FormalPara Key Summary Points

National and international guidelines recommend testing patients with advanced breast cancer (ABC) for germline breast cancer susceptibility gene 1 or 2 (BRCA1/2) mutations.

This real-world study evaluated BRCA1/2 mutation testing rates in patients with human epidermal growth factor receptor 2–negative (HER2−) ABC in the USA, the European Union 4 (EU4; France, Germany, Italy, and Spain), and Israel.

Among patients with hormone receptor–positive/HER2− ABC, the BRCA1/2 testing rate was 99% in Israel, 37% in the EU4, and 68% in the USA.

Among patients with triple-negative breast cancer, the BRCA1/2 testing rate was 100% in Israel, 78% in the EU4, and 93% in the USA.

Given the high risk of breast cancer in BRCA1/2 mutation carriers and the efficacy of new therapies in treating ABC with a BRCA1/2 mutation, efforts should be made to improve BRCA1/2 testing in Europe and the USA.

Introduction

Women in the general population have an approximately 13% risk of developing breast cancer in their lifetime [1]. By contrast, women with genetic mutations in breast cancer susceptibility gene 1 or 2 (BRCA1/2) have a 45–90% risk for developing breast cancer [1, 2]. Approximately 3–6% of all breast cancer cases are caused by BRCA1/2 mutations [3,4,5,6]. Importantly, a recent study found that BRCA1/2 mutations in over 50% of individuals would have gone undetected when using traditional clinical criteria (e.g., family history) for genetic testing [7].

Higher risk populations have also been identified. As a result of the founder effect, BRCA1/2 mutations occur at higher rates in some countries with populations that arise from a small number of individuals and a more homogeneous gene pool. In Israel, for example, 12% of Ashkenazi Jewish women with breast cancer have a BRCA1/2 mutation [8]. Also, BRCA1/2 mutation-related breast cancers are more likely to be triple-negative breast cancer (TNBC), which has a worse prognosis, often a higher stage, and therefore may require more intensive therapies [9].

The poly(adenosine diphosphate-ribose) polymerase inhibitors (PARPi) olaparib and talazoparib are approved by the US Food and Drug Administration, the European Medicines Agency, and in Israel for the treatment of patients with germline BRCA1/2 (gBRCA1/2)–mutated, human epidermal growth factor receptor 2–negative (HER2−) advanced breast cancer (ABC) [10, 11]. These approvals were based on findings from the OlympiAD [12] and EMBRACA [13] studies, both of which demonstrated improved progression-free survival outcomes in patients with HER2− gBRCA1/2-mutated ABC who received olaparib or talazoparib, respectively, compared with patients who received physician’s choice of chemotherapy (OlympiAD: capecitabine, vinorelbine, or eribulin; EMBRACA: capecitabine, vinorelbine, eribulin, or gemcitabine). In the OlympiA trial, olaparib also significantly prolonged invasive disease-free survival, compared with placebo, when taken as an adjuvant therapy in patients with HER2– early breast cancer who had a gBRCA1/2 mutation [14]. On the basis of these findings, the US Food and Drug Administration recently approved olaparib as an adjuvant treatment for patients with deleterious or suspected deleterious gBRCA1/2 mutation and HER2– high-risk early breast cancer [15]. These findings underscore that, in addition to hormone receptor (HR) status, HER2 status, and programmed death ligand 1 (PD-L1) status in TNBC, BRCA1/2 germline status should also be available for a therapy decision before the start of therapy.

With the approval of the PARPi olaparib and talazoparib and the potential for effective therapeutic intervention in patients with BRCA1/2 mutations, eligibility criteria have broadened for gBRCA1/2 mutation testing, as recommended in national and international guidelines [16, 17]. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) now recommend that all patients with locally advanced or metastatic breast cancer be tested for BRCA1/2 mutation [18]. In addition, identifying carriers of germline BRCA1/2 mutations affords the opportunity for testing of family members, who can then access risk-reducing interventions [19, 20]. The present analysis evaluated differences in patient demographics, clinical characteristics, and genetic counseling in a real-world population of adult patients who have been diagnosed with locally advanced or metastatic HER2− breast cancer, and who underwent BRCA1/2 mutation testing, across different regions: the USA, the European Union 4 (EU4; France, Germany, Italy, and Spain), and Israel.

