It is rare that treatment guidelines make sweeping changes to treatment recommendations, yet the American Society of Breast Surgeons is urging that the National Comprehensive Cancer Network guidelines on breast cancer treatment be changed to indicate that genetic testing be offered to all patients with breast cancer.
It is rare that treatment guidelines make sweeping changes to treatment recommendations, yet the American Society of Breast Surgeons (ASBrS) is urging that the National Comprehensive Cancer Network (NCCN) guidelines on breast cancer treatment be changed to indicate that genetic testing be offered to all patients with breast cancer.1
Although the guidelines are updated often, most recently in January of 2019,2 those changes have not kept pace with research, the Society determined.
“We’ve been struggling with the guidelines for a while. The guidelines are still lagging because we miss people [who should be offered test- ing],” said Walton A. Taylor, MD, president of the ASBrS, in an interview withTargeted Therapies in Oncology(TTO). “Common sense says they, too, would benefit.”
Investigators continue to identify additional hereditary drivers of the disease, making it likely that more patients could benefit from testing. At the same time, the age cutoff points in the guidelines seem arbitrary, he said.
For example, a patient with triple-negative breast cancer who is ≤60 years currently qualifies for testing. “But the moment she turns 60, she does not,” Taylor said. “Yet it is hard to say a woman who is diagnosed at 61 did not have that tumor before she was 60.”
That unease was heightened by a December 2018 study in theJournal of Clinical Oncology, in which investigators analyzed 959 patients with breast cancer who had been sorted into 2 groups: those who met the current NCCN guidelines for testing (n = 479) and those who did not (n = 480).3
In the overall cohort, 8.65% had a pathogenic or likely pathogenic (P/LP) variant. More importantly, the results were strikingly similar for the 2 groups. Of those patients who had indications for testing under the current guidelines, 9.39% had a P/LP variant. Of those who did not qualify for testing under the current guidelines, 7.9% had a P/LP variant. The difference between the 2 groups was not statistically significant (P = .4241).
These results suggest that nearly half of patients with breast cancer and a genetic variant are being missed by current testing guidelines, with the authors of the study concluding that “guidelines should be expanded immediately to include genetic testing of all patients with breast cancer.”
The ASBrS announcement urges its members to make genetic testing their default approach. Now, instead of ruling out testing in patients who do not have a family history or other motivating risk factors, surgeons should order testing in all patientsunless there is a specific reason not to.
However, there may be patients for whom testing makes little sense. For someone who has no children or is of an advanced aged so they will not be screened for future cancers, there may be little practical reason for testing, Taylor said. He recounted the experience of Eric R. Manahan, MD, MBA, a member on the board of directors for the ASBrS and medical director of Southeastern Breast Care Specialists in Dalton, Georgia, who chaired the Society’s working group on the topic. The first patient Manahan tested off guidelines turned out to have theBRCA2mutation.
“I told him, ‘There’s your sign. You did the right thing,’” Taylor recalled. “For that woman’s life and her kids’ lives and their kids’ lives, this knowledge is massive.”
The ASBrS consensus policy says patients who have had genetic testing may benefit from updated testing even if they previously came up empty for pathogenic variants.
“Genetic testing performed prior to 2014 most likely would not have hadPALB2or other potentially relevant genes included and may not have included testing for large genomic rearrangements inBRCA1orBRCA2,” the policy says.
Genetic testing should also be offered to patients without a history of breast cancer who otherwise meet the current NCCN guidelines, according to the report. Unaffected patients should be told that testing an affected relative, if possible, will yield more informative results than undergoing testing themselves.
The new approach comes with a caveat since variants of uncertain significance are DNA sequences that are not clinically actionable. “This type of result needs to be considered as inconclusive, and the patient should be managed based on their risk factors and not influenced by this result,” the report states.
Treatment Significance to Genetic Variants
The rapidly expanding roster of oncogenic agents means genetic testing results can sometimes be used immediately to drive treatment choices, said George W. Sledge Jr, MD, chief of the division of oncology and professor of medicine (oncology) at Stanford University Medical Center in California, as well as past president of the American Society of Clinical Oncology (ASCO), in an interview with TTO.
“It is no longer just a matter of, ‘I want to be able to tell my daughters if they have this gene,’” he said. “What many people do not realize is that genetic testing has moved from diagnostics into therapeutics. If you have theBRCAgene [mutation] and ovarian cancer, you will be treated with a PARP inhibitor. The reality is that real patients are being treated with real drugs [based on] these results.”
Another treatment example is cited in the ASBrS report and involves patients with TP53 variants, the gene associated with Li-Fraumeni syndrome, who have an increased risk of developing radiation-induced secondary malignancies, which should be factored into any decision about undergoing radiation.
AlthoughBRCA1/2 mutations are well known by both clinicians and patients for increasing a patient’s genetic risk for breast and other can- cers, modern day testing panels should include Li-Fraumeni syndrome (TP53 pathogenic variant), Cowden syndrome (PTEN pathogenic variant), hereditary diffuse gastric cancer syndrome (CDH1 pathogenic variant), and Peutz-Jeghers syndrome (STK11 pathogenic variant.)
