Genetic Testing Recommended for All Patients With Pancreatic Cancer

Elena M. Stoffel, MD, MPH

In a provisional clinical opinion (PCO), an expert panel convened by the American Society of Clinical Oncology (ASCO) has recommended that patients with pancreatic cancer undergo assessment of risk for hereditary syndromes that contribute to higher likelihood of pancreatic cancer. The PCO also defines criteria for those with a familial history of pancreatic cancer who should receive testing.¹

The PCO notes that recent evidence suggests that up to 10% of patients with pancreatic cancer have germline mutations that predispose them to cancers, adding that “pathogenic germline variants in specific genes have been associated with lifetime risks of pancreatic cancer ranging from 4% to 40%.” Common mutations in pancreatic cancer include BRCA1 and BRCA2, for which patients are screened in the setting of breast and ovarian cancers.

“The prevalence of genetic predisposition among patients with pancreatic cancer was much higher than we had originally anticipated, lead author Elena M. Stoffel, MD, MPH, said in an ASCO podcast about the PCO.² “This is relevant because in talking about pancreatic cancer as one of the deadliest cancers in the United States and worldwide, we are very interested in finding ways to reduce the morbidity from this cancer to patients and their families.”

The PCO recommends use of a multigene panel that tests for germline variants known to be associated with increased risk for pancreatic cancer, including BRCA1/2, CDKN2A, Lynch syndrome mutations, PALB2, and STK11, which is associated with Peutz- Jeghers syndrome (Table 1).³

The PCO does not carry the weight of a guideline change because the body of evidence is not strong enough, but the evidence trends in support of recommendations for germline and familial history pancreatic cancer testing do warrant issuance of the opinion at this time, said Stoffel, assistant professor of internal medicine and director of the Cancer Genetics Clinic at the University of Michigan in Ann Arbor. Stoffel is a member of the ASCO Committee for Cancer Genetics.

Recommendation for Comprehensive Review

Table 1. Syndromes and Gene Mutations Associated With Pancreatic Cancer³

Table 2. Modifiable Risk Factors Associated With Pancreatic Cancer⁷

The PCO recommends that a comprehensive review of family history of cancer be performed for patients with pancreatic cancer. Those with cancer affecting 2 firstdegree relatives fit the classification of having familial pancreatic cancer (FPC) under the PCO, and those with FPC and a history of 3 or more diagnoses of pancreatic cancer on the same side of the family, as well as patients identified as having genetic susceptibility for pancreatic cancer, are candidates for testing, according to the PCO. “Even if family cancer history is unremarkable,” it is appropriate to discuss genetic testing with individuals with a diagnosis of pancreatic cancer, the PCO states. The benefits and limitations of genetic testing for susceptibility should also be discussed with patients, the PCO states. This approach to screening will help answer questions commonly asked by patients with pancreatic cancer about the significance their own cancer has for family members and how to prevent them from developing pancreatic cancer, Stoffel said. “If 1 out of 10 patients with pancreatic cancer develops their cancer in the setting of a genetic predisposition syndrome, this has tremendous implications for management for them and their family members. One of the most common inherited cancer syndromes identified in families affected with pancreatic cancer is hereditary breast/ovarian cancer,” Stoffel said.

Incidence of Pancreatic Cancer

According to the PCO, results from recent studies suggest pathogenic germline variants predispose patients in 4% to 20% of pancreatic cancers. “The prevalence of germline mutations is especially high among individuals of Ashkenazi Jewish ancestry, as a result of the high prevalence of BRCA1 and BRCA2,” the PCO states. However, hereditary syndromes are not always apparent. “Approximately half of patients with pancreatic cancer found to carry pathogenic genetic variants have no family history of pancreatic cancer and/or do not meet clinical criteria for the hereditary syndrome corresponding to their genetic diagnosis,” according to the PCO.

