Updated guidelines from the United States Preventive Services Task Force on BRCA1/2 genetic testing recommend risk assessment, counseling, and genetic test-ing for women who meet certain criteria but fall short of encompassing important groups of individuals who are at risk for developing BRCA1/2 mutation–driven disease
Allison Kurian, MD, MSc
Updated guidelines from the United States Preventive Services Task Force (USPSTF) on BRCA1/2 genetic testing recommend risk assessment, counseling, and genetic testing for women who meet certain criteria but fall short of encompassing important groups of individuals who are at risk for developing BRCA1/2 mutation—driven disease, according to critics of the update.
For example, the USPSTF added ancestry associated with pathogenic BRCA1/2 gene variants as a criteria for assessment and genetic testing, and emphasized the use of trained health professionals for genetic counseling, including trained primary care providers. Yet critics say the guideline does not adequately consider some ethnic groups with high incidence of mutations, does not address access to and costs of testing, and rules out broader population-based testing based on an excessive concern over the potential harms of testing, among other issues (Figure 11-9).
The new guideline was published in August to update the USPSTF’s 2013 recommendations on BRCA assessment.2 It recommends that primary care clinicians use a familial risk assessment tool to assess women with a personal or family history of breast, ovarian, tubal, or peritoneal cancers or who have an ancestry associated with BRCA1/2 gene mutations. The panel said women with a positive result on the tool should receive genetic counseling and, if indicated, testing.
“It is a conservative move toward appropriate guideline-based testing,” said Allison Kurian, MD, MSc, director of the Stanford Women’s Clinical Cancer Genetics Program at Stanford University, in Palo Alto, California.
Many patients who were treated for breast and ovarian cancer decades ago “had fallen through the cracks” and never underwent genetic tests that are now standard, said Susan M. Domchek, MD, executive director of the Basser Center for BRCA at the University of Pennsylvania in Philadelphia. Testing for pathogenic mutations in the BRCA DNA-repair genes remains underused even among patients who have had those cancers more recently.
Patients With a History of Cancer
“We’re not doing as well as we can for the patients who are at the highest risk of having BRCA1 and 2 mutations,” Domchek said. “It requires all of us to take a minute and say, ‘This is my patient. She’s here for her hypertension, but she had ovarian cancer 15 years ago and I don’t think she’s gotten genetic testing.’ It’s really kind of putting this in the forefront for everyone.”
The USPSTF recommendations are largely consistent with National Comprehensive Cancer Network guideline, which recommends that breast cancer survivors be considered for BRCA1/2 testing if they meet at least 1 additional criterion, including diagnosis at age 45 or younger, diagnosis between 45 and 50 with family history of breast or prostate cancer or an unknown family history, diagnosis of additional breast cancers, or Ashkenazi Jewish heritage.3
The NCCN guideline on genetic/familial high-risk assessment for breast and ovarian cancer also says patients who have had ovarian, pancreatic, metastatic prostate, or male breast cancer should be tested, as should men who have had high-grade prostate cancer if they meet 1 of several additional criteria. The NCCN also recommends that people from families with a known BRCA1/2 pathogenic or likely pathogenic variant be considered for testing. Unlike the NCCN, however, the USPSTF does not offer any recommendation regarding BRCA assessment in male patients, because evidence on the benefits and harms of genetic testing in men was not reviewed as part of the update. The USPSTF also declined to recommend population-based testing for BRCA1/2 mutations, saying that more research is needed.
J. Leonard Lichtenfeld, MD, MACP, deputy chief medical officer for the American Cancer Society, also called the USPSTF recommendation “conservative,” noting its lack of attention to male patients and population-based testing, and its recommendation of genetic counseling before testing. But, he said, it usefully highlights the importance of considering patients’ family histories.
“We, as health professionals, have done a pretty poor job of not only [asking about] family history, but [also] paying attention to family histories. It’s one thing to have someone take a family history and put it in a medical record. It’s quite another for someone to actually take a look at that family history and raise the question of whether someone should be tested,” Lichtenfeld said.
In the general population, BRCA1/2 mutations occur in an estimated 1 in 300 to 500 women and account for 5% to 10% of breast cancer cases and 15% of ovarian cancers, according to studies cited by the USPSTF. BRCA mutations raise breast cancer risk 45% to 65% by age 70. Risk of ovarian, fallopian tube, or peritoneal cancers increases to 39% for BRCA1 mutations and 10% to 17% for BRCA2 mutations.
Potentially harmful BRCA1/2 mutations occur in 0.2% to 0.3% of all women, while the estimated prevalence is 6% in women with cancer onset before age 40 and 2.1% among women of Ashkenazi Jewish descent.
