Introduction

BRCA1 and BRCA2 mutations are associated with a large proportion of hereditary breast and ovarian cancers in the general population. Specific founder mutations (185delAG and 5382insC in BRCA1 and 6174delT in BRCA2) account for ~95% of BRCA mutations in the Ashkenazi Jewish (AJ; central and eastern European Jewish) population.1 While the BRCA mutation carrier rate in the general population is approximately 1 in 400 to 1 in 800, roughly 1 in 40 to 1 in 100 individuals of AJ ancestry are believed to be BRCA carriers.2,3 This carrier frequency applies to the AJ population as a whole and increases with personal or family history of BRCA-related cancers.4,5

Women carrying BRCA mutations are at significantly increased risk for breast, ovarian, and pancreatic cancer, and men with the mutations are at increased risk for breast, prostate, and pancreatic cancer, among other types.5,6 BRCA carriers also have a 50% chance of passing their mutation to each of their offspring. Carriers have options in terms of screening (e.g., mammograms/magnetic resonance imaging), medical therapies, and risk-reducing strategies (e.g., prophylactic surgeries) to manage their cancer risks.7 Carriers also have reproductive options such as childbearing at a younger age and/or preimplantation genetic diagnosis.7 The increasing uptake of these strategies in the United States is likely to reduce cancer-related mortality in BRCA carriers.8,9 Nonetheless, pursuing cancer genetic testing is a personal and complex decision because the results have significant ramifications.10

Individuals from families with a high incidence of BRCA-related cancer types and cancer onset at young ages are recommended to undergo a genetics evaluation and to consider testing.11,12 In the United States, genetic counseling and testing for such individuals often are covered by health insurance.13 The National Comprehensive Cancer Network (NCCN) has set a low threshold for recommending BRCA testing for AJ individuals—testing is recommended for those with a personal or family history (first- or second-degree relative) of breast, ovarian, or pancreatic cancer at any age.7,11 The NCCN further recommends that BRCA testing for an AJ individual begin with the BRCA founder mutations and proceed to more comprehensive testing, especially if ancestry includes non-AJ ancestry or if the history is sufficiently compelling.11

BRCA mutation testing for individuals without a significant personal or family history of BRCA-related cancers is currently not considered a standard of care.12 Recently, however, the conversation about screening for BRCA in the general population—and, more specifically, in the AJ population—has intensified. Mary-Claire King14 has suggested that all women in the United States undergo BRCA genetic testing after age 30. This suggestion remains controversial for several reasons, including the resulting need for more comprehensive testing technologies for screening, which would be expensive and also uncover variants of uncertain significance.15,16,17

Because of the higher carrier frequency of three known BRCA founder mutations in the AJ population, the notion of offering them screening for these mutations has been suggested over many years.5,18,19,20 In 2008, in a free population screening program conducted by Steven Narod and colleagues in Canada, 2,080 unselected Jewish women were tested for the founder mutations.21 Twenty-two new carriers were identified, only 10 of whom would have met the Canadian BRCA testing guidelines in place at that time.21 Additional AJ BRCA testing programs have been piloted in Israel and England,22,23,24 and the findings have been similar with respect to the clinical value and utility (also reviewed by Foulkes et al.17). Data from the Gabai-Kapara study also suggest that the cancer risks may be equivalent for BRCA carriers from families with and without significant incidences of cancer.22

Together, these studies and related ones3,25,26 support offering BRCA founder mutation testing to the AJ population, even for those without a personal/family history of BRCA-related cancers. However, concerns about how to implement this in a clinical setting in the United States have been raised. Financial concerns related to insurance coverage and potential out-of-pocket costs often play a large role in patient decision making about whether to pursue genetic counseling and testing.27 These concerns may be magnified for individuals without a personal and/or family history of BRCA-related cancers because BRCA testing in these cases is typically not covered by insurance. Another concern regarding population-wide BRCA genetic testing relates to the limited supply of health-care professionals with expertise in cancer genetics.28

An initiative called BRCA community was launched in New York in early 2015 with the clinical objective of making BRCA1/2 testing accessible to all interested AJ individuals and the research objective of determining the receptivity and barriers to this testing in the United States. Here, we describe the model of and results from the pilot year of this initiative and outline some of the lessons learned.