Methods

Study Design

Data were drawn from the Adelphi Real World ABC Disease Specific Programme (DSP™) from October 2019 through March 2020 in the USA, EU4, and Israel. DSPs are large, multinational, point-in-time surveys conducted in clinical practices, the results of which help describe disease burden, disease management strategies, and responses to treatment as assessed by treating physicians [21].

Participating physicians, recruited by local fieldwork teams, were medical oncologists evaluating at least five patients with ABC per month and were personally responsible for making their treatment decisions. Eligible patients were at least 18 years of age with stage IIIb–IV breast cancer and receiving therapy for ABC at the time of data collection. Patients with an unknown HR status and those participating in a clinical trial at the time of data collection were excluded.

Physicians provided patient record forms (PRFs) for the next eight eligible consulting patients: four patients receiving first-line advanced treatment and four patients receiving second- or later-line advanced treatment. The PRFs included detailed questions on patient demographics, clinical assessments, diagnosis patterns, comorbidities and symptoms, treatment history and pathways, reasons behind current treatment choice and areas of improvement, current treatment side effects, compliance and satisfaction with current treatment, current treatment goal, future treatment choices and patient life expectancy, resource utilization, market access, and physician satisfaction with treatment. Physicians also reported on tumor and biomarker testing, including, but not limited to, estrogen and progesterone receptor, HER2, PD-L1, progesterone and estrogen receptor, PIK3CA, homologous recombination repair genes, and were asked the proportion of patients tested and the proportion returning a positive result. No guidance was provided on BRCA1/2 testing; therefore physicians were invited to report any patient regardless of BRCA1/2 status to prevent any bias in patient selection. BRCA1/2 mutation testing was focused on in depth, with physicians asked to report patient characteristics for those tested, the type of test used to determine BRCA1/2 status, cancer stage of patient during the tests, and whether the results were somatic or germline. Patient age at time of data collection, but not at genetic testing, was reported. The treating physicians abstracted data using patient medical records as well as their clinical judgement and diagnostic skills consistent with their decision-making process during routine clinical practice.

All patients provided informed consent for use of their anonymized and aggregated data for research and in scientific publications. Data were aggregated and de-identified before receipt by Adelphi Real World. This research was approved by the Western Institutional Review Board (study protocol AG8643). Data collection was undertaken in line with European Pharmaceutical Marketing Research Association guidelines [22] and as such did not require ethics committee approval. Each survey was administered in full accordance with relevant legislation at the time of data collection, including the US Health Insurance Portability and Accountability Act of 1996 [23] and the Health Information Technology for Economic and Clinical Health Act [24].

Outcomes and Measures

BRCA1/2 mutation testing rates and the characteristics of patients undergoing these tests were stratified by the type of test performed: testing for all BRCA1/2 mutations, testing for a gBRCA1/2 mutation with or without testing for a somatic BRCA1/2 (sBRCA1/2) mutation, testing for a sBRCA1/2 mutation only, unknown BRCA1/2 mutation test (i.e., the physician was not aware of testing results or it could not be verified if mutations were somatic or germline), or no BRCA1/2 mutation test. Results were also stratified by region (i.e., USA, EU4, Israel) and HR status (i.e., HR+/HER2−, TNBC). Characteristics of patients who did and did not receive a BRCA1/2 mutation test were compared to identify possible factors that may have contributed to the decision to test these patients. Physicians also reported whether patients had undergone genetic counseling before, during, or after BRCA1/2 mutation testing.

Physicians were asked to designate the sample used for testing and if reported as done on blood, saliva, and buccal samples, this information was used to confirm that BRCA1/2mut testing was germline; for USA-based patients, this was also verified by inquiring the name of the laboratory where the testing was performed, whereas data for laboratory confirmation of test type was not available for the EU4 and Israel. For gBRCA1/2 mutation testing, tissue-only samples were used for sBRCA1/2 mutation testing (Fig. 1). For USA-based patients, this was verified by the laboratory where the testing was performed; data for laboratory confirmation of test type was not available for the EU4 or Israel.

