Comparison of risk management strategies between women testing positive for a BRCA variant of unknown significance and women with known BRCA deleterious mutations

PurposeThe aim of this article is to describe cancer risk–reducing behaviors of women with BRCA variants of unknown significance.MethodsA retrospective chart review from 1995 to 2012 identified women with BRCA mutations in a northern California community system. Exclusion criteria included loss of membership/death within 1 year of testing, prior ovarian cancer, or bilateral salpingo-oophorectomy. Primary outcomes were rate of risk-reducing mastectomy and risk-reducing salpingo-oophorectomy.ResultsThe mean age of the 69 variant of unknown significance carriers was 50 vs. 47 years for the 305 women with a deleterious mutation. Women with a variant of unknown significance were followed for a median of 69 months. Among women with a variant of unknown significance, 30% underwent risk-reducing salpingo-oophorectomy and 11% underwent risk-reducing mastectomy, as compared with 74 and 44%, respectively, for women with a deleterious mutation. Women with a deleterious mutation were more likely to undergo surveillance in the first year after testing. The odds ratios are as follows: 2.1 for mammogram, 6.0 for magnetic resonance imaging, 7.7 for Ca-125, and 5.0 for transvaginal ultrasound. Fifty-six percent of women with a variant of unknown significance were reclassified after a median of 39 months, longer than the median time to risk-reducing salpingo-oophorectomy (18.6 months) or risk-reducing mastectomy (20.1 months).ConclusionUptake of risk-reducing strategies among women with a variant of unknown significance is lower than among women with a deleterious mutation. Given the prognostic uncertainty and high rate of reclassification for women with a variant of unknown significance, individualizing counseling and directing efforts toward surveillance, chemoprevention, or salpingectomy are recommended.Genet Med16 12, 896–902.     

Are There Regional Differences in Triple Negative Breast Cancer among Non-Hispanic Black Women?

BackgroundNon-Hispanic black women (NHB) are diagnosed with triple negative breast cancer (TNBC) more often than other ethnic or racial groups in the United States (US). This study describes regional differences in TNBC incidence among NHB women in the US from 2011 to 2015.MethodsWe analyzed data from the United States Cancer Statistics (USCS) that includes incidence data from the Centers for Disease Control and Prevention's National Program of Cancer Registries (NPCR) and the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) programs.ResultsCompared to the incidence rate for NHB women in the South, rates were significantly lower in the Northeast (22.6 per 100,000), higher in the Midwest (25.5 per 100,000) and similar in the West. These regional differences might be explained by genetic admixture among people with different geographic ancestral origins.ConclusionsResults from this study highlight the need to extend etiological research and evidence-based cancer prevention and control efforts to women at high risk of this disease in order to decrease cancer disparities.     

Survival difference between non-Hispanic black and non-Hispanic white women with localized breast cancer: the impact of guideline-concordant therapy

OBJECTIVES: This study examined the impact of guideline-concordant therapy on the survival difference between non-Hispanic black (NHB) and non-Hispanic white (NHW) women with localized breast cancer. METHODS: Data analyzed were from the CDC's NPCR Patterns of Care study in which seven population-based state cancer registries participated. We randomly selected 2,362 women who were diagnosed with a first primary localized breast cancer in 1997. Data were abstracted from hospital records, supplemented by information from physician offices and by linkages with state vital records and the National Death Index database. RESULTS: NHB women were more likely than NHW women to receive breast conserving surgery without radiation therapy. In addition, the percentage of NHB women with hormone receptor-positive tumors who received hormonal therapy was lower than that of NHW women. Among those with a tumor size > 3 cm, NHB women were more likely than NHW women to receive multiagent chemotherapy. After controlling for age, the risk of dying from all causes of death was 2.35 times as high for NHB women compared to NHW women. Controlling for treatment further reduced black-white difference in survival with adjustment for sociodemographic and clinical variables. CONCLUSION: NHB women were less likely than NHW women to receive guideline-concordant radiation therapy after breast conserving therapy and hormonal therapy but were more likely to receive chemotherapy. Racial differences in treatment contribute significantly to the worse survival of NHB women compared with NHW women.     

