Medical history-based BRCA1/2
screening has been in place for two decades, offering testing based on personal and family history criteria. Recent data suggests that less than half of the individuals with BRCA1/2
risk are identified through this approach [1
]. Failure to identify cases are attributable to both the insensitivity of the approach and failure to universally apply screening [1
]. Genomic screening programs in the general population for primary prevention is an alternative to identify individuals at risk for developing diseases who can benefit from enhanced preventive services, providing an intervention opportunity to reduce mortality and morbidity attributable to the screened conditions. There is increasing interest in implementing genomic screening programs for the general population as part of precision health, as evidenced by the All of Us research program and initiatives [3
]. Genomic screening is likely to focus on the CDC tier 1 genomic applications [4
], which are for conditions that have relatively higher prevalence, strong evidence for a gene–disease relationship, high penetrance with the potential for serious health impacts, and evidence-based effective interventions available for improving population health [6
]. These include hereditary breast and ovarian cancer syndrome (HBOC), Lynch syndrome, associated with increased risk of colorectal, endometrial, and other cancers; and familial hypercholesterolemia, associated with increased risk of premature heart disease. Genetic testing is currently recommended for all these conditions in people at high risk (e.g., due to family history) [5
]. An estimated two million people in the US have one of these conditions. Currently, these conditions are poorly ascertained by the healthcare system, and many individuals and their family members are not aware that they are at risk [8
]. This has recently been shown in HBOC in two diverse settings [1
]. It has been postulated that early detection through population genomic screening and intervention could potentially improve identification of risk and significantly reduce morbidity and mortality [5
A central tenet of genomic screening in the general population is to proactively identify and manage risk at a reasonable cost [11
]. However, while offering the potential to improve public health outcomes, it is unknown whether reporting population-based genomic screening results is followed by reasonable and appropriate healthcare utilization and costs. This is compounded by patient uncertainty concerning non-diagnostic genomic results, including how to use the result in the absence of other risk factors [12
]. Thus, there are concerns as to whether returning genomic results from population genomic screening without a clinical indication could promote excessive and inappropriate utilization of services with the associated increases in costs, thus reducing or eliminating the potential value [13
This study focused on one of the most prevalent and actionable conditions—HBOC, for which there is the support that genomic screening programs may better identify patients at high risk [1
] compared to current guideline-based methods used to identify BRCA1
]. Screening for pathogenic/likely pathogenic (P/LP) variants in HBOC susceptibility genes in unselected individuals can be used to assess risk and guide decision-making about surveillance (MRI/mammogram) and prophylaxis (surgical and chemopreventive) for prevention and early detection of breast and ovarian cancer [17
]. To date, evidence has not been available using real-world data on healthcare utilization and costs for the follow-up period after disclosure of P/LP BRCA1/2
results via genomic screening. The objectives of this study are to: (1) determine whether there is a difference in healthcare utilization and costs following results disclosure, and (2) estimate the uptake of risk management per National Comprehensive Cancer Network (NCCN) guidelines within the first year of having a P/LP result returned.
This study provides real-world evidence to directly address the concern that genomic screening may lead to excessive and unnecessary increases in healthcare service utilization and costs [22
]. The results of this study have not identified any statistically significant increase in overall use of healthcare services and associated costs even in a sub-cohort of patients who had previously unknown P/LP status and were assumed to be likely to have higher utilization and costs post-disclosure. The results also demonstrate the use of guideline-recommended preventive services. It is important to emphasize that these results are from a structured genomic screening program reporting results to patients with support offered from genetic counseling as part of the results disclosure process [18
]. It is also noteworthy that the initial genetic counseling visits were considered part of the research study and thus were not charged; insurance and/or the patient covered the cost of any subsequent care. In practice, however, the initial genetic counseling visit might not be free of charge.
