This study assessed real-world patient demographics and BRCA1/2 mutation testing rates in 2015 and 2017 in over 6000 adult women with HER2-negative ABC in the US and EU5. Overall, the rate of BRCA1/2 mutation testing in this study was low (28%); testing was significantly less frequent in the EU5 than in the US across both years. For both regions, the proportion of women with HER2-negative ABC who received BRCA1/2 mutation testing declined significantly from 2015 to 2017. This decrease may have been due to the approval of cyclin-dependent kinase (CDK)4/6 inhibitors, which became a new standard in combination with endocrine therapy during this same time period (starting in 2015/2016). Although CDK4/6 inhibitors can be used regardless of BRCA1/2 mutation status, optimal sequencing of PARP inhibitors (which were not available when this study was conducted) and CDK4/6 inhibitors has not been established in patients with BRCA1/2-mutated ABC [4, 28].
The lower rates of BRCA1/2 mutation testing among women aged ≥ 45 years, those with HR-positive/HER2-negative ABC and those without a known family history of breast or ovarian cancer are consistent with the known risk factors for BRCA1/2 mutations [29, 30]. While many physicians may be aware of the higher risk groups, it is important to consider other patient populations, such as those with HR-positive/HER2-negative ABC. Only 23% of women with HR-positive/HER2-negative ABC underwent BRCA1/2 mutation testing, compared with 41% of patients with TNBC. The rate of BRCA1/2 mutation testing among adult women with HR-positive/HER2-negative ABC was much lower in the EU5 than in the US, and was particularly low (16%) among women with HR-positive/HER2-negative ABC in the EU5 without a known family history of these BRCA1/2 mutation-related cancers. While germline BRCA1/2 mutations are more common in patients with TNBC (~ 10–15% of unselected patients), they also occur in approximately 5% of unselected patients with HR-positive/HER2-negative ABC [18, 19, 29]. Moreover, because HR-positive BC accounts for 70–80% of all BC cases [31], it follows that numerically more patients with a BRCA1/2 mutation have HR-positive BC than TNBC. Increasing BRCA1/2 mutation testing in this population is therefore an important and clinically meaningful consideration, particularly for patients without a known family history of breast or ovarian cancer, due to the lack of awareness for this patient group.
BRCA1/2 mutation testing rates were largely similar between academic and non-academic settings for patients with TNBC, although a surprisingly lower rate of testing was observed in academic versus non-academic centres for the HR-positive/HER2-negative population. A recent study found that germline BRCA1/2 mutation testing rates were significantly lower among oncologists in community practice than among those at academic medical centres [23]. Our results likely reflect the fact that oncologists were asked to exclude patients who were enrolled in clinical trials from the data they abstracted for this study, which may have caused bias in the data collected from academic centres.
Consistent with other studies [20–22], the overall BRCA1/2 mutation testing rates observed in this study were low, indicating suboptimal uptake of BRCA1/2 mutation testing. Although the European Society for Medical Oncology guidelines available in 2015 and 2017 encouraged genetic testing and counselling to explore the possibility of hereditary BC [17, 24, 25], low uptake of BRCA1/2 mutation testing in the EU5 was identified even among patients with a known family history of breast and/or ovarian cancer. Additionally, the varying rates of BRCA1/2 mutation testing across the US and EU5 and across the individual European countries is likely the result of different healthcare systems, local guidelines and policies. Therefore, there is a need to improve rates of BRCA1/2 mutation testing through focused education about genetic risk, incidences of mutations in metastatic BC, testing pathways, reimbursement of testing, and availability and efficacy of PARP inhibitors. Increased awareness of recent guideline recommendations, especially following the approval and availability of targeted therapies, should also help to improve BRCA1/2 mutation testing rates. It is possible that the disparity in BRCA1/2 mutation testing rates between the US and EU5, and across the individual European countries is likely the result of different healthcare systems, local guidelines, policies, and renumeration aspects. A systematic review of international guidelines on screening and management of BRCA-mutant BC published between January 2007 and February 2018 identified regional and organisational differences regarding genetic screening, counselling and treatment of BRCA1/2-mutant BC [32]. Genetic testing guidelines have also evolved over time, with more recent guidelines advocating broader criteria regarding family history [32]. Overall, a greater consensus and harmonisation of guidelines across geographic regions may help to optimise identification and management of patients with HER2-negative BC harbouring BRCA1/2 mutations [32].