Utilization of multigene panels in hereditary cancer predisposition testing: analysis of more than 2,000 patients

PurposeThe aim of this study was to determine the clinical and molecular characteristics of 2,079 patients who underwent hereditary cancer multigene panel testing.MethodsPanels included comprehensive analysis of 14–22 cancer susceptibility genes (BRCA1 and BRCA2 not included), depending on the panel ordered (BreastNext, OvaNext, ColoNext, or CancerNext). Next-generation sequencing and deletion/duplication analyses were performed for all genes except EPCAM (deletion/duplication analysis only). Clinical histories of ColoNext patients harboring mutations in genes with well-established diagnostic criteria were assessed to determine whether diagnostic/testing criteria were met.ResultsPositive rates were defined as the proportion of patients with a pathogenic mutation/likely pathogenic variant(s) and were as follows: 7.4% for BreastNext, 7.2% for OvaNext, 9.2% for ColoNext, and 9.6% for CancerNext. Inconclusive results were found in 19.8% of BreastNext, 25.6% of OvaNext, 15.1% of ColoNext, and 23.5% of CancerNext tests. Based on information submitted by clinicians, 30% of ColoNext patients with mutations in genes with well-established diagnostic criteria did not meet corresponding criteria.ConclusionOur data point to an important role for targeted multigene panels in diagnosing hereditary cancer predisposition, particularly for patients with clinical histories spanning several possible diagnoses and for patients with suspicious clinical histories not meeting diagnostic criteria for a specific hereditary cancer syndrome.     

Awareness and use of genetic testing: An analysis of the Health Information National Trends Survey 2020

PurposeGenetic testing is a tool used in a variety of settings for medical and nonhealth related purposes. The goal of this analysis was to better understand the awareness and use of genetic testing in the United States.MethodsData from the 2020 Health Information National Trends Survey 5 cycle 4 were used to assess the awareness and use of genetic testing by demographic characteristics, personal cancer history, and family cancer history.ResultsOverall, 75% of participants were aware of genetic testing and 19% of participants had genetic testing. Ancestry testing was the most common type of testing that the participants were aware of and had received. Non-Hispanic Asian, Non-Hispanic Black, and Hispanic respondents and participants with incomes less than $20,000 were less likely to be aware of and have received any type of genetic testing than the Non-Hispanic White participants and participants with higher income, respectively. Participants with a family history of cancer were more likely to be aware of cancer genetic testing than those without, and participants with a personal history of cancer were more likely to have had cancer genetic testing.ConclusionIt appears awareness of genetic testing is increasing in the United States, and differences in awareness persist by race/ethnicity and income.     

Follow-up of carriers of BRCA1 and BRCA2 variants of unknown significance: Variant reclassification and surgical decisions

PurposeApproximately 5–10% of patients who undergo genetic testing of BRCA1 and BRCA2 receive a variant of unknown significance (VUS) result. The ambiguous nature of a VUS may increase difficulty in patient understanding and decision making regarding risk reduction and surveillance options, including cancer risk-reducing surgeries. VUS reclassification to benign or deleterious may occur in time; however, clinical decisions may need to be made expeditiously, and some patients may pursue irreversible treatments before VUS reclassification.MethodsWe reviewed the surgical decisions of 107 women postdisclosure of a BRCA VUS result counseled at our institute between 1998 and 2009.ConclusionAmong women receiving a BRCA VUS result at our center, 11 of 107 (10.3%) pursued cancer risk-reducing mastectomy and 22 of 107 (20.6%) pursued cancer risk-reducing bilateral salpingo-oophorectomy. Reclassification of VUS occurred up to 9 years after testing, and 5 of 22 (22.7%) women followed up for 8 or more years continue to have a VUS result. We discuss considerations for providers of genetic services to discuss with patients who receive a VUS result.     

