key: cord-0750229-jwmq72ok authors: Reid, Sonya; Spalluto, Lucy B.; Lang, Katie; Weidner, Anne; Pal, Tuya title: An overview of genetic services delivery for hereditary breast cancer date: 2022-01-26 journal: Breast Cancer Res Treat DOI: 10.1007/s10549-021-06478-z sha: 44cb1c0fbc3dabd772a2d9821b8cb6936497e25c doc_id: 750229 cord_uid: jwmq72ok Breast cancer is the most common cancer diagnosed in women worldwide, with approximately 5–10% of cases attributed to high penetrance hereditary breast cancer (HBC) genes. The tremendous advances in precision oncology have broadened indications for germline genetic testing to guide both systemic and surgical treatment, with increasing demand for cancer genetic services. The HBC continuum of care includes (1) identification, access, and uptake of genetic counseling and testing; (2) the delivery of genetic counseling and testing services; and (3) initiation of guideline-adherent follow-up care and family communication of results. Challenges to delivering care on the HBC care continuum include factors such as access to services, cost, discrimination and bias, and lack of education and awareness, which can be mitigated through implementing a multi-level approach. This includes strategies such as increasing awareness and utilization of genetic counseling and testing, developing new methods to meet the growing demand for genetic services, and improving the uptake of follow-up care by increasing patient and provider awareness of the management recommendations. Breast cancer is the most common cancer diagnosed in women worldwide, with high penetrance inherited cancer predisposing genes accounting for approximately 5-10% of cases [1, 2] . An additional 20% of cases are thought to be familial; thus, they not attributable to a single inherited high penetrance gene and include additional genetic contributors including moderate penetrance genes and polygenic inheritance [3] [4] [5] . The indications to test for hereditary breast cancer (HBC) have expanded to encompass testing to guide cancer treatment which in turn has further increased the demand for breast cancer risk assessment and testing services. Breast cancer risk spans a continuum. Although no standard definition currently exists, for the purposes of this paper, genes considered to be highly penetrant are defined as > 4-fold risk (and generally 10-20 fold risk) and those considered moderately penetrant have a 2-4-fold risk of cancer [6, 7] . Prior studies suggest that the majority of HBC genes are attributed to the BRCA1 and BRCA2 (BRCA ) [8] . There are also "non-BRCA " inherited breast cancer genes which include both high (e.g., PALB2, TP53, PTEN, and CDH1) [9] and moderate (e.g., ATM and CHEK2) penetrance genes [7] . Additionally, there are single nucleotide polymorphisms (SNPs) identified within or outside of genes, which individually impart < 2-fold risk, considered as 'low penetrance' [7] , which in combination may be used to generate a polygenic risk score (PRS). The delivery of services focused on HBC may be considered through the lens of a 'care delivery continuum' (as outlined in Fig. 1 ). This continuum includes (1) identification, access, and uptake of genetic counseling and testing; (2) the delivery of genetic counseling and testing services; and (3) initiation of guideline-adherent follow-up care and family communication of results, upon completion of risk assessment and testing. Identification of individuals with pathogenic or likely pathogenic (P/LP) variants in an HBC gene (often referred to as 'gene carriers') offers an opportunity to manage patients at increased risk for cancer through early detection, chemoprevention, and risk-reducing surgeries (Fig. 2 ) [10] . For example, individuals with a BRCA P/LP variant have a 60-70% lifetime risk of developing breast cancer [11] , up to a 50% risk of developing a second primary breast cancer [12] , and up to a 44% lifetime risk of developing ovarian cancer [11, 12] . Thus, identification of a P/LP variant in a HBC gene informs cancer risks, which then guides cancer risk management (as outlined in Fig. 2 ). Analogous to the BRCA genes, other HBC genes have specific ranges of lifetime cancer risks and corresponding management recommendations to mitigate these elevated risks [7] . Yet, despite meeting the national guidelines for genetic testing referral, few patients with breast cancer who meet guideline criteria for HBC testing are actually tested, with even lower rates among minority, rural, and underserved populations [2, [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] . Relatively higher genetic testing rates at academic centers [24, 25] are not reflective of the much lower national testing rates reported through administrative databases and registries [14, 18, 20] . In fact, a recent study based on national claims data reported that genetic testing rates were less than 20% in patients with breast or ovarian cancer who met national criteria for testing [14] . The traditional model for cancer genetic risk assessment services for women with breast cancer has involved a pretest genetic