Primary Prevention and Early Detection of Hereditary Breast Cancer

Background: Primary prevention and early detection of hereditary breast cancer has been one of the main topics of breast cancer research in recent decades. The knowledge of risk factors for breast cancer has been increasing continuously just like the recommendations for risk management. Pathogenic germline variants (mutations, class 4/5) of risk genes are significant susceptibility factors in healthy individuals. At the same time, germline mutations serve as biomarkers for targeted therapy in breast cancer treatment. Therefore, management of healthy mutation carriers to enable primary prevention is in the focus as much as the consideration of pathogenic germline variants for therapeutic decisions. Since 1996, the German Consortium has provided quality-assured care for counselees and patients with familial burden of breast and ovarian cancer. Summary: Currently, there are 23 university centers with over 100 cooperating DKG-certified breast and gynecological cancer centers. These centers provide standardized, evidence-based, and knowledge-generating care, which includes aspects of primary as well as secondary and tertiary prevention. An important aspect of quality assurance and development was the inclusion of the HBOC centers in the certification system of the German Cancer Society (GCS). Since 2020, the centers have been regularly audited and their quality standards continuously reviewed according to quality indicators adapted to the current state of research. The standard of care at GC-HBOC’ centers involves the evaluation as well as evolution of various aspects of care like inclusion criteria, identification of new risk genes, management of variants of unknown significance (class 3), evaluation of risk-reducing options, intensified surveillance, and communication of risks. Among these, the possibility of intensified surveillance in the GC-HBOC for early detection of breast cancer is an important component of individual risk management for many counselees. As has been shown in recent years, in carriers of pathogenic variants in high-risk genes, this approach enables the detection of breast cancer at very early, more favorable stages although no reduction of mortality has been demonstrated yet. The key component of the intensified surveillance is annual contrast-enhanced breast MRI, supplemented by up to biannual breast ultrasound and mammography usually starting at age 40. Key Messages: Apart from early detection, the central goal of care is the prevention of cancer. By utilizing individualized risk calculation, the optimal timeframe for risk-reducing surgery can be estimated, and counselees can be supported in reaching preference-sensitive decisions.


Introduction
Breast cancer remains the most common cancer among women, making prevention and risk management crucial aspects of care.In recent years, there has been increasing knowledge about risk factors for developing breast cancer.Among them, pathogenic germline variants (mutations, class 4/5 [1]) as genetic susceptibility factors are increasingly important [2].The focus of researchers worldwide is on managing healthy mutation carriers to enable primary prevention, as well as considering results of genetic analyses in therapeutic decisions.Healthy women from families with history of cancer require specialized care and personalized risk management [3].Additionally, an increasing number of breast or ovarian cancer patients need information about the significance of a genetic germline mutation for their ongoing therapy, follow-up care, and secondary prevention.The spectrum of risks for potential mutation carriers is diverse [4].A crucial task of the counseling physician is to guide patients through the complex information, address their fears, and not to further unsettle them, but to provide individual and comprehensive information based on their needs and questions [5].Moreover, the constant conflict between optimal individual information and the right not to know, as established in the German Gene Diagnostic Act, must be considered [6].As a result, a prerequisite of any counseling should be to enable preference-sensitive decisions regarding individual risk management.

German Consortium Hereditary Breast and Ovarian Cancer (GC-HBOC)
The German Consortium Hereditary Breast and Ovarian Cancer (GC-HBOC) was founded in 1996 to provide specialized counseling and standardized care for counselees and patients [7].It currently comprises 23 university centers and numerous cooperating breast and gynecological cancer centers certified by the German Cancer Society.All procedures at GC-HBOC centers follow guidelines and procedural instructions that are continuously adapted based on the concept of established evidence-based care as well as knowledge generation [3].Most health insurances in Germany support this specialized care for high-risk patients (special care and transsectoral cooperation).
Since 2020, the GC-HBOC centers have been part of the certification system of the German Cancer Society (GCS) [8].Quality indicators for GCS-certified HBOC centers were defined as part of an interdisciplinary process.In addition, suitability requirements for centers as well as standards of care have been defined and are regularly reviewed in the certification process.An important focus of the work of a certified HBOC center is the contribution to registry data for the consortial database HerediCaRe [9].The registry, which is funded by the German Federal Ministry of Education and Research until 2024, aims at structured and quality-assured data collection to further individualize the risk management.If evaluated positively, the registry could be a paradigm for the implementation of further structured oncology programs.
The standard of care at GC-HBOC centers involves the evaluation und evolution of various aspects of care for risk patients and counselees.This includes the continuous review and further development of inclusion criteria, identification of new genes, management of variants of unknown significance (VUS), evaluation of risk-reducing options, intensified surveillance, and risk communication.

