The last decade has witnessed a rapid expansion of genetic testing, including new tools to inform patients diagnosed with breast cancer of their risk 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 torn over when and how to use each of the new tests available. Patients sometimes pay out of pocket for tests that are not yet the standard of care, and even the most sophisticated oncologists may be unsure how to integrate the flood of new information into previously standard care protocols.
A quarter century ago, Myriad Genetics introduced the first breast cancer genetic test for BRCA mutations, two genes associated with a significantly increased 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 inherited breast cancers, and people with a problematic mutation in any of these genes have a 45% to 72% chance of developing breast cancer in their lifetime. They may also be at higher risk of ovarian and other cancers than people without harmful BRCA mutations.
But the clinical significance is more murky for many other genetic tests.
Testing for BRCA1 and BRCA2 genes used to cost thousands of dollars. Now, for a fraction of that, doctors can order multigene test panels from commercial labs that look for mutations in dozens of genes. Some direct-to-consumer companies offer screening panels for a few hundred dollars, although their reliability varies.
When Jen Carbary 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. Guidelines suggest that breast cancer patients with a PALB2 mutation, similar to patients with BRCA1 and BRCA2 mutations, should consider having a mastectomy to reduce the chance of breast cancer recurring.
“I wish genetic testing was the standard of care,” said Carbary, who owed nothing for the test because her insurer covered the cost.
Carbary, who lives in Sterling Heights, Michigan, said the test results confirmed her previous decision to have a double mastectomy and provided important information for family members, including her 21-year-old daughter and 18-year-old son. who are likely to be tested in their mid-20s or early 30s.
However, some breast cancer experts are concerned that widespread testing could also identify genetic mutations whose effects are unclear, creating fear and leading to more tests and treatments of questionable value that could increase health care system costs.
It can also confuse patients.
“It often happens that patients find their way to us after getting confusing results elsewhere,” said Dr. Mark Robson, director of breast medicine 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 who have been diagnosed with breast cancer, many professional groups, including the influential National Comprehensive Cancer Network (NCCN), recommend restricting testing to certain individuals, including those with high risk factors, such as: B. Family history of breast cancer; those who are 45 or younger when 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 who have been diagnosed with breast cancer or have a personal history of breast cancer. The recommendation was controversial.
“The NCCN Guidelines [cover] most of the women who needed to be tested, but we wanted to get them all,” said Dr. Eric Manahan, General Surgeon in Dalton, Georgia, and a member of the Surgeons Group Board of Directors.
Mutations in other genes associated with breast cancer are much rarer than BRCA1 and BRCA2 mutations and generally do not increase the risk of developing breast cancer as much. The carcinogenic effect of these genes may be less clear than that of the BRCA genes, which have been tested for since the mid-1990s.
And the appropriate response to the less common mutations — whether to consider risk-reducing mastectomy or increased screening — is often unclear.
“Things get sloppy and sloppy when you look at other genes,” said Dr. Steven Katz, Professor of Medicine and Health Management and Policy at the University of Michigan. “Risks tend to be lower and less certain and more variable for different types of cancer. You might walk away and be like, ‘Why did I need to know that?’”
After breast cancer is diagnosed, genetic testing can help inform their decisions about the type of surgery to perform — for example, a high risk of recurrence or new breast cancer might persuade some to opt for more extensive surgery, such as a breast cancer. B. a double operation to decide mastectomy. The test can also provide important information for family members about their potential cancer risk.
(This type of “germline” genetic testing, as it’s called, looks for mutations in the genes people inherit from their parents. It’s different from tumor genomic testing, which looks at specific genes or proteins in the cancer cells, and doctors say can help them understand, for example, the rate at which cancer cells divide and the likelihood of cancer recurring.)
Increasingly, germline genetic testing can also be helpful in other treatment decisions. Some metastatic breast cancer patients who have BRCA1 or BRCA2 mutations could be good candidates for PARP inhibitors, cancer drugs that target tumors with mutations in these genes.
But genetic testing, which reveals inherited mutations in many other genes, provides less definitive information, even if positive results can alarm people.
At Memorial Sloan Kettering, cancer specialists are focused on “therapeutic feasibility,” Robson said. Will the test help someone decide if she should have a double mastectomy or any other important clues? “A policy of testing everyone will identify very few additional breast BRCA mutations, but it will cost a lot,” he said.
As a result, physicians debate how best to use and integrate new genetic knowledge. Insurers are trying to figure out what to pay for.
There is both underuse of tests that science says are relevant, and overuse of tests that experts say provide information that cannot be interpreted with scientific certainty.
The result can create confusion for patients with newly diagnosed breast cancer as they face the cost of genetic testing and sometimes little guidance on proper treatment.
Some doctors say the first step is to make sure the small group of people who would clearly benefit get the genetic testing, the importance of which is clearly understood. Only 15% of breast cancer patients who met select NCCN testing guidelines for hereditary cancer received genetic testing, according to a 2017 study examining data from a national household health survey between 2005 and 2015.
“I would argue that we need to focus on the people who are at high risk of breast cancer who haven’t even been identified,” said Dr. Tuya Pal, Associate Director of Health Disparities in Cancer at Vanderbilt-Ingram Cancer Center and Vice Chair of the NCCN Guidance Panel on High-Risk Genetic/Familial Assessment of Breast, Ovarian and Pancreatic Cancer.
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 when doctors recommend genetic testing, they may lack the expertise to determine what tests people need and how to interpret the results. That is the role of genetic counselors, but their ranks are few and far between.
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 revealed “variations of uncertain significance” that are clinically unfeasible. As many as half of the surgeons said they treated such patients in the same way as patients with cancer-causing mutations.
“Most of our research would say that there is still room for improvement when it comes to giving clinicians the understanding they need,” said Dr. Allison Kurian, director of the Women’s Clinical Cancer Genetics Program at Stanford University and co-author of the Learn.
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