Materials and Methods

Study design

The BRCAcommunity initiative was approved by the institutional review board at the Albert Einstein College of Medicine and is led by the Montefiore Medical Center Reproductive and Medical Genetics team in conjunction with the Program for Jewish Genetic Health (http://einstein.yu.edu/genetichealth/). The overarching design of the initiative is shown in Figure 1 . “Registrants” were those who registered initially, and “participants” were those who followed through with appointments and consented for research and testing. Demographic information and surveys were collected using the secure Web-based REDCap application.29 The study was managed using a secure portal (Citrix) that is compliant with Health Insurance Portability and Accountability Act guidelines. Data were evaluated using descriptive statistics, and significance was assessed using Fisher’s exact test (where indicated). Themes also were identified from weekly team meetings at which the study process and progress were reviewed.

Figure 1
figure 1

Overarching design of the BRCA community initiative (pilot year). AJ, Ashkenazi Jewish; NCCN, National Comprehensive Cancer Network.

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Recruitment

During the pilot year (1 February 2015–31 January 2016), the target audience was AJ adults in the tristate area (New York, New Jersey, and Connecticut). The recruitment mechanism was primarily by word of mouth. All interested individuals were directed to the initiative’s website (http://brcacommunitystudy.einstein.yu.edu/) to access educational materials and link to the registration forms. Eligibility criteria included being at least 25 years old, having at least 1 AJ grandparent, and never having undergone BRCA testing.

Interested individuals completed a health-history form online that was reviewed by genetic counselors. These initial registrants were classified as being at “high risk” (HR) or “low risk” (LR) based on their reported personal and family cancer histories. Those deemed at LR for having a BRCA mutation still had a 1 in 40 to 1 in 100 chance based on their AJ ancestry.5,22 Classifications were made using the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Genetic/Familial High-Risk Assessment: Breast and Ovarian, version 1.2015.11)

Clinical component

HR registrants were invited to make appointments for standard-of-care, one-on-one genetic counseling sessions. There were offered clinically appropriate testing based on their personal and family histories of cancer through a typical health insurance–based model. LR registrants (a more homogeneous group) were invited to attend a complimentary group genetic counseling session and were offered clinical genetic testing for the AJ BRCA founder mutations at a subsidized price of $100. The targeted founder mutation testing of saliva samples was performed in a Clinical Laboratory Improvement Amendments–approved laboratory by multiplex polymerase chain reaction amplification and allele-specific primer extension. The subsidized testing model is in line with the way in which preconception carrier screening had previously been made accessible to the Jewish community.30

All participants were given their genetic testing results via telephone and received a copy of their results in the mail. Results for all HR participants and LR carriers also were communicated to their health-care providers. All carriers were strongly encouraged to return for follow-up genetic counseling.

Survey-based research

Participants were given an initial risk-perception survey and a posttesting evaluation survey after disclosure of genetic testing results. Surveys focused on participants’ attitudes toward their own cancer and BRCA mutation risk, their stated motivations for pursuing genetic testing, and an evaluation of the counseling and testing process. During the sessions, LR participants were also asked to complete pre- and postcounseling questionnaires evaluating the group genetic counseling model.

Results

Over the pilot year, 407 individuals from 19 US states registered and met eligibility criteria. Almost two-thirds of these initial “registrants” (n = 254) were classified as HR. Only 47% of total registrants (n = 191) followed through with making appointments, with those classified as LR being more likely to do so (58% of LR vs. 41% of HR; P = 0.001). For registrants classified as HR who did not follow through with making an appointment, common reasons cited were distance from location and insurance/cost concerns. Some HR registrants indicated they would pursue testing with a local provider. For LR registrants who did not follow through, the top barriers cited were distance from location and scheduling conflicts.

At the end of the 1-year pilot, 189 individuals (189/191, consent rate of 99%) attended appointments and consented for research and genetic testing (101 HR and 88 LR study “participants”). Additional characteristics of the 189 participants are presented in Table 1 . For these participants, the top motivations for pursuing BRCA testing were to use the information to better manage medical care, to inform family members of the results, and because of AJ ancestry (Supplementary Figure S1 online, left). The top fears were concerns about cancer risk and insurance discrimination (Supplementary Figure S1, right).

