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 significance of many of the inherited mutations that can now be detected remains unclear, and experts are torn about when and how to deploy all the new tests available. Patients are sometimes paying out-of-pocket for tests that are not yet standard of care, and even the most up-to-date oncologists may 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 associated with a substantially higher risk of developing breast cancer, ushering in a new era of genetic testing. BRCA1 and BRCA2 mutations account for half of all hereditary breast cancers, and people with a problematic mutation in one of these genes have a 45% to 72% chance of developing breast cancer in their lifetime. Those without the deleterious BRCA mutation may have a higher risk of ovarian and other cancers.
But the clinical significance is more unclear for many other genetic tests.
Testing for the BRCA1 and BRCA2 genes used to cost thousands of dollars. Now, for a fraction of that, doctors can order multi-gene testing panels from commercial labs that look for mutations in dozens of genes. Some direct-to-consumer companies offer screening 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 increases the risk of developing breast cancer. The guidelines recommend that breast cancer patients with PALB2 mutations, much like BRCA1 and BRCA2 mutations, consider a mastectomy to reduce the chance of breast cancer recurrence.
“I wish genetic testing was the standard of care,” said Carberry, who paid nothing for the test because her insurer covered the cost.
Carberry, who lives in Sterling Heights, Michigan, said the test results already confirmed the decision to have a double mastectomy and provided important information for family members, including her 21-year-old daughter and 18-year-old son. Those who are most likely to be tested are in their mid-20s or early 30s.
But some breast cancer experts worry that the comprehensive tests could also identify genetic mutations whose effects are unclear, creating anxiety and leading to more tests and treatments of questionable value that could raise costs for the health care system.
This can confuse patients.
“It happens a lot that patients find their way to us after getting confusing results elsewhere,” said Dr. Mark Robeson, chief of breast medicine services at Memorial Sloan Kettering Cancer Center in New York City. Robson said the cancer center has a clinical genetics service, staffed by doctors and genetic counselors, that helps people make decisions about how to handle genetic test results.
For people with breast cancer, many professional groups, including the influential National Comprehensive Cancer Network, or NCCN, recommend limiting testing to certain people with high-risk factors, such as a family history of breast cancer; who are 45 or younger when they are diagnosed; and those of Ashkenazi Jewish descent.
But in 2019, the American Society of Breast Surgeons recommended a different approach: offer genetic testing to all patients with or with a personal history of breast cancer. The recommendation was controversial.
“NCCN Guidelines [cover] Most were women who needed the test, but we wanted to get them all,” said Dr. Eric Manahan, a general surgeon in Dalton, Georgia, and a member of the Surgeon Group’s board of directors.
Mutations in other genes associated with breast cancer are much less common than BRCA1 and BRCA2 mutations and usually do not increase the risk of developing breast cancer as much. The cancer-causing effects of these genes may be less clear than the BRCA gene, which has been tested since the mid-1990s.
And the appropriate response to less common mutations – whether risk-reducing mastectomy or step-up screening should be considered – is often unclear.
“Things get sloppier and sloppier when you look at other genes,” said Dr. Steven Katz, professor of medicine and health management and policy at the University of Michigan. “The risk of different cancers is lower and less specific and more variable. You might be thinking, ‘Why do I need to know this?’
After people are diagnosed with breast cancer, genetic testing can help inform their decisions about the type of surgery – for example, a high risk of recurrence or a new breast cancer may prompt some to opt for more extensive surgery, such as a double mastectomy, to test family members for their Important information about possible cancer risks can also be given.
(This type of “germline” genetic testing, as it’s called, looks for mutations in genes that people inherit from their parents. This is different from genomic tumor testing, which looks for specific genes or proteins in cancer cells and can help doctors understand the rate at which cancer cells are growing. division, for example, and the possibility of cancer recurrence.)
Increasingly, germline genetic testing can help guide other treatment decisions. Some patients with metastatic breast cancer who have BRCA1 or BRCA2 mutations may be good candidates for PARP inhibitors, cancer drugs that target tumors with mutations in those genes.
But genetic tests that uncover inherited mutations in many other genes provide less clearly functional information, although positive results can alert people.
At Memorial Sloan Kettering, oncologists focus on “therapeutic actionability,” Robeson said. Will the test help someone decide whether to have a double mastectomy or provide other important guidance? “A policy of testing everyone would detect very few additional BRCA breast mutations but would cost a lot,” he said.
As a result, physicians are debating how best to deploy and incorporate new genetic knowledge. Insurers are trying to figure out which ones to pay for.
Science says the unnecessary use of tests and the overuse of tests that experts say provide information that cannot be explained with any scientific certainty.
The results can be confusing for patients newly diagnosed with breast cancer as they face the cost of genetic testing and sometimes receive little guidance on proper treatment.
Some doctors say the first step is to make sure that the small group who will clearly benefit are getting genetic tests that are clearly understood. Only 15% of breast cancer patients who met selected NCCN testing guidelines for inherited cancers received genetic testing, according to a 2017 study that examined data from a National Family Health Survey between 2005 and 2015.
“I would argue that our focus should be on individuals who are at high risk of breast cancer who have not yet been diagnosed,” said Dr. Tua Pal, associate director of cancer health disparities at the Vanderbilt-Ingram Cancer Center. NCCN Guidelines Panel Chair for Risk Assessment.
Patients can fall through the cracks because no one tells them they should be tested. In one analysis, 56% of high-risk breast cancer patients who did not receive genetic testing said their doctors did not recommend it.
Even if doctors recommend genetic testing, they may lack the skills to decide which tests people need and how to interpret the results. This is the role of genetic counselors, but their ranks are stretched thin.
The consequences can be serious. In a study of 666 breast cancer patients who received genetic testing, half of those at average risk for hereditary cancer received a double mastectomy based on test results that found “variants of uncertain significance,” which are not clinically relevant. About half of surgeons report managing such patients in the same way as those with cancer-causing mutations.
“Most of our research suggests that there is still room for improvement in the understanding that clinicians need,” said co-author Dr. Alison Kurian, director of the Women’s Clinical Cancer Genetics Program at Stanford University. study.
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