Fig. 1
figure 1

BRCA1/2 mutation status. ABC advanced breast cancer, BRCA1/2 breast cancer susceptibility gene 1 or 2, HER2−  human epidermal growth factor receptor 2–negative. aIncludes not tested; not known to have a BRCA1/2 germline mutation test result; not known to have BRCA1/2 germline and somatic wild-type test results

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Statistical Analyses

Descriptive statistics were calculated for intergroup comparisons. For the BRCA1/2 mutation tested and untested subgroups, differences in demographic and/or clinical characteristics and BRCA1/2 mutation testing rates were analyzed using Student’s t tests and Fisher’s exact tests. Missing data were not imputed; thus, the sample size varied among variables assessed and is reported separately for each analysis.

Results

Physicians and Patients

Physicians (305) completed PRFs for 2527 patients: 407 in the USA, 1926 in the EU4, and 194 in Israel. Among all patients, 56% (n = 1421) were undergoing treatment at academic medical centers and 44% (n = 1106) were undergoing treatment at community-based centers. All Israeli patients were treated at academic medical centers. A larger percentage of US versus EU4 patients was treated at community-based centers (62% vs 44%; p < 0.001).

Patient demographic and clinical characteristics are summarized in Table 1. There were statistically significant regional differences in many of these characteristics, particularly for Israeli patients compared with those in the USA and EU4. Overall, mean (SD) age was 63 (12) years: 57 (13) years in Israel, 63 (11) years in the EU4 (p < 0.0001 vs Israel), and 64 (11) years in the USA (p < 0.0001 vs Israel). The vast majority of EU4 patients (94%) were White, compared with 65% in the USA and none in Israel. In Israel, 41% of patients (n = 80) were of Ashkenazi Jewish heritage. All Black patients were from the USA. Overall, 18% of patients (n = 458) had full- or part-time employment, ranging from 5% in Israel (p < 0.0001 vs USA and EU4) to 17% in the EU4 and 29% in the USA (p < 0.0001 vs EU4). A significantly larger percentage of patients in the EU4 was retired (43%) compared with in the USA (35%; p = 0.003) and Israel (13%; p < 0.0001). Overall, a family history of BRCA-related cancer was recorded for 21% of patients (n = 531); the percentage was significantly larger in Israel (69%) compared with the USA (18%; p < 0.0001) and EU4 (18%; p < 0.0001). Eighty-six percent of patients (n = 2169) had HR+/HER2− ABC and 14% (n = 358) had TNBC. Eighty-eight percent of patients (n = 2214) had stage IV breast cancer, and 78% (n = 1969) had an Eastern Cooperative Oncology Group performance status score of 0 or 1.

Table 1 Patient demographic and clinical characteristics
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BRCA1/2 Testing

BRCA1/2 mutation testing rates overall and by type differed across regions and are listed in Table 2. Overall, 51% of patients (n = 1295/2527) underwent BRCA1/2 mutation testing. Of these, 70% of patients (n = 904) had gBRCA1/2 mutation testing with or without sBRCA1/2 mutation testing and 20% (n = 264) had sBRCA1/2 mutation–only testing. Test type was unknown for 10% of patients (n = 127). Testing rates were significantly higher in Israel compared with other regions. In patients with HR+/HER2− ABC, 99% (n = 139/141) underwent testing in Israel, compared with 68% (n = 222/325) in the USA (p < 0.0001) and 37% (n = 631/1703) in the EU4 (p < 0.0001). Significantly more patients with HR+/HER2− ABC in the USA underwent sBRCA1/2 mutation-only testing (18%) compared with patients in the EU4 (9%; p < 0.0001) and Israel (1%; p < 0.0001). In patients with TNBC, 100% (n = 53/53) underwent testing in Israel, compared with 93% (n = 76/82) in the USA (p < 0.081) and 78% (n = 174/223) in the EU4 (p < 0.0001). Regardless of cancer type, nearly all testing in Israel was for a gBRCA1/2 mutation with or without an sBRCA1/2 mutation versus for an sBRCA1/2 mutation only (HR+/HER2− breast cancer, 99% vs 1%; TNBC, 96% vs 4%). In the USA, testing rates were 68% (n = 222/325) and 93% (n = 76/82) for patients with HR+/HER2− breast cancer and TNBC, respectively. Testing rates were lowest in the EU4 (37% [n = 631/1703] and 78% [n = 174/223] for patients with HR+/HER2− breast cancer and TNBC, respectively). In both the USA and EU4, larger percentages of patients, regardless of cancer type, underwent gBRCA1/2 mutation testing with or without sBRCA1/2 mutation testing versus sBRCA1/2 mutation–only testing (HR+/HER2− breast cancer, 43% vs 18% in the USA and 24% vs 9% in the EU4; TNBC, 61% vs 20% in the USA and 57% vs 14% in the EU4; Table 2).

