The past decade has seen a rapid expansion of genetic testing, including new tools to inform breast cancer patients about their risk of recurrence and guide their treatment.
But the clinical relevance of many inherited mutations that can now be detected remains unclear, and experts disagree about when and how to roll out newly available tests. Patients sometimes have to pay out of pocket for tests that aren’t yet standard of care, and even the most up-to-date oncologists can be unsure how to incorporate the flood of new information into standard treatment protocols.
A quarter of a century ago, Myriad Genetics launched the first breast cancer genetic test for BRCA mutations, two genes linked to a higher risk of breast cancer, ushering in a new era of genetic testing.
Mutations in the BRCA1 and BRCA2 genes account for up to half of hereditary breast cancers, and people with a problematic mutation in one of these genes have a 45% to 72% lifetime chance of developing breast cancer. They may have a higher risk of ovarian cancer and other types of cancer than people who do not have a deleterious mutation in BRCA.
But the clinical significance for other genetic tests is less clear.
Testing for the BRCA1 and BRCA2 genes used to cost thousands of dollars. Now, for a fraction of that price, doctors can order multi-gene test panels from commercial labs that look for mutations in dozens of genes. Some direct-to-consumer companies offer detection panels for several hundred dollars, although their reliability varies.
When Jane Carberry was diagnosed with breast cancer in 2017 at the age of 44, genetic testing identified a mutation in a gene called PALB2 that significantly increased her risk of developing breast cancer. The guidelines recommend that breast cancer patients with PALB2 mutations, such as those with BRCA1 and BRCA2 mutations, consider a mastectomy to reduce the chance of cancer recurrence.
“I wish genetic testing was the standard of care,” said Carberry, who paid nothing for the test because her insurer covered it.
Carberry, who lives in Sterling Heights, Michigan, said the test results confirmed her decision to have a double mastectomy and provided important information to her family members, including her 21-year-old daughter and her husband. They will likely be tested in their mid-20s or early 30s.
But some breast cancer experts worry that comprehensive testing may also identify genetic mutations whose effects are unclear, creating anxiety and leading to more tests and treatments of questionable value that could drive up system costs. Sanitary.
It can also confuse the patient.
“Patients come to us after having mixed results elsewhere,” says Dr. Mark Robeson, chief of breast medicine services at Memorial Sloan Kettering Cancer Center in New York. Robson explained that the cancer center has a clinical genetics service, made up of doctors and genetic counselors, who help make decisions about how to handle the results of these types of tests.
For people with breast cancer, many professional groups, including the influential National Comprehensive Cancer Network (NCCN), recommend limiting screening to some people with high-risk factors, such as a family history of breast cancer; who are 45 years of age or younger when diagnosed; and those of Ashkenazi Jewish descent.
But in 2019, the American Society of Breast Surgeons (ASBrS) recommended a different approach: offer genetic testing to all patients with or with a personal history of breast cancer. The recommendation was controversial.
“The NCCN guidelines cover most women who need testing, but we wanted to test them all,” said Dr. Eric Manahan, a surgeon general in Dalton, Ga., and a member of the ASBrS board of directors.
Mutations in other genes associated with breast cancer are much less common than mutations in BRCA1 and BRCA2 and usually do not increase the risk of developing breast cancer as much. The effect of these genes on cancer may be less clear than the BRCA gene, which has been screened since the mid-1990s.
And the appropriate response to less common mutations—be it a risk-reducing mastectomy or intensive screening—is often unclear.
“Things get even more confusing when you look at other genes,” said Dr. Steven Katz, a professor of medicine and health policy at the University of Michigan. “The risk of different types of cancer is less and less specific and more variable. You might be thinking to yourself, ‘Why do I need to know this?
Once breast cancer is diagnosed, genetic testing can help decide the type of surgery; For example, a high risk of recurrence or a new breast cancer may lead some people to opt for more extensive surgery, such as a double mastectomy. Testing can also give family members important information about their potential cancer risk.
(This type of genetic testing, called “germline,” looks for mutations in genes that people inherit from their parents. It’s different from tumor genomic testing, which looks for genes or proteins specific to cancer cells and can help doctors understand the rate. where cancer cells divide, for example, and how likely the cancer is to return).
Increasingly, genetic testing of germs can also help guide other treatment decisions. Some patients with metastatic breast cancer who have mutations in the BRCA1 or BRCA2 genes may be good candidates for PARP inhibitors, anticancer drugs that target tumors with mutations in those genes.
But genetic tests that look for inherited mutations in many other genes provide less clear information, although positive results can alert people.
At Memorial Sloan Kettering, oncologists have “therapeutic power,” Robeson said. Will the tests help provide guidance on whether someone should have a double mastectomy or something else? “A global testing policy would detect very few additional breast BRCA mutations, but it would cost a lot,” he added.
As a result, physicians debated how best to deploy and incorporate new genetic knowledge. And insurers are trying to figure out what they should pay.
There is an underuse of tests that science says are relevant and an overuse of tests that experts say provide information that cannot be explained with any scientific certainty.
The results can be confusing for newly diagnosed breast cancer patients, as they face the cost of genetic testing and sometimes little guidance on appropriate treatment.
Some doctors say the first step is to make sure that the small group who will clearly benefit get genetic testing that has clear meaning. Only 15% of breast cancer patients who met the NCCN’s selected screening guidelines for hereditary cancers received genetic testing, according to a 2017 study examining data from a National Health Survey between 2005 and 2015.
“I would say our focus should be on people at high risk of breast cancer who have not yet been diagnosed,” said Dr. Tua Pal, director of cancer health disparities at Vanderbilt-Ingram Cancer Center and vice president of the NCCN Guidelines Panel for Genetics/high-risk breast, ovarian and Family screening for pancreatic cancer.
Patients can fall through the cracks because no one tells them they need to be tested. In one analysis, 56% of high-risk breast cancer patients who did not undergo genetic testing said their doctors did not recommend it.
Even if physicians recommend genetic testing, they may lack the expertise to determine what testing is needed and how to interpret the results. This is the role of genetic counselors, but there aren’t many available.
The consequences can be serious. In a study of 666 breast cancer patients who underwent genetic testing, half of those at average risk of hereditary cancer underwent double mastectomy because they found “variants of uncertain significance,” which did not require clinical action. Up to half of surgeons reported treating these patients as having cancer mutations.
“Much of our research suggests that clinicians still have room for improvement in the training they need,” said study co-author Dr. Alison Kurian, director of the Women’s Cancer Clinical Genetics Program at Stanford University and co-author of the study.
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