Inclusion Criteria
The least invasive and most straightforward way to assess a person's potential risk for cancer is to obtain an accurate family history.Different guidelines have established inclusion criteria for genetic counseling and testing which have been scrutinized in recent years [10,11].Based on these findings and studies in the German cohort, the GC-HBOC has collaborated with the German Cancer Society (GCS) to establish a checklist that maps criteria of family cancer burden [12].Evaluation of these checklists indicated that more than 30% breast cancer patients are at risk for genetic mutation.The prevalence of pathogenic germline variants was as high as 10.9% [13].The 10% risk of heterozygosity for a pathogenic variant has been adopted as the threshold for genetic analysis in other guidelines [10,11].In a recent study, data from the GC-HBOC showed elevated prevalence rates in patients with triple-negative breast cancer (TNBC).Therefore, the set of criteria has been extended to include patients with TNBC under the age of 60 without further family history of cancer [14,15].Since 2023, as a result of the knowledge-generating healthcare research of the GC-HBOC, a further criterion has been added: as the risk of a pathogenic germline variant in male breast cancer patients is increased compared to the general population, especially for BRCA2 and also for BRCA1, genetic counseling and analysis should start with one single male breast cancer patient [16,17].

Identification of New Genes and Management of VUS
BRCA1 and BRCA2 (breast cancer genes 1 and 2), first described almost 30 years ago [18,19], are still the most significant high-risk genes for a predisposition to breast and/or ovarian cancer.The prevalence of pathogenic germline variants in BRCA1/2 in the general population is low, at 0.1-0.2%.The frequency of heterozygosity increases up to 5-7% in breast cancer patients and to an average of 8% in ovarian cancer patients [20].In families with pronounced history of breast or ovarian cancer, the frequencies of pathogenic germline variants in BRCA1/2 could increase up to 20-40% [21].Pathogenic germline alterations in moderate and low-risk genes occur less frequentlywith the exception of pathogenic germline variants in CHEK2their frequency is mostly below 1% [22,23].
Until 2014, genetic analysis was mostly limited to BRCA1/ 2. Since then, the analysis of CHEK2 and RAD51C has been added, before finally, panel analysis was introduced in 2016.At GC-HBOC, the TruRisk™ panel, which is continuously evaluated and updated, includes in addition to BRCA1/2 BARD1, BRIP1, CDH1, CHEK2, PALB2, PTEN, RAD51C, RAD51D, STK11, and TP53 as core genes.For these genes, scientific data are sufficient to reach clinical validity and associated risks for breast and/or ovarian cancer can be used in the counseling [4].In an interdisciplinary consensus process within the GC-HBOC, clinical risks associated with pathogenic variants in these genes are updated on a regular basis.
In recent years, associated cancer risks arising from pathogenic germline variants in these genes, apart from risks for breast and ovarian cancer, are becoming ever more important.For example, pathogenic germline variants in PALB2 could convey elevated risks for pancreatic cancer apart from increased risks for breast and ovarian cancer So far, recommendations for pancreatic cancer screening are based on expert consensus rather than evidence-based assessments.Any surveillance options offered in this specific situation should therefore be in study context.Since increased risks are communicated here without any real option of risk reduction, counseling requires special sensitivity with regard to the patient's mental situation.
Many genetic analyses yield clinically unambiguous results, and polymorphisms can be distinguished from pathogenic germline variants.Yet, interpretation of variants of uncertain clinical significance (VUS) can be challenging.Fortunately, the proportion of VUS in BRCA1/2 has dropped to 5% [25], but the percentage is increased in moderate-risk genes of the TruRisk™ panel [26].To limit the ambiguity of VUS as much as possible and enable clinically unequivocal statements, the classification model according to Plon et al. [1] is applied [1,27].As the data on genetic variants are constantly changing, the GC-HBOC implemented a recall system for counselees and patients with VUS, which are reviewed and assessed by an expert committee on a regular basis [28].If the committee decides on a change in clinical significance, the respective patients will be informed by their HBOC centers.All genetic and non-genetic information on counselees and patients is recorded in the GC-HBOC database HerediCaRe [9].
Based on these data, the actual individual risk assessment is more complex.To guide mutation carriers individually toward their most effective risk management measures, lifetime risks are insufficient [30].Instead, 5and 10-year risks, and comprehensive information on the counselee's individual situation should be used to enable preference-sensitive decisions [3].To calculate individual cancer risks, including genetic as well as non-genetic risk factors, at GC-HBOC centers the CE-marked tool Can-Risk™ based on the algorithm, Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) is used [31].The algorithm is based on large population-and family-based targeted sequencing studies.Apart from family history, the current version includes the effects of several high and moderate-risk genes (BRCA1/2, PALB2, CHEK2, ATM, BARD1, RAD51C, RAD51D) as well as hormonal, reproductive, and anthropometric factors.Additionally, mammographic density is incorporated in the risk model.Counselees are informed that the calculation should be repeated after few years or if there are changes in their individual risk factors (e.g., family history, non-genetic risk factors).To refine this information, several recent studies focus on the implementation of a suitable polygenic risk score (PRS) [32].Just recently, the incorporation of a PRS into the BOADICEA risk prediction model has been described to enable more accurate risk assessment [33][34][35].Currently, PRS is being introduced into clinical routine at GC-HBOC's centers, evaluating its clinical utility in the knowledge-generating concept of the GC-HBOC.

