Effective HRD detection has a pivotal role in both accurately selecting breast cancer patients to avail of targeted therapies and in identifying the patients with an inherited risk of breast cancer who will benefit from prophylactic measures. Methods of HRD testing have undergone significant technological advancements, playing a crucial role in research on HRD-positive breast cancer and the development of targeted HRD-based therapeutic treatments. Nonetheless, measuring HRD involves several diagnostic challenges. One primary issue is that the definition of HRD varies across different testing methods and commercial entities. Additionally, testing methods often rely on expensive next-generation sequencing (NGS) or labor-intensive functional assays. Despite these challenges, the increased affordability of NGS and advancements functional assays have made testing more feasible in recent years.

Recent research has introduced several effective methods for HRD and BRCA screening, particularly in patients with a family history of breast cancer. A significant breakthrough is the development of the Bayesian probabilistic model, BRCAPRO, noted for its accuracy in identifying individuals for BRCA1 and BRCA2 mutation testing. This model outperforms traditional clinical scoring methods by incorporating breast cancer pathology data, such as tumor grade and hormone receptor status, thereby enhancing its precision [5]. Furthermore, morpho-clinical parameters, notably estrogen receptor (ER) negativity and poor tumor differentiation, have shown effectiveness in detecting BRCA1 mutations. This approach is particularly valuable in instances where there is a weak or absent family history of these cancers [6].

Traditional screening methods have primarily relied on Sanger sequencing of a multigene panel or a Multiplex Ligation-dependent Probe Amplification (MLPA) assay for detecting copy number variations in blood or saliva samples. While these techniques are accurate, they are less cost-effective compared to NGS [7, 8]. High-resolution melting (HRM) analysis has also gained prominence as a promising rapid screening technique for identifying BRCA1/2 mutations. This method is adept at distinguishing genetic variants in PCR products [9]. Furthermore, population-based studies indicate that a significant portion of breast cancer cases, irrespective of subtype, may exhibit defects in the HRR pathway. Consequently, there is a recommendation for population-based genetic testing to achieve a broader identification of individuals at risk [10].

Several commercially available sequencing tests for HRD in diagnosed breast cancer, such as FoundationOne CDx and MyChoice, offer insights into the genetic underpinning of the disease [11]. Typically, these tests involve whole genome sequencing (WGS) or whole exome sequencing (WES) performed on formalin-fixed paraffin-embedded (FFPE) tumor samples. These tests are utilized to identify mutations in BRCA1/2 or other HRD-related genes. Additionally, genomic data is utilized to calculate a ‘genomic scar score’ which is derived from parameters of DNA damage, including loss of heterozygosity (LOH), telomeric allelic imbalance (TAI), and large-scale state transitions (LST). These measures serve as indicators of genomic instability [1].

An alternative approach is the RAD51 assay, which estimates the amount of nuclear RAD51, a gene involved in HRR and crucial for template strand invasion [11]. This assay represents an effort to develop direct functional assays. However, it is one of many functional assays that face limitations rendering them less practical in a clinical setting [11]. Despite demonstrating 90% sensitivity in BRCA-deficient tumors, when refined using formalin-fixed paraffin-embedded FFPE samples, the higher costs and longer lab turnaround times associated with clinical assays undermine their effectiveness compared to WGS or WES [11]. Emerging assays, including SOPHiA Genetics DDM HRD and the AMOY HRD Focus Panel, are under development [11]. Additionally, advancements in machine learning (ML) technologies hold substantial promise for the future of HRD detection in breast cancer tumors, particularly in the analysis of histopathological specimens and NGS [12, 13].

The field of HRD testing methods is rapidly evolving, with developments focusing on becoming more cost-effective and precise. However, there is a critical need for cohesive international efforts to ensure these technologies continue progress and to become accessible to all patients, regardless of geographical location. This global approach is essential for leveraging the full potential of these technologies, ensuring equitable access to cutting-edge diagnostic tools, and ultimately improving outcomes for patients with breast cancer worldwide.

The identification of a germline mutation in an HRD gene through screening of patients at high-risk of hereditary breast cancer plays a crucial role in determining optimal management strategies for breast cancer prevention. This includes a range of risk-reducing surgical approaches,pharmacological interventions and increased patient monitoring.

