Evidence is mounting for multigene panel testing in women with suspected familial breast and/or ovarian cancer.
Leif W. Ellisen, MD, PhD
Evidence is mounting for multigene panel testing in women with suspected familial breast and/or ovarian cancer. In a group of women who were candidates for genetic testing and who lacked the more commonBRCA1/2mutations, multigene panel testing identified almost 4% of individuals with less common deleterious mutations. Moreover, the majority of these mutations were actionable, meaning that identifying them warranted a change in clinical management.
The study, published online inJAMA Oncology, identified 63 individuals from more than 1046 study participants who tested positive for potentially deleterious genes other thanBRCA1/ BRCA2. The genetic test results led to a change in care for more than 50% of these patients, based on current National Comprehensive Cancer Network (NCCN) guidelines. Results also suggested that multigene panel assays could change management of more than 70% of family members of patients with breast and/or ovarian cancer, leading to more aggressive screening and prevention for those who test mutation positive.
"Multigene panel testing for hereditary cancer risk is becoming common and now costs less than single-gene testing used to cost. For this and other reasons, physicians are driven to order these tests for their patients. We were concerned about whether the findings do change management, which was the impetus for our study," said senior author, Leif W. Ellisen, MD, PhD, Breast Cancer Program Director at Massachusetts General Hospital in Boston, in an interview withTargeted Oncology. "We showed case by case that the majority of people with a family history who tested positive for other deleterious genes warrant a change in management, following current NCCN guidelines."
"Our study is a conservative estimation of actionability. We only included clear-cut cases as actionable, and we did not include negative findings, which would change management in some cases," Ellisen explained.
As distinct from most other genetic studies, these authors set out not just to identify other deleterious genes in this population, but also to evaluate the actionability of those findings.
"Actionability is a critical reason to order genetic testing, but defining actionability is not trivial. The authors use NCCN guidelines, but the NCCN recommendations are incomplete for many genes. [Thus], ... the utility of testing may be undervalued by current guidelines," wrote Elizabeth M. Swisher, MD, University of Washington Medical Center, in an accompanying editorial inJAMA.
The study included 1046 participants seen at three academic centers between 2001 and 2014: Massachusetts General Hospital, Beth Israel Deaconess Medical Center, and Stanford University School of Medicine. All participants were appropriate candidates for hereditary breast and/or ovarian cancer screening, and they lackedBRCA1/2mutations. Eighty-three percent had a personal history of breast and/or ovarian cancer, and 14% did not have cancer. Of those with cancer, more than 70% were younger than age 50 years at diagnosis.
Two multicenter tests were used: the 29-gene Hereditary Cancer Syndromes Test (Invitae) or the 25-gene MyRisk Test (Myriad Genetics). Multigene testing revealed that 3.8% (n = 40) of patients harbored other deleterious mutations, most commonly those associated with moderate-risk breast and ovarian cancer genes (CHEK2, ATM, andPALB2) and Lynch syndrome. An additional 23 patients were included in this analysis, because they were referred to the centers for similar criteria and family histories, and they had mutations comparable to the rest of the cohort. This brought the total of patients with deleterious mutations other thanBRCA1/2to 63.
The next part of the study looked at whether or not the positive test result would change management based on personal and family history alone. Thirty-three of 63 patients (52%) would receive additional recommendations for cancer screening, and/or prevention that followed gene-based and risk-based NCCN guidelines.
Nearly one-third of patients who were mutation positive (20 of 63) harbored mutations in high-risk genes associated with NCCN management guidelines, and in each case, the mutation finding would change the recommendations for screening and/or preventive surgery. For example, in 9 participants with mutations associated with Lynch syndrome, the finding would lead to heightened colorectal cancer screening for the participant and additional familial testing.
The majority of deleterious mutations were found in genes associated with moderate-to-low increased risk of breast or ovarian cancer. These mutations would alter risk estimates and management recommendations for testing in 20 of 36 families; a positive result would lead to a change in management.
Tests results can lead to changes in management, and sometimes, negative results can also impact management. For example, in sisters with a positive family history of ovarian cancer who areBRCA1/2negative, negative multigene panel results can avoid unnecessary risk-reducing salpingo-oopherectomy for first-degree relatives, Swisher noted in her editorial.
"Negative results can be difficult to interpret. To interpret them, you have to be confident that the cancer history is caused by mutations. In general, the higher the risk conferred by the gene, the more important a negative result," Ellisen commented.
Desmond A, Kurian AW, Gabree M, et al.JAMA Oncol. doi:10.1001/jamaoncol.2015.2690. published online August 13, 2015.