Another development that might positively affect BRCA1/2 mutation testing rates is the availability of next-generation sequencing, which enables simultaneous sequencing of multiple cancer susceptibility genes and may be more efficient, faster and less expensive than testing for individual genes [33]. A recent cost-effectiveness analysis found that, compared with BRCA1/2 mutation testing based on clinical criteria or family history, multigene testing of BRCA1/2 and PALB2 in unselected patients with BC could reduce BC incidence and mortality, and would be cost-effective for UK and US healthcare systems [34]. Although the diagnostic and prognostic implications for many genes on existing multigene panels are not yet clear [4, 35], the potential for simultaneous detection of pathogenic variants other than BRCA1/2 may influence future uptake of genetic testing.
Key strengths of this study are that it included a relatively large sample (> 6000) of unselected patients treated in real-world clinical practice and captured data from multiple countries and across two distinct time periods. Analysis of patient demographics also allowed evaluation of the relationship between age and BRCA1/2 mutation testing. Because patient charts were randomly sampled, this analysis likely accurately reflects BRCA1/2 mutation testing in selected US and EU5 patient populations. Nonetheless, the study has some limitations relating to the self-reported nature of the data, as no independent verification was possible. Accuracy of the collected data was dependent on reporting by the physician and patient, and recall bias or missing information may have existed. All data were anonymised and aggregated prior to analysis; therefore, it was not possible to prevent double counting of patients in 2015 and 2017. The study was also more likely to collect data on patients who consult their physician more frequently. Of note, data collection in 2015/2017 was conducted before the US and EU approvals of PARP inhibitors for BRCA1/2-mutated HER2-negative ABC; thus, the therapeutic utility of BRCA1/2 mutation testing at the time was limited to informing patient eligibility for platinum-based chemotherapy, along with the aforementioned advantages for identification of familial risk, planning of intensified follow-up care and early detection of ovarian cancer [16, 17, 32, 36, 37]. It will therefore be interesting to evaluate patterns of BRCA1/2 mutation testing in the PARP inhibitor era to determine whether uptake is increasing following the availability of targeted treatments. Finally, BRCA1/2 mutation testing in the current study was not confined to testing for germline BRCA1/2 mutations, and germline and somatic BRCA1/2 mutations were not differentiated; therefore, some reports may have been for somatic BRCA1/2 mutations. The therapeutic implications of somatic BRCA1/2 mutations are not clear, as PARP inhibitors are approved only for HER2-negative ABC harbouring germline BRCA1/2 mutations [4, 10, 11, 13, 14].
In summary, BRCA1/2 mutation testing rates were low in this study, and disparities in testing were observed, including between years (2015 vs 2017) and regions (US vs EU5). BRCA1/2 mutation testing rates also varied with certain demographic and baseline characteristics, including age, HR status and family history of breast or ovarian cancer, consistent with previous reports [20, 30]. Opportunities exist to increase BRCA1/2 mutation testing in patients with ABC, regardless of physician setting and particularly among those with HR-positive/HER2-negative disease, patients aged ≥ 45 years and patients without a known family history of breast or ovarian cancer. Hence, educational efforts about therapeutic implications, remuneration of testing and genetic regulations are needed to increase oncologists’ awareness about the relevance of BRCA1/2 mutation testing in the context of therapeutic decision making, particularly in the EU5 region. Further studies evaluating trends in germline-specific BRCA1/2 mutation testing are also warranted.