counseling session during which an evaluation is done and informed consent for testing is obtained, followed by a post-test genetic counseling session, during which results are disclosed and interpreted in the context of the personal and family history [7, 26] . Multiple professional organizations endorse the importance of genetic counseling in the context of genetic testing, with components of discussion items aligned across multiple professional [7, [26] [27] [28] . The plummeting cost of DNA sequencing in conjunction with expanding indications for genetic testing has led to increased demand for genetic services which has outpaced the supply of certified and credentialed genetics health professionals (GHPs) to provide these services [29] . A recent survey of genetic counselors across specialties reported that 54% perceived their current delivery model is inadequate to address the needs of their patients and 65% reported plans to change their model [30] . The national shortage of GHPs [31] coupled with limited access to GHPs in rural areas [32] and community oncology practices in many states [33] has resulted in the majority of genetic tests being ordered without the inclusion of a GHP. In fact, we and others have previously reported that the minority of breast cancer patients are tested through a GHP [34, 35] . Similar to our findings which showed that only 20% of young breast cancer survivors had genetic testing services provided by a GHP [34] , another study showed that approximately 21% of patients who received genetic testing reported that a genetic counselor ordered their genetic test [35] . Yet there are insurance policies which mandate pre-test genetic counseling be conducted with involvement of a GHP, which may disproportionately reduce genetic testing rates among minority and underserved populations who have decreased access to genetic services [36, 37] . Moreover, the increasing use and decreasing cost of nextgeneration sequencing-based tests has shifted the paradigm toward use of multi-gene panel tests. This in turn has led to the option of testing for genes beyond the clinical indication based on personal or family history of cancer [38] ; as well as inclusion of high and moderate penetrance genes, 'preliminary evidence' genes with uncertain or unproven cancer associations, and single nucleotide polymorphisms (SNPs) identified through genome wide association studies (GWAS) to generate a PRS. Given that data to generate PRS are based on existing data in Caucasian populations, risk predictions are also limited to this population and not standardized across labs [39] . In fact, a recent study of breast cancer patients reported that PRS did not improve risk prediction among women of African ancestry compared to European ancestry [40] . Moreover, accuracy to predict disease risk using data generated primarily from European GWAS has been reported to be about a quarter among Black patients [41] . With increasing numbers of genes clinically available for testing through multi-gene panels, there has been an upsurge of testing for genes of uncertain clinical utility and genes that may not be clinically indicated based on personal or family history thereby raising the complexity of pre-test genetic counseling [27] . Alongside these developments, the traditional pre-test genetic counseling model has continued to be refined for effective integration into clinical practice [27] . Furthermore, interpretation of results becomes increasingly complex as broad germline panels are ordered, there is a need for recognition that "bigger is not always better". In fact, current NCCN guidelines acknowledge that "not all genes included on available multi-gene tests are necessarily clinically actionable" [7] . Additionally, variant of uncertain significance (VUS) results, which become increasingly common as more genes are tested, have added another layer of complexity to the pre-test genetic counseling risk assessment [42] . These uncertainties must be shared with patients as part of the process of informed consent for testing [29] , recognizing that VUS results do not inform medical care and results should be interpreted similar to negative test results. VUS results may present a complication for patients if not properly explained, and there is data to suggest significant gaps in both provider understanding and confidence to guide medical management patients with VUS results. A study based in the United Kingdom reported that 71% of providers expressed uncertainty about the clinical utility of BRCA VUS results and 39% did not know how to communicate results to patients with no family history [43] . Another registry-based study of breast cancer survivors reported that 50% of average-risk breast cancer patients with a BRCA VUS underwent bilateral mastectomy, which highlights the limited understanding and interpretation of VUS results among some providers [35] . There are many factors to consider when ordering genetic testing for patients, given the variations in multigene panel tests offered across laboratories, including: (1) multi-gene panel tests