ASCO reported that in the United States in 2018, an estimated 44,330 deaths were expected to result from pancreatic cancer and new diagnoses would number 55,440 (29,200 in men and 26,240 in women).⁴ The disease is responsible for approximately 3% of all cancers, and incidence rates are 25% higher in black people than in white people. Most cases of pancreatic cancer (94%) are exocrine adenocarcinoma, and the above statistics represent that form of the disease.

The average individual has about a 1% chance of developing the disease, and most pancreatic cancers (90%) are somatic and do not result from hereditary factors. Most who develop pancreatic cancer are >45 years of age; 90%, >55; and 70%, >65.5

African Americans have an approximately 50% to 90% higher risk of pancreatic cancer compared with white Americans.⁶ Established risk factors for pancreatic cancer such as smoking, long-term diabetes mellitus, and family history of pancreatic cancer account for 46% of instances of the disease in blacks and 37% in whites, “potentially explaining all of the excess risk among blacks.”⁶ Among women, heavy alcohol consumption (>7 drinks per week) and elevated body mass index are less accepted risk factors that in combination with established risk factors explain 88% of cases of the disease in black women and 47% in white women.⁶

Some of the above are considered modifiable risk factors for pancreatic cancer. Modifiable risk factors include smoking, alcohol, chronic pancreatitis, obesity, dietary factors, and infection. Nonmodifiable risk factors include age, sex, ethnicity, blood group, gut microbiota, diabetes, and family history and genetic susceptibility (Table 2).⁷

Pancreatic cancer is the eighth-most-common cancer in women and the fourth-leading cause of cancer mortality in both sexes, accounting for 7% of all cancer deaths. The 5-year survival rate for pancreatic cancer is 8%, although cancer stage is a factor. If the pancreatic cancer is detected early when resection remains a possibility, the 5-year survival rate is 32%. This includes 10% of cases of pancreatic cancer. Following spread to surrounding tissues or organs, the 5-year survival rate drops to 12%. The 5-year survival rate is 3% for the 52% of people who receive a diagnosis after metastasis to a distant part of the body.⁴

The overall incidence of pancreatic adenocarcinoma increased by 1.03% per year from 1974 to 2014.⁸

Surveillance for Individuals at High Risk

There are no large studies confirming that pancreatic cancer screening offers a mortality benefit; however, surveillance offers the potential for early identification of pancreatic neoplasms and downstaging of cancers, according to the PCO. In a study of 354 individuals at high risk for pancreatic ductal adenocarcinoma (PDAC) who were enrolled in screening studies, patients were evaluated at study entry by endoscopic ultrasonography and underwent surveillance with endoscopic ultrasonography, magnetic resonance imaging (MRI), and computed tomography. Pancreatic lesions with worrisome features (solid mass, multiple cysts, cyst size >3 cm, thickened/ enhancing walls, mural nodule, dilated main pancreatic duct >5 mm, or abrupt change in duct caliber) or rapid cyst growth (>4 mm/year) were observed in 19% (n = 68) of patients. Overall, 7% had neoplastic progression over a 16-year period. The authors concluded that 90% of PDACs detected during surveillance were resectable and that 85% of these patients survived 3 years.⁹

“There is still some controversy about how to screen individuals at risk for pancreatic cancer, [but] certainly there are some emerging data suggesting that this may have a role for early detection,” Stoffel said. “While there are some studies that have demonstrated that screening with MRI and endoscopic ultrasound has led to early detection and downstaging of cancers in some cases, larger studies are needed to be able to refine more specifically who and how to screen in individuals at risk for pancreatic cancer.” Risks of surveillance, including limitations and potential for overtreatment, should be discussed with patients.

For 90% of families who meet the criteria for FPC, genetic testing does not detect a pathogenic variant, and therefore environmental, epigenetic, or genetic factors may be involved and contribute to pancreatic cancer risk, according to the PCO. For this reason, healthcare providers with familiarity with diagnosis and management of hereditary cancer syndromes should be involved in determining the best strategies for testing and discussing findings with family members. The PCO also recommends a shared-decision path between physician and individual.