Table 2 BRCA1/2 mutation testing across regions according to HR status
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BRCA1/2 Testing and Patient Characteristics

Tested Versus Not Tested

Overall rates of any type of BRCA1/2 mutation testing were significantly higher in Israel (99%) compared with the USA (73%; p < 0.0001) and EU4 (42%; p < 0.0001). The rate of testing was also significantly lower in the EU4 compared with the USA (p < 0.0001).

HR+/HER2− ABC

In patients with HR+/HER2− ABC, the mean age of tested USA-based patients was significantly higher than that of EU4-based patients (64 vs 59 years; p < 0.0001; Table 3). The mean age of Israeli patients was significantly lower (56 years) compared with patients in the USA (p < 0.0001) and EU4 (p = 0.016). Of the patients with HR+/HER2− ABC that were tested for any BRCA1/2 mutation, the majority in the USA (55%) were 65 years of age or older, whereas in the EU4 and Israel, 35% and 31% of these patients, respectively, were 65 years of age or older (Fig. 2a). A significantly larger percentage of patients in the EU4 versus the USA was White (93% vs 69%; p < 0.0001); there were no Black patients in the EU4 or Israel. Forty percent of Israeli patients were of Ashkenazi Jewish descent.

Table 3 Demographic and clinical characteristics of patients with ABC who did and did not receive BRCA1/2 testing
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Fig. 2
figure 2

Testing patterns across regions according to age group and family history of BRCA-related cancers. BRCA1/2 mutation status of patients with HR+/HER2− breast cancer (a, c) and TNBC (b, d) stratified into four different age groups (a, b) and stratified by family history of BRCA-related cancer (c, d). BRCA1/2mut breast cancer susceptibility gene 1 or 2 mutation, HR+/HER2− hormone receptor–positive/human epidermal growth factor receptor 2–negative, TNBC triple-negative breast cancer

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With regard to employment status, similar percentages of tested patients in the USA and EU4 were working full or part time (31% and 25%, respectively). In Israel, significantly fewer patients were working full or part time (5%) compared with the USA (31%; p < 0.0001) or EU4 (25%; p < 0.0001), and significantly larger percentages of patients were on long-term sick leave in the EU4 (15%; p < 0.0001) and Israel (18%; p < 0.0001) compared with patients in the USA (2%). According to the age distribution, the largest percentage of premenopausal patients was in Israel (28%), followed by the EU4 (14%) and USA (5%).

The largest percentage of tested patients with a family history of BRCA1/2 mutation–related cancer was in Israel (72%), followed by the EU4 (27%; p < 0.0001 vs Israel) and USA (16%; p < 0.0001 vs Israel). Furthermore, for only 1% of patients in Israel tested for any type of BRCA1/2 mutation was it unknown if the patient had a family history of BRCA1/2 mutation–related cancer, whereas in the EU4 and USA, 3% and 14% of tested patients, respectively, had an unknown family history of BRCA1/2 mutation–related cancer (Fig. 2c). Also, a similar pattern of family history of BRCA1/2 mutation–related cancer was observed in the subgroup of patients who had a gBRCA1/2 mutation test with or without an sBRCA1/2 mutation test; 73%, 30%, and 16% of patients in Israel, the EU4, and the USA, respectively, had a family history of BRCA1/2 mutation–related cancer, and in those who had sBRCA1/2 mutation testing only, 100%, 21%, and 19% of patients in Israel, the EU4, and the USA, respectively, had a family history of BRCA1/2 mutation–related cancer (Table 4).