A clinical guide to hereditary cancer panel testing: evaluation of gene-specific cancer associations and sensitivity of genetic testing criteria in a cohort of 165,000 high-risk patients

PurposeDespite the rapid uptake of multigene panel testing (MGPT) for hereditary cancer predisposition, there is limited guidance surrounding indications for testing and genes to include.MethodsTo inform the clinical approach to hereditary cancer MGPT, we comprehensively evaluated 32 cancer predisposition genes by assessing phenotype-specific pathogenic variant (PV) frequencies, cancer risk associations, and performance of genetic testing criteria in a cohort of 165,000 patients referred for MGPT.ResultsWe identified extensive genetic heterogeneity surrounding predisposition to cancer types commonly referred for germline testing (breast, ovarian, colorectal, uterine/endometrial, pancreatic, and melanoma). PV frequencies were highest among patients with ovarian cancer (13.8%) and lowest among patients with melanoma (8.1%). Fewer than half of PVs identified in patients meeting testing criteria for only BRCA1/2 or only Lynch syndrome occurred in the respective genes (33.1% and 46.2%). In addition, 5.8% of patients with PVs in BRCA1/2 and 26.9% of patients with PVs in Lynch syndrome genes did not meet respective testing criteria.ConclusionOpportunities to improve upon identification of patients at risk for hereditary cancer predisposition include revising BRCA1/2 and Lynch syndrome testing criteria to include additional clinically actionable genes with overlapping phenotypes and relaxing testing criteria for associated cancers.     

Informational needs of individuals from families harboring BRCA pathogenic variants: A systematic review and content analysis

PurposePersonalized information is paramount to patient-centered communication and decision-making regarding risk management in hereditary cancer syndromes. This systematic review identified information needs of individuals from families harboring BRCA pathogenic variants and compared findings based on gender (women vs men) and clinical characteristics (patients with cancer vs previvors and BRCA heterozygotes vs untested relatives).MethodsWe screened 8115 studies identified from databases and citation searching. The quality of selected studies was assessed using the Mixed Methods Appraisal Tool. Narrative synthesis was conducted based on content analysis.ResultsFrom 18 selected studies including 1063 individuals, we identified 9 categories of information needs. Risk of bias in the selected studies was moderate. Men, untested relatives, and racial and ethnic minorities were underrepresented. Frequently required information was personalized cancer risk and risk-reducing strategies, including decision-making, family implications of hereditary cancers, psychological issues, and cascade testing. Subgroup analyses showed that information needs depended on gender, personal cancer history, and cascade testing in relatives.ConclusionWe identified comprehensive and detailed informational needs of individuals from families harboring BRCA pathogenic variants and gaps in international guidelines. Needs for personalized information varied based on gender, health, and genetic testing status. Findings of this study have implications for genetic counseling, tailoring educational materials, and personalizing interventions.     

Implementing digital systems to facilitate genetic testing for hereditary cancer syndromes: An observational study of 4 clinical workflows

PurposeNational efforts have prioritized the identification of effective methods for increasing case ascertainment and delivery of evidence-based health care for individuals at elevated risk for hereditary cancers.MethodsThis study examined the uptake of genetic counseling and testing following the use of a digital cancer genetic risk assessment program implemented at 27 health care sites in 10 states using 1 of 4 clinical workflows: (1) traditional referral, (2) point-of-care scheduling, (3) point-of-care counseling/telegenetics, and (4) point-of-care testing.ResultsIn 2019, 102,542 patients were screened and 33,113 (32%) were identified as at high risk and meeting National Comprehensive Cancer Network genetic testing criteria for hereditary breast and ovarian cancer, Lynch syndrome, or both. Among those identified at high risk, 5147 (16%) proceeded with genetic testing. Genetic counseling uptake was 11% among the sites with workflows that included seeing a genetic counselor before testing, with 88% of patients proceeding with genetic testing after counseling. Uptake of genetic testing across sites varied significantly by clinical workflow (6% referral, 10% point-of-care scheduling, 14% point-of-care counseling/telegenetics, and 35% point-of-care testing, P < .0001).ConclusionStudy findings highlight the potential heterogeneity of effectiveness attributable to different care delivery approaches for implementing digital hereditary cancer risk screening programs.     