Not Enough Testing
Kurian said increasing awareness of assessment and testing is an urgent matter because current testing rates are so low (Figure 21). A study she coauthored found that less than a quarter of patients with breast cancer (24.1%) and a third of those with ovarian cancer (30.9%) had genetic test results.4 Also, when tested for all genes that current guidelines designate as associated with their cancer type, 7.8% of patients with breast cancer and 14.5% of those with ovarian cancer had pathogenic variants.
“Patients with ovarian cancer absolutely should get genetic testing. There’s just no question; that’s been known and accepted in lots of guidelines for 10 years or more. We found, egregiously, that these patients are grossly undertested. Only 30% get tested when 100% should,” Kurian said.
The study included all women 20 years or older with diagnosed breast or ovarian cancer in California and Georgia between 2013 and 2014 and reported to the Surveillance, Epidemiology, and End Results registries. There were 77,085 patients with breast cancer and 6001 with ovarian cancer.
The study also found racial and economic disparities. Among those with ovarian cancer, testing rates were lower in black patients (21.6%; 95% CI, 18.1%-25.4%) than in whites (33.8%; 95% CI, 32.3%-35.3%), and in uninsured patients (20.8%; 95% CI, 15.5%26.9%) versus insured patients (35.3%; 95% CI, 33.8%-36.9%). Prevalent pathogenic variants in patients with breast cancer were BRCA1 (3.2%), BRCA2 (3.1%), CHEK2 (1.6%), PALB2 (1.0%), ATM (0.7%), and NBN (0.4%); in patients with ovarian cancer, they were BRCA1 (8.7%), BRCA2 (5.8%), CHEK2 (1.4%), BRIP1 (0.9%), MSH2 (0.8%), and ATM (0.6%).
Positive BRCA1/2 status can inform preventive care and shape treatment decisions for patients with breast, ovarian, prostate, and pancreatic cancers and with melanoma, according to the Basser Center. For women with BRCA mutations who have not had cancer, periodic breast exams, breast magnetic resonance imaging (MRI), and mammograms are recommended; male carriers should have breast exams, prostate exams, and prostate-specific antigen blood tests, also according to Basser. Both men and women should be examined annually by a dermatologist and may consider screening for pancreatic cancer.5
Women with BRCA mutations may also consider using chemopreventive drugs such as tamoxifen, which reduces the risk of developing hormone receptor—positive breast cancer in high-risk patients; raloxifene; or an aromatase inhibitor.6 Other options are prophylactic mastectomy, which reduces risk of breast cancer in high-risk women by about 90%, and removal of the ovaries and fallopian tubes, which reduces breast cancer risk by up to 50% and reduces ovarian cancer risk by 80%.7
Among women with diagnosed breast cancer, BRCA1 carriers are more likely to develop triple-negative cancers that require chemotherapy. They are at increased risk of developing second breast cancers and may want to consider mastectomy. BRCA1/2 mutation carriers may also benefit from use of PARP inhibitors. Olaparib (Lynparza) and talazoparib (Talzenna) are approved for treatment of certain metastatic breast cancers, and olaparib, rucaparib (Rubraca), and niraparib (Zejula) are approved for ovarian cancer. PARP inhibitors are also being studied for treatment of prostate, colorectal, pancreatic, skin, and non—small cell lung cancers.
Calls For a Broader Guideline
In an editorial accompanying the USPSTF statement, Domchek and co-author Mark E. Robson, MD, chief of the Breast Medicine Service at Memorial Sloan Kettering Cancer Center in New York, New York, note that the new recommendation does not mention the relevance of BRCA1/2 status to decision making for patients with newly diagnosed early stage breast cancer and for determining treatment of advanced cancers.8 They called for consideration of further expansion of the recommendation.
“In ovarian cancer now, if you have a BRCA1 or 2 mutation, your ovarian cancer will be treated differently from the beginning. It all of a sudden becomes critically important that that information is known,” Domchek said.
Knowledge of BRCA status also allows prospective parents to avoid passing mutations on to their children, she said. They can choose to do in vitro fertilization and preimplantation genetic diagnosis to screen out embryos that carry germline BRCA1/2 mutations.
Domchek and Robson note that although the USPSTF recommendation adds ancestry associated with BRCA1/2 mutations as a risk factor, it does not specifically endorse testing for unaffected Ashkenazi Jewish women with no family history of relevant cancers. Results of studies of genetic testing in Ashkenazi Jews have shown that up to 50% of those found to have a pathogenic variant had no or minimal family history (ie, they have a small family with few women who reached high-risk age).9 However, the USPSTF statement “may be interpreted as a step toward supporting unselected testing” in Ashkenazi Jews, Domchek and Robson write.