Table 4 Demographic and clinical characteristics of patients with ABC who received gBRCA1/2 and/or sBRCA1/2 testing and those who received sBRCA1/2 only testing
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Rates of testing, any BRCA1/2 mutation tested, gBRCA1/2+/− sBRCA1/2 tested, and sBRCA1/2-only tested, among patients with HR+/HER2− ABC by demographic and clinical characteristics in the individual EU4 countries are show in Supplementary Tables 1 and 2. Among patients with BRCA1/2 mutation–tested HR+/HER2− ABC in the four individual EU4 countries evaluated (France, Germany, Italy, and Spain), the mean ages and percentages of patients with a family history of BRCA1/2 mutation–related cancer were generally similar, although the percentage of patients treated in academic medical centers was relatively small in Germany (26%) compared with France (79%), Italy (69%), and Spain (77%; Supplementary Table 1).

Triple-Negative Breast Cancer

For patients with TNBC who were tested for any BRCA1/2 mutation, there were fewer significant regional differences in patient characteristics. In contrast to patients with HR+/HER2− ABC, there were no significant differences in mean age (Table 3). Of the patients with TNBC who were tested for any BRCA1/2 mutation, 37% in the USA, 25% in the EU4, and 40% in Israel were 65 years of age or older (Fig. 2b). Consistent with patients with HR+/HER2− ABC, a significantly larger percentage of patients in the EU4 versus the USA was White (96% vs 61%; p < 0.0001). Forty-two percent of Israeli patients with TNBC were of Ashkenazi Jewish descent (Table 3).

In Israel, significantly fewer tested patients were working full or part time (2%) compared with the USA (39%; p < 0.0001) or EU4 (29%; p < 0.0001). The largest percentage of patients on long-term sick leave was in the EU4 (24%), followed by Israel (15%) and the USA (5%); only the difference between the USA and EU4 reached statistical significance (p < 0.001).

The largest percentage of tested patients with a family history of BRCA1/2 mutation–related cancer was in Israel (57%), which was significantly larger than the percentages for both the EU4 (29%; p < 0.001) and USA (26%; p < 0.001). Among patients with TNBC who were tested, 4%, 3%, and 6% in the USA, EU4, and Israel, respectively, had an unknown family history of BRCA1/2 mutation–related cancer (Fig. 2d). A similar pattern of family history of BRCA1/2 mutation–related cancer was observed in the subgroup of patients who had gBRCA1/2 mutation testing with or without sBRCA1/2 mutation testing; 59%, 30%, and 28% of patients in Israel, the EU4, and the USA, respectively, had a family history of BRCA1/2 mutation–related cancer, and in those who had sBRCA1/2 mutation testing only, 0%, 19%, and 25% of patients in Israel, the EU4, and the USA, respectively, had a family history of BRCA1/2 mutation–related cancer (Table 4).

Rates of testing, any BRCA1/2 mutation tested, gBRCA1/2+/− sBRCA1/2 tested, and sBRCA1/2-only tested, among patients with TNBC by demographic and clinical characteristics in the individual EU4 countries are show in Supplementary Tables 3 and 4. Among patients with BRCA1/2 mutation–tested TNBC in the four individual EU4 countries evaluated (France, Germany, Italy, and Spain), the mean ages were generally similar. As with patients with HR+/HER2− ABC, the percentage of patients treated in academic medical centers was relatively small in Germany (42%) compared with France (69%), Italy (61%), and Spain (70%; Supplementary Table 3).

Genetic Counseling

Overall, genetic counseling was more common in Israel than in the USA or EU4. Among tested patients, counseling rates were 38% (n = 114/298) in the USA, 40% (n = 321/805) in the EU4, and 98% (n = 188/192) in Israel (p < 0.0001 vs USA and EU4; Fig. 3). Among patients receiving genetic counseling in the USA, the rates of patients receiving pre-BRCA1/2 mutation testing only, post-BRCA1/2 mutation testing only, and pre- and post-BRCA1/2 mutation testing only were similar (13%, 13%, and 10%, respectively; Fig. 3). In the EU4, 24% of patients received pretest counseling only, 11% received posttest counseling only, and 4% received both pretest and posttest counseling (Fig. 3). In Israel, 16% received pretest counseling only; however, a large percentage of patients (81%) received posttest counseling only (Fig. 3). No patients in Israel received both pretest and posttest counseling. Genetic counseling was provided by the patient’s oncologist for 11% of patients in the USA, 25% of patients in the EU4, and none of the patients in Israel. Across all regions, genetic counseling was face to face for the vast majority of patients (Israel, 99%; EU4, 95%; and USA, 92%).

