Multigene panels can detect significant pathogenic mutations in a proportion of breast cancer patients who have tested negative for BRCA1/2 gene mutations, according to a new study.
The discovery of novel genes associated with cancer risk has led to new technologies to identify hereditary predisposition to breast cancer. “This has prompted re-evaluation of patients who previously tested negative for BRCA1/2 gene mutations, with a possibility of discovering new genes which may impact management,” said lead author Siddhartha Yadav, MD, of the Nancy and James Grosfeld Cancer Genetics Center, Beaumont Health System in Royal Oak, Mich.
Dr. Yadav presented the results of the study at the 2015 American Society of Clinical Oncology (ASCO) Breast Cancer Symposium in San Francisco, September 25-27, 2015 (Abstract 23).
Select patients who had tested negative for BRCA1/2 mutations, and had significant personal and family history of cancer, were referred back to the Cancer Genetics Center for additional testing by their medical oncologist or primary care physician between February 1, 2012, and May 30, 2015.
A detailed, updated personal and family history was obtained on 122 patients with a median age 54 years. The median duration between first testing and repeat testing was 4 years. Patients were counseled about the genetics and clinical implications of panel testing for multiple breast cancer genes.
Panel testing using next-generation sequencing technologies was ordered on five to 43 genes. Patients underwent repeat testing with multigene panels during the study period, and then were seen in follow-up for discussion of results and management.
The vast majority of the patients (92%) were Caucasian; 21 patients (17.2%) were of Ashkenazi Jewish ancestry. Almost all (94.3%) of the patients had a personal history of cancer, with a median age of first diagnosis of 45 years; 106 patients had a history of breast cancer.
“A total of 14 pathologic mutations (11%) were identified on repeat testing, which were deemed actionable and had an impact on patient management,” said Yadav.
About one-quarter of patients had at least one variant of unknown significance; five of these were seen in patients with a known pathogenic mutation and three others were later classified as benign.
The genes and frequencies of these mutations were: CHEK2(3), PALB2(3), ATM(2), APC(1), BARD(1), CDH(1), MUTYH(1).
In conclusion, Yadav said, “this study demonstrates the feasibility and potential clinical benefit of retesting individuals who previously tested negative for BRCA1/2 mutations. This approach had a significant management impact on patients and their families, with an 11% detection rate of pathogenic mutations.”
To be successful, retesting must have “an adequate infrastructure of provider and patient education, and access to and coverage of multigene panels,” Yadav said.