Testing For Hereditary Cancer Research Articles

Malignant tumors in tuberous sclerosis complex: a case report and review of the literature

BackgroundTuberous sclerosis complex (TSC) is a rare, autosomal dominant genetic disease that arises from TSC1 or TSC2 genetic mutations. These genetic mutations can induce the development of benign tumors in any organ system with significant clinical implications in morbidity and mortality. In rare instances, patients with TSC can have malignant tumors, including renal cell carcinoma (RCC) and pancreatic neuroendocrine tumor (PNET). It is considered a hereditary renal cancer syndrome despite the low incidence of RCC in TSC patients. TSC is typically diagnosed in prenatal and pediatric patients and frequently associated with neurocognitive disorders and seizures, which are often experienced early in life. However, penetrance and expressivity of TSC mutations are highly variable. Herein, we present a case report, with associated literature, to highlight that there exist undiagnosed adult patients with less penetrant features, whose clinical presentation may contain non-classical signs and symptoms, who have pathogenic TSC mutations.Case presentationA 31-year-old female with past medical history of leiomyomas status post myomectomy presented to the emergency department for a hemorrhagic adnexal cyst. Imaging incidentally identified a renal mass suspicious for RCC. Out of concern for hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome, the mass was surgically removed and confirmed as RCC. Discussion with medical genetics ascertained a family history of kidney cancer and nephrectomy procedures and a patient history of ungual fibromas on the toes. Genetic testing for hereditary kidney cancer revealed a 5’UTR deletion in the TSC1 gene, leading to a diagnosis of TSC. Following the diagnosis, dermatology found benign skin findings consistent with TSC. About six months after the incidental finding of RCC, a PNET in the pancreatic body/tail was incidentally found on chest CT imaging, which was removed and determined to be a well-differentiated PNET. Later, a brain MRI revealed two small cortical tubers, one in each frontal lobe, that were asymptomatic; the patient’s history and family history did not contain seizures or learning delays. The patient presently shows no evidence of recurrence or metastatic disease, and no additional malignant tumors have been identified.ConclusionsTo our knowledge, this is the first report in the literature of a TSC patient without a history of neurocognitive disorders with RCC and PNET, both independently rare occurrences in TSC. The patient had a strong family history of renal disease, including RCC, and had several other clinical manifestations of TSC, including skin and brain findings. The incidental finding and surgical removal of RCC prompted the genetic evaluation and diagnosis of TSC, leading to a comparably late diagnosis for this patient. Reporting the broad spectrum of disease for TSC, including more malignant phenotypes such as the one seen in our patient, can help healthcare providers better identify patients who need genetic evaluation and additional medical care.

Abstract PS10-07: A second-generation polygenic risk score (PRS) based on genetic ancestry improves breast cancer (BC) risk prediction for all ancestries

Abstract Background: Common genetic variants, mainly single-nucleotide polymorphisms (SNPs) explain substantial genetic susceptibility to BC. PRS have been developed to quantify the combined effects of BC-associated SNPs, providing important information about BC risk. Historically, genome-wide association studies have been conducted in predominantly European populations, resulting in miscalibrated and inaccurate PRS for non-Europeans. We previously described a multiple-ancestry PRS (MA-PRS-149) based on 56 ancestry-informative and 93 BC-associated SNPs. The MA-PRS-149 achieved accuracy for all women by characterizing the genetic ancestry of each BC-associated SNP in terms of three reference ancestries (African, East Asian, and European), applying ancestry-specific SNP risks and frequencies, and combining the results as a weighted sum of three ancestry-specific PRS. Here, we aimed to improve the predictive accuracy of MA-PRS-149, particularly for non-Europeans, through the inclusion of additional BC-associated SNPs. Methods: Women referred for hereditary cancer testing and negative for pathogenic variants in BC-associated genes were divided into consecutive study cohorts to (1) quantify ancestry-specific SNP risks, (2) combine the three ancestry-specific PRS, and (3) pre-specified clinical validation. To select an optimal set of BC-associated SNPs, we developed a novel synthetic stepwise regression methodology that accounts for linkage disequilibrium. Ancestry-specific SNP risks were determined from meta-analyses of literature with clinical cohorts of 57,827 Black/African and 26,992 East Asian women. Ancestry-specific PRS were combined based on a diverse cohort of 157,740 women. Clinical validation was conducted in an independent cohort of 77,774 women. We used multivariable logistic regression adjusted for age, ancestry, and cancer history to test for improved BC risk prediction over clinical factors. We tested for improvement over the MA-PRS-149, and a European PRS, by including additional PRS as covariates. Calibration was assessed through goodness-of-fit tests. All analyses were conducted within the full cohort and ancestral subpopulations. Odds ratios (ORs) and 95% confidence intervals (CIs) are reported per standard deviation within the corresponding population. Results: An optimal set of 383 SNPs (56 ancestry-informative and 327 BC-associated) was included in the final PRS (MA-PRS-383). MA-PRS-383 added significant predictive information to clinical factors in the full cohort and within each ancestry (Table 1). MA-PRS-383 had greater predictive accuracy than MA-PRS-149 or a 383-SNP PRS with European weights. Goodness-of-fit tests showed that MA-PRS-383 was well-calibrated and predicted risk accurately in the tails of the distribution for both European and non-European women. Conclusion: MA-PRS-383 was well-calibrated and substantially improved upon existing PRS in all tested ancestral populations. Incorporation of MA-PRS-383 into BC risk assessment may lead to more accurate identification of women who are most likely to benefit from screening and preventive medications. Citation Format: Timothy Simmons, Elisha Hughes, Dmitry Pruss, Matthew Kucera, Benjamin Roa, Thaddeus Judkins, Thomas Slavin, Victor Abkevich, Ryan Hoff, Srikanth Jammulapati, Susanne Wagner, Dale Muzzey, Jerry Lanchbury, Alexander Gutin. A second-generation polygenic risk score (PRS) based on genetic ancestry improves breast cancer (BC) risk prediction for all ancestries [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS10-07.

