Genetic Testing: A Breakdown of One Study Examining Clinical Decision-Making

By Michelle Bloom, PhD

The BRCA1 and BRCA2 genes are the two most commonly mutated and prominent genes linked to breast cancer susceptibility. Strong links between specific mutations and increased risk for the development of breast cancer have made BRCA1 and BRCA2 ideal targets for genetic testing. Prior to the recent technological revolution in gene sequencing, when it was more difficult and expensive, testing for hereditary breast cancer susceptibility was limited to mutations in BRCA1 and BRCA2 that had the highest prevalence and disease risk. Early on, financial burden also limited testing to people who were most at risk for having a mutation (i.e. had family history of breast cancer). Unlike tests for other genetic disorders, such as Down’s Syndrome and Huntington’s Disease, BRCA1 and BRCA2 test results came with uncertainty of breast cancer development. Understanding the meaning of these test results, therefore, was important to help guide patients through preventative options. Genetic testing is now becoming more widespread as the cost of gene sequencing decreases and as we learn more about which mutations leave us at risk for disease. One could even say we are currently in the midst of a gene sequencing revolution and it is, therefore, important for us to understand the impact of having more knowledge about our genetic make up.

Dr. Allison Kurian, an Associate Professor of Medicine and of Health Research and Policy at Stanford University and the Director of the Stanford Women’s Clinical Cancer Genetics Program, studies how gene sequencing is used in clinical decision-making. Her research focuses on analyzing the impact genetic testing has on patients, as well as how use of genetic testing is spreading. A recent study led by Dr. Kurian examined how different types of genetic tests are being used in clinical settings and how the those results effect treatment of breast cancer patients. By tracking genetic testing methods, results and cancer treatments in a large population, she and her colleagues were able to learn how testing patterns are changing over time and how testing for more than just the BRCA1 and BRCA2 genes affects patient treatment.

The study, published in May 2018 in JAMA Oncology, centered around a primary question: Does genetic testing for multiple cancer-susceptibility genes change treatment and cancer outcomes compared to testing only for BRCA1 and BRCA2? To answer this question, Dr. Kurian and investigators from around the country recruited breast cancer patients from Georgia and Los Angeles as a part of the iCanCare study. The Individualized Cancer Care study, which took place between 2012 and 2015, sought to understand how women with breast cancer and their doctors decide on test and treatment options. The study merged information from a survey given to each participant, clinical data about participants, and their genetic test results. The study, in total, analyzed data from 5,026 patients.

One of the main focuses of the study was to determine how testing for mutations in solely the BRCA1 and BRCA2 genes differs from testing for mutations in a panel of cancer-susceptibility genes, in addition to BRCA1 and BRCA2. As DNA sequencing technology becomes more powerful, costs are decreasing, making it easier to screen more genes at once. Genetic testing is offered by a number of different companies, each of which uses different methods for testing. Until the recent revolution in gene sequencing, tests for hereditary breast cancer risk only looked for specific known mutations, such as the three mutations in BRCA1 and BRCA2 that are common in Ashkenazi Jewish populations. In my first article, The Double-Edged Sword of Mutation, I discussed that mutations such as these common BRCA1 and BRCA2 mutations increase in frequency within specific populations, making them easy to identify, due to breeding within isolated communities. Other mutations, however, may also be hereditary, but do not arise in the population at such a high frequency. Now that companies sequence entire genes, identify all mutations and classify the likelihood that they could be pathogenic in the development of cancer, these tests are becoming more useful to a greater number of people. Dr. Kurian’s study focused on genetic testing from four laboratories: Ambry Genetics, GeneDx, Invitae, and Myriad. Each of these companies provides multiple types of tests geared toward breast cancer testing, some of which only test for mutations in BRCA1 and BRCA2 while others test additional known cancer-susceptibility genes.