Table 1 Characteristics of BRCA community participants: pilot year
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With respect to the HR cohort, results from their initial risk-perception surveys indicated that 42% did not think they were at HR for having a BRCA mutation, even given their AJ ancestry and family cancer histories. Of this 42%, 31% reported having a mother with either breast or ovarian cancer. Moreover, 61% of the HR cohort reported that a health-care provider had not previously recommended BRCA testing (despite all HR participants meeting NCCN criteria). Individual genetic counseling appointments enabled HR participants to discuss their personal and family histories and appropriate genetic testing options. By contrast, one of the unique components of the initiative design was the use of group pretest genetic counseling sessions for the LR cohort. Survey responses indicated that 97% of LR participants expressed comfort with meeting in this setting, and virtually no one felt intimidated or pressured by the group ( Table 2 ).

Table 2 Group counseling for LR cohort: survey results
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Overall, 10 BRCA carriers were identified ( Figure 2 ). Eight of the 10 carriers were from the HR cohort (8 carriers/101 tested), and 6 of these 8 HR carriers had reported a known familial mutation ( Figure 2 ). Nine other participants in the HR cohort had reported familial mutations, and 6 of these tested negative for their familial mutations. The 3 others did not have documentation of their specific familial mutation and declined additional testing beyond the AJ founder mutations.

Figure 2
figure 2

Type of testing pursued by HR and LR participants and carriers identified. For the 66 HR individuals who pursued BRCA1/2 AJ founder mutation testing only, 23 did so because AJ founder mutation testing was clinically sufficient. For the other 43, reasons for not continuing with further testing when negative included high deductibles and lack of insurance coverage. No pathogenic mutations were identified in other genes when panels were used for HR individuals. AJ, Ashkenazi Jewish; HR, high risk; LR, low risk.

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The two carriers found in the LR cohort (2 carriers/88 tested) did not meet criteria for testing/insurance coverage; therefore, they benefited from the availability of subsidized testing. Although their family cancer histories were very different, as shown in Figure 3a , b , both LR BRCA carriers were from families with a limited family structure (few female relatives). Both subsequently told selected blood relatives who then pursued testing, and both underwent risk-reducing surgical interventions.

Figure 3
figure 3

Representative pedigrees of newly identified carriers. (a) LR AJ BRCA carrier with some family cancer history, although not necessarily BRCA-related cancers. (b) LR AJ BRCA carrier with negligible cancer family history. For this family, we had no record of which members were deceased. (c) HR AJ BRCA carrier with no personal cancer history and no coverage for testing, despite family history of pancreatic cancer. For all of these pedigrees, maternal and paternal ancestry is Ashkenazi Jewish. d., died; dx, diagnosed; NOS, not otherwise specified; AJ, Ashkenazi Jewish; HR, high risk; LR, low risk.

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Finally, one of the eight carriers found in the HR cohort was a 70-year-old participant with a family history of cancer who met NCCN criteria due to pancreatic cancer in a maternal aunt ( Figure 3c ). Because Medicare would not cover her testing given her lack of personal cancer history,31 she, too, was able to utilize the subsidized AJ BRCA founder mutation test. She subsequently underwent a risk-reducing bilateral salpingo-oophorectomy and was able to inform her family members. Notably, 22 of the 101 individuals in the HR cohort had Medicare coverage but no personal cancer history and benefited from the availability of subsidized testing.

Discussion

Many of the objectives of BRCAcommunity were met in the pilot year, including providing affordable testing for interested individuals who would not be covered by their health insurance, identifying carriers who would have been missed by current mechanisms, and determining the receptivity and barriers to this testing in the United States and its Jewish community. Several poignant findings emerged; these are discussed here in relation to concerns raised previously about how to effectively implement AJ population-wide BRCA testing.15,16 We recognize that the small sample size of our cohorts poses a limitation with respect to drawing broad conclusions. Participant bias may also be present if the profiles of our early adopters do not match those of the general population. These early adopters could be individuals who are more proactive about their health, more attracted to the availability of subsidized genetic testing, or more eager to participate in research endeavors.