offered; (2) genes included on the various panels; (3) testing methodologies; (4) detection rates; and (5) additional offerings including RNA testing and paired tumor/germline testing [44] . Furthermore, results interpretation vary across genetic testing laboratories due to different internal approaches to variant classification along with different sets of patient data. This can result in discrepant results where one lab may call a variant likely pathogenic, which would lead to changes in medical management, while another lab calls the exact same variant a VUS which typically would not alter medical management [45] . Moreover, even the terminology to classify results differs across labs, with some using the American College of Medical Genetics variant terminology [46] , while others use their own internal "home grown" terminology. Additionally, as data on specific variants become more robust, some labs are choosing to provide additional commentary beyond the typical "pathogenic" or "VUS" classifications, such as "moderate risk variant", "special interpretation", or "carrier". While this information is critical to include in the interpretation of test results, there is often a lack of differentiation between two very different concepts: pathogenicity versus penetrance. While classification of pathogenicity is an indication of gene function (or dysfunction), penetrance indicates level of cancer risks in the context of a P/LP variant. An example is the CHEK2 I157T variant. Most major labs agree that this variant is associated with lower cancer risks than other pathogenic CHEK2 mutations, particularly the 1100delC variant. However, in the absence of any guiding recommendations, communication of this information varies with labs reporting it as: (1) a "Special Interpretation" comment (with an asterisk to a 'see below' comment for explanation); (2) "moderate risk mutation"; (3) "pathogenic (low penetrance) variant"; or (4) VUS. These disparate ways to document the same variant illustrating the challenges ahead as more robust genotype/phenotype data become available. When performing testing through next-generation sequencing, it is important to recognize that variations larger than a few base pairs in size cannot readily be recognized across all testing platforms. Thus, most laboratories supplement next-generation sequencing with additional techniques to provide evaluation of larger, structural genomic mutations [29] . Additionally, some germline testing labs are now offering upfront RNA analysis in addition to their standard testing which has the potential to detect intronic pathogenic mutations and clarify VUS's up front so they are not reported (particularly splice variants) [47] . One study found that concurrent RNA analysis led to 1 in 43 patients having different medical management than standard testing [47] . Consequently, providers offering genetic testing services, as well as those who order the tests in the clinics as part of routine patient care, must be familiar with the different labs' testing approaches to select the most appropriate lab for their patients' genetic testing needs [29] . As more genes are tested for, the chance for detecting a VUS increases [48] [49] [50] . Additionally, the likelihood of finding a VUS with larger multi-gene cancer panels is even higher for racial and ethnic minority groups [49, 50] , who may also have lower diagnostic yield when compared to patients from European ancestry [51] . Standardizing the quality of genetic services provided to all racial and ethnic groups is of paramount importance as gene-based care expands. The purpose of genetic testing is to provide personal genetic information to individuals, with the goal of improving outcomes for individuals and their at-risk family members through cancer risk management, cancer treatment, and family communication of genetic test results (see Fig. 2 ). Appropriate delivery of follow-up care after genetic testing is critical, without which outcomes from genetic testing will not be improved. The identification of HBC may empower individuals and their families with options to detect cancers early or prevent them [52] [53] [54] . In an effort to guide appropriate cancer risk management, a clinical validity framework has been developed through the Clinical Genome Resource (ClinGen) to classify genes based on the strength of evidence for association to a particular disease into definitive, strong, moderate, limited, disputed, or no reported evidence [55] . High and moderate penetrance genes are generally established to have an increased risk of HBC, in contrast to other genes with insufficient data to establish an association with breast cancer and penetrance [7] . Consequently, penetrance data in conjunction with clinical utility inform risk management [56] , and management recommendations are based on both lifetime breast cancer risks and age distribution of risks. For example, earlier age of breast cancer screening with breast MRI and consideration of prophylactic surgery is advised for those with high penetrance HBC genes; in contrast, breast MRI