A pathogenic germline mutation rate of about 5% has been identified in women who had a family history of breast or ovarian cancer but no personal history of either disease.
A question assessed the risk of hereditary breast and ovarian cancer (HBOC) based on current National Comprehensive Cancer Network (NCCN) guidelines and identifed a pathogenic germline mutation rate of about 5% in women who had a family history of breast or ovarian cancer but no personal history of either disease. These women were designated as "unaffected" in the study. The rate is comparable to the rate found in women with known breast cancer, who were identified as affected patients in the study conducted at The Outer Banks Hospital (OBH) in North Carolina. Among women unaffected by breast or ovarian cancer, 21% screened met the NCCN criteria for testing. Results were presented during the 2020 American Society of Clinical Oncology (ASCO) Virtual Scientific Program.1 The initiative was funded by a grant from the Association of Community Cancer Centers.
“We assumed that about 5% to 10% of women would need to be seen and counseled for genetic testing for BRCA and other genes related to breast and ovarian cancers,” said lead investigator, Charles H. Shelton, MD, a radiation oncologist and chair of the cancer committee at OBH. “We were shocked to find that 21% of women with no personal history of cancer met the guidelines for testing.” (FIGURE 1).1
In the first 8 months of the study, investigators screened more than 3000 women at the OBH, which typically conducts 4500 mammograms annually. The questionnaire was offered at the time of routine screening mammography for all women presenting to the OBH, including both unaffected and affected patients. It was also offered in a primary gynecology care setting to study younger patients who had not undergone mammography screening. These patients were unaffected and younger than 40 years old.
In this unaffected population, 1 in 590 patients screened for hereditary breast and ovarian cancer (HBOC) carried a known BRCA mutation. Further, investigators found in the unaffected population that some pathogenic mutations (BRCA or non-BRCA) occurs at a rate of 1 out of 295, which increases a patient’s risk for developing HBOC-related cancer.
Previously, these investigators examined various risk factors for breast cancer in the population and noted a high percentage of patients with breast cancer who had family members with the disease.2 In their initial study, they found that more than 50% of women with breast cancer had a family history with 1 or more direct relatives with the same type of cancer—either breast or ovarian cancer, Shelton said during an interview with Targeted Therapies in Oncology. This was the first indication that there was inherent familial risk that was higher than expected.
Efforts to carry out population screening in the current study were hampered because of a lack of available genetic counselors to interpret and educate screened women about their results. Patients would often wait 3 months before being seen by a local geneticist, Shelton said. To address this challenge, he received online training from Stanford University to provide genetic counseling. In addition to Shelton’s training, a staff nurse with an interest in genetic counseling also participated in online genetics courses.
“We now counsel and test 100% of our patients who consent to testing,” Shelton said. Although the OBH only sees about 50 patients with breast cancer a year, the main focus of the initiative is to target the unaffected population. “Instead of only focusing on women with breast and ovarian cancer, we decided to be more proactive and identify women at risk for cancer when prevention could be offered,” added Shelton. OBH added additional clinic time to help address the patients who were interested in learning more, although Shelton says a small percentage of women did not want to be tested for reasons relating to life or disability insurance.
The women underwent multigene panel testing for 19 to 24 genes, with a median of 19 gene high- or moderate-risk panels for breast and gynecological cancers. At the time of the conference, 210 patients had completed counseling with 204 patients each completing panel testing and receiving post-testing counseling.
Shelton said that 10 pathogenic mutations were found out of 2950 unaffected patients screened by the family history questionnaires. Among patients who had completed panel testing, 5 were found to have a BRCA mutation, 5 were found to have a non-BRCA mutation (2 with PMS2, 2 with CHEK2, and 1 with PALB2). One patient had both a BRCA and PMS2 mutation and 1 patient had both a CHEK2 and PALB2 mutation.
A total of 183 patients who were counseled and tested were affected by cancer, resulting in 60% meeting the NCCN criteria, 57% eligible for testing, and 6% of those tested were found positive for a pathogenic mutation (FIGURE 2).
A total of 2950 patients with no cancer were screened, and 21% (613 patients) met the NCCN criteria, 33% were eligible for testing (204 patients), and 5% tested positive (10 patients) for a pathogenic mutation (FIGURE 3).1
During the study, 13 patients who had been screened developed a new breast cancer, but only 4 met the NCCN guidelines for testing and all 4 were negative.
Shelton also emphasized the high percentage of families with ovarian cancer. He had expected about a 1% incidence rate of ovarian cancer in women’s family histories. “We found 8% of women had a positive family history of ovarian cancer and almost 1% had multiple cases of ovarian cancer in their family. Similarly, 41% of women in our rural area have a family history of breast cancer, whereas in the general population, it is 15% to 20% with a positive family history,” he said.
Patients who the investigators were not able to reach will be contacted again on subsequent intake to establish a much larger data set. “I would like to see a larger population-based targeted screening and more compliance with follow-up attempts as a future way to get larger percentages of the population screened,” Shelton added.
Shelton said that for the next steps, he would like to see a similar model for at-risk screening in the urology clinic as well as a tool to screen for Lynch syndrome because it is a more common familial risk syndrome in the population. Whereas BRCA occurs in 1 in 800 people in the population, Lynch syndrome occurs in 1 in 279 people, almost 2 to 3 times more commonly.
“Testing of the population at risk can be done,” Shelton said. “We are a small critical access hospital and if we can do it and screen thousands of women, anybody can. We created a process for this that we think is a great model for a community hospital,” he concluded.
1. Shelton CH, Boehmer L, Weldon CB, et al. Population genetic screening for hereditary breast and ovarian cancer in at-risk patients: a novel testing and prevention model for community hospitals reveals high mutation rates rurally. J Clin Oncol. 2020;38 (suppl 15):1575. doi:10.1200/JCO.2020.38.15_suppl.1575
2. Shelton CH. Commission on Cancer Quality Study looking at risk factors for breast cancer at the Outer Banks Hospital, years 2015-2018, updated in 2019. American College of Surgeons Commission on Cancer. Accessed June 22, 2020. https://bit.ly/3e54FuI.