Claudine Isaacs, MD, on the Limitations of At-Home Genetic Tests for Hereditary Breast/Ovarian Cancers

More than 95% of BRCA1 or BRCA1 pathogenic variants would have been missed by DTC testing, largest such study showed

By Mark Fuerst

Direct-to-consumer (DTC) genetic testing has limited use as a screening tool for identifying individuals at risk of hereditary breast or ovarian cancer, especially in those of non-Ashkenazi Jewish descent, researchers reported.

Most current DTC genetic tests evaluate three Ashkenazi Jewish founder mutations in BRCA1/2, which represent only a small proportion of pathogenic or likely pathogenic variants in cancer predisposing genes, the team explained in their study in JCO Precision Oncology. This cost-effective way of testing can analyze common genetic variants within a population to determine traits such as ancestry, but performs poorly when genotyping rare genetic variants, such as those that can occur in cancer predisposition genes. Also, false positives can result from analytic issues or clinical misclassification.

The multicenter group of U.S. and British researchers by Claudine Isaacs, MD, of Georgetown University Medical Center, Lombardi Comprehensive Cancer Center in Washington, D.C., and colleagues designed a study to assess the potential limitations of DTC genetic screening for hereditary breast or ovarian cancer, as well as for other hereditary cancer syndromes.

In the following interview, Isaacs, medical director of the Jess and Mildred Fisher Center for Hereditary Cancer and Clinical Genomics Research, explains why DTC genetic testing has limited utility as a screening tool for these patients.

 

What does the study add to the literature?

Isaacs: This was the largest study conducted to date examining this question, including more than 300,000 individuals who underwent genetic testing through a CLIA [Clinical Laboratory Improvement Amendments of 1988]-approved laboratory. It demonstrated that DTC testing misses more than 90% of the mutations in actionable genes in individuals who are not of Ashkenazi Jewish descent.

Additionally, given the size of the study, it included substantial numbers of historically under-represented populations (about 25,000 Black and Hispanic individuals and about 15,000 Asians). Thus, it was able to demonstrate that more than 95-99% of BRCA1 or BRCA1 pathogenic variants would have been missed by DTC testing.

We also looked at mutations in other actionable genes and found that among the approximately 83,000 individuals undergoing more comprehensive testing — beyond BRCA1/2 — DTC would have missed 89% of mutations in one of the seven high-risk breast cancer genes, and about 95% of the mutations in 41 cancer risk gene panels. For individuals who reported partial Ashkenazi Jewish ancestry, about 30% of BRCA1/2 mutations would have been missed by DTC testing only the founder mutations.

 

What are the concerns with DTC testing?

Isaacs: The primary concern with DTC testing is that it tests for only a very limited number of mutations. Even with the recent addition of a number of other mutations to the DTC panel, the vast majority of actionable mutations would be missed in individuals of non-Ashkenazi Jewish descent. The major concern is that individuals who order these tests may have a false sense of security regarding their cancer risk upon receiving a negative DTC test result.

Additionally, individuals undergoing DTC testing can access raw DTC screening results and can enter their data into a publicly available database. We were also able to evaluate 287 individuals who reported positive results in a cancer risk gene in those who reported a non-Ashkenazi Jewish founder mutation. We found a very high false-positive rate — about 70% of the positives were in fact false positives.

 

What public and healthcare provider education do you think is needed to increase awareness about the limitations of DTC genetic testing?

Isaacs: The key is for providers and the public to understand that DTC testing provides very limited information about an individual’s risk of having a mutation in a hereditary breast cancer gene, and that a negative result from DTC testing should not provide false reassurance about cancer risk (this refers to individuals of non-Ashkenazi Jewish descent).

 

What future studies should be designed to garner data on family history and motivations for DTC testing?

Isaacs: It is clear that we need more accessible testing for a hereditary predisposition to cancer. A number of studies are underway addressing the utility of chatboxes and other techniques to enhance access to genetic testing.

 

What is your bottom-line message for practicing oncologists?

Isaacs: Do not rely on a result from DTC testing. This is true for individuals of non-Ashkenazi Jewish descent who receive a negative result, but it is also very important to confirm a positive result in a CLIA-approved laboratory, even for individuals of Ashkenazi Jewish descent who are found to have a mutation on DTC testing.

Read the study here.