In terms of prophylactic measures, guidelines for risk-reducing mastectomy (RRM) from the European Society of Medical Oncology (ESMO), the National Institute for Health and Care Excellence (NICE), and the National Comprehensive Cancer Network (NCCN) provide crucial frameworks for individuals at increased risk of hereditary breast cancer [4, 14, 15].

ESMO particularly advocates for bilateral risk-reducing mastectomy (BRRM) as a highly effective treatment, extending its recommendations to carriers of various high-risk genes [4]. NICE places a strong emphasis on informed decision-making, facilitated by genetic counselling, and considers individual factors such as age and family history [14]. It underlines the importance of verifying family history and, if necessary, seeks consensus from a multidisciplinary team. The NCCN aligns with both ESMO and NICE in endorsing RRM as an effective risk-reduction strategy, strongly emphasizing the importance of health maintenance post-RRM [4]. Risk-reducing medications (RRMeds), such as selective estrogen receptor modulators (SERMs) and aromatase inhibitors (AIs), are an alternative for women who postpone or decline RRMs [4]. A network meta-analysis by Mocellin et al. found, that in women with above average risk, both AIs and SERMs reduced breast cancer incidence [16]. They concluded SERMs were less effective than AIs and are associated with a risk of endometrial cancer and venous thromboembolic disease [16]. However, even in patients with diagnosed breast cancer, adherence to endocrine therapy presents a major challenge [17]. The cost, side effects and the long-term nature of endocrine therapy are among the causes of poor adherence [18]. Strategies for promoting adherence include lowering medication cost and psychosocial and reminder counselling.

It is important to note both RRM and conservative management require adequate follow-up. While yearly MRIs/ Ultrasound and 6-monthly/yearly physical examinations (depending on mutation type) are advised for conservative management, an MRI one year post RRM to establish a baseline may be sufficient in the absence of further clinical findings [4].

In a study which included 2,677 mutation carriers, Metcalfe et al. examined the international variation in subsequent management of BRCA1/2 mutation carriers [19]. 41 centers across nine countries, including Austria, Canada, France, Israel, Italy, Norway, Holland, Poland, and the US were included [19]. Individuals who received genetic test results indicating a BRCA1/2 mutation were subsequently questioned about the preventive practices they adopted following receipt of their results [19]. This study highlights that management post genetic testing, in reality, is dictated by a combination of guidelines, patient preferences and the availability of resources.

Therapeutically targeting HRD in breast cancer leverages genetic abnormalities within cancer cells to induce cell death. Poly (ADP-ribose) polymerase inhibitors (PARPis) have become a crucial treatment for breast cancer with BRCA mutations. The primary action of PARPis is their effectiveness against tumors exhibiting HRD, utilizing a process called synthetic lethality [20]. Synthetic lethality arises when the loss of a single gene is tolerable for cell survival, but the concurrent disruption of two genes leads to cell death [20]. PARPis inhibit PARP by competing with NAD + at the catalytic domain (CAT) of PARP, thus impeding PARP's catalytic activity and the formation of PAR polymers [21]. These actions compromise the cellular capacity to repair DNA single-strand breaks (SSBs). Furthermore, PARP inhibition can transform unrepaired SSBs into double-strand breaks (DSBs) due to replication fork collapse, a process known as the PARP trapping mechanism [21]. An additional proposed mechanism involves the trapping of PARP1 on DNA, causing substantial damage that cells with HRD are unable to repair [22].

Clinical trials like EMBRACA, OlympiA, and OlympiAD have demonstrated the efficacy of PARPis, leading to the FDA approval of talazoparib and olaparib in the treatment of breast cancer [23,24,25]. Summary in Table 1. Both olaparib and talazoparib are licensed for patients with BRCA-mutated or suspected germline deletions, HER2-negative locally advanced or metastatic breast cancer) [22]. By 2022, olaparib received FDA approval as an adjuvant treatment for germline BRCA-mutated or suspected deletions, HER2-negative, or high-risk early-stage breast cancer in patients who had undergone neoadjuvant or adjuvant chemotherapy [26]. In ovarian cancer, olaparib's approval was further expanded to include patients with non-BRCA HRD, as defined by the MyChoice CDx genomic instability score. This underscores the importance of identifying all HRD types in breast cancer and suggests the potential to broaden the cohort of patients receiving PARPi treatment [26].