“Not all pathogenic variants identified are medically actionable,” the Society recommendation cautions. “Just because a hereditary pathogenic mutation that predisposes to breast cancer is identified does not mean that the risk-reducing mastectomy is indicated.”
Risk-reducing mastectomies can be considered for findings ofBRCA1,BRCA2,PTEN, andTP53mutations (FIGURE1). However, patients with eitherBRCA1/2variant should also consider a bilateral salpingo-oophorectomy after child-bearing or between the ages of 35 and 40 to reduce their risk of ovarian and fallopian tube cancer. For BRCA1 carriers, the recommended age range for surgery is 35 to 40, while BRCA2 carriers should consider it between ages 40 and 45.
For some of the less common pathogenic mutationssuch as ATM, CDH1, CHEK2, NBN, NF1, PALB2, and STK11—enhanced screening is recommended, yet current data are not sufficient to support prophylactic mastectomies unless factors, like strong family history, reinforce that approach. “There are substantial gaps in our ability to predict individual risk associations with mutations in some of these genes,” the report states.
A third category covers mutations for which some data suggest an elevated lifetime risk of breast cancer but for which there are currently insufficient data to support a change in breast cancer management. These includeBARD1, MSH2, MLH1, MSH6, PMS2, EPCAM, BRIP1, RAD51C, and RAD51D. Specifically,MSH2, MLH1, MSH6, andPMS2are associated with Lynch syndrome, which requires multidisci- plinary management.
Implications of Broad Genetic Testing
Sledge foresaw this sea change in favor of expanded testing and noted it in his 2013 keynote lecture at the ASCO Breast Cancer Symposium, for which 1 of the 5 predictions he offered was that BRCA testing would become “ubiquitous” thanks to the availability of less expensive assays.4
The United States Supreme Court had just stripped Myriad Genetics, Inc, the groundbreaking genetics-testing company, of its 2 BRCA pat- ents, so marketplace competition was predicted to drive down the price of testing. At the time, the test cost $2000 to $5000; just 5 years later, it plummeted to a tenth of that.3
That price is so low that some patients are not waiting for insurance companies to cover the cost. According to Sledge, Stanford Cancer Center’s genetic counselors are increasingly seeing patients who arrive with their testing results. Concern is being voiced about the ability of the existing healthcare system to accommodate a flood of new patients should the NCCN guidelines expand so drastically. The ASBrS recommends that every patient being tested receive counseling before and after the test, and suggests that can usually be provided by surgeons. Doctors often develop long-term bonds with their patients, Taylor said, and many patients stay in touch with their surgeons. However, “for complex scenarios, referral to a genetics professional is recommended,” the statement says.
The Society offers refresher courses and training as knowledge about pathogenic mutations increases. Taylor recommended surgeons consult the website, All Syndromes Known to Man Evaluator (ask2me.org), developed by the BayesMendel Lab at Dana-Farber Cancer Institute and the Hughes Lab at Massachusetts General Hospital, headed by the surgical director of the hospital’s Breast Cancer Screening Program, Kevin S. Hughes, MD.
Another concern relates to timing. Surgeons often see patients very soon after they receive their cancer diagnosis. Scott Weissman, MS, a certified genetic counselor in Northbrook, Illinois, and a member of the board of directors of the National Society of Genetic Counselors, estimated 30% to 40% of patients choose not to be tested at that moment “because they are overwhelmed with the diagnosis.”
Furthermore, a 2018 study found that less than 50% of patients with clinical indications received formal genetic counseling.5
That 2-tiered approach concerns Weissman. “It would be nice to see just 1 level of high-quality care for women,” he said in an interview with TTO.
Breast cancer surgeons may feel competent to discuss aBRCAmutation finding with a patient, but Weissman pointed out other results could fall out of their comfort zone. For example, theCDH1mutation carries an extra risk for diffuse gastric cancer, the treatment for which might entail a preventive removal of the stomach. Clearly, not every breast cancer surgeon would be prepared for counseling such a patient, he said.
Sledge worries most surgeons simply do not have enough time for such discussions. Even a conversation about aBRCAmutation, with which patients often have some knowledge, includes such topics as removal of both ovaries, chemotherapy prevention, MRI screenings, and whether family members need to be tested.
“I have never yet had a discussion about cancer genetics that lasted 5 minutes,” Sledge said. “These discussions take a lot of time. They are emotional, and they are not easy. If you are a busy surgeon and you have a bunch of new patients and you have to be in the [operating room] in 10 minutes, are you going to have the time to give this discussion [the time] it deserves?”
“One of the reasons we love genetic counselors is that they actually get paid for doing that,” he added.
However, access to them is uneven. “If you live in rural Wyoming, your chance of seeing a genetic counselor is probably less than seeing a coyote,” Sledge said. Luckily, results of a 2016 study suggest that telephone counseling was just as effective as in-person sessions.6