The past decade has seen a rapid proliferation of genetic tests, including new tools to inform patients who have been 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 don’t know when and how to use all the new tests available. Patients sometimes have to pay out of pocket for tests that are not yet standard of care, and even the most modern oncologists may not know 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 associated with a substantially increased risk of breast cancer, opening the door to a new era in genetic testing. Mutations in BRCA1 and BRCA2 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 at higher risk for ovarian and other cancers than people without harmful BRCA mutations.
But the clinical significance of many other genetic tests is more obscure.
Testing for the BRCA1 and BRCA2 genes used to cost thousands of dollars. Now, for a fraction of that amount, doctors can order multi-gene test panels from commercial labs that look for mutations in dozens of genes. Some direct-to-consumer companies offer shielding panels for several hundred dollars, although their reliability varies.
When Jen Carbury was diagnosed with breast cancer in 2017 at the age of 44, genetic testing revealed a mutation in a gene called PALB2 that significantly increases the risk of developing breast cancer. The guidelines suggest that patients with PALB2-mutated breast cancer, like those with BRCA1 and BRCA2 mutations, consider mastectomy to reduce the chance of breast cancer recurrence.
“I would like genetic testing to be the standard of care,” said Carbury, who owes nothing for the test because her insurance company covered the costs.
Karbury, who lives in Sterling Heights, Michigan, said the test results confirmed her decision to have a double mastectomy already made and provided important information to family members, including her 21-year-old daughter and 18-year-old son. which are likely to be tested in the mid 20s or early 30s.
But some breast cancer experts are concerned that widespread testing may also reveal genetic mutations whose impact is unclear, creating concern and leading to further testing and treatments of dubious value, which could increase costs to the healthcare system.
It can also be confusing for patients.
“It often happens that patients come to us after receiving confusing results elsewhere,” he said. Dr. Mark Robson, Chief of Breast Medicine at Memorial Sloan-Kettering Cancer Center in New York. Robson said the cancer center has a clinical genetics service, staffed by physicians and genetic counselors, to help people make decisions about how to handle genetic testing results.
For people diagnosed with breast cancer, many professional groups, including the influential National Comprehensive Cancer Network, or NCCN, recommend limiting testing for certain people, including those with high risk factors such as a family history of breast cancer; those who are 45 years of age or younger at the time of diagnosis; and those of Ashkenazi Jewish descent.
But in 2019, the American Society of Thoracic Surgeons recommended a different approach: Offer genetic testing to all patients who are diagnosed with or have a personal history of breast cancer. The recommendation was controversial.
“NCCN Guidelines [cover] most women needed testing, but we wanted to get them all,” said Dr. Eric Manahangeneral surgeon in Dalton, Georgia and member of the Board of Directors of the Group of Surgeons.
Mutations in other genes associated with breast cancer are much rarer than mutations in BRCA1 and BRCA2 and generally do not increase the risk of breast cancer as much. The impact of these genes on cancer may be less clear than the effect of the BRCA genes, which have been tested since the mid-1990s.
And the proper response to less common mutations—whether risk-reducing mastectomy or extended screening should be considered—is often unclear.
“Things get sloppier and sloppy as you look at other genes,” said Dr. Steven Katz, Professor of Medicine, Management, and Health Policy at the University of Michigan. “Risks tend to be lower for different types of cancer, less certain and more variable. You may walk away wondering, “Why would I need to know this?”
Once people are diagnosed with breast cancer, genetic testing can help them decide what types of surgery to take – for example, a high risk of recurrence or new breast cancer may convince some to opt for more extensive surgery, such as double operation. mastectomy. Testing can also provide important information to family members about their potential risk of developing cancer.
(This type of “germline” genetic testing, as it’s called, looks at mutations in genes that people inherit from their parents. It’s different from genomic tumor tests, which look at specific genes or proteins in cancer cells and can help doctors, for example, the rate of division cancer cells and the likelihood of cancer recurrence.)
Increasingly, germline genetic testing may 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, anti-cancer drugs that target tumors with mutations in these genes.
But genetic testing, which looks for inherited mutations in many other genes, is less clear-cut, even if positive results may alarm people.
At Memorial Sloan Kettering, cancer specialists are focused on “therapeutic impact,” Robson said. Will testing help someone decide if she should have a double mastectomy, or make other important recommendations? “A policy of testing everyone will reveal very few additional BRCA breast mutations, but will be expensive,” he said.
As a result, physicians are debating how best to use and exploit new genetic knowledge. Insurers are trying to figure out what to pay for.
There is both an underuse of tests that science says are relevant, and an overuse of tests that experts say provide information that cannot be interpreted with any scientific certainty.
As a result, patients with newly diagnosed breast cancer can experience confusion as they face the costs of genetic testing and sometimes lack of advice on the correct treatment.
Some doctors say the first step is to make sure that a small group of people who will clearly benefit from it undergo genetic tests that are clearly understood. Only 15% of breast cancer patients who met the NCCN guidelines for testing for hereditary cancer received genetic testing. 2017 study which examined data from the National Household Health Survey between 2005 and 2015.
“I would say that our focus should be on people at high risk of developing breast cancer that hasn’t even been diagnosed yet,” he said. Dr. Tuya PalAssociate Director of Cancer Health Disparities at Vanderbilt-Ingram Cancer Center and Vice Chair of the NCCN Guidelines Group on Genetic/Family Evaluation of High Risk Breast, Ovarian, and Pancreatic Cancer.
Patients can fail because no one tells them they need to be tested. In one analysis, 56% of high-risk breast cancer patients who did not receive genetic testing said that their doctors did not recommend.
Even if doctors recommend genetic testing, they may lack the experience to determine which tests people need and how to interpret the results. This is the role of genetic consultants, but their ranks stretched thin.
The consequences can be serious. AT the study of 666 breast cancer patients who underwent genetic testing, half of the patients at average risk of hereditary cancer underwent a double mastectomy based on test results that found “options of uncertain significance” that are not clinically effective. Half of the surgeons reported that they treat such patients in the same way as patients with cancer-causing mutations.
“Most of our research suggests that there is still room for improvement in terms of clinicians getting the insight they need,” he said. Dr. Allison KurianDirector of the Women’s Clinical Cancer Genetics Program at Stanford University and co-author of the study.
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