Genetic tests create treatment opportunities and confusion for breast cancer patients.

The past decade has seen a rapid expansion of genetic tests, including new tools to inform patients diagnosed with breast cancer about their risk of recurrence and to guide their treatment.

But the clinical significance of many inherited mutations remains unclear, and experts are torn over when and how to deploy all the new tests available. Patients are sometimes left paying out-of-pocket for tests that are not yet standard of care, and even the most sophisticated oncologists can be unsure whether standard treatment protocols are in place. How to incorporate the flood of new information. .

A quarter of a century ago, Myriad Genetics introduced the first breast cancer genetic test for BRCA mutations, two genes associated with a substantially increased risk of developing breast cancer, ushering in a new era in genetic testing. The door is open. BRCA1 and BRCA2 mutations account for about half of all hereditary breast cancers, and people who have a mutation in one of these genes are more likely to develop breast cancer during their lifetime. The probability ranges from 45% to 72%. They may also be at higher risk of ovarian and other cancers than people without harmful BRCA mutations.

But clinical significance is more complex 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 a multigene test panel from commercial labs that looks for mutations in dozens of genes. Some direct-to-consumer companies offer screening panels for a few 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. Guidelines recommend that breast cancer patients with PALB2 mutations, as with BRCA1 and BRCA2 mutations, consider mastectomy to reduce the chance of breast cancer recurrence.

“I wish genetic testing was the standard of care,” said Carberry, who owed nothing for the test because her insurer covered the cost.

Carberry, 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 for family members. , including his 21-year-old daughter and 18-year-old son, will likely be tested in their mid-20s or early 30s.

But some breast cancer experts worry that widespread testing may also identify genetic variants whose impact is unclear, causing anxiety and leading to more testing and treatments of questionable value. can increase the costs of the health care system.

It can also confuse patients.

“It happens a lot, that patients find their way to us after getting confusing results elsewhere,” said Dr. Mark Robeson, chief of the breast medicine service at Memorial Sloan Kettering Cancer Center in New York City. The cancer center has a clinical genetics service, staffed by doctors and genetic counselors, that helps people make decisions about how to manage genetic testing results, Robson said.

For people diagnosed with breast cancer, many professional groups, including the influential National Comprehensive Cancer Network, or NCCN, recommend limiting screening to certain people, including those with high risk factors. are, such as a family history of breast cancer; People who are 45 years or younger when diagnosed. and those of Ashkenazi Jewish ancestry.

But in 2019, the American Society of Breast Surgeons recommended a different approach: offer genetic testing to all patients diagnosed with or with a personal history of breast cancer. This recommendation was controversial.

“NCCN Guidelines [cover] Most women who needed testing, but we wanted to get them all,” said Dr. Eric Manahan, a general surgeon in Dalton, Georgia, and a member of the Surgeons 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 effect of these genes may be less pronounced than the BRCA genes, which have been tested since the mid-1990s.

And the appropriate response to less common mutations—whether to consider risk-reducing mastectomy or step-up screening—is often unclear.

“When you look at other genes, things get messier and messier,” said Dr. Steven Katz, professor of medicine and health management and policy at the University of Michigan. “The risks of different cancers are smaller, and less certain and more variable. You might go away thinking, ‘Why do I need to know this?’

After people are diagnosed with breast cancer, genetic testing can help inform their decisions about what types of surgery — for example, the high risk of recurrence or new breast cancer some people are more likely to have. May prompt the choice of extensive surgery, such as a double. Mastectomy screening can also provide family members with important information about their potential cancer risk.

(This type of “germline” genetic testing, as it’s called, looks for mutations in genes that people inherit from their parents. This differs from genomic tumor tests that look for specific genes in cancer cells. (or look at proteins and can help doctors understand the rate at which cancer cells are dividing, for example, and the likelihood of cancer recurrence.)

Increasingly, genetic testing of germs 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, cancer drugs that target tumors with mutations in these genes.

But genetic testing that uncovers inherited mutations in many other genes provides less clearly actionable information, even though positive results can put people at risk.

At Memorial Sloan Kettering, cancer specialists focus on “curability,” Robson said. Will the test help someone decide whether to have a double mastectomy or provide other important guidance? “A policy of testing everyone would identify very few additional BRCA breast mutations but would be very costly,” he said.

As a result, physicians are debating how to deploy and incorporate new genetic knowledge. Insurers are trying to figure out who to pay.

There is less use of tests that science says are relevant and more use of tests that experts say provide information that cannot be interpreted with any scientific certainty.

The results can be confusing for newly diagnosed breast cancer patients as they face the costs of genetic tests and sometimes little guidance on appropriate treatment.

Some doctors say the first step is to make sure that the small group of people who will clearly benefit are getting genetic tests that are clearly understood. According to a 2017 study that examined data from the National Home Health Survey between 2005 and 2015, only 15% of breast cancer patients who met selective NCCN testing guidelines for inherited cancers. Received genetic testing.

“I would argue that we need to focus our attention on those who are at high risk of breast cancer that have not yet been identified,” said Dr. Tuya Paul, director of Cancer Health Disparities at Vanderbilt-Ingram Cancer Center. Associate Director and Vice President of Chair of the NCCN Guidelines Panel for Genetic/Familial High-Risk Assessment of Breast, Ovarian, and Pancreatic Cancer.

Patients can fall through the cracks because no one tells them to get tested. In one analysis, 56 percent of high-risk breast cancer patients who did not undergo genetic testing said their 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 their ranks are thin.

The consequences can be serious. In a study of 666 breast cancer patients who received genetic testing, half of whom had an average inherited risk of cancer, underwent double mastectomies based on test results that found “variants of uncertain significance.” , which are not clinically viable. More than half of the surgeons reported that such patients were managed in the same way as those with cancer-causing mutations.

“The bulk of our research would suggest that there is still room for improvement in terms of getting clinicians to understand what they need,” said co-author Dr. Alison Koren, director of the Women’s Clinical Cancer Genetics Program at Stanford University. ” the study

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