Risk Management and Risk Communication
The continuous expansion of knowledge has led to various options in risk management based on individual risk assessment.First and foremost, evaluation of intensified breast cancer surveillance offered at HBOC centers has established key standards.There is now broad consensus that early detection efforts in high-risk women should primarily be based on annual contrast-enhanced breast MRI, which is by far the most sensitive test for early detection of breast cancer [36].The recommended starting age for routine annual MRI screening for highrisk women will vary depending on individual risk and is as early as 20 for carriers of pathologic variants in TP53 and may be delayed until age 35-45 in high-risk women without a proven pathologic variant in one of the known breast cancer risk genes [37].MRI screening can be supplemented by mammography (e.g., starting between the age of 35 and 40 in healthy women) and optionally breast ultrasound [38][39][40].
In women with an increased risk of developing TNBC (e.g., carriers of pathologic variants in BRCA1/2, PALB2, TP53), annual surveillance regimes may not be sufficient, and the interval between screening rounds should be reduced to 6 months, either by adding a 6-month interval ultrasound between the annual MRI exams or by alternating MRI and mammography every 6 months [37,40].It has also been suggested to perform MRI in these patients every 6 months [41], although this would significantly increase the costs and negative side effects of the program.Although reliable, direct evidence on the reduction of breast cancer mortality through MRI-based high-risk surveillance programs is still missing, several studies were able to show a low rate of interval cancers and a favorable stage distribution as surrogate parameters for mortality in women undergoing MRI-based surveillance [38,[42][43][44].In carriers of pathogenic variants in high risk genes, imaging-based surveillance may be a temporary bridging the time until risk-reducing surgery as more definitive primary prevention measure is performed later in life [45].Probably, the most difficult and controversial question is whether, and if so, when to offer MRI-based surveillance to high-risk women without a proven pathogenic variant in a breast cancer risk gene [46].If the underlying breast cancer incidence in the screened cohort is too low, screening may not be feasible as adverse effects of screening (e.g., false-positive findings) will dominate [37].The GC-HBOC therefore now uses a threshold of 5% for the calculated current 10-year breast cancer risk as an entrance criterion for the MRIbased surveillance.For comparison, the UK uses a threshold of 8% for the 10-year breast cancer risk at age 40 to define high-risk.Unfortunately, due to the existing insurance contracts, the GC-HBOC can offer MRI-based surveillance to non-carriers only up to the age of 49, even though the calculated 10-year breast cancer risk will often remain well above the 5% threshold for another 10-15 years [37,47].On the other hand, MRI-based screening in non-carriers should probably not be extended beyond age 60-65 as due to the long lead time of MRI-based screening [42], the risk of overdiagnosis will increase in older patients [37].
Although the demand for chemoprevention among patients is continuously increasing, no study to date has been able to yield significant risk reduction for first-time breast cancer with tolerable side effects [48].An international study from 2019 showed that only 6% of mutation carriers opted for chemoprevention [49].It is still not completely clear, if mutation carriers could benefit from chemoprevention, above all from primary prevention: a recent prospective analysis of tamoxifen in chemoprevention and the risk of breast cancer in women with a BRCA1 or BRCA2 mutation showed no effect, although the authors discussed limitations of the study and recommended further research on the topic [50].In Germany, none of the examined drugs have yet been approved for primary prevention of breast cancer.In recent years, data on non-surgical breast cancer risk reduction in BRCA1 mutation carriers using a RANK-L antibody were published for the first time [51].RANK is above all expressed in tumors with higher grading und ki67 but without hormone receptorsall features of BRCA1-associated breast cancer [52].Former studies showed a significant decrease in breast cancer risk in population-based cohorts [53].As to side effects, RANK-L antibodies have been used for years in the treatment of osteoporosis and bone metastases.Whether this drug can be recommended to BRCA1 mutation carriers for risk reduction is currently being tested in the BRCA-P study [54].