Initiative interest and influencers

Registration for the initiative was spurred by a variety of mechanisms, including recommendation from a friend/family member/provider, by an educational event, or from an online search. An interesting trend, which has been discussed previously,32 was the effect of trusted “influencers.” Notably, there were two specific “influencers” that led to an increase in registration. One was a New York Times opinion piece written by American writer Elizabeth Wurtzel, in which she described her personal experience of learning she was a BRCA carrier only after she developed cancer and underwent treatments (http://www.nytimes.com/2015/09/27/opinion/sunday/elizabeth-wurtzel-the-breast-cancer-gene-and-me.html?_r=1). Another “influencer” was a local genetic counselor who knew that the initiative was able to provide subsidized AJ BRCA founder mutation testing for those of her patients who would not have insurance coverage for testing.

Participants’ reported fears (Supplementary Figure S1 online), along with the concerns of those who registered but did not follow through with scheduling appointments, may help to explain why more people in the AJ community have not responded to this call for preventive action. Although the initiative intentionally was not publicized broadly during its pilot year, we expected a greater word-of-mouth response, considering the robust responses to similar initiatives abroad.21,22,23 Of note, these other initiatives offered free testing through a research protocol, whereas our initiative either held participants responsible for $100 toward the cost of their testing or required them to use their health insurance.

We may also have anticipated a greater response to our initiative given the US Jewish community’s prior experience with and acceptance of AJ-specific preconception carrier testing for conditions that could affect offspring (e.g., Tay-Sachs disease, OMIM 272800).30 We recognize that acceptance has matured over many decades, but confrontation of hereditary cancer risk by the broad Jewish community is still in its infancy. This undoubtedly relates in part to the fact that the very nature of these genetic tests has vastly different implications for the identified carrier. Those who do choose to pursue BRCA testing may be doing so in relation to where they are in their life cycles and their own personal experiences with friends and family with cancer diagnoses. Consistent with this is the fact that the average age of our participants was 50 years old ( Table 1 ).

Barriers to engaging genetic services: patients and health-care providers

Numerous studies have examined barriers to engaging the services of genetics professionals, and these were recently reviewed by Delikurt et al.33 Our data, gleaned from participants’ risk-perception surveys, highlight similar barriers for both patients and providers. First, many individuals may not realize the significance of their family’s cancer history, especially in the context of their AJ ancestry. Some of these individuals even had known familial mutations and/or family members affected with BRCA-related cancers at young ages. This lack of awareness of personal risk could explain why individuals did not previously seek genetic services. Alternatively, some HR participants may have been subconsciously aware of their risk factors and our initiative then served as the catalyst for them to pursue testing.

Physicians’ lack of awareness of patient risk factors and their failure to obtain an adequate family history are two additional factors described by Delikurt et al.33 Our findings support this shortcoming because >60% of participants who met NCCN criteria reported that a health-care provider had not previously recommended BRCA testing. Our data suggest that both community education and provider education about the risk for BRCA mutations in the AJ population need improvement. It is also important to clarify for both contingents the value of testing, including a review of the screening, cancer-risk-reducing, and reproductive options that would be available for carriers and their families. Other issues that probably need to be considered include the optimal age for such testing and whether AJ BRCA founder mutation testing should be included on the AJ preconception carrier screening panel. Learning one’s BRCA status early during the childbearing process may allow carriers to take full advantage of reproductive options.7 Finally, the psychosocial, communal, and religious implications of identifying carriers and carrier families also need to be integrated into these conversations.

Stratification and resulting routine clinical care for those deemed at higher risk

In most prior studies exploring models of AJ population screening,21,22,23 genetic testing for the BRCA founder mutations was performed for “all-comers,” with little distinction made on the basis of family history. In the planning phases of our initiative, we debated using this type of model wherein all participants could initially undergo group genetic counseling and AJ BRCA founder mutation testing regardless of risk level, and follow-up would differ based on reported cancer histories. This would allow for inclusion of more HR participants—specifically those who hesitated to use their health insurance—and more efficient use of resources in the classification and pretest counseling phases.