at later ages is advised for those with moderate penetrance HBC genes with additional guidance based on family history and other modifying factors [7, 46, 57] . It is also important that 'preliminary evidence' genes with unconfirmed or uncertain cancer risks on multi-gene panel tests, are not used to guide cancer risk surveillance and management [7] . Among female BRCA1/2 carriers, risk-reducing mastectomy and risk-reducing salpingo-oophorectomy are two surgical options that reduce the risk of developing breast and ovarian cancer by ~ 90% [58] . While rates of contralateral prophylactic mastectomy for breast cancer patients have increased [59] , cancer risk management guidance is imperative to prevent over-or under-treatment. We and others have previously shown overtreatment through risk-reducing surgeries among women with BRCA1/2 VUS results and moderate penetrance HBC genes [35, [60] [61] [62] . In fact, our recently published study showed that 52% of women with a ATM or CHEK2 P/LP variant had contralateral prophylactic mastectomies [60] . Similarly, 43% of non-BRCA carriers of a P/LP variant had bilateral mastectomies [61] and 10-15% of women with moderate penetrance or VUS results had prophylactic oophorectomies [62] , which suggests potential overtreatment. On the other hand, studies have also shown reduced uptake of cancer risk management strategies when indicated, especially among minority groups [13] . In fact, we previously reported on the reduced uptake of risk-reducing salpingo-oophorectomy among young Black women with breast cancer, compared to Whites and Hispanics [13] . These studies highlight the importance of promoting guideline-adherent, risk-appropriate gene-based care across all populations. Identification of HBC may impact therapeutic options, including the expansion of genetic testing to guide eligibility for specific drugs based on genetic test results [63] . For example, PARP inhibitors are now FDA approved for use among women with germline BRCA1/2 P/LP variants with high-risk, localized and metastatic HER2 breast cancer, after they were shown to improve breast cancer outcomes [63] [64] [65] . In addition to the impact of identifying HBC on cancer risk management and treatment, this information may be shared with at-risk family members to identify those with P/LP variants in whom cancer risk management strategies may be implemented to improve outcomes [66, 67] . We have previously shown BRCA carriers are likely to disclose genetic test results with at least one relative [68] , while women with P/LP variants in non-BRCA genes had lower rates of family sharing and family testing (i.e., cascade testing) [69] . In one study, 97% of BRCA carriers informed at least one relative, yet only 48% had cascade testing [70] . Without the identification of family members with P/LP variants (through cascade testing), the promise of cancer risk management strategies to improve outcomes cannot be realized. Furthermore, our prior study in young Black women with breast cancer showed lower rates of family disclosures [68] , which is unfortunate given the implications for prevention and early detection in an already high-risk population. Barriers to identification of HBC carriers and access to care include cost, geographic access to services, potential provider discrimination and bias, and lack of patient and provider education and awareness (Fig. 3) . A multi-level approach to address barriers to identification, access, and uptake relevant to genetic counseling and testing services includes increasing awareness and utilization of services through community outreach, as well as patient and provider education (Table 1) . Patient-level strategies to increase genetic counseling and testing uptake for breast cancer patients include increasing patient awareness of genetic testing and patientcentered education tools tailored to meet the needs of a widely diverse patient population. Future work to better understand the patient experience, needs of patients during genetic counseling and testing, patient-reported outcomes, and the barriers patients face in receiving genetic services is necessary. Provider-level strategies include targeted education to improve overall proficiency in genetics across the healthcare workforce including nurses, advanced practice providers and physicians in internal medicine, and numerous specialty fields including radiology, surgery, and obstetrics/gynecology. Educational provider tools might include in-person didactic learning presentations, webinars, printed education materials, and opportunities for feedback. System-level approaches to improve uptake of genetic testing among appropriate breast cancer patients include the implementation of electronic health record (EHR) prompts, integrated risk assessment tools in the EHR, web-based screening applications and telehealth [71] [72] [73] [74] [75] . Technology-based solutions including efforts to identify and alert treating physicians through EHR prompts have shown promise to increase the number of appropriate referrals of cancer patients for genetic counseling [76] . To meet the demand for genetic services for HBC and overcome barriers to providing appropriate, effective, and equitable services, multi-level solutions (Table 1) at the system, provider, and patient levels have been proposed. Point-ofcare genetic testing, defined as testing in the context of existing appointments and care through providers without formal training in genetics (i.e., non-GHP), is a model increasingly being used across clinics. As most hereditary cancer genetic counseling and testing is provided by non-GHPs, this model is supported through non-GHPs partnering with GHPs to provide decision support [77] . Furthermore, technologybased solutions may be used to streamline pre-test genetic education, as we and others have previously reported on [78, 79] , and is an example of an alternative delivery model (ADM) which has tremendous potential to increase throughput and utilize the expertise of GHPs where they may have the most impact. ADMs were developed to enable genetic counselors to work at the top of their scope of practice while improving access to their services, and various ADMs serve to solve different problems [80] . One ADM which can help lower wait times involves genetic counseling assistants (GCAs). GCAs can be used to complete administrative tasks and pre-and post-appointment activities that traditionally were completed by genetic counselors including family history collection/pedigrees, obtaining relevant records prior to consult and in some models, result disclosure after genetic counseling. This model has been found to increase patient volume and save costs per patient [81] . The goal of some ADMs is to reduce geographic and access barriers to patients receiving genetic counseling. In particular, the COVID-19 pandemic created barriers to many in-person medical services, including cancer genetics services. Studies of telephone genetic counseling related to BRCA testing found that it is non-inferior to in-person genetic counseling when cancerspecific distress and genetic knowledge were measured [82] . Ultimately, there will not be one single solution to the various challenges, but clinics are likely to use a combination of these models to improve and expand access to genetics services. Strategies to increase the uptake of follow-up care include increasing patient and provider awareness of the management recommendations. The integration of technology in the management of HBC has the potential to improve the follow-up care for patients by providing patients and providers with updates on changes in the management of HBC that are relevant to each patient. For example, there are digital health companies that provide personalized materials based on genetic test results to both patients and providers on upto-date HBC management options [83] . In addition, implementation of EHR prompts is a system-based tool that can be used to standardize and automate recommendations based on genetic test results. As a result of our prior work [69, 78, 84] , we developed a public facing website (www. genes hare. net) to provide tools and resources to enhance family communication of genetic test results. As a further extension of these efforts, we have secured funding to conduct a clinical trial to test interventions focused on guideline-adherent cancer risk management and family communication among those with inherited cancer predisposing genes (NCI U01CA254832). Given the tremendous advancements in precision oncology, there is an increasing demand for cancer genetic services. There are, however, barriers to equitable access and uptake of cancer genetic services. Strategies focused on identification of individuals at risk for HBC, delivery of genetic services, and appropriate follow-up care are paramount to improve the quality of care delivered to patients with HBC. 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The Inherited Cancer Registry (ICARE) initiative: an academic-community partnership for patients and providers Pal T (2020) A web-based tool to automate portions of pretest genetic counseling for inherited cancer Video-assisted genetic counseling in patients with ovarian, fallopian and peritoneal carcinoma The past, present and future of service delivery in genetic counseling: keeping up in the era of precision medicine Positive impact of genetic counseling assistants on genetic counseling efficiency, patient volume, and cost in a cancer genetics clinic A systematic review and meta-analysis of telephone vs in-person genetic counseling in BRCA1/BRCA2 genetic testing How-Often-Do-Medic al-Manag ement-Guide lines-Change. pdf? utm_ source= mailc himp& utm_ campa ign= 0300b 2cee1 f0& utm_ medium= page Sharing genetic test results with family members of BRCA, PALB2, CHEK2, and ATM carriers Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations Acknowledgements Sonya Reid's research was supported by a NIH training grant (5K12CA090625-20).Data availability Data sharing not applicable to this article as no data sets were generated or analyzed during the current study. The authors declare that they have no conflict of interest.