Improving mutation notification when new genetic information is identified in research: a trial of two strategies in familial breast cancer

PurposeThe Kathleen Cuningham Foundation Consortium for Research into Familial Aspects of Breast Cancer (kConFab) is a large-scale research study that notifies participants when new, personally relevant, information is discovered. In 2009, the (kConFab) instituted an intensive notification process to ensure at-risk individuals were effectively notified. This study (i) evaluated the impact of intensive notification on genetic testing uptake; (ii) identified those most likely to undergo testing postnotification; and (iii) identified those most likely to acknowledge that they had been notified.MethodsClinical/demographic data were retrieved from the (kConFab) database. Logistic regression analyses were conducted to identify potential predictors of testing uptake and notification acknowledgment using IBM SPSS.ResultsA total of 155 of 1,812 individuals underwent testing after standard notification (8.6%). In comparison, 23/291 individuals (7.9%) notified using the “intensive” approach underwent testing (χ² = 0.14; P = 0.71). After controlling for notification process, females and participants with a previous cancer were most likely to have undergone testing (P < 0.006). Older individuals (50+ years) were most likely to acknowledge they had been notified (P = 0.038).ConclusionIncreasing the intensity of participant follow-up did not increase genetic testing uptake. The challenge to effectively notify participants, and increase the proportion whose risk is managed clinically, remains, particularly for males and individuals unaffected by cancer.Genet Med 2013:15(3):187–194     

Eligibility criteria in private and public coverage policies for BRCA genetic testing and genetic counseling

PurposeCoverage policies for genetic services for hereditary cancers are of interest because the services influence cancer risk reduction for both persons with cancer and their family members. We compared coverage policies for BRCA genetic testing and genetic counseling among selected payers in the United States to illuminate eligibility criteria variation that may explain differential access by insurance type. We compared these policies with policies for breast cancer screening with magnetic resonance imaging to consider whether payers apply a unique policy approach to genetic services.MethodsWe conducted a case study of large private and public payers selected on number of covered lives. We examined coverage policies for BRCA genetic testing, genetic counseling, and screening with magnetic resonance imaging and the eligibility criteria for each. We compared eligibility criteria against National Comprehensive Cancer Network guidelines.ResultsEligibility criteria for BRCA testing were related to personal history and family history of cancer. Although private payers covered BRCA testing for persons with and without cancer, the local Medicare carrier in our study only covered testing for persons with cancer. In contrast, Arizona's Medicaid program did not cover BRCA testing. Few payers had detailed eligibility criteria for genetic counseling. Private payers have more detailed coverage policies for both genetic services and screening with magnetic resonance imaging in comparison with public payers.ConclusionDespite clinical guidelines establishing standards for BRCA testing, we found differences in coverage policies particularly between private and public payers. Future research and policy discussions can consider how differences in private and public payer policies influence access to genetic technologies and health outcomes.     

Population prevalence of familial cancer and common hereditary cancer syndromes. The 2005 California Health Interview Survey

PurposeFamily history guides cancer prevention and genetic testing. We sought to estimate the population prevalence of increased familial risk for breast, ovarian, endometrial, prostate, and colorectal cancers and hereditary cancer syndromes that include these cancers.MethodsUsing the 2005 California Health Interview Survey data, a weak, moderate, or strong familial cancer risk was assigned to 33,187 respondents. Guidelines were applied to identify individuals with hereditary breast-ovarian cancer and hereditary nonpolyposis colon cancer.ResultsAmong respondents without a personal history of cancer, familial breast cancer was most prevalent; 7% had a moderate and 5% a strong familial risk. Older individuals and women were more likely to report family history of cancer. Generally, whites had the highest prevalence, and Asians and Latinos had the lowest prevalence. Among women without a personal history of breast or ovarian cancer, 2.5% met criteria for hereditary breast-ovarian cancer, and among individuals without a personal history of colorectal, endometