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Muddy waters for cancer detection?
SAN FRANCISCO—After watching her 33-year-old mother and 39-year-old aunt battle breast cancer, Amanda Burris, 23, was tested at Invitae Corp. for genetic markers BRCA1 and BRCA2. The results, like that of her grandmother, mother and aunt, came back positive—thus, significantly increasing her risk of developing breast cancer.
Rather than pity herself, the college student went into action, pumping up her cancer-prevention measures like scheduling an annual MRI rather than a mammogram and having children sooner than later before possibly opting for a mastectomy.
“Getting genetic testing really helped because we have a plan and now we understand our options better,” Burris stated on the Invitae website, Patient Stories. “It’s all about taking back control of my life.”
Invitae and collaborators announced this summer the publication of new data describing the clinical actionability of multigene testing for hereditary breast and ovarian cancer (HBOC) risk in JAMA Oncology. The study was a collaboration among Massachusetts General Hospital, Harvard Medical School, Stanford University, Beth Israel Deaconess Medical Center and Invitae, the company stated in a news release.
Surprisingly, the study found that multigene testing of women negative for BRCA1 and BRCA2 revealed some of them harbored other harmful genetic mutations, most commonly moderate-risk breast and ovarian cancer genes and Lynch syndrome genes, which increase ovarian cancer risk.
Multigene panel genetic tests are increasingly recommended for patients evaluated for a predisposition to HBOC. However, the rapid introduction of these tests has raised concerns because many of the tested genes are low- to moderate-risk genes for which consensus management guidelines have not been introduced or which were introduced only very recently.
In the beginning, more than 1,000 patients were tested with multigene panels, and the clinical actions that would be considered were reviewed for all patients testing positive for cancer genes other than BRCA1 or BRCA2.
For more than half of these patients, the genetic test would suggest a change in care over and above any recommendations based on the patient’s personal and family history alone.
“Our study is distinguished from previously published work by the size of our cohort together with the availability of detailed personal and family history data collected directly from involved participants,” the JAMA Oncology study authors stated. “In addition, our study avoids biases inherent in studies conducted exclusively on samples available to genetic testing laboratories because our participants were all enrolled directly at the site of referral under uniform criteria.”
Lead author Dr. Leif W. Ellisen of Massachusetts General Hospital Cancer Center and coauthors wanted to determine how often multigene panel testing would identify mutations that warranted some clinical action among women appropriately tested but lacking BRCA1 and BRCA2 mutations.
Ellisen tells DDNews, “We found that for women with a personal and/or family history of breast cancer, if you calculate that woman’s risk of future breast cancer (without a genetic test), finding a mutation through multigene testing often leads to a substantially increased calculation of her risk.”
“As a result, you might, for example, not offer breast MRI screening to that woman without knowing the test result, but you would offer it once you had the additional genetic information,” Ellisen notes. “For some women, finding a risk gene mutation could lead to a recommendation for prophylactic breast surgery, and that would not be a standard recommendation in the absence of the genetic information.”
“For other women, finding a mutation might mean they are at risk for a cancer they did not suspect,” Ellisen said. “For example, several women with a personal and/or family history of ovarian cancer were found to have a mutation that causes risk of ovarian cancer but also a high risk of colon cancer. These women would immediately be recommended to start frequent colonoscopy screening and in some cases to consider preventive colon surgery—recommendations that would not be considered without the genetic mutation.”
While the clinical implementation of genetic testing for BRCA1/2 preceded the development of firm mutation-based management guidelines, “the wide availability of a validated platform for this testing contributed to our understanding of genetic cancer risk and ultimately to more effective management of these patients,” he says.
The impetus for the study was to ask an unresolved question regarding genetic testing, which Ellisen puts as: “If we do a multigene test as opposed to simply a test for BRCA1/2, does finding a mutation in one of the other genes actually change how we think about that woman’s risk—and what measures we would recommend for screening and prevention?”
“In other words, we know that screening and preventive action need to be based on our best assessment of risk for that patient, and the question was whether finding a mutation through multigene testing is likely to change the risk assessment and consequently the recommendations,” he continues. “We found that in the majority of cases, finding these mutations did change what we would recommend.”
Prophylactic mastectomy is “well established to dramatically decrease breast cancer incidence (risk) in high-risk woman,” Ellisen points out. “However, making a decision for such a surgery should be based on the best risk information possible, and most believe that such surgery is not indicated in those who have average or only moderately elevated risk.”
For the study, the authors enrolled 1,046 women and carried out multigene panel testing on all the participants. Among the 1,046 women, 3.8 percent of them (40 women) who were negative for BRCA1 and BRCA2 had harmful mutations in other moderate-risk genes.
The authors included an additional 23 patients in the study’s clinical management analysis and results indicate that among 63 women positive for mutations, the majority of them (33 women, or 52 percent) would be considered for additional disease-specific screening and/or prevention measures beyond those based on personal and family history alone. Additional family testing also would be considered for first-degree relatives, according to the results. In the large majority of mutation-positive cases—58 of 63, or 92 percent—personal and/or family histories included cancer associated with the mutant genes.
“Multigene panel testing for patients with suspected HBOC risk identifies substantially more individuals with relevant cancer risk gene mutations than does BRCA1/2 testing alone,” the study authors wrote. “Identifying such mutations is likely to change management for the majority of these individuals and their families in the near term, and in the long term should lead to development of effective management guidelines and improved outcomes for at-risk individuals.”
Not everyone in the medical field agrees.
In the JAMA Oncology “Invited Commentary,” entitled, “Usefulness of Multigene Testing—Catching the Train That’s Left the Station,” Dr. Elizabeth M. Swisher of the University of Washington Medical Center in Seattle wrote: “Multigene testing is rapidly becoming the norm for genetic cancer risk assessment. We must continue to assess the effect of such testing on clinical care and patient experience and work to provide meaningful guidelines for cancer-preventive care for those with less common genetic findings.”
A major argument against multigene testing has been the “need to avoid harm by providing mutation information on genes for which guidelines about care management are not well defined,” she said. “However, in many high-risk families, we already are harming patients by having inadequate knowledge about who is at risk.”
“An example is two sisters with ovarian cancer who tested negative for BRCA1/2 mutations,” Swisher said. “With this information, most physicians would offer age-appropriate risk-reducing salpingo-oophorectomy to first-degree female relatives, half of whom are really not at risk.”
A more comprehensive genetic assessment may identify the cause of the ovarian cancer in the affected women ( i.e, RAD51C mutation), Swisher said. By identifying the cause of ovarian cancer in the family, at- risk relatives can be tested, eliminating unnecessary interventions in women without the familial risk.
“In this case, non-testing is more harmful than multigene testing,” she said.
Others have been critical about the cost of genetics tests because these kinds of life-saving tests are not readily available to the poor.
Dr. Robert Nussbaum, Invitae’s chief medical officer, tells DDNews that his company has tried to make genetic testing more affordable for the common woman.
“Invitae now offers a patient-pay price that really brings the price of a test, that used to be in the $3,000 to $4,000 range a few years ago, down to $475,” Nussbaum said. “And, of course, we have institutional and third-party payer prices that are still far below what they had been in the past few years. We know price has been one of the biggest barriers to getting valuable genetic testing into the hands of physicians and patients, and Invitae is committed to making testing as affordable and accessible as possible.”