Abstract PO1-08-07: Utilization Management: The Impact of Laboratory Genetic Counseling Oversight on BRCA1 and BRCA2 Targeted Analysis Orders

Abstract INTRODUCTION: While multigene hereditary cancer testing has become a common order for individuals with personal and/or family histories of cancer, targeted genetic testing (TGT) remains a cost-effective test option for cascade testing of individuals with a known gene mutation in the family. In order to proceed with TGT, the genetic testing laboratory must receive documentation of the specific variant. Intervention of a genetic counseling team (GCT), which includes laboratory genetic counselors and genetic counseling assistants, can play a major role in utilization management for genetic testing companies, including obtaining and reviewing mutation reports and offering clinically appropriate and cost-effective test options. Given previously reported low rates of cascade testing for family members of mutation carriers and the potential barriers of ordering TGT testing, we sought to review the success of providers ordering BRCA1 and BRCA2 TGT testing and the GCT role in management of these orders. METHODS: Per standard operating procedure at Labcorp, the GCT reviews all hereditary cancer genetic test orders before they begin processing through prior authorization and laboratory analysis. When societal guidelines dictate, GCT intervention may occur to request genetic testing reports and offer to update testing appropriately. A retrospective review of GCT notes on TGT orders was conducted, with review of all BRCA1 and BRCA2 TGT orders accessioned between January 1 and February 28, 2023. Orders that were updated or cancelled before GCT review were excluded from analysis. All other TGT orders were coded into one of seven categories: (1) ordered for TGT, mutation report provided, proceed without GCT intervention; (2) ordered for TGT, mutation report obtained after GCT intervention, proceed with TGT; (3) ordered for TGT, no report obtained, updated to BRCA1 and BRCA2 comprehensive sequencing and deletion/duplication analysis with or without other hereditary cancer genes (COMP) with authorization from ordering provider via GCT intervention; (4) ordered for TGT, report obtained, updated to COMP via GCT intervention; (5) ordered for TGT, no report or authorization to update testing obtained during GCT intervention, testing cancelled; (6) ordered for TGT and COMP, no report, TGT cancelled; and (7) ordered for COMP, mutation report obtained, updated to TGT with authorization from ordering provider after GCT intervention. Time between accessioning and initial GCT resolution was also collected. RESULTS: A total of 198 TGT orders and associated GCT notes were reviewed. 24 orders (12.1%) proceeded with TGT without GCT intervention (category 1) with an average turn-around-time of 1 day. GCT intervention was required for 158 (79.8%) of TGT orders with an average turn-around-time of 5 days. After GCT review and/or intervention, 60 (30.3%) orders proceeded with TGT analysis (categories 1, 2, and 7); 23 (11.6%) of these were originally ordered for COMP, then updated when a mutation report was obtained (category 7). Testing was updated from TGT to COMP because no mutation report was obtained in 78 (39.3%) cases (category 3). In 7 (3.5%) TGT orders, testing was updated to COMP even though a mutation report was obtained (category 4). CONCLUSION: TGT analysis is beneficial for cascade testing, but access to a mutation report as a requirement to proceed can be a barrier. More strategies are needed to provide education for ordering providers and patients on the benefit of sharing familial mutation reports for cascade testing. Efficiency of testing increases when patients and providers have access to records and provide this information to laboratories up-front. Laboratory GCTs are invaluable resources in reviewing nuanced genetic test orders, educating providers in the strengths and limitations of different genetic test options, and working to ensure patients receive clinically appropriate and cost-effective testing. Citation Format: Rebecca Vanderwall, Dagny Noeth, Angelica Goulbourne, Katherine Goode, Teresa Ruegg, Melissa Hayden, W. Christine Spence. Utilization Management: The Impact of Laboratory Genetic Counseling Oversight on BRCA1 and BRCA2 Targeted Analysis Orders [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-08-07.

