From the Guidelines
Pancreatic adenocarcinoma causes significant morbidity and mortality through several mechanisms, primarily due to its late diagnosis and aggressive nature, as evident from the high mortality rates and poor 5-year survival rates 1.
Mechanisms of Morbidity and Mortality
The disease leads to:
- Obstructive jaundice when tumors in the head of the pancreas block the bile duct, resulting in yellowing of the skin and eyes
- Weight loss and malnutrition due to decreased food intake and cancer-induced metabolic changes
- Severe abdominal and back pain as the tumor invades surrounding nerves and tissues
- Digestive problems from insufficient pancreatic enzyme production, causing malabsorption and diarrhea
- Diabetes development when the tumor destroys enough insulin-producing cells
- Frequent metastasis to the liver, lungs, and peritoneum, causing organ dysfunction
- Blood clots (thromboembolism) due to cancer-associated hypercoagulability These effects collectively contribute to the poor prognosis associated with pancreatic adenocarcinoma, with most cases being diagnosed at advanced stages when these symptoms become apparent 1.
Risk Factors
The major risk factors for pancreatic adenocarcinoma include:
- Tobacco
- Helicobacter pylori infection
- Factors related to dietary habits (high red meat, high alcohol intake, low fruit and vegetable intake, overweight/obesity, and type 2 diabetes mellitus) 1
- Chronic pancreatitis, irrespective of the cause (alcohol abuse, smoking, genetic mutations)
- Familial pancreatic cancer, defined as at least two first-degree relatives with pancreatic cancer, accounts for only 4%-10% of all cases, with variants in BRCA2 being the most common genetic abnormalities seen in familial pancreatic cancer 2
Prevention and Early Detection
Given the high mortality rates and poor prognosis associated with pancreatic adenocarcinoma, early detection and prevention are crucial, with a focus on identifying and screening high-risk populations before symptoms arise 1. Individuals from families at risk should receive genetic counseling and be considered for enrollment in investigational screening registries, with annual endoscopic ultrasound (EUS) and/or pancreatic magnetic resonance imaging (MRI) being the procedures of choice for surveillance 1.
From the Research
Causes and Characteristics of Pancreatic Adenocarcinoma
- Pancreatic ductal adenocarcinoma (PDAC) is a clinically challenging cancer due to its late stage at diagnosis and resistance to chemotherapy 3.
- The incidence of PDAC is increasing by 0.5% to 1.0% per year, and it is projected to become the second-leading cause of cancer-related mortality by 2030 4.
- More than 90% of pancreatic tumors are formed from ductal epithelium as pancreatic ductal adenocarcinoma (PDAC), which often accompanies the expression of mutant K-ras 5.
- The dismal prognosis of this malignancy is contributed to its susceptibility to tumor micro-metastasis from inception and the lack of methods to detect precursor lesions at very early stages of the onset until clinical symptoms occur 5.
Risk Factors and Genetic Mutations
- Environmental pollution, obesity epidemics, and genetic mutations are expected to contribute to the increasing incidence of pancreatic cancer 5.
- Alterations in germline BRCA and PALB2 are detected in approximately 5-9% of patients with PDAC and can lead to homologous repair deficiency (HRD) 6.
- PDAC with HRD is more susceptible to cytotoxic agents, such as platinum salts and topoisomerase inhibitors, that cause DNA damage 6.
- Germline mutations in other genes involved in the homologous DNA repair pathway, such as ATM and RAD51, are potential targets for therapy 6.
Current Treatment Options and Challenges
- Effective screening is not available for PDAC, and most patients present with locally advanced or metastatic disease at diagnosis 4.
- A multidisciplinary management approach is recommended, including surgery, chemotherapy, and radiation therapy 4.
- Current treatment paradigms for pancreatic cancer have shortcomings, and targeting major driver mutations in pancreatic cancer has failed to improve survival outcomes compared with nontargeted chemotherapy 7.
- Novel targets and drug development, such as Ras-binding pocket inhibitors, nanomedicine, and drug delivery, are being explored to overcome these clinical challenges 7.