers have been successfully treated with targeted therapies which block specific mutations, but these drugs have not been developed specifically for pancreatic cancer so far. 
• Combination therapy
  Treating early-stage disease with new combinations of chemo- and immunotherapy, together with radiotherapy, could shrink tumours before surgical removal. 

How to help 

The Anticancer Fund is committed to developing more effective treatment strategies. Our ongoing STEREOPAC trial is a testament to this mission. This phase II, prospective, randomised, interventional study is currently examining the potential benefits of preoperative treatment with mFOLFIRINOX (or Gem-Nab-P) combined with or without isotoxic high-dose Stereotactic Body Radiation Therapy (iHD-SBRT) for patients with borderline resectable pancreatic adenocarcinoma. With 256 patients planned to be enrolled across more than 10 Belgian hospitals, our primary objectives are clear: to potentially improve surgical success rates and extend disease-free survival. 

Support our research 

Your support fuels these essential efforts. Every contribution brings us closer to breakthroughs that could alter the treatment landscape. 

For more information on how you can help, or to make a donation, please visit this webpage.

References 

Conroy, T. at el., Ann Oncol. 2023;34(11):987-1002 

NIH, cancer stat facts, https://seer.cancer.gov/statfacts/html/pancreas.html 

Hu, Z.I. et al, Nat. Rev. Gastroenterol. Hepatol. 2024; 21: 7–24 

Hallbrook C.J., et al., Cell 2023; 186: 1729-1754 

Kolbeinsson, H.M., J Invest Surg. 2023; 36(1):2129884 

Park, W. et al., JAMA. 2021; 326(9):851–862