Abstract PO3-16-06: Perceptions and experiences of patients and healthcare providers on genetic testing and treatment of early breast cancer: qualitative findings

Abstract Background: Olaparib is approved as adjuvant therapy for high-risk HER2-negative early breast cancer (eBC) patients with germline BRCA mutations (BRCAm). Understanding patients’ preferences for genetic testing and treatment in the context of shared decision-making is needed to support optimal care in eBC. This study elicited the perspectives of patients with eBC and healthcare providers (HCP) treating eBC regarding treatment decision-making, and drivers and barriers to BRCA testing. Methods: Semi-structured interviews were conducted in the United States from Jan-Feb 2023 with women (n=12) diagnosed with eBC from 2017-2021. Community and academic oncologists treating eBC (n=12) and genetic counselors (GCs; n=8) were also interviewed. Patients who were tested (n=7) and untested (n=5) for BRCAm were included. A content and thematic analysis was performed which identified key factors from the data; these analyses provided both a range and common responses that may influence BRCA testing and treatment decisions. Results: BRCA-tested patients considered testing beneficial. In choosing to receive testing, >50% of patients reported HCP recommendation (n=7) and the opportunity to have “all of the information” about their eBC (n=7) as strong influencers. Patients declined genetic testing noting fear around negative impact to their insurance coverage (n=2) or mental health (n=3), or if they did not have family who would benefit from the information. Cost did not strongly influence testing choice. In choosing a treatment, patients sought to maintain their quality of life (QoL) with fewer side effects while minimizing chance of recurrence. They expressed the dual goals of normalcy during treatment, including curtailing side effects that impact QoL, and returning to normalcy after treatment (n=7). Patients were willing to accept unpleasant side effects to have a more effective treatment if those side effects do not severely impact their QoL and the treatment is highly effective (n=9). Side effects that may lead to hospitalization were the least accepted as they disrupt normalcy. HCPs reported that patients eagerly accept testing and face minimal familial or access barriers to testing. HCPs observed that among their non-Medicare patients, testing is usually covered by insurance with minimal out-of-pocket costs, thus alleviating financial constraints observed in previous years. HCPs believe BRCA testing is driven by updated hereditary cancer testing guidelines (e.g., NCCN), lower testing costs, closer collaborations of physicians and genetic counselors, and greater awareness among patients. HCPs reported that they embrace patient-led decision-making in eBC, especially as it relates to patients with BRCAm considering additional prophylactic surgery, and GCs further emphasized patient autonomy. Oncologists mentioned that they discuss risk status starting at diagnosis and these conversations evolve over the patient journey as new information emerges. In HR+ eBC, oncologists offered most patients with BRCAm adjuvant olaparib, which they perceive as well tolerated. In triple-negative eBC, oncologists opted for neoadjuvant Keytruda regimen prior to considering adjuvant olaparib for gBRCAm patients. Conclusions: Patients value information that empowers them to achieve their goals of normalcy and remission that can be achieved by addressing QoL, side effects, and patients' goals of living “normally”. Though prior research highlighted insurance coverage and costs as significant barriers to BRCA testing, results from this study suggest that cost was not a major factor in testing decisions. Prior barriers to testing access have been mitigated making it more available and affordable than in the past, which could be broadly communicated to patients and HCPs to minimize misperception. Citation Format: Jagadeswara Earla, Emily Mulvihill, Josh Lankin, Lauren Howell, Alex Kissling, Weiyan Li, Jaime Mejia. Perceptions and experiences of patients and healthcare providers on genetic testing and treatment of early breast cancer: qualitative findings [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-16-06.

Mixed-Methods Evaluation of the Implementation of a Hereditary Cancer Risk Screening Questionnaire in a Safety Net Hospital [ID 2683409