NCT03344965 is an ongoing phase 2 study that aims to extend the use of olaparib monotherapy in metastatic breast cancer patients with germline or somatic mutations in DNA repair genes, with completion expected in December 2024 [27]. The genes under investigation include BRCA1/2, CHEK2, ATM, PALB2, RAD51, BRIP1, and NBN [27]. Other clinical trials are exploring alternative PARPis in non-BRCA HRD. The PETRA trial, a phase 1/2 study, is examining AZD5305 in several advanced cancers, including triple-negative breast cancer (TNBC), with mutations in BRCA1/2, PALB2, or RAD51C/D [28]. These mutations are amongst the most common recognized in HRD [26]. AZD5305 is noted for being a potent, highly selective PARP1 inhibitor, significantly more selective for PARP1 than PARP2, and particularly effective in HRD [26].

Additionally, the University of California, San Francisco is conducting a phase 1 clinical trial (NCT05694715) to assess the impact of the combination of niraparib and irinotecan on managing solid tumors with HRD-positivity [29]. This trial includes individuals with metastatic solid tumors and mutations in BRCA1/2, ATM, or PALB2 [29]. The combination of niraparib and irinotecan has garnered considerable interest, and the dose–response results from phase II will inform the ongoing NCI ComboMatch trial [29].

In the rapidly changing field of HRD research, technological advancements have been pivotal in both understanding HRD-positive breast cancer and developing targeted therapeutic strategies. Presently, small molecule inhibitors aimed at key proteins such as Polymerase theta (Polθ), RAD51 homolog 1 (RAD51), ubiquitin carboxyl-terminal hydrolase 1 (USP1), poly (ADP-Ribose) glycohydrolase (PARG), and Werner syndrome helicase (WRN) are under clinical investigation [30]. Notably, synergistic effects have been observed in BRCA-deficient models with combinations of PARPis and Polθ inhibitors, indicating potential new therapeutic pathways [30]. The commencement of the first in-human study (NCT05787587) of IDE161 (a PARG inhibitor) as monotherapy in solid HRD breast and ovarian tumors underscores the ongoing commitment to advancing targeted HRD-based treatments [30].

The advantage of HRD screening lies in its ability to identify high-risk patients who may benefit from an RRM and/or regular breast screenings. When applied to confirmed cases of breast cancer, HRD testing facilitates the identification of specific targets for personalized management. This evolving understanding of HRD leads to more individualized and effective patient treatments. However, the accessibility to such testing and the availability of these often expensive treatments are not universal, contributing to the increasing healthcare disparity between developed and developing countries, as well as among different socioeconomic groups.

The cost-effectiveness of HRD screening and its implications for prophylactic management involve a significant financial consideration. The feasibility of HRD testing and the affordability of subsequent treatments exhibit substantial variation across the globe, compounded by differences in healthcare systems, insurance approval processes, and pricing structures.

A study from Switzerland highlighted the potential cost-effectiveness of more invasive prophylactic strategies, such as prophylactic bilateral mastectomy, for BRCA1/2 mutation carriers, suggesting that such measures could be economically viable in the long term [31]. However, access disparities remain a challenge, with some individuals struggling to obtain necessary healthcare due to insurance constraints or personal coverage limitations [31]. In the United States, financial hurdles, including lack of insurance, insufficient coverage, or direct costs of testing, contribute to the underutilization of BRCA screening, particularly affecting vulnerable populations [32, 33]. This issue is exacerbated in developing countries, where the costs of genetic testing and associated travel expenses pose significant barriers [33].

Xi et al. conducted a scoping review focused on the economic evaluations of predictive genetic testing, including studies on BRCA1/BRCA2 testing for hereditary breast and ovarian cancer (HBOC) [34]. This review identified three primary cost components: the cost of testing, prevention, the disease management. The majority of the reviewed studies concluded that genetic testing is cost-effective compared to no testing, with some suggesting that multigene testing could be economically viable under certain conditions. However, there was variability in the cost-effectiveness of different gene panels and the overall savings associated with population-based testing [34].

