Study population
The sample of counselees (
n = 2531) included in this study is larger than the samples of other monocentric studies [
22,
23]. Our sample size can partly be explained by the relatively large catchment area of our center which comprises Berlin and large parts of the adjacent federal states. Comparing the sociodemographic characteristics with other collectives of facilities of the GC-HBOC, the rate of female counselees of 98.5% (
n = 2493), the mean age of 42.9 years and the employment rate of 72.3% (
n = 1830) were relatively similar [
20,
21]. However, with only 38 male counselees, a calculable analysis of male carriers of PVs was not possible despite the large study group. This underlines the well-established fact that men are much more reluctant to seek genetic advice than women [
22]. Since male carriers of PVs have a higher risk for the development of breast cancer or other associated malignomas than the general male population and since their descendants (male or female) have a 50% chance of inheritance the PV, counseling more men with PVs ought to remain one of the primary objectives.
Rate of pathogenic variants detected and therapeutic relevance
As previously demonstrated in several studies, PVs are most commonly found in the genes
BRCA1/2 [
22,
23]. With a rate of 22.7% (
n = 209) of PVs among index patients, our analysis confirms the considerably high prevalence of PVs in
BRCA1/2 in Germany as published by Meisel and colleagues as well as Kast and associates [
24,
25]. Regarding PVs in
CHEK2 (
n = 35; 12.2%) and
ATM (
n = 16; 5.6%), similar detection rates were ascertained by Schroeder et al., who analyzed test results of 620 counselees at two centers of the GC-HBOC [
27]. Globally, however, there seems to be a substantial disparity as reported by Armstrong and colleagues, who conducted a systematic review to collate the prevalence of PVs in
BRCA1/2 [
28]. Since they included studies with unselected study populations without familial breast and ovarian cancer, the prevalence rates are not comparable though.
By contrast, the present analysis lays emphasis on individuals that already have an increased risk for breast and ovarian cancer due to familial aggregation and meeting the GC-HBOC inclusion criteria. In a population properly counseled and selected by validated criteria, the frequency of a clinically relevant PV can amount to 30.3% (
n = 278), as shown in this analysis, proving this process to be highly efficient. And taking into consideration triple-negative breast cancer alone, a rate of 40.7% (
n = 72) for PVs detected indeed surpasses most previously reported data, yet a similar rate and an age dependence have been noted by Hahnen et al. in a comprehensive review [
29]. Since triple-negative breast cancer before the 51st year of age alone is a sufficient inclusion criterion (Fig.
1), this observation emphasizes the relevance of this breast cancer subtype for genetic analysis. Whether an additional case of breast and/or ovarian cancer increases the probability of attesting a PV even further was not evaluated and poses need for more comprehensive investigation. However, with a mean age of 42.9 years and a PV detection rate of 53.4% (
n = 39) among patients with triple-negative breast cancer before the age of 40, the present analysis supports the before mentioned age dependence. Furthermore, in light of the recently published data on the OlympiA trial [
30] and the above-mentioned rate of 40.7% (
n = 72) of PVs among counselees with triple-negative breast cancer as well as the predominance of the genes
BRCA1/2 among these PVs, the clinical relevance of genetic analysis as an essential part of therapy planning is underlined by these data. Since patients with germline PVs in
BRCA1/2 and residual invasive breast cancer or a CPS + EG score of 3 or higher after having received neoadjuvant chemotherapy clearly benefit from a 12 month adjuvant therapy with the PARP-inhibitor Olaparib, genetic analysis of all patients eligible for postneoadjuvant PARPi-therapy seems mandatory. Apart from the therapy with PARPi, the knowledge of an existing PV constitutes an essential factor when planning the operative therapy (i.e., prophylactic mastectomy and prophylactic salpingo-oophorectomy), as well as follow-up and screening (i.e., intensified breast cancer screening). The latter has been established to detect breast cancer reliably at an early stage [
13] and can therefore benefit all carriers of a PV as well as their relatives afflicted by the same PV.
As reported by previous studies [
31‐
33], the rate of PVs detected was highest among families with both ovarian and breast cancer (
n = 187; 50.5%). Since, for instance, Kast et al. merely considered PVs in
BRCA1/2, though the reported rate of PVs amounted to only 41.6%. Furthermore, the detection rate among families with breast cancer only was reported to range between 3.7 and 22.7% depending on additional factors like age at diagnosis and unilateral or bilateral occurrence [
19]. While our study does not differentiate in the same fashion, it does include all ten core genes of the TruRisk
® panel relevant at the time of analysis. Altogether, 31.9% (
n = 240) of counselees with breast cancer presenting at the HBOC-Center at Charité and meeting who underwent genetic analysis, were diagnosed with a clinically relevant PV. This substantially higher rate can be attributed to the population analyzed with a mean age of 42.9 years as well as the standardized implementation of the TruRisk
® panel comprising eight more relevant genes with partially considerable PV detection rates in addition to
BRCA1/2 [
6]. The inverse correlation between age of diagnosis and rate of PVs detected proved to be statistically significant (
p = 0.001), which concurs with other studies [
34‐
36]. More interestingly, the detection rate among counselees between the age of 50 and 59 years in this subgroup came to 26.3% (
n = 10) and 18.2% (
n = 2) beyond the age of 60. Similar findings led to an expansion of inclusion criteria at the GC-HBOC for triple-negative breast cancer to be eligible for genetic analysis below the age of 60. Other authors arrived at similar yet slightly lower rates motivating them to propose an extension of genetic analysis for triple-negative breast cancer diagnosed before the age of 60 [
34,
36], since the underlying heterozygosity risk of 10% for the indication for genetic analysis seems to be present in this subgroup. Therefore, the recommendation to offer genetic analysis to these patients has long been adopted by the National Comprehensive Cancer Network [
36].
Challenges and perspectives for the future
The assessment of PVs and especially of VUS underlies continuous scrutiny. Regarding the prevalence of VUS in
BRCA1/2 found in the present analysis (5.9%;
n = 59), Meisel et al. found a slightly higher rate after evaluating the results of index analysis from 2000 to 2013 at one center of the GC-HBOC [
26]. If only
BRCA1/2 are considered, the rate of VUS could be significantly reduced by reclassifications in the past [
37]. The higher prevalence of VUS in the genes
ATM (
n = 50; 21.1%) and
CHEK2 (
n = 42; 17.7%) can be attributed to the relatively common detection of alterations in these genes and the briefer period for which they have been analyzed standardly. Further and more extensive analysis such as the HerediVar project which aims at integrating bioinformatics and functional genomics into clinical classification of genetic variants promises to reduce the rate of VUS in the future [
37]. For the time being however, only comprehensive counseling can help to apprehend the risk involved and thereby dissolve possibly unfounded fears.
The complexity of the counseling process is increasing due to a growing number of genes with clinical relevance as well as more differentiated prophylactic and therapeutic options. As a result of public coverage in recent years, the demand for genetic counseling seems to be increasing even more rapidly [
37,
38]. Interestingly, a considerable number of counselees of the study population at hand (
n = 244; 9.6%) did not meet the inclusion criteria according to the GC-HBOC but did wished to receive counseling due to a subjectively perceived risk. To accommodate the growing demand, the HBOC-Center at Charité has been offering video consultations since 2019. The use of such digital resources seems justified, given telephone consultation has been proven to be non-inferior [
39‐
41]. To account for the complexity of the counseling process, the HBOC-Center has been developing and applying a digital counseling tool that is adjusted to individual needs and can be used permanently to promote self-efficacy of counselees.