Ovarian cancer risks could be elevated in association with several pathogenic germline variants as described above.In contrast to breast cancer, the options for early detection of ovarian cancer remain very limited to nonexistent [55].Therefore, depending on the type of pathogenic germline variant and the calculated agespecific risk, risk-reducing salpingo-oophorectomy is a valid option to improve overall and cancer-specific survival for mutation carriers [56].As described before, the optimal timing of surgery should be discussed with patients based on an individual risk calculation using the BOADICEA [31].If risk-reducing salpingooophorectomy has to be performed before the natural onset of menopause, in patients without former diagnosis of breast cancer, hormone replacement therapy should be discussed to avoid long-term consequences of early menopause such as osteoporosis or vascular problems [57].Reassuringly, in a recent study, no negative longterm effect of premenopausal risk-reducing salpingooophorectomy on cognition could be found [58].
Apart from intensified surveillance as described above, risk-reducing mastectomy (RRM) is an important option for healthy female harboring a pathogenic germline variant with high breast cancer risk.Risk-reducing surgery as primary prevention has long been implemented in national and international guidelines [2,4,10,59].In healthy mutation carriers, RRM was associated with lower mortality than surveillance for BRCA1-mutation carriers, but not for BRCA2-mutation carriers, where RRM may lead to similar BC-specific survival as surveillance [60].Older studies suggested that in BRCA1/2mutation carriers with a history of breast cancer contralateral RRM is associated with improved overall survival [61].Data from the GC-HBOC could clearly show that this finding has to be associated to the age at first breast cancer and specific type of pathogenic variant [62,63].This should be taken into account in counseling mutation carriers.Part of the risk management is the recommendation to measure remaining breast tissue after surgery via breast MRI as differences were detected considering different surgical options [64].As the risk for contralateral breast cancer is elevated in breast cancer patients with high-risk germline variant, secondary preventive contralateral mastectomy should be discussed, including type of germline variant, age at first disease andabove allconcurring risks of relapse and/or metastases [62,63,65].In addition to that, pros and cons of different surgery techniques as well as possible side effects of surgery (e.g., scaring, capsular fibrosis, re-operation, and cosmetic outcome) must be discussed at length with mutation carriers as part of their decision-making process.
Risk communication and counseling are not to be underestimated challenges for counseling physicians to convey extensive information on individual risk combined with comprehensive information on risk management to enable counselees to preference-sensitive decisions while at the same time preventing counselees from intellectual or emotional overload.It has been shown that perceived control and reduction of psychological distress are eminent for comprehensive decision making [5,66].Several approaches to support medical counseling have been developed [67].The implementation of digital health concepts could be useful for counselees as well as counseling physicians by tailoring individual information using low-threshold communication [68].

Conclusion
The impact of pathogenic germline variants on healthcare is continuously increasing.Risk assessment and optimal risk management are crucial for improving quality of life for healthy mutation carriers, while additional therapeutic options need to be considered for cancer patients with pathogenic germline variants.Knowledge of genetic analyses, indications for genetic testing, and the resulting clinical implications are therefore essential to optimize individual care.Individualized counseling at GC-HBOC centers is an important prerequisite for making preference-sensitive decisions on optimal risk reduction.