The past decade has seen a rapid expansion of genetic testing, including new tools to inform patients diagnosed with breast cancer about the 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 about when and how to implement all the new tests available. Patients are sometimes left to pay out of their own pockets for tests that are not yet the standard of care, and even the most up-to-date oncologists can be unsure how to incorporate the flood 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 high risk of contracting 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 on one of these genes have a 45% to 72% chance of developing breast cancer during their lifetime. They may also be at a higher risk for ovarian and other cancers than people without harmful BRCA mutations.
But the clinical significance is darker for many other genetic tests.
Tests for the BRCA1 and BRCA2 genes cost thousands of dollars. Now, for a small fraction, doctors can order multi-gene 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 her risk of developing breast cancer. The guidelines suggest that breast cancer patients with a PALB2 mutation, just like those with BRCA1 and BRCA2 mutations, consider having a mastectomy to reduce the chance of breast cancer recurrence.
“I wish genetic testing was the standard of care,” said Carbary, who owed nothing for the test because her insurer covered the costs.
Carbary, who lives in Sterling Heights, Michigan, said the test results confirmed the decision she had already made to undergo a double mastectomy and provided important information to family members, including her 21-year-old daughter and his 18-year-old son, who will likely be tested between the ages of 20 and 30.
But some breast cancer experts worry that widespread testing may also identify genetic mutations whose impact is unclear, creating anxiety and leading to further testing and treatment of questionable value that could increase costs to the healthcare system.
It can also confuse patients.
“It often happens that patients find their way to us after getting confusing results elsewhere,” said Dr. Mark Robson, head of breast medicine at Memorial Sloan Kettering Cancer Center in New York City. Robson said the cancer center has a clinical genetics service, made up of doctors and genetic counselors, that helps people make decisions about how to manage genetic test results.
For people diagnosed with breast cancer, many professional groups, including the influential National Comprehensive Cancer Network, or NCCN, recommend limiting testing to certain people, including those with high-risk factors, such as a family history of cancer. breast; those who are 45 or younger at the time of diagnosis; and those with Ashkenazi Jewish origins.
But in 2019, the American Society of Breast Surgeons recommended a different approach: offer genetic testing to all patients who have been diagnosed with or have a personal history of breast cancer. The recommendation was controversial.
“The guidelines of the NCCN [cover] most of the women who needed tests, but we wanted to do them all, ”said Dr. Eric Manahan, surgeon general in Dalton, Georgia, and board member of the surgeons group.
Mutations on other genes associated with breast cancer are much less common than BRCA1 and BRCA2 mutations and generally do not increase the risk of developing breast cancer as much. The carcinogenic impact of these genes may be less clear than that of the BRCA genes, for which they have been tested since the mid-1990s.
And the appropriate response to less common mutations – whether to consider a mastectomy for risk reduction or intensified screening – is often unclear.
“Things get sloppier when looking at other genes,” said Dr. Steven Katz, professor of medicine and health management and policy at the University of Michigan. “The risks tend to be lower for different types of cancer, and less certain and more variable. You may walk away wondering, ‘Why should I know?'”
After people have been diagnosed with breast cancer, genetic testing can help make decisions about the types of surgery to pursue – for example, a high risk of recurrence or new breast cancer may persuade some to opt for surgery. more extensive surgery, such as a double mastectomy. The tests can also provide important information to family members about their potential cancer risk.
(This type of “germline” genetic test, as it is called, examines mutations in genes that people inherit from their parents. It is different from genomic tumor tests that look at specific genes or proteins in cancer cells and can help doctors to understand how quickly cancer cells divide, for example, and the likelihood of 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, anticancer drugs that target cancers with mutations in those genes.
But genetic tests that reveal inherited mutations in many other genes produce less clearly usable information, even if positive results can alarm people.
At Memorial Sloan Kettering, cancer specialists focus on “therapeutic viability,” Robson said. Will the test help someone decide if they should have a double mastectomy or provide other important guidance? “An all-in-one testing policy will identify very few additional BRCA breast mutations, but it will cost a lot,” she said.
As a result, doctors are debating how best to distribute and incorporate new genetic knowledge. Insurers are trying to figure out who to pay for.
There is both an underuse of tests that science says is relevant and an overuse of tests that experts say provide information that cannot be interpreted with scientific certainty.
The result could be confusing for newly diagnosed breast cancer patients who face the expense of genetic testing and sometimes little guidance on proper treatment.
Some doctors say the first step is to make sure that the small group of people who would clearly benefit from it receives genetic tests whose meaning is clearly understood. According to a 2017 study that looked at data from a national household health survey between 2005 and 2015, only 15 percent of breast cancer patients who met selected guidelines for NCCN cancer testing hereditary received genetic testing.
“I’d say our attention needs to be on people at high risk for breast cancer who haven’t even been identified,” said Dr. Tuya Pal, associate director for cancer health disparities at the Vanderbilt-Ingram Cancer Center and vice chair of the NCCN’s guideline panel for high-risk genetic / familial assessment of breast, ovarian and pancreatic cancers.
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.
Although doctors recommend genetic testing, they may not have the experience to determine which tests people need and how to interpret the results. This is the role of genetic counselors, but their ranks are small.
The consequences can be severe. In a study of 666 breast cancer patients who received genetic testing, half of those at average risk of hereditary cancer had a double mastectomy based on test results that found “variants of uncertain significance,” which are not clinically actionable. About half of the surgeons reported that they managed such patients in the same way as those with cancer mutations.
“Most of our research would say that there is still room for improvement in terms of understanding by physicians,” said Dr. Allison Kurian, director of the female cancer clinical genetics program at Stanford University and co-author of the study.