The results of insignificance in healthcare utilization and cost differences are consistent with findings from the one other study identified providing similar evidence based on genome or exome sequencing and return of secondary findings (P/LP variants with associated phenotypes unrelated to the test indication), which concluded it added only modestly to near-term healthcare costs [24
]. In the study by Hart et al., for 21 participants with P/LP BRCA1/2
positive results, the average cost of follow-up medical actions per finding from a payer perspective for up to a one-year period was $
115 and assuming all patients followed recommended actions $
576 (2017 US dollars) based on nationally representative Medicare reimbursement rates, published estimates, wage data, and commercial lab sources to assign costs [24
Our results on uptake of mastectomy (3.5%) and oophorectomy (11.8%) during the first year post-genomic screening in MyCode population was approximately a third of what is reported in published literature (uptake of mastectomy and oophorectomy about 10% and 30%–45%, respectively) [25
] based on high-risk unaffected female BRCA
1/2 carriers in the first year post-genetic testing. We conclude that the uptake of risk-reducing surgery may be lower in women ascertained through genomic screening among the general population versus a high-risk population based on family history. However, studying uptake at the population level is challenging because of differences in risk profiles, e.g., age, family history, socioeconomic status, and other population characteristics.
The major strength of this study is the results are based on real-world data of unaffected patients in a genomic screening program with the return of P/LP BRCA1/2
positive results. To date, information of this type has not been available in other published studies that either have relied on high-risk populations [26
] and/or imputed or estimated values in economic evaluation models [29
]. This study has several limitations. The study population is composed of volunteers within a single state and a limited geographic area (central and northeastern Pennsylvania). The study population is relatively small (n
= 59), although this is a common feature in previous studies of BRCA1/2
positive populations, and is not broadly representative as it contains larger proportions of key subgroups (older age, non-Hispanic European ancestry, and family history of breast and ovarian cancer). Thus, the results cannot be generalized to other populations. The study results encompass healthcare services obtained within a single healthcare system (Geisinger), although individuals in the study population may have used healthcare services outside the system which were not included in the study data sources. Geisinger is the largest healthcare system in central Pennsylvania and all recommended services are provided within the Geisinger system so participants did not have to leave the system to obtain these services. The study’s post-disclosure time period was limited to one year, which may have resulted in lower estimates for both research questions concerning overall healthcare utilization, costs and guideline-recommended services. Lastly, due to the nature of the billing data source for costs, the costs of outpatient visits, the most relevant for this study, could not be analyzed separately.
An important role of BRCA1/2
testing is to identify high-risk variant carriers before they develop breast or ovarian cancer, so they may start cancer screening and preventive interventions to reduce cancer risk. However, evidence shows that current clinical genetic testing practice, which is primarily based on family history criteria and a predefined mutation probability threshold, is inefficient, resource-intensive, and misses >50% of individuals or mutation carriers at risk [1
]. In a 2018 systematic review of population-based testing, the authors concluded that large scale general population-based screening can overcome these limitations as genetic-testing costs are falling and acceptability and awareness are increasing, yet there are few large-scale programs for unaffected women and a lack of evidence for their costs and consequences [14
]. Despite the positive trend in rates of BRCA1/2
] the majority of at-risk women do not get a referral for genetic counseling and testing, and a large majority of BRCA1/2
variant carriers in the US have not been identified [32
]. Consequently, genomic screening has been suggested for the general population to prevent hereditary breast and ovarian cancers [8
]. This study attempts to address the concern that population-based genomic screening programs may lead to an unnecessary increase in healthcare service utilization and costs, particularly in comparison to criteria-based genetic testing programs targeting those at higher risk, and offers initial evidence to mitigate such concerns.
While population genomic screening for BRCA1/2
offers the potential to transform public health by preventing disease and saving lives, there are challenges to implementing such programs that constrain the possibility of widespread adoption despite declining sequencing/testing costs. There remains a substantial need for evidence development of population genomic screening [19
] including: how to and who should provide testing and the recommended health services for those at high risk to ensure quality and equitable access to services; whether it causes more good than harm and can provide good value in terms of cost-effectiveness or other measures; and whether and under what conditions is there consumer demand. In addition, there are complex ethical, legal, and social issues including privacy and discrimination as well as cultural, religious, psychological, and economic factors.
Future studies within integrated healthcare systems and including larger and more diverse study populations and longer follow-up periods can provide further evidence of the medical care, costs, and health outcomes of BRCA1/2 positive individuals identified by genomic screening programs. Rigorous and context-specific models are needed to assess a range of possible scenarios in which a broader population genomic screening might have added value. Careful assessment of the benefits, risks, and cost-effectiveness of population screening is needed before the introduction of costly large-scale interventions, as published evidence is sparse on the potential effects on individuals and the healthcare system. This additional evidence is an initial step that informs the implementation of genomic medicine and enables the timely realization of its benefits.