INTRODUCTION: Patients belonging to medically underserved groups who meet testing criteria for hereditary cancer syndromes are less likely to be referred for genetic services and to complete testing. In our safety net hospital women’s health clinics, we introduced a novel National Comprehensive Cancer Network (NCCN)-based screening questionnaire as part of a community health worker (CHW)-supported hereditary cancer risk assessment and testing program. METHODS: We quantified program effect and conducted semistructured interviews with nurses and providers (n=12). We used rapid qualitative analysis to assess familiarity with screening questionnaire and barriers to its utilization. Institutional review board approval was obtained. RESULTS: Since January 2020, 2,282 patients were screened: 169 via provider referral and 2,113 via questionnaire. 312 met NCCN criteria for testing, with 30 ultimately testing positive. Nurses were familiar with the screening questionnaire and assumed an active role in facilitating completion. They reported minimal familiarity with the process after questionnaire completion. Providers reported minimal familiarity with the screening questionnaire but did assess family history and refer for genetic services. Barriers to successful utilization of the questionnaire included time constraints, patient literacy, language barriers, and gaps in patients' knowledge of their family history. CONCLUSION: Implementation of a targeted questionnaire may increase access to testing for hereditary cancer syndromes. We identified the following opportunities for implementation improvement: staff education, increased clinic efficiency, and CHW support with collection of accurate histories from patients with limited literacy/knowledge of their family's health history. Replication of a CHW-supported questionnaire-based screening program could reduce disparities in access to genetic services for patients in safety net settings.

Psychosocial barriers and facilitators for cascade genetic testing in hereditary breast and ovarian cancer: a scoping review.

Despite increased awareness and availability of genetic testing for hereditary breast and ovarian cancer (HBOC) syndrome for over 20years, there is still significant underuse of cascade genetic testing among at-risk relatives. This scoping review synthesized evidence regarding psychosocial barriers and facilitators of family communication and/or uptake of cascade genetic testing in relatives from HBOC families. Search terms included 'hereditary breast and ovarian cancer' and 'cascade genetic testing' for studies published from 2012-2022. Through searching common databases, and manual search of references, 480 studies were identified after excluding duplications. Each article was reviewed by two researchers independently and 20 studies were included in the final analysis. CASP, RoBANS 2.0, RoB 2.0, and MMAT were used to assess the quality of included studies. A convergent data synthesis method was used to integrate evidence from quantitative and narrative data into categories and subcategories.Evidence points to 3 categories and 12 subcategories of psychosocial barriers and facilitators for cascade testing: (1) facilitators (belief in health protection and prevention; family closeness; decisional empowerment; family support, sense of responsibility; self-efficacy; supportive health professionals); (2) bidirectional concepts (information; perception of genetic/cancer consequences; negative emotions and attitude); and (3) barriers (negative reactions from family and negative family dynamics). Healthcare providers need to systematically evaluate these psychosocial factors, strengthen facilitators and alleviate barriers to promote informed decision-making for communication of genetic test results and uptake of genetic testing. Bidirectional factors merit special consideration and tailored approaches, as they can potentially have a positive or negative influence on family communication and uptake of genetic testing.

Cascade testing for hereditary cancer in Singapore: howpopulation genomicshelp guide clinical policy.

Hereditary Cancer makes up around 5-10% of all cancers. It is important to diagnose hereditary cancer in a timely fashion, as not only do patients require long-term care from a young age, but their relatives also require management. The main approach to capture at-risk relatives is cascade testing. It involves genetic testing of relatives of the first detected carrier of a pathogenic variant in a family i.e. the proband. The current standard of care for cascade testing is a patient-mediated approach. Probands are then advised to inform and encourage family members to undergo genetic testing. In Singapore, cascade testing is inefficient, around 10-15%, lower than the 30% global average. Here, we describe the cascade testing process and its effort to increase testing in Singapore. Precision Health Research, Singapore (PRECISE), was set up to coordinate Singapore's National Precision Medicine strategy and has awarded five clinical implementation pilots, with one of them seeking to identify strategies for how cascade testing for hereditary cancer can be increased in a safe and cost-efficient manner. Achieving this will be done through addressing barriers such as cost, manpower shortages, exploring a digital channel for contacting at-risk relatives, and getting a deeper insight into why genetic testing gets declined. If successful, it will likely result in care pathways that are a cost-effective public health intervention for identifying individuals at risk. Surveillance and management of those unaffected at-risk individuals, if caught early, will result in improved patient outcomes, and further reduce the healthcare burden for the economy.

Germline mutations in patients with metastatic prostate cancer: A prospective cohort study in South Korea (KCSG GU20-19).

193 Background: Several clinical guidelines recommend screening for hereditary prostate cancer in high-risk groups for metastatic prostate cancer. However, despite the recent increase in the diagnosis of prostate cancer in Korea, genetic testing for hereditary prostate cancer is not being performed, making it impossible to know the frequency of hereditary prostate cancer. This study aimed to determine the prevalence of germline mutations in unselected Korean patients with metastatic prostate cancer. Methods: Between July 2021 and December 2022, metastatic prostate cancer patients were enrolled prospectively, without any specific selection based on age or family history. Germline mutation analysis was performed on DNA from blood via next generation sequencing using SOLIDaccuTestTM DNA HRD (NgeneBio, Korea). Results: A total of 301 patients were enrolled and the prevalence of germline mutation was analyzed. At diagnosis, the median age was 67 (46-91 years old), and the median PSA was 150 ng/mL (3.07-5000). 250 patients had a Gleason score of 8 or higher. 36 patients (12.0 %) carried a pathogenic (14/301, 4.6 %)/likely pathogenic (22/301, 7.3 %) variant in a germline mutation. Of these patients, 11 patients (3.65 %) had BRCA2 mutations. ATM (6/301, 1.99 %) was the second most frequently mutated gene, followed by FH (4/301, 1.33 %), FANCA, FANCD2, MRE11, SLFN11, SMO (0.66 % of each, 2/301), BLM, CHEK2, ERBB3, MAP2K1, and VHL (0.33 % of each, 1/301). Further analysis will be conducted to evaluate the impact of germline mutations on somatic mutation results, treatment patterns, and clinical outcomes. Conclusions: The prevalence of pathogenic germline mutations among unselected Korean patients with metastatic prostate cancer was 12.0 %. Germline mutation prevalence in this cohort was comparable to previous reported results. This study provides the framework for the development of preventive and treatment strategies based on hereditary genetic factors for prostate cancer in the Korean population. [Table: see text]

Germline Genetic Testing for Hereditary Breast and Ovarian Cancer: Current Concepts in Risk Evaluation.

Our understanding of hereditary breast and ovarian cancer has significantly improved over the past two decades. In addition to BRCA1/2, pathogenic variants in several other DNA-repair genes have been shown to increase the risks of breast and ovarian cancer. The magnitude of cancer risk is impacted not only by the gene involved, but also by family history of cancer, polygenic risk scores, and, in certain genes, pathogenic variant type or location. While estimates of breast and ovarian cancer risk associated with pathogenic variants are available, these are predominantly based on studies of high-risk populations with young age at diagnosis of cancer, multiple primary cancers, or family history of cancer. More recently, breast cancer risk for germline pathogenic variant carriers has been estimated from population-based studies. Here, we provide a review of the field of germline genetic testing and risk evaluation for hereditary breast and ovarian cancers in high-risk and population-based settings.

Recontact to return new or updated PALB2 genetic results in the clinical laboratory setting.

The purpose of this study was to recontact individuals with clinically actionable test results identified through a retrospective research study and to provide a framework for laboratories to recontact patients. Genetic testing was conducted on 2977 individuals originally referred for BRCA1 and BRCA2 hereditary breast and ovarian cancer testing that had a negative genetic test result. A gene panel was used to identify pathogenic variants in known or newly discovered genes that could explain the underlying cause of disease; however, analysis was restricted to PALB2 for the purposes of this study. A patient recontact decision tree was developed to assist in the returning of updated genetic test results to clinics and patients. Novel clinically actionable pathogenic variants were identified in the PALB2 gene in 18 participants (0.6%), the majority of whom were recontacted with their new or updated genetic test results. Eight individuals were unable to be recontacted; five individuals had already learnt about their new or updated findings from genetic testing outside the context of this study; three individuals prompted cascade testing in family members; two individuals were deceased. Novel pathogenic variants in PALB2 were identified in 18 individuals through retrospective gene panel testing. Recontacting these individuals regarding these new or updated findings had a range of outcomes. The process of conveying genomic results within this framework can be effectively accomplished while upholding patient autonomy, potentially leading to advantageous outcomes for patients and their families.

Direct letters to relatives at risk of hereditary cancer—study protocol for a multi-center randomized controlled trial of healthcare-assisted versus family-mediated risk disclosure at Swedish cancer genetics clinics (DIRECT-study)

Background The results of germline genetic testing for hereditary cancer are of importance not only to the patients under investigation but also to their genetic at-risk relatives. Standard care is to encourage the proband (first family member under investigation) to pass on this risk information to the relatives. Previous research suggests that with family-mediated disclosure, only about a third of at-risk relatives contact health care to receive genetic counselling. In some studies, complementing family-mediated risk disclosure with healthcare-assisted risk disclosure almost doubles the uptake of genetic counselling in at-risk relatives. In this study, we evaluate healthcare-assisted direct letters to relatives at risk of hereditary cancer syndromes in a randomized controlled trial.MethodsProbands are recruited from Swedish outpatient cancer genetics clinics to this two-arm randomized controlled trial. The study recruits probands with either a pathogenic variant in a cancer susceptibility gene (BRCA1, BRCA2, PALB2, MLH1, MSH2, MSH6, PMS2) or probands with familial breast and colorectal cancer based on clinical and pedigree criteria. In both arms, probands receive standard care, i.e., are encouraged and supported to pass on information to relatives. In the intervention arm, the proband is also offered to have direct letters sent to the at-risk relatives. The primary outcome measure is the proportion of at-risk relatives contacting a Swedish cancer genetics clinic within 12 months of the proband receiving the test results.DiscussionThis paper describes the protocol of a randomized controlled clinical trial evaluating a healthcare-assisted approach to risk disclosure by offering the probands to send direct letters to their at-risk relatives. The results of this study should be informative in the future development of risk disclosure practices in cancer genetics clinics.Trial registrationClinicalTrials.gov. Identifier NCT04197856 (pre-trial registration on December 13, 2019).Also registered at the website “RCC Cancerstudier i Sverige” as study #86719.