Koldehoff et al. performed a systematic review analyzing the cost-effectiveness of targeted genetic screening for breast cancer [35]. Their findings indicated variable cost-utility ratios from a payer’s perspective, influenced by factors such as discount rates, the choice of prophylactic surgery, and mutation penetrance. Probabilistic analyses showed a high likelihood of cost-effectiveness for BRCA testing in several studies, though results varied for multigene tests, highlighting the economic complexity of genetic testing for breast cancer susceptibility [35].

These studies underscore the economic benefits of genetic testing for breast cancer and susceptibility, with variations in the optimal testing strategies influenced by numerous factors. The economic implications are complex, requiring tailored considerations to enhance the accessibility and affordability of HRD screening globally. These findings stress the importance of developing and implementing strategies that address the economic challenges associated with genetic testing, ensuring equitable access to life-saving interventions.

Screening for HRD presents significant ethical challenges, particularly in cases where a cancer syndrome or familial inheritance pattern is suspected [36]. Clinicians must understand that knowledge of an individual's mutational status can profoundly affect their family life, personal finances, and potentially, their psychosocial well-being [36]. The benefits of disclosing genetic mutations must be carefully weighed against the ethical and social implications stemming from the increased availability of HRD testing.

A study analyzing 50 subjects who underwent BRCA1/2 gene testing for suspected BRCA gene mutations found that genetic testing facilitated easier communication within families [36]. Patients who had undergone testing were more inclined to discuss the possibility of genetic testing with their family, in contrast to 50% of the non-genetic testing group who deemed it inappropriate to discuss such matters with relatives [36]. This study highlighted the role of good communication in enhancing family cohesion and influencing the decision to undergo genetic testing for BRCA mutations [36]. Nevertheless, it is essential to consider the impact of cultural norms and the openness of discussions within families.

Conversely, the presence of a stable partner was observed to discourage patients from undergoing genetic testing to determine their mutational status [36]. This reluctance aligns with findings from studies indicating the significant distress associated with BRCA testing, leading many women to prefer not disclosing decisions about testing and oncogene counselling [36, 37]. The concept of 'geneticization' raises deep questions about responsibility, education, and the societal impacts of HRD testing. Mediation analyses on a sample of 178 women undergoing their first genetic counselling session for breast/ovarian cancer showed that cancer-related worry and risk perception based on genetic counselling were associated with increased levels of depression and anxiety [38]. Further analysis revealed that cancer-related worry, but not risk perception, was heightened among those with a prior cancer diagnosis [38]. Additionally, the number of family members affected by cancer was linked to increased cancer-related worry and risk perception [38]. Understanding patients' genetic health literacy, risk perception, and beliefs about disease and prevention is therefore paramount [38].

Disclosing information about cancer susceptibility carries significant implications for patients and their families [39]. A study found that women with higher depression scores reported elevated risk estimates of developing breast cancer [39]. As depression levels increased, so did the intensity and frequency of cancer-related worry and risk perception [39]. While genetic testing aims to enable preventative measures, the psychological impact of such tests and their ability to affect various aspects of a patient's life must be considered [39].

The ESMO recommendations highlight the importance of post-test genetic counselling, personalized risk management, and specialized high-risk clinics, emphasizing the need for awareness and accessibility of testing for at-risk relatives [4]. The psychological impact of genetic counselling and testing post-cancer diagnosis varies, with some reporting distress while others find it acceptable, highlighting its role in informed treatment decisions. Larger, prospective studies are encouraged to provide conclusive evidence [40,41,42]. However, the right to undergo genetic testing raises discussions about access, cost, and familial rights [39]. The 'right not to know' is contested between individual autonomy and societal obligations, with concerns about genetic discrimination posing significant challenges, especially in relation to health insurance [43].

Research by Tercyak et al. on quality of life after contralateral prophylactic mastectomy indicates that, in the first year post-surgery, patients' quality of life and distress levels do not significantly differ from those opting for alternative treatments [44]. A 10-year follow-up study by Frost et al. suggests that despite negative impacts on body image and relationships, a significant majority express satisfaction with their decision [45].

Navigating the multifaceted ethical landscape of HRD screening requires balancing individual liberties, societal responsibilities, and the evolving medical knowledge landscape. Adequate patient counselling on the benefits and pitfalls of HRD testing at an individual level is crucial. This approach empowers patients to be involved in their care and make decisions that are right for them.

The global landscape of HRD screening and testing is marked by diverse approaches and guidelines, with Europe playing a significant role in shaping these practices. ESMO has