The study tracked 5,026 participants over two years and analyzed their care and testing decisions and demographics. Of the 5,026 participants, one quarter had a genetic testing of either type. Although more participants had only BRCA1/2 testing, as compared to testing for additional genes (called multi-gene testing), the split between the number of participants who took one of the two tests was almost even. The investigators found, however, that over the two-year span of the study, the number of participants who opted for multi-gene testing increased significantly. Between 2013 and 2015 the rate of multi-gene testing grew from 4.8% to 19.6%, while the rate of BRCA1/2 testing decreased.

Genetic tests can provide a variety of results based on confidence that a mutation, also called a variant, is pathogenic. Negative results indicate that no variants with known pathogenicity are detected, while positive results indicate the presence of known pathogenic variants. A variant of uncertain significance (VUS) result, on the other hand, indicates that a mutation is present, but its pathogenicity is undetermined. The study compared results between the different types of genetic tests and revealed that VUS results were 10 times more frequent in the multi gene-sequencing test than in the BRCA1/2 test. The increase in uncertainty seen in the multi-gene test likely reflects the lack of clinically-relevant knowledge of, and research about, non-BRCA gene function in breast cancer development. As scientists test functions of these genes and mutations in cancer susceptibility, more VUS’s will be classified as either pathogenic or benign.

The most significant findings of the study were about the racial differences in test results. The study uncovered that there were higher rates of VUS results in Black and Asian populations as compared to White populations for both the BRCA1/2 and multi-gene tests. Awareness of breast cancer susceptibility has historically been high in the Ashkenazi population due to the prevalence of the three common BRCA1 and BRCA2 mutations. People in this group, therefore, are more likely to get tested. Due to this awareness, the lower rate of VUS results in White populations could be skewed if a high proportion of participants were of Ashkenazi descent. The study, however, importantly, identifies the need to study mutations in BRCA1, BRCA2, and other cancer susceptibility genes in order to classify more VUS and bridge the gap between ethnic and racial populations.

An additional goal of this study was to analyze how test results influenced treatment options, and prophylactic mastectomies, in particular. This study focused on how genetic tests affected individuals diagnosed with breast cancer and revealed that pathogenic variants found in non-BRCA genes did not influence patients’ decisions to have the procedure; this is compared to participants who received negative test results. The investigators pointed out that the lack of influence of these test results on decision-making is likely because pathogenic variants in non-BRCA genes have little-to-no effect on susceptibility to breast cancer. It is important to note this study analyzed patients who already had cancer diagnoses and thus may consider mastectomy as a treatment option, regardless of test result. It would, therefore, be interesting to study how genetic testing prior to cancer diagnosis is influencing preventative measures such as mastectomy.

The field of genetic testing has grown rapidly over the past few years. As use of these tests expands, it is important to understand how test outcomes influence the actions of people who get tested. Hereditary cancer genetic tests, specifically, have complicated consequences for patients due to the uncertainty of disease development. Ethical debates have swirled around how genetic testing for cancer mutations should be handled, most recently with the FDA approval of the 23andMe direct-to-consumer breast cancer test. Studying how patients approach these tests and the impact results have on decision-making can influence how to best guide patients in making the best decisions regarding preventative measures and treatment.

The study discussed in this article also explored how different genetic tests are being utilized and influence clinical decision-making. The study revealed that over time, multi-gene tests are beginning to replace BRCA1/2 only tests. Non-BRCA gene tests currently mainly confer results of mutations with unknown pathogenicity. Both BRCA1/2 and multi-gene test results in this study also showed a disparity in the amount of ambiguous (i.e. VUS) test results between different racial groups. Both of these findings highlight the need for additional research to determine the effects of genetic mutations on cancer susceptibility.

In order to improve the utility of genetic tests, scientists need to continue to study the function of cancer-susceptibility genes and how mutations affect the growth and properties of cells. Analysis of big data sets collected from genetic testing and precision medicine studies, as discussed previously in the BRCA Foundation Journal post, How "All of Us" can Contribute to Precision Medicine, can also help us classify more genetic variants. The more people who participate in genetic testing, whether or not they have a genetic disease, the more scientists can learn about the genes that are being tested.