Those with familial history or germline susceptibility should be offered the option of consulting a genetic counselor and be informed that early-detection strategies have not been proved to prevent pancreatic cancer. In addition, such individuals should be told that germline variants associated with pancreatic cancer are also risk factors for other cancers, such as melanoma, breast and ovarian, prostate, brain, and colorectal.

Clinical Features in Hereditary Disease

Many patients who are genetically predisposed to pancreatic cancer do not demonstrate clinical features or a family cancer history typically associated with hereditary cancer; therefore, germline testing should be discussed with these patients with pancreatic cancer regardless of family history, the recommendation states. The opinion states that genetic risk evaluation should be offered to those with pathogenic cancer susceptibility gene variants, those without pancreatic cancer who meet criteria for evaluation for hereditary syndromes, and unaffected individuals who meet criteria for familial pancreatic cancer.

Regarding surveillance for individuals who are not affected by pancreatic cancer but have familial history or may have hereditary syndromes associated with pancreatic cancer, the PCO recommends use of MRI, magnetic resonance cholangiopancreatography, or endoscopic ultrasound but not cancer antigen 19-9 testing, which has low specificity and sensitivity and no established value in pancreatic screening of individuals at high risk.

No consensus exists for appropriate pathological targets for surveillance, but the PCO panel agreed that detection of high-grade dysplasia should be the “ultimate goal” to prevent invasive cancer.

Authors of the opinion noted that noninvasive biomarkers are not available for early detection of pancreatic cancer. Efforts have been made to develop tests for circulating tumor DNA, microRNA, exosomes, and immunological markers; however, none have proven utility for early detection of pancreatic cancer in asymptomatic individuals. This has partly to do with the relatively low incidence of pancreatic cancer (12.5 instances per 100,000 individuals) and a 1.6% lifetime risk in the United States.¹⁰

“For this reason, even the most diagnostically accurate blood tests may be only suitable for those at increased risk of developing the disease,” the authors wrote. Similarly, outside clinical trials, there is no evidence supporting circulating tumor DNA testing. The percentage of patients with stage I cancer who have detectable circulating tumor DNA is low, although its detection is associated with worse outcomes. “High circulating tumor marker levels will often reflect higher tumor burden rather than early detection.”

Although genetic testing has the potential to enable earlier treatment decisions in the course of a pancreatic cancer, there is a need for greater understanding of the significance and clinical value of the data that result from this testing, Stoffel noted. “I think that what we’re learning is with genetic testing, and particularly with multigene panel testing, we often find unexpected results. Certainly, variants of uncertain significance are not uncommon when multigene panel tests are used. And being able to interpret the clinical significance of some of these genetic test results can pose some challenges, especially for clinicians who don’t have specific expertise in genetics,” she added.

That said, genetic testing is a valuable tool that, given the trends supporting its value as a predictor of susceptibility, must be made available to patients who fit the criteria, Stoffel said. “We want to make sure that we have the resources to offer genetic testing to everyone who needs it.”

References

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8. Saad AM, Turk T, Al-Husseini MJ, Abdel Rahman O. Trends in pancreatic adenocarcinoma incidence and mortality in the United States in the last four decades; a SEER-based study. BMC Cancer. 2018;18(1):688. doi: 10.1186/s12885-018-4610-4.
9. Canto MI, Almario JA, Schulick RD, et al. Risk of neoplastic progression in individuals at high risk for pancreatic cancer undergoing long-term surveillance. Gastroenterology. 2018;155(3):740-751.e2. doi: 10.1053/j.gastro.2018.05.035.
10. Cancer stat facts: pancreatic cancer. Surveillance, Epidemiology, and End Results Program website. seer.cancer.gov/statfacts/html/pancreas. html. Accessed March 26, 2019.