African Americans and Hispanic women also have a well-documented high incidence of BRCA1/2 mutations, and these groups are not adequately represented in the USPSTF recommendations for risk assessment or genetic testing, according to critics.10
The USPSTF recommends against routine risk assessment or genetic testing for women who do not meet its criteria, citing potential harms from assessment, testing, and use of risk-reducing interventions that outweigh the benefits. Pat W. Whitworth, MD a breast cancer surgeon at Saint Thomas Health in Nashville, Tennessee, said that position leaves the task force’s recommendation “way behind what needs to be happening.” He argued that the potential harms are minimal and noted that studies of unselected populations have found that about half of BRCA1/2 carriers detected do not meet published guidelines for clinical testing.11
“It’s always nice to see a step forward from the organizations that write guidelines, but this field is moving forward too quickly for guidelines to keep up. The guidelines for testing people are really functioning as a barrier,” said Whitworth, who helped craft a more expansive testing recommendation for the American Society of Breast Surgeons (ASBrS). In March, the ASBrS recommended that genetic testing for BRCA1/2 and other actionable alterations be made available to all patients with new diagnoses of breast cancer.12
Whitworth said BRCA1/2 testing via multigene panel testing (MGPT) should be done for all patients with breast cancer, followed by cascade testing of family members when appropriate, rather than testing only those who meet existing guidelines. He said that recommendation is supported by a clinical registry study he co-authored that used an 80-gene panel to test 959 patients with breast cancer, half of whom met NCCN screening guidelines. The investigators found pathogenic or likely pathogenic mutations in 9.39% of those who met the guidelines and 7.9% of those who did not, a difference that was not statistically significant (P = .4241).13
However, in another article, Domchek and Robson note that Whitworth and his colleagues found pathogenic variants of BRCA1/2 specifically in only 3 of 480 patients who did not meet testing guidelines.8 The positive rate of the in-guideline group was 4 times higher (2.51% vs 0.63%; P = .0201).
Genetics Training is Lagging
Large-panel gene testing has dropped sharply in cost and is becoming common in oncology—although it remains controversial. Domchek and Robson acknowledge that panel testing has largely replaced BRCA1/2-only tests, but they argue in their edittorial that “the clinical utility of the indiscriminate use of MGPT has not been established, and genetics education of primary care clinicians has not kept pace with either the influx of new information or the changes in the genetic testing marketplace.”14
Domchek cited several concerns about the widespread use of panel testing to detect BRCA mutations. They include the low incidence of BRCA mutations in unselected populations, the low or uncertain utility of knowing other types of mutations, the cost of testing, and the potential harms from unnecessary prophylactic surgery and of overuse of magnetic resonance imaging in follow-up screening.
Whitworth responded by pointing to a new modeling study of unselected BRCA1/BRCA2/ PALB2 testing at breast cancer diagnosis published in JAMA Oncology.15 Using data from 11,836 women in the United Kingdom and United States, investigators concluded unselected testing was “extremely cost-effective” compared with testing based on clinical criteria or family history. The incremental cost-effectiveness ratio to test all US patients with breast cancer was $65,661 per quality-adjusted life year (QALY) from the payer perspective and $61,618/QALY from the societal perspective, well below standard thresholds. One year’s unselected panel genetic testing could prevent 2101 cases of breast or ovarian cancer and 633 deaths in the United Kingdom, and 9733 cases and 2406 deaths in the United States, they reported.
One challenge to broadening BRCA1/2 testing is the practice of requiring genetic counseling in advance, which can take several hours and may be stymied by the shortage of genetic counselors in rural areas. The USPSTF recommends a multi-step process that begins with the primary care physician using a familial risk-assessment tool, such as the Tyrer-Cuzick instrument. If indicated, the patient should then receive genetic counseling from a trained professional, possibly a suitably trained primary care provider, who can discuss whether the patient should be tested.
“Plain and simple, genetic counseling is a barrier. I have met with genetic counselors. They were uniformly in favor of using other techniques for doing counseling for BRCA testing,” Lichtenfeld said. “They’re now dealing with a substantial increase in the number of genetic syndromes and genetic findings that may require their specific services. So, they feel like BRCA is one place where their services aren’t as valuable as they could be elsewhere.”
To facilitate testing, particularly if all patients with breast cancer are to be tested, Whitworth and the ASBrS recommend dispensing with a standard pretest genetic counseling appointment. Instead, the physician briefly explains genetic testing and orders the test if the patient agrees. If the test is positive, the patient is referred to a counselor. Whitworth said that system would help enable a huge increase in genetic testing and allow for the identification of the estimated 1 million BRCA1/2 carriers in the United States and 5 million carriers of other actionable pathogenic variants.
“We think that the genetic counseling model that everybody grew up on needs to change, because if we start doing this right, we are going to be finding a lot of patients who have a pathogenic variant, and it’s not necessarily going to be in BRCA. They’re going to need genetic counselors. So, genetic counselors, we think, will go from gatekeepers to real counselors for folks who have a finding,” he said.