October 2015, Vol. 4, No. 5

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New Data Suggest Clinicians Should Consider Genetic Counseling and BRCA1/2 Testing for Any Patient with Pancreatic Adenocarcinoma

Cristi Radford, MS, CGC

Genetic Counseling

Pancreatic cancer represents 3% of new cancer cases each year, with the average age of diagnosis being 71 years.1 The most common type of pancreatic cancer is pancreatic ductal adenocarcinoma (PDAC), which originates from exocrine cells. Although pancreatic cancer accounts for a small percentage of cancers each year, its survival rate is low. Only approximately 7% of individuals diagnosed with pancreatic cancer will survive 5 years.1 Part of the poor prognosis has to do with the rapid progression of the disease and difficulty detecting it early. However, even when diagnosed early, the majority of patients do not survive. Its etiology is poorly understood, and surveillance and treatment options are lacking. Similar to other cancers though, at least 10% of cases are due to inherited factors. Additionally, the gene change that placed the individual at an increased risk of developing pancreatic cancer also places him or her at an increased risk of other cancers. Family members are at risk of carrying the same mutation, and identifying these at-risk family members provides an opportunity for prevention and/or early detection.

Until recently, data surrounding the prevalence of BRCA mutations in unselected, consecutive clinic-based patients with incident PDAC was not available. Previous studies did not include full analysis of both BRCA1 and BRCA2, were ancestry based, called for probands to meet certain family history requirements, and/or were retrospective cohorts. The recent study by Holter and colleagues is unique in that it analyzed BRCA1 and BRCA2 in 306 incident patients with PDAC who were not selected based on family history.2 Pathogenic BRCA mutations were found in 4.6% of individuals. BRCA2 mutations (3.6% of individuals) were more common than BRCA1 mutations (1% of individuals). When ancestry was considered, the chance of having a mutation if of Ashkenazi descent was 1 in 10 and if of non-Ashkenazi descent, 1 in 27.

Further, individuals with more than 1 cancer, as well as those who met 2014 National Comprehensive Cancer Network (NCCN) BRCA testing criteria were more likely to have a BRCA mutation than those who did not. Of interest, however, is that over half of the individuals with more than 1 cancer did not have cancers typically associated with BRCA1/2. These cancers included Hodgkin lymphoma, transitional cell carcinoma of the bladder, and thyroid cancer. Relying on a testing strategy depending only on meeting NCCN BRCA testing criteria would have missed 8 individuals, or 57% of those who tested positive for a BRCA mutation.

In addition to BRCA1/2 analysis, the first 79 patients were also tested for PALB2 mutations, and 44 individuals with a personal and/or family history of colorectal or endometrial cancer also underwent analysis for 3 of the 5 genes associated with Lynch syndrome (MLH1, MSH2, and MSH6). No pathogenic mutations were found in PALB2, MLH1, MSH2, or MSH6. Although no mutations were found, it should not be concluded that these genes do not have a role in increasing risk for PDAC, but rather that the chance of a mutation is low. Although this study did not, other studies did analyze other genes associated with Lynch syndrome (PMS2, EPCAM) or other genes suspected to have an association with PDAC, such as CDKN2A, STK11, APC, ATM, PRSS1, SPINK1, CTRC, and CFTR.3-5

Identifying individuals with pancreatic cancer who carry a mutation in BRCA1/2 is important as it provides an opportunity to test at-risk family members. BRCA mutations also confer an increased risk for breast cancer, ovarian cancer, and melanoma—cancers that have risk-reducing and surveillance options. As the paper by Holter and colleagues demonstrated, many of the individuals with mutations did not have family histories consistent with BRCA1/2 mutations. Therefore, as these family histories are not suggestive of a BRCA1/2 mutation, it is likely these family members would never be offered BRCA1/2 testing without the genetic knowledge provided from the individual with pancreatic cancer. Additionally, identification of BRCA mutations may have treatment implications in individuals with pancreatic cancer as the use of platinum-based chemotherapy and/or PARP inhibitors may result in increased survival. Further, long-term survivors of pancreatic cancer who carry a BRCA1/2 mutation are at increased risk of other cancers and should be managed accordingly.

In conclusion, the authors recommend that “…all Ashkenazi Jewish patients with PDAC and all non-Ashkenazi Jewish patients with PDAC and one or more first- or second-degree relatives with breast or ovarian cancer be offered genetic testing for BRCA1 and BRCA2” at the time of diagnosis. In addition, clinicians could consider adding other genes associated with pancreatic cancer to their analysis. At this time, the authors recommend panels be ordered only if the family history is consistent with more than 1 hereditary cancer syndrome. However, similar to the data presented in this study, the use of multigene panels in clinical practice continues to expand clinical phenotypes, and patients are continually being found to carry a mutation in an inherited cancer gene associated with their diagnosis and/or cancers in their family, even though they do not necessarily meet diagnostic, testing, or insurance criteria. Therefore, although the detection rate of each individual gene may be low, when analyzed together the chance of finding deleterious mutation increases. Genetic counseling is crucial in helping to tailor a testing strategy best suited for the individual patient.

References
  1. National Cancer Institute. Surveillance, Epidemiology, and End Results Program. Fact Sheet. Pancreatic Cancer. http://seer.cancer.gov/statfacts/html/pancreas.html. Accessed May 29, 2015.
  2. Holter S, Borgida A, Dodd A, et al. Germline BRCA mutations in a large clinic- based cohort of patients with pancreatic adenocarcinoma [published online May 4, 2015]. J Clin Oncol.
  3. Becker AE, Hernandez YG, Frucht H, et al. Pancreatic ductal adenocarcinoma: risk factors, screening, and early detection. World J Gastroenterol. 2014;20:11182-11198.
  4. Axilbund JE, Wiley EA. Genetic testing by cancer site: pancreas. Cancer J. 2012;18:350-354.
  5. Landi S. Genetic predisposition and environmental risk factors to pancreatic cancer: a review of the literature. Mutat Res. 2009;681:299-307.
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