Fig. 3
figure 3

Genetic counseling in the USA, EU4, and Israel in patients with HER2− breast cancer. The figure shows the rates and timing of counseling. EU4 European Union 4 (France, Germany, Italy, Spain)

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When genetic counseling rates were compared in the individual European countries, receipt of genetic counseling was higher in Spain (60%) relative to France (46%), Germany (29%), and Italy (30%; Supplementary Table 5). These patients also received pre-genetic testing only at a higher rate in Spain (36%) compared with France (29%), Germany (16%), and Italy (17%; Supplementary Table 5).

Discussion

In this retrospective analysis of data drawn from the Adelphi Real World ABC DSP, we evaluated potential differences in patient demographics, clinical characteristics, and genetic counseling for different BRCA1/2 mutation testing subgroups in the USA, EU4, and Israel in a real-world population of patients with HER2− ABC. By design, DSPs are large, multinational, point-in-time surveys conducted in clinical practices, and the results contribute to our understanding of disease burden, treatment strategies, and responses to treatment as assessed by treating physicians [21].

BRCA1/2 Testing

International guidelines for genetic testing of patients with breast cancer are generally similar across regions (Supplementary Table 6); however, we found significant differences in BRCA1/2 testing rates across regions. The most striking finding is that 99% of patients with HR+/HER2− ABC and 100% of patients with TNBC had undergone any type of BRCA1/2 mutation testing in Israel. Corresponding percentages were 68% and 93% in the USA and 37% and 78% in the EU4. A significantly larger percentage of Israeli patients (69%) had a family history of BRCA1/2-related cancer compared with the USA (18%) and EU4 (18%), likely due to a founder effect among Ashkenazi Jews from Israel. This founder effect in Ashkenazi Jews may contribute to an increased awareness of genetic predispositions to cancer and, hence, the high rate of genetic testing in Israel. Across regions, larger percentages of patients had gBRCA1/2 mutation testing with or without sBRCA1/2 mutation testing compared with sBRCA1/2 mutation testing only. There were many more statistically significant between-region differences in BRCA1/2 mutation testing and testing type for patients with HR+/HER2− ABC compared with patients with TNBC. Israel was one of the first countries to enact legislation to protect the confidentiality of genetic data and prohibit discrimination by employers and health insurance companies based on genetic information. As a result of patient organizations such as BRACHA, public awareness of BRCA1/2 mutations is increasing; however, eligibility criteria for publicly funded testing need to be expanded so that more high-risk patients can be tested [25]. Although Israel has the infrastructure for free genetic testing and care for BRCA1/2 mutation carriers, waiting times can be long.

Our results for testing rates in the USA were higher than those reported by Katz et al. for nearly 2000 USA-based patients with early-stage breast cancer surveyed between 2013 and 2015, of which 53% received some form of genetic testing [26]. The difference may be due, at least in part, to the earlier time frame for testing and a lower clinical impact at this time, as genetic testing rates are increasing rapidly. Also, patients in the study by Katz et al. had early-stage breast cancer versus ABC in the current study.

In our study, patients from France, Germany, Italy, and Spain were included in the results for the EU4. In a 2019 report of genetic testing for BRCA1/2 mutations, individual country profiles were detailed for France, Germany, and Italy; Spain was not included in the report [25]. Briefly, in France, prevention of genetic cancers is a strategic priority, and legislation has been enacted to prevent genetic discrimination by employers or insurers. France has well-defined and up-to-date referral and diagnostic systems and a nationally coordinated system for testing and monitoring those with BRCA1/2 mutations. In 2015, BRCA-France was established as the only patient organization focused on people with or at risk for BRCA1/2 mutations. Their work includes advocacy to expand genetic testing criteria. Genetic testing and consultation are available in every region, but utilization is not equal. Thus, efforts are needed to ensure that patients at high risk of BRCA1/2-related breast cancer throughout the country can access BRCA1/2 testing and timely genetic counseling. As of 2019, waiting times were 12 and 22 weeks for a genetic consultation and testing, respectively. France is one of two countries in Europe to have a legal framework for the profession of genetic counseling, and the country offers standardized training for genetic counseling. Despite this, France has a relatively low number of genetic counselors compared with other European countries. Although genetic counseling is not mandatory, it is recommended and prioritized. Between 2003 and 2017, the number of genetic consultations increased more than sixfold, which is promising [25].