However, reflecting on the pilot year, we favor the model of stratification into HR and LR groups. For the LR AJ population, BRCA founder mutation testing is an appropriate way to assess BRCA-related cancer risk.1 In contrast, such testing is not sufficient if there is a significant personal or family history of cancer because other nonfounder BRCA mutations, and mutations in other cancer risk–predisposition genes have been reported in the AJ population.34,35 Stratification aligns well with best clinical practice because each participant, based on his or her initial risk level, can be offered the most appropriate genetic counseling and testing. For those with significant cancer histories, that testing often can include panels of cancer-susceptibility genes that are cost-effective and time-efficient.36 Stratification also enabled participants to utilize insurance coverage for their genetic testing when possible, so that philanthropic support could be reserved for those without coverage.

Undoubtedly, the one-on-one standard-of-care genetics appointments for the HR cohort were more labor-intensive and time-consuming relative to an “all-comers” approach. Moreover, cost and insurance coverage became a significant issue and was cited as the reason that many initial registrants did not become study participants. Although most individuals with a known family history of cancer had insurance coverage for genetic counseling/testing, they may still have faced steep out-of-pocket costs if they had a high, unmet deductible or if our medical center was not “in network.” Additionally, some patients did not meet their own insurance company’s criteria for genetic testing even though they met NCCN criteria (e.g., Medicare patients with a family but not personal history of BRCA-related cancers). Fortunately, the initiative was able to accommodate these individuals with subsidized AJ BRCA founder mutation testing. However, it should be noted that, most likely due to cost, some participants declined further testing beyond that, even though more was recommended based on their family histories ( Figure 2 ).

Efficient pretest counseling model for the LR cohort

Group genetic counseling for the LR cohort proved to be an efficient and well-received way of handling this homogeneous group ( Table 2 ). Although group counseling currently is utilized in several settings, it is not the predominant method for genetic counseling in the United States.37 However, when considering offering BRCA testing to the AJ population at large, models such as this can be helpful in the context of a limited supply of practicing genetic counselors.28 Although alternative approaches have been utilized (e.g., brochures, videos)21,38 and proposed (online platforms), we preferred the in-person pretest group session model. Our sessions were made more personal by keeping them relatively small (maximum of nine participants) and by allowing for questions both during the session and privately thereafter.

Counseling LR carriers about cancer risk levels

According to the Gabai-Kapara study,22 cancer risk for those with a known BRCA mutation may not differ for individuals with or without family history. Others argue that genetic and environmental modifiers exist39,40 that could reduce cancer risk for BRCA carriers lacking a family history of cancer. The two sides of this discussion were incorporated into our pretest counseling sessions for LR participants. However, once LR carriers were identified, the question of how to counsel them about their various options moved from theoretical to practical. Because no concrete data are currently available to help adjust cancer risk based on the absence of family-history data, the LR carriers were counseled that they should consider cancer screening and/or risk-reducing surgery options. Upon results disclosure and at their posttest genetic counseling sessions, LR carriers expressed anger regarding their decision to pursue testing as well as disbelief in the positive results. These responses only touch the surface of the wide range of emotions possible when patients learn their carrier status, let alone in an LR population that would generally not anticipate receiving positive results. Interestingly, both of our LR carriers asked to be retested in a second clinical laboratory. Both eventually conveyed gratitude for learning their status and, as noted, both underwent risk-reducing surgical interventions and informed family members.

In closing, although national guidelines have highlighted the AJ population as one that is at risk for BRCA mutations,11,12 beginning to confront this population risk will require further education of health-care providers, support of medical professional societies, and improvements in insurance coverage. Without coverage, this testing remains inaccessible for interested AJ individuals whose only indication may be their AJ ancestry. Going forward, the Jewish community may be able to play a role in spreading awareness and encouraging the use of genetic services, especially for individuals and families at the highest levels of risk. Ultimately, however, the decision of whether to pursue genetic testing remains in the hands of the individual. Although there are medical benefits to BRCA testing, the multifaceted implications of identifying carriers and carrier families in the context of a population need to be considered carefully.

Disclosure

Subsidies for testing were provided to the Program for Jewish Genetic Health by the Foundation for Medical Evaluation and Early Detection. The authors declare no conflict of interest.