NEW YORK (GenomeWeb) – Genetic tests don't always give clear-cut results, which can make applying them to clinical cases complicated.
Women sometimes seek genetic breast cancer testing to learn whether or not they carry familial risk variants in genes like BRCA1 or BRCA2 that increase their lifetime risk of developing cancer between 45 percent and 80 percent. Knowing their mutation status can help women and their physicians choose disease surveillance and treatment approaches.
But the impact of some variants isn't as certain. According to some estimates, the chance of finding a variant of uncertain significance, or variant of unknown significance (VUS), can be as high as 30 percent in panel gene testing. Guidelines suggest that VUS be treated like a negative test result, but studies have found that while some physicians and patients follow that advice, not all do. Even with an unknown or negative result, most women who have sought testing still have a strong family history of disease to contend with.
"This is where we talk about the art of what we do, not just the science," said Christine Rizk, a breast surgeon who runs the women's health center at St. Francis Hospital and Medical Center in Hartford, Connecticut.
Guidelines like those from the National Comprehensive Cancer Network and elsewhere recommend genetic testing for women who are at high risk of developing breast cancer, typically because of a strong family history of disease. Prior to testing, they also encourage women to meet with genetic counselors to discuss whether testing is right for them.
Both women who have and have not been diagnosed with breast cancer seek testing, Rizk noted. Many women who seek genetic testing for breast cancer variants who haven't been diagnosed with disease are often trying to be proactive in preventing disease or discovering it early, she added, while women who have been diagnosed are both seeking answers as to why they developed disease and what treatment option might be best for them.
In cases of women who are cancer-free, but have a risk variant, Mounika Mandadi, a medical oncologist who runs a high-risk breast cancer clinic at the University of Louisville, offers them screening from a younger age, such as from age 30, and may offer annual MRIs in addition to annual mammograms and twice-a-year breast exams. Women could also be offered risk-reducing medications like tamoxifen or Evista, or even surgery, Rizk added.
Whereas for women with a cancer diagnosis, knowing they have a risk variant could help them decide between a lumpectomy and a mastectomy, or even a bilateral mastectomy.
Mandadi noted that there is typically no difference in outcomes between women who receive lumpectomies versus mastectomies, even though a 2015 JAMA Surgery study found that an increasing number of women are opting for mastectomies. At her clinic, she said, they are recommending lumpectomies more often because there are fewer complications.
But that situation changes when a woman has a high-risk mutation. For instance, Rizk noted that BRCA mutation carriers have about a 20 percent chance of developing breast cancer in the other breast, a higher risk than non-carriers. In that case, she said healthcare providers are much more likely to discuss the possibility of a bilateral mastectomy than they would with an average-risk woman.
However, a negative test result or the finding of a VUS can make such decisions more difficult, Rizk said.
VUS are supposed to be treated just like negative findings, said Allison Kurian, the director of the Women's Clinical Cancer Genetics Program at Stanford University School of Medicine. She noted that when VUS have been classified, they typically are moved to the normal variation column.
But she found in a recent study that surgeons don't always follow those guidelines. She and her colleagues surveyed breast cancer patients about their genetic testing experience. They also then surveyed the women's surgeons about how genetic testing results influenced patient management.
As they reported in April in the Journal of Clinical Oncology, Kurian and her colleagues found high-risk women with a pathogenic mutation were much more likely to undergo bilateral mastectomies. But slightly more than half the average-risk women with a VUS also had a bilateral mastectomy, they found.
When Kurian and her colleagues queried the women's surgeons, about half of the surgeons who had a low volume of breast cancer patients and a quarter of surgeons with a high volume of breast cancer patients said they would manage a woman with a VUS the same way they'd manage a woman who had a BRCA1 or BRCA2 mutation. "We know they shouldn't be managed the same way because they don't mean the same thing," Kurian said.
Similarly, a 2013 study in the Archives of Internal Medicine found that about 12 percent of women who'd received an uninformative BRCA testing result underwent ovarian cancer risk-reducing surgery such as a salpingo-oophorectomy.
Kurian noted, though, that her survey didn't ask patients why they received mastectomies — some may have chosen such a path despite their clinician's recommendations — but she added that she thinks "it is concerning that so many surgeons endorsed a practice that is counter to our standard guidelines."
Rizk and Mandadi pointed out that most patients who are sent for genetic testing and who come back negative or with an uncertain finding still have a strong family history of disease. That is still taken into consideration when drawing up treatment plans. "You can't look away from that history," Rizk said. "Clearly, there is a predisposition there."
"If done appropriately, these people were tested for a reason," she added. "The fact that they come back either negative or with a mutation of uncertain significance really doesn't get us off the hook at all."
Currently, both Rizk and Mandadi noted that VUS are a problem because not enough data has been collected about them to be able to judge whether that variant is pathogenic or benign. That means, Rizk said, that there's less data to offer patients.
"It gets very difficult to have these conversations," Rizk said. For women with BRCA1 or BRCA2 mutations, she noted that she can tell them what their risk of developing breast cancer is, but that she can't provide that same data to patients with a VUS. "What do you tell them their risk is?" she added. "I don't even know what gene you have, how am I going to tell you what your risk is?"
In the future, Mandadi noted that VUS would likely become less of an issue. As more information is amassed — particularly about variants found among less-studied populations, such as people of Asian or Native American descent — researchers and clinicians will be able to better make determinations regarding whether a variant is cause for worry or not.
"Down the line, the next 10 years, the VUS rate is probably going to go down, and we are really going to know what to do with it," she said. "But right now, the way we handle it is, we just look at their family history and offer strategies based on the family history, but not so much based on the VUS itself."
Her clinic applies a risk model to gauge the patients' lifetime risk of disease to help determine what approach might be best for patients with VUS. If in that therapeutic model, they estimate the patients' lifetime risk to be greater than 20 percent for breast cancer, they offer the same screening they would to higher-risk patients.
Rizk added that sometimes a sort of mini-study with the patients' affected relatives could also gauge whether that variant might be behind the cases in that particular family.
The treatment course taken also comes down to patients' wishes. Some women who've had breast cancer might not want to deal with the chance of developing it again and chose a more radical approach, while others will opt for screening and see whether new data on their variant emerges.
"I think that we as healthcare providers, the onus is on us to present the patients with the information and then allow them to make those informed decisions," Rizk said.
That's also where genetic counselors and further education may fit in. Genetic counselors may help not only educate patients, but also physicians, Mandadi noted. Her clinic at Louisville recently conducted a retrospective chart review of their genetic testing and referral rates. They found that those rates changed once a genetic counselor joined their clinic staff. "That just goes to show that not everyone is up to date, unless they have a special interest," she said.
Kurian added her survey also underscores the need for expertise. "This is a tough field, this is very specialized and, believe me, there are many things I don't know that surgeons know," she said. "I think it just clarifies the fact that it's important for experts to be involved, and there I would say genetic counselors and others with genetic counseling expertise."
Indeed, not every breast cancer patient in the US is seen by a specialist. "It's not just breast cancer surgeons who are taking care [of breast cancer patients], but also general surgeons like me," said Hassan Aziz, a general surgery resident at the University of Arizona, who wrote a recent review in JAMA Oncology on breast cancer genetic testing for general surgeons. "And maybe they need to know more about this, too."