In Germany, guidelines are in place that significantly advance the provision of care for women who have or are at risk for hereditary breast cancers [25]. The current national cancer plan is designed to improve upon the risk-adjusted early detection of people at high risk of cancer, which includes women who may carry a BRCA1/2 mutation. Nevertheless, more attention is needed to ensure that BRCA1/2 mutation carriers and those at risk for carrying a mutation can access comprehensive and affordable care. This would address the geographic barriers and differences in insurance coverage that have resulted in disparities in access to comprehensive BRCA1/2-related care. Although Germany has several hereditary tumor and cancer registries that collect information on BRCA1/2 carriers, the data are not aggregated, which limits the potential to support policymakers, clinicians, and researchers. Finally, efforts to increase awareness of BRCA1/2 mutations, understanding of genetic testing, and the importance of interdisciplinary care among the general population of Germany should be undertaken [25].

In Italy, the prevention of hereditary breast cancer is a stated priority; however, several challenges exist. First, comprehensive national clinical guidelines are not available, and thus there are wide regional variations and inconsistencies in the implementation and provision of comprehensive care pathways. There is a geographic imbalance in the location of testing facilities and insufficient information about these facilities, which present significant barriers for patient access. Awareness among the general public and health care professionals is low but appears to be improving, due at least in part to the efforts of active national organizations that support patients. To address these challenges and to improve the prevention of BRCA1/2-related breast cancer, policymakers should consider several priorities: improving equal, consistent, and timely access to BRCA1/2 testing and genetic counseling for women at high risk of BRCA1/2-related breast cancer; establishing a national registry for BRCA1/2 mutation carriers to support evidence-based policymaking and programming; increasing knowledge about BRCA1/2-related cancers among health care professionals; and reducing the cost of testing and ongoing management of asymptomatic BRCA1/2 mutation carriers to mitigate the real and significant financial barriers for some people with BRCA1/2 mutations across the country [25].

We also note that at the time of data collection, Italy and Spain did not have reimbursement for use of PARPi to treat BRCA1/2-associated ABC and thus had limited access to PARPi. This potentially impacted the rates of BRCA1/2 mutation testing and counseling in the EU4. In addition, we infer that as a result of the limited access to PARPi, BRCA1/2 mutation testing in Italy and Spain was predominantly for diagnostic use (i.e., clarification of risk), not for therapeutic testing.

Genetic Counseling

Overall, genetic counseling rates for patients who had any type of BRCA1/2 mutation testing were significantly higher in Israel (98%) than in the USA (38%) or EU4 (40%). Although, when provided, counseling was given most often by a genetics counselor (100% of Israeli patients, 90% of USA-based patients, and 78% of EU4-based patients) across regions. Globally, Israel has one of the highest ratios of genetic counselors to patients [27]. Under Israel Ministry of Health policies, pretest and posttest genetic counseling is supposed to be offered to all patients who undergo BRCA1/2 mutation testing [28]. These factors likely contribute to the reason that rates of genetic counseling and testing in Israel are higher than in the USA and EU4 and are consistent with guidelines. Our results for the USA were similar to those reported by Katz et al., where 61–68% of tested patients received formal counseling [26]. However, our results may not be directly comparable to the study by Katz et al. because, as indicated earlier, the patients in the study by Katz and colleagues had early-stage breast cancer versus ABC in the current study [26]. Furthermore, statutory differences in genetic testing must also be taken into account. For example, for therapeutic testing (e.g., to check whether a drug is suitable) in Germany, advice from a human geneticist is not mandatory but is recommended in the event of a positive result. However, the oncologists need to be better informed in this case so that they can initiate the test themselves. Thus, on a legal basis, the hurdle for testing is lower, but awareness is still lacking.

