Pancreatic Cancer: what we could do to catch it earlier

Many people may be surprised to learn that pancreatic cancer is currently the third leading cause of cancer deaths in the United States and expected to increase to the second leading cause by 2030 (1, 2). While other types of cancer are more commonly diagnosed, the difficulty with pancreatic cancer is that survival is often poor due to detection at an advanced stage of disease. (1)(3). Patient survival can be significantly improved with early detection and treatment, thus a need to identify higher risk patients for screening is critical. (4) 

The lifetime risk for pancreatic cancer in the general population is about 1.5%, however, some individuals are at an increased risk given their family and personal histories. (1). Individuals with a lifetime risk of approximately 5% are considered high risk.  Factors that make a person high risk include pancreatic cancer in a close relative, pathogenic/likely pathogenic variants (sometimes called a mutation) in genes known to increase pancreatic cancer risk, multiple affected relatives, or certain personal risk factors.   Empiric data suggests up to 10% of pancreatic cancer is due to a hereditary cancer syndrome or familial risk.  Knowing a patient’s personal and family history, and whether they carry a pathogenic or likely pathogenic variant associated with an increased risk of pancreatic cancer is critical in identifying patients who could benefit from appropriate high-risk cancer screening and surveillance. (1)

Several genes are known to increase the risk for pancreatic cancer. Although primarily thought of as hereditary breast and ovarian cancer genes, inherited mutations in BRCA1 and BRCA2 are found in about 5 to 9% of patients with exocrine pancreatic cancer and are known to increase the risk for this type of cancer. (1) Beyond BRCA1 and BRCA2, pathogenic and likely pathogenic variants in genes such as APC, ATM, CDKN2A, STK11, MLH1, MSH2, MSH6, PALB2, and TP53 have all been associated with an increased risk for exocrine pancreatic cancer, as well as other cancers. In addition, it is likely there are other genes that increase the lifetime risk for pancreatic cancer that have not yet been discovered. Multi-gene panels can analyze several genes simultaneously that are associated with pancreatic cancer and are available at many laboratories including Quest diagnostics.  

It is critical to obtain a thorough family history that includes 3 generations and inquire about cancer and tumor type, as many pancreatic cancer genes also increase the risk for other cancers.   Knowing the age at diagnosis is also important, as hereditary cancers are associated with younger ages at diagnosis.  Whenever possible, it is preferable to begin genetic testing with the affected person. When an affected family member is not available, testing an unaffected individual may be performed. In these cases, a panel test including multiple genes associated with pancreatic cancer risk should be considered.  Risk prediction models, like PancPRO, are also useful tools to estimate the likelihood of carrying a pathogenic or likely pathogenic variant associated with an increased risk for pancreatic cancer, as well as estimating possible future risk of developing pancreatic cancer.

 Genetic testing for pancreatic cancer susceptibility may be clinically indicated for the following reasons:

• Someone is affected with an exocrine pancreatic cancer
• People with first-degree relatives diagnosed with exocrine pancreatic cancer
• Those with any blood relative who has a known pathogenic or likely pathogenic variant in a cancer susceptibility gene
• There are multiple affected relatives, especially those of a younger age on the same side of the family with pancreatic cancer or a personal history of pancreatitis
• Patients with pancreatic neuroendocrine tumors

Screening, surveillance, and management of patients at high risk for pancreatic cancer is complicated and not without risk itself, as it could lead to unnecessary surgery.  The strategy may differ depending on several factors such as the presence of a specific germline variant and family history. Currently surveillance options include imaging by endoscopic ultrasound (EUS) or magnetic resonance cholangiopancreatography (MRCP). Referral to an experienced center is recommended. (5)

If you have questions about genetic testing for hereditary pancreatic cancer susceptibility genes additional information can be found at www.questhereditarycancer.com or by calling 866-436-3463.  For help with finding a genetic counselor in your area, see www.nsgc.org

References

1. Klatte DCF, Wallace, MB, et al, Hereditary pancreatic cancer, Best Practice & Research. Clinical Gastroenterology, Jan 2022, doi: 10.1016/j.bpg.2021.101783
2. An Update on Cancer Deaths in the United States | CDC
3. Wang W, Chen S, Brune KA, Hruban RH, Parmigiani G, Klein AP. PancPRO: risk assessment for individuals with a family history of pancreatic cancer. J Clin Oncol. 2007;25(11):1417-1422. doi:10.1200/JCO.2006.09.2452
4. Kartal K, Guan, Z et al, Familial pancreatic cancer: who should be considered for genetic testing? Irish Journal of Medical Science (2022) 191: 641-650. doi.org/10.1007
5. NCCN Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic Version 1.2023-Sept 7, 2022; https://www.nccn.org/professionals/physician_gls/pdf/genetics_bop.pdf