The current national Comprehensive Cancer Network Guidelines for Genetic/Familial High-Risk Assessment, Version 1.2020, have been expanded to provide information about pancreatic cancer in addition to recommendations regarding genetic testing in patients with breast and ovarian cancer.
Mary B. Daly, MD, PhD
The current national Comprehensive Cancer Network (NCCN) Guidelines for Genetic/Familial High-Risk Assessment, Version 1.2020, have been expanded to provide information about pancreatic cancer in addition to recommendations regarding genetic testing in patients with breast and ovarian cancer. This update was necessary because of evidence suggesting that a sufficient number of patients with pancreatic cancer carry alterations in high-penetrance breast and ovarian cancer susceptibility genes that warrant testing, includingBRCA1,BRCA2,CDH1,PALB2,PTEN, andTP53, among others.1Identifying a mutation in 1 of these genes in a patient could have significant implications for clinical decision making.
“The gene with the most mutations and, therefore, the greatest potential impact isBRCA2,” Mary B. Daly, MD, PhD, a medical oncologist in the Department of Clinical Genetics at Fox Chase Cancer Center, Philadelphia, Pennsylvania, and chair of the NCCN Guidelines Panel for Genetic/Familial High- Risk Assessment: Breast, Ovarian, and Pancreatic, said during an interview with Targeted Therapies in Oncology (TTO). Because BRCA2 mutations are also associated with pancreatic cancer, it was appropriate to add pancreatic cancer to the existing guidelines, Daly added.
The guidelines recommend that all patients with pancreatic cancer undergo genetic testing because the results of these tests can help determine the most effective treatments (eg, PARP inhibitors) and whether family members would benefit from screening and preventive action.1The updated guidelines now include more information about specific genes associated with pancreatic cancer.
“There’s been an explosion of recent data showing that roughly 4% to 10% of individuals with pancreatic cancer harbor inherited genetic mutations, including [in]BRCA1,BRCA2,ATM, the Lynch syndrome genes, and others,” Matthew B. Yurgelun, MD, a medical oncologist at Dana-Farber/Brigham and Women’s Cancer Center, Boston, Massachusetts, and member of the NCCN Guidelines panel, said in a statement.2 “Such data have, surprisingly, shown that classic ‘high-risk’ features of inherited cancer risk (eg, young age at diagnosis, strong family histories of cancer) are often absent in individuals with pancreatic cancer who carry these mutations. Based off of these data, there is now a compelling reason for all individuals with pancreatic cancer to be offered genetic counseling and germline testing for such variants, particularly given the possibility that their at-risk family members could greatly benefit from known, effective cancer riskreducing interventions (eg, surgical removal of the ovaries for female BRCA1/2 mutation carriers). Emerging data have also begun to suggest possible benefits to pancreatic cancer screening in select high-risk individuals who harbor such mutations. These new guidelines address many of the important nuances and limitations of this exciting and rapidly evolving body of literature.”
In both the previous and current versions of the guidelines, the testing criteria for high-penetrance breast cancer susceptibility genes recommend testing in scenarios that include patients who have Ashkenazi Jewish ancestry, any blood relative with a known pathogenic variant, or a personal history of breast cancer that was either diagnosed at age ≤45 years; diagnosed at age 46 to 50 years along with unknown or limited family history or a second breast cancer diagnosed at any age; or diagnosed at ≤60 years with triple-negative breast cancer.
Ashkenazi Jewish ancestry is of particular interest and is addressed in the updated guidelines, noted Daly, a member of the TTO Editorial Board, because of the increased risk of breast and ovarian cancer in that population. “There is a multisite study [NCT03351803] looking at universal testing for all people of Ashkenazi Jewish ancestry to determine which populations are affected and the rate of prevalence of mutations.” In a newly added guide for individuals of Ashkenazi Jewish ancestry who have not been diagnosed with cancer, the guidelines recommend genetic testing for the 3 Ashkenazi Jewish founder mutations in BRCA1/2. These individuals should be encouraged to consult with a cancer genetics professional. If the test results are negative for the founder mutations, and if the patient’s ancestry includes non-Ashkenazi ethnicity, comprehensive genetic testing should be considered. It should be noted that many physicians are moving away from this stepped approach, and the use of comprehensive multigene testing is increasing.
In the ovarian cancer setting, the guidelines recommend that any woman diagnosed with the disease, regardless of age or family history, undergo testing because the rate of finding a pathogenic genetic variant is high and the options for prevention are good, said Daly. The emergence of PARP inhibitors has ushered in a new realm of treatment possibilities and has expanded the implications of testing for these genes. “Now, PARP inhibitors are being made available to patients with pancreatic cancer who have BRCA mutations and also to men with prostate cancer,” Daly said.
The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic are created and maintained by an interdisciplinary panel of experts from the alliance of 28 leading cancer centers that make up the NCCN. NCCN panels also include patients and advocates to ensure that treatment recommendations meet the needs of people with cancer and their caregivers. Because this is an area that experiences constant change with the emergence of new evidence, the panel meets at least yearly to discuss questions, share ideas about how to update the existing guidelines, and review the literature.
Daly noted that the guidelines are evidence based and rely on solid evidence, rather than small, underpowered trials or studies involving extremely homogeneous populations. “The guidelines are driven by the best evidence that we have available,” she said.
“There is always an effort to streamline the information because one of the comments the panel receives is that the information is complex, lengthy, and dense,” Daly said. “We focused on the importance [for the clinician] of becoming familiar with genetic mutations in certain tumor types for therapy, and that’s going to continue to evolve as more and more new agents that target genetic mutations are developed.”
The guidelines also address what community oncologists or any clinician not specifically trained in genetics should consider when evaluating a patient who is considering genetic testing. “These guidelines give the clinician a guidepost for the kinds of questions to ask and the answers that are received,” said Daly. By becoming familiar with the guidelines, “physicians can determine if they can handle treatment themselves or if they need to refer the patient for further counseling and decision making.”
Li-Fraumeni Syndrome and Cowden Syndrome
The guidelines recognize that hereditary breast and ovarian cancers are linked to pathogenic or likely pathogenic variants in other genes besides BRCA1/2. Specifically, investigators have noted an increased risk of breast cancer in patients with Li-Fraumeni syndrome and Cowden syndrome, which are associated with germline variants in the TP53 and PTEN genes, respectively. These genes encode tumor suppressor proteins involved in processes such as DNA repair and regulation of the cell cycle. These syndromes can lead to the onset of breast cancer at an early age, as well as other cancers.1
Patients with Li-Fraumeni syndrome should receive breast cancer awareness education, breast screening, and a clinical breast examination every 6 to 12 months starting at 20 years of age. Breast screening recommendations are stratified by age: women aged 20 to 75 years should receive annual MRI screening with contrast, with the addition of mammography with consideration of tomosynthesis beginning at age 30. For women older than 75 years, management of cancer risk should be considered on an individual basis.
Patients with Cowden syndrome should be screened for breast cancer and other types of cancer, such as endometrial. At age 18 years, women with this syndrome should receive breast cancer awareness education. A clinical breast examination should be performed every 6 to 12 months, starting at age 25 years or 5 to 10 years before the earliest known breast cancer in the family, whichever comes first. The option of risk-reducing mastectomy should be discussed with patients if pathogenic or likely pathogenic variants have been identified through genetic testing.