The past decade has seen a rapid expansion of genetic testing, including new tools to inform patients diagnosed with breast cancer about the risks of recurrence and to guide their treatment.
But the clinical significance of many of the inherited mutations that can now be identified remains unclear, and experts are confused about when and how to publish all the new tests available. Patients are sometimes left paying out of their own pocket for exams that have not yet become the standard of care, and even the newest oncologists may be unsure how to incorporate the flow of new information into what used to be standard treatment protocols.
A quarter of a century ago, Myriad Genetics introduced the first breast cancer genetic test for BRCA mutations, two genes linked to a higher risk of breast cancer, opening the door to a new era in genetic testing. BRCA1 and BRCA2 mutations account for up to 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 during their lifetime. They may also be more likely to develop ovarian cancers and other people who do not have harmful BRCA mutations.
But the clinical significance is more murky 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 polygenic test panels from commercial labs that look for mutations in dozens of genes. Some consumer-oriented companies offer check panels for a few hundred dollars, although their reliability varies.
When Gene Carpari was diagnosed with breast cancer in 2017 at age 44, genetic testing identified a mutation in a gene called PALB2 that greatly increases the risk of breast cancer. Guidelines suggest that breast cancer patients with a PALB2 mutation, such as those with BRCA1 and BRCA2 mutations, consider having a mastectomy to reduce the chance of breast cancer recurring.
“I hope genetic testing is the standard of care,” said Karpari, who didn’t owe anything for the test because her insurance company covered the cost.
Karpari, who lives in Sterling Heights, Michigan, said the test results confirmed the decision she had already made to have a double mastectomy and provided important information to family members, including her 21-year-old daughter and 18-year-old son, who will likely have both. Test them in their mid-twenties or early thirties.
But some breast cancer experts worry that large-scale testing may also identify genetic mutations whose effect is unclear, which leads to concern and leads to more testing and treatment of questionable value that may raise costs for the health care system.
It can also confuse patients.
“It often happens that patients find their way to us after getting confusing results elsewhere,” he said. Dr. Mark Robson, chief of the breast medicine service 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 manage genetic test results.
For people diagnosed with breast cancer, there are many professional groups, including the influential National Comprehensive Cancer Network, or NCCN, We recommend limiting testing For some people, including those with high-risk factors, such as a family history of breast cancer; Those 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 recommended a different approach: Provide genetic testing to all patients Those who have been diagnosed with or have a personal history of breast cancer. The recommendation was controversial.
NCCN Guidelines [cover] Most of the women who needed the test, but we wanted to get them all” Dr. Eric Manahana general surgeon in Dalton, Georgia, and a board member of the Surgeons Group.
Mutations in other genes associated with breast cancer are much less common than BRCA1 and BRCA2 mutations and generally do not increase the risk of breast cancer to the same extent. The carcinogenic effect of these genes may be less clear than that of the BRCA genes, which have been tested since the mid-1990s.
The appropriate response to less common mutations—whether considering a mastectomy to reduce risk or more extensive screening—is often unclear.
“It gets a lot dirtier when you look at other genes,” he said. Dr. Stephen Katz, Professor of Medicine, Health Administration and Policy at the University of Michigan. “The risks tend to be lower for different cancers, less certain and more varied. You might go away wondering, ‘Why should I know that?'”
After people are diagnosed with breast cancer, genetic testing can help make their decisions about what types of surgery to pursue — for example, a higher risk of recurrence or new breast cancer may persuade some to choose more extensive surgery, such as double surgery. Mastectomy. The test can also provide important information to family members about potential cancer risks.
(This type of “germline” genetic test, as it’s called, looks at mutations in the genes people inherit from their parents. It differs from oncology tests that look at specific genes or proteins in cancer cells and can help doctors understand the rate at which they divide. Cancer cells, for example, and the potential for cancer recurrence.)
Increasingly, germline genetic testing can also help guide other treatment decisions. Some patients with metastatic breast cancer who have BRCA1 or BRCA2 mutations may be good candidates for PARP inhibitors, which are cancer drugs that target tumors with mutations in those genes.
But genetic tests that detect inherited mutations in many other genes produce less clear-cut information to work, although positive results may worry people.
Cancer specialists focus on “therapeutic capacity,” said Robson at Memorial Sloan Kettering. Will the test help someone decide if they should have a double mastectomy or provide other important guidance? “A policy of testing everyone will identify very few additional BRCA breast cancer mutations but it will cost a lot,” he said.
As a result, clinicians are discussing how best to disseminate and integrate new genetic knowledge. Insurance companies are trying to figure out which one to pay for.
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 by any scientific certainty.
The result can be confusing for patients newly diagnosed with breast cancer because they face the cost of genetic testing and sometimes little guidance about the appropriate treatment.
Some doctors say the first step is to make sure that the small group of people who would clearly benefit from getting genetic tests are clearly understood. Only 15% of breast cancer patients who met the NCCN testing guidelines specific for hereditary cancer received genetic testing, according to a 2017 study It examined data from a national household health survey between 2005 and 2015.
“I would argue that our focus should be on people at high risk of developing breast cancer who have not yet been identified,” he said. Dr.. Toya PalD., associate director of the Cancer Health Disparities at Vanderbilt-Ingram Cancer Center and vice chair of the NCCN Guidelines Committee for High-Risk Genetic/Family Assessment of Breast, Ovarian, and Pancreatic Cancer.
Patients may fall through the cracks because no one tells them they should be tested. In one analysis, 56% of high-risk breast cancer patients who had not undergone genetic screening said they were Doctors did not recommend it.
Even if doctors recommend genetic testing, they may lack the expertise to determine which tests people need and how to interpret the results. This is the role of genetic counselors, but so are their ranks thin stretched.
The consequences can be dire. in study Of the 666 breast cancer patients who underwent genetic testing, half of those at high risk of hereditary cancer underwent a double mastectomy based on test results that foundVariables of uncertain significancewhich is not clinically feasible. Up to half of surgeons reported managing such patients in the same manner as those with cancer-causing mutations.
The bulk of our research said there is still room for improvement in terms of understanding what clinicians need. Dr. Alison Kuriandirector of the Women’s Clinical Cancer Genetics Program at Stanford University and co-author of the study.