In general, other reported barriers for patients to receive genetic counseling include limited knowledge among health care providers about genetic counseling; misperception about its relevance and utility; and concerns among patients about the genetic counseling process, costs, and insurance coverage [29]. Others have reported lack of referral by an oncologist as the most significant barrier among patients meeting the National Comprehensive Cancer Network’s criteria for genetic testing and counseling [30].

BRCA1/2 mutations substantially increase the risk of development of breast cancer. Therefore, women who know they carry a BRCA1/2 mutation after genetic testing and counseling may reduce their risk of developing the disease by undergoing chemoprevention and/or preventive surgery [20], and they may reduce their risk of breast cancer-related mortality by being evaluated on an intensified basis. For health care providers, knowing the BRCA1/2 mutation status of women with breast cancer can help inform their decisions about disease management. Finally, identifying carriers of BRCA1/2 mutations affords the opportunity for testing of family members, who can then access risk-reducing interventions themselves [20].

Several limitations should be considered with regard to the evaluation of our findings. First, the survey participants may not be representative of the general ABC population. Because these patients were visiting their physicians, they may be more severely affected by their disease and/or treatment than those who have not consulted with their physicians. The DSP is not based on a true random sample of physicians or patients. Although minimal inclusion criteria were used to select the physicians, participation is influenced by willingness to complete the survey. Physicians were asked to provide data for a consecutive series of patients to avoid selection bias; however, no formal patient selection verification procedures were applied. Identification of the target patient group was based on physician judgement rather than a formalized diagnostic checklist. Nevertheless, this process is representative of physicians’ real-world classification of their patients. The point-in-time design of DSPs prevents any conclusions about causal relationships, although the identification of some associations was certainly possible. Recall bias may have affected physician responses to the questionnaires, which is a common limitation of surveys. However, the data for these analyses were collected at the time of the patient’s appointment, which is expected to reduce the likelihood of recall bias. Furthermore, it is possible that influences of the individual countries on the testing rates that may not be known were not taken into account (differences in accounting, legal regulations, and guidelines). In addition, the exact time of genetic testing is not known. The high testing rate in Israel may also be due to tests occurring earlier, before the illness or during the initial breast cancer diagnosis. Finally, physician-reported mutation testing in blood was used as a proxy for germline BRCA1/2mut testing. As blood is used as a source material for testing of circulating tumor DNA, it cannot be verified that all testing done on blood samples was germline testing only.

Despite such limitations, real-world studies play an important part in highlighting areas of concern that are not addressed in clinical trials. Patients treated in the real-world setting may be less likely to be adherent to medication and more representative of the general population than those included in clinical trials [31]. As a result, data from real-world studies can complement clinical trials.

Conclusions

In this retrospective analysis of demographic and clinical variables of patients with ABC in Israel, the EU4, and the USA, rates of any type of testing for BRCA1/2 mutation and genetic counseling were found to be consistent with guidelines in Israel and much higher than rates in the EU4 and USA. The rate of a family history of BRCA1/2-related cancer was significantly higher in Israel (68%) compared with the EU4 (17%) and USA (15%). Additionally, compared with the EU4 and USA, Israeli patients had a higher rate of TNBC and, among those with HR+/HER2− ABC, were significantly younger. Such demographic and clinical variables, in addition to proactive national policies for genetic testing, may contribute to the high rates of BRCA1/2 mutation testing and counseling in Israel. Among patients with TNBC, in the EU4 and USA, BRCA1/2 testing rates were much higher among patients with TNBC (78% and 93%, respectively) compared with testing rates in patients with HR+/HER2− ABC (37% and 68% in the EU4 and USA, respectively). Genetic counseling rates were also lower in the EU4 (40%) and USA (38%) compared with Israel (98%). Given the high risk of breast cancer in BRCA1/2 mutation carriers and the efficacy of recently developed PARPi in treating patients with HER2− ABC with a BRCA1/2 mutation, efforts should be made to improve BRCA1/2 testing rates and genetic counseling in Europe and the USA, particularly in patients with HR+/HER2− ABC. Also, as population sizes in this study were relatively small, additional studies of germline BRCA1/2 mutation and genetic counseling rates in larger populations and in different countries are warranted.