Abstract B060: Hereditary cancer testing across race and ethnicity: Differences in patient characteristics and genetic test results

Abstract Rates of pathogenic/likely pathogenic variants (PGVs) and variants of uncertain significance (VUS) in genes associated with hereditary cancer syndromes vary across race and ethnicity. Here, we report on differences in physician orders and test results across race and ethnicity in patients referred for hereditary cancer testing at a single laboratory in the United States. Patients (N=109,264) with self-reported Ashkenazi Jewish (AJ; N=2,788), Black (N=19,538), East Asian (E Asian; N=1,953), Hispanic (N=19,920), South East Asian (SE Asian; N=845), South Asian (S Asian, N=626), and White (N=63,594) ethnicities who had hereditary cancer testing between 2020 and 2022 were included. Patient characteristics were summarized and genetic test results were compared (Chi-Square test, White as the reference group). Across all races and ethnicities, most patients were female (94-96%) and reported a family history of cancer (88-96%), while 29%-32% reported a personal history of cancer. Mean age at testing varied across groups (AJ 48.4±15.5 years, Black 43.4±13.5 years, E Asian 45.1±12.8 years, Hispanic 42.8±13.2 years, SE Asian 45.2±13.2 years, S Asian 43.9±14.4 years, White 46.1±14.3 years). The number of genes tested (small panel <20, medium panel 20-53, large panel >53) varied across ethnicities: White (14%, 80%, 5.4%), AJ (8.2%, 86%, 5.6%), Black (14%, 83%, 3.1%), E Asian (9.2%, 88%, 2.4%), Hispanic (15%, 81%, 4.5%), S Asian (15%, 82%, 3.2%), SE Asian (12%, 82%, 5%). Compared to White patients (10%), PGV rates were significantly lower in Black (4.7%, p<0.0001), E Asian (5.2%, p<0.0001), Hispanic (6.5%, p<0.0001), and SE Asian (4.3%, p<0.0001) patients, and significantly higher in AJ patients (15%, p<0.0001). No differences were observed compared with S Asian patients (7.7%, p=0.0522). Across all groups, most patients with PGVs had findings in actionable genes (AJ 96%, Black, 81%, E Asian 92%, Hispanic 88%, S Asian 90%, SE Asian 94%, White 86%). The most common genes with actionable PGVs were BRCA2 (Black, E Asian, SE Asian), CHEK2 (AJ, White), and MUTYH (Hispanic, S Asian). VUS rates, in the absence of any PGVs, when compared with White patients (20%) were significantly higher in Black (29%, p<0.0001), E Asian (34%, p<0.0001), Hispanic (25%, p<0.0001), S Asian (33%, p<0.0001), and SE Asian (38%, p<0.0001) patients, and were significantly lower in AJ patients (12%, p<0.0001). For all races and ethnicities, the two most common genes with VUS were ATM and APC. In this relatively diverse sample (~36% Hispanic or Black), these data demonstrate that there are variations in hereditary cancer testing with respect to provider ordering patterns (i.e., patient age, panel size) and test results (i.e., PGV rates) across ethnicities. These differences may reflect ancestral PGV patterns, other biologic correlates, or variable application of selection criteria. As previously reported, VUS rates are higher in non-White patients. Improved access to testing and additional evidence generation across all races and ethnicities will help to improve variant curation. Citation Format: Shifra Krinshpun, Breeana L. Mitchell, Jingwen Zhang, Nicholas Sun, Sara L. Bristow, Antony Tin, Minetta C. Liu, Adam ElNaggar, Alexey Aleshin, Jeffrey N. Weitzel. Hereditary cancer testing across race and ethnicity: Differences in patient characteristics and genetic test results [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr B060.

Simultaneous bilateral mastectomy and RRSO for BRCA2-positive non-invasive breast cancer in Japan: a case report and analysis of initial experience.

In Japan, genetic testing, surveillance, and risk-reducing surgery for hereditary breast and ovarian cancer (HBOC) syndrome have been covered by the Japanese national insurance system since April 2020. On the other hand, the current situation is that medical care, including surveillance of undiagnosed (cancer-free) patients, is self-funded even for individuals with HBOC. We report a case in which breast cancer was diagnosed at an early stage during surveillance for cancer-free HBOC at the patient's own expense, and risk-reducing surgery was performed at the same time as treatment for breast cancer. The patient was a 63-year-old woman. Her sister had a history of breast cancer in her 30s and was found to be a BRCA2 pathogenic variant carrier by genetic testing. The patient therefore presented to the genetic department of our hospital and underwent genetic testing (out-of-pocket). A pathogenic variant was found at the same site. During annual breast and ovarian surveillance at the patient's own expense, a physician with sufficient expertise in contrast-enhanced breast magnetic resonance imaging (MRI) noticed a change in the contrast enhancement pattern on breast MRI and performed needle biopsy, revealing ductal carcinoma in situ. At the request of the patient, she underwent concurrent contralateral risk-reducing mastectomy and risk-reducing salpingo-oophorectomy in addition to breast cancer treatment. We encountered a case in which cancer treatment and risk-reducing surgery were performed at the same time for a pathogenic variant carrier who was very anxious about developing cancer. Surveillance of cancer-free BRCA1/2 mutation carriers and expansion of insurance coverage for surgery are important future issues.

Diagnostic Outcomes of Concurrent DNA and RNA Sequencing in Individuals Undergoing Hereditary Cancer Testing

Personalized surveillance, prophylaxis, and cancer treatment options for individuals with hereditary cancer predisposition are informed by results of germline genetic testing. Improvements to genomic technology, such as the availability of RNA sequencing, may increase identification of individuals eligible for personalized interventions by improving the accuracy and yield of germline testing. To assess the cumulative association of paired DNA and RNA testing with detection of disease-causing germline genetic variants and resolution of variants of uncertain significance (VUS). Paired DNA and RNA sequencing was performed on individuals undergoing germline testing for hereditary cancer indication at a single diagnostic laboratory from March 2019 through April 2020. Demographic characteristics, clinical data, and test results were curated as samples were received, and changes to variant classification were assessed over time. Data analysis was performed from May 2020 to June 2023. Main outcomes were increase in diagnostic yield, decrease in VUS rate, the overall results by variant type, the association of RNA evidence with variant classification, and the corresponding predicted effect on cancer risk management. A total of 43 524 individuals were included (median [range] age at testing, 54 [2-101] years; 37 373 female individuals [85.7%], 6224 male individuals [14.3%], and 2 individuals of unknown sex [<0.1%]), with 43 599 tests. A total of 2197 (5.0%) were Ashkenazi Jewish, 1539 (3.5%) were Asian, 3077 (7.1%) were Black, 2437 (5.6%) were Hispanic, 27 793 (63.7%) were White, and 2049 (4.7%) were other race, and for 4507 individuals (10.3%), race and ethnicity were unknown. Variant classification was impacted in 549 individuals (1.3%). Medically significant upgrades were made in 97 individuals, including 70 individuals who had a variant reclassified from VUS to pathogenic/likely pathogenic (P/LP) and 27 individuals who had a novel deep intronic P/LP variant that would not have been detected using DNA sequencing alone. A total of 93 of 545 P/LP splicing variants (17.1%) were dependent on RNA evidence for classification, and 312 of 439 existing splicing VUS (71.1%) were resolved by RNA evidence. Notably, the increase in positive rate (3.1%) and decrease in VUS rate (-3.9%) was higher in Asian, Black, and Hispanic individuals combined compared to White individuals (1.6%; P = .02; and -2.5%; P < .001). Findings of this diagnostic study demonstrate that the ability to perform RNA sequencing concurrently with DNA sequencing represents an important advancement in germline genetic testing by improving detection of novel variants and classification of existing variants. This expands the identification of individuals with hereditary cancer predisposition and increases opportunities for personalization of therapeutics and surveillance.

24P Germline genetic testing for hereditary cancer: A retrospective analysis in a single site referral centre in Malaysia

24P Germline genetic testing for hereditary cancer: A retrospective analysis in a single site referral centre in Malaysia

Experiences of Family Communication and Cascade Genetic Testing for Hereditary Cancer in Medically Underserved Populations-A Qualitative Study.

This study of intrafamilial communication and cascade genetic testing experiences of patients with hereditary cancer and their relatives from diverse, medically underserved populations identified relatives' perceived susceptibility to hereditary cancer risks, distress, and fear as frequent reactions and barriers to testing. These results may inform future hereditary cancer prevention efforts.

Hereditary cancer testing in a diverse sample across three breast imaging centers

PurposeUp to 10% of all breast cancers (BC) are attributed to inherited pathogenic variants (PV) in BC susceptibility genes; however, most carriers of PVs remain unidentified. Here, we sought to determine the yield of hereditary cancer gene PVs among diverse women attending breast imaging centers, who could benefit from enhanced surveillance and/or risk reduction interventions.MethodsThis cross-sectional retrospective cohort study included consecutive women, unselected for personal or family cancer history, who were offered genetic testing for hereditary cancer genes at the time of breast imaging at three centers (November 2020–March 2022).ResultsAmong 1943 patients (median age: 66 years), self-reported race/ethnicity was White (34.5%), Hispanic (27.7%), African American (17.9%), Asian (4.5%), Ashkenazi Jewish (0.6%), Other (3.5%), and missing (13.0%). Thirty-nine patients (2%) were identified as carriers of a PV in an autosomal dominant clinically actionable hereditary breast and ovarian cancer (HBOC)-related or Lynch syndrome gene, most frequently, BRCA2 (6/39; 15.4%), PALB2 (8/39; 20.5%), CHEK2 (10/39; 25.6%), and PMS2 (5/39; 12.8%). Of the 34 PVs with known race/ethnicity, 47% were detected among non-White patients. Overall, 354/1,943 (18.2%) of patients met NCCN guidelines for HBOC gene testing and only 15/39 (38.5%) patients with an autosomal dominant clinically actionable PV met guidelines.ConclusionThis population health approach extended the reach of genetic cancer risk assessment in a diverse population and highlighted the limits of a guideline-based approach. This may help address inequity in access to risk-appropriate screening and cancer prevention.

Cascade testing for hereditary cancer: comprehensive multigene panels identify unexpected actionable findings in relatives.

Current guidelines recommend single variant testing in relatives of patients with known pathogenic or likely pathogenic germline variants in cancer predisposition genes. This approach may preclude the use of risk-reducing strategies in family members who have pathogenic or likely pathogenic germline variants in other cancer predisposition genes. Cascade testing using multigene panels was performed in 3696 relatives of 7433 probands. Unexpected pathogenic or likely pathogenic germline variants were identified in 230 (6.2%) relatives, including 144 who were negative for the familial pathogenic or likely pathogenic variant but positive for a pathogenic or likely pathogenic variant in a different gene than the proband and 74 who tested positive for the familial pathogenic or likely pathogenic variant and had an additional pathogenic or likely pathogenic variant in a different gene than the proband. Of the relatives with unexpected pathogenic or likely pathogenic germline variants, 36.3% would have qualified for different or additional cancer screening recommendations. Limiting cascade testing to only the familial pathogenic or likely pathogenic variant would have resulted in missed, actionable findings for a subset of relatives.

A mixed methods analysis of patient- and provider-perceived barriers and facilitators to cascade genetic testing for hereditary breast, ovarian, endometrial and colorectal cancer (2153)

A mixed methods analysis of patient- and provider-perceived barriers and facilitators to cascade genetic testing for hereditary breast, ovarian, endometrial and colorectal cancer (2153)

A Community Health Worker Model to Support Hereditary Cancer Risk Assessment and Genetic Testing.

To evaluate the effects of a community health worker-supported hereditary cancer risk-assessment and genetic testing program in a safety-net hospital serving more than 70% medically underserved patients. This community health worker pilot program began in January 2020 at women's health clinics by administering original National Comprehensive Cancer Network (NCCN)-based questionnaires. Patients meeting high-risk criteria were offered video-based genetic education and testing, notified of results using telehealth, and offered indicated counseling. We compared the rate of genetic counseling and testing in the first 18 months of the pilot program with that in the prior 18 months. In the first 18 months of the pilot program, 940 patients were screened through the community health worker program: 196 were identified as high-risk, 103 patients were tested, and pathogenic variants were identified in 10 (9.7%), two of whom had a personal cancer history. In addition, 73 patients were tested per usual practice by a certified genetic counselor: pathogenic variants were identified in 16 (21.9%), 11 (68.8%) of whom had a personal cancer history. In the 18 months before the program, 68 patients underwent genetic testing with a certified genetic counselor, pathogenic variants were identified in 16 (23.5%), 13 (81.3%) of whom had a personal cancer history. The community health worker program led to a significant increase in testing among unaffected patients based on family history alone (odds ratio [OR] 7.0; 95% CI 3.7-13.2; P <.001), paralleled by a respective significant increase in the identification of pathogenic variants (OR 4.33; 95% CI 1.0-18.9; P =.051). This pilot program demonstrates the feasibility of a community health worker-supported program, using self-administered questionnaires and telehealth-based genetic services in a primarily medically underserved population. This program improved the detection of unaffected high-risk patients based on family history, increasing the volume of tests performed for this indication. Programs of this type may improve family history-based hereditary cancer testing in medically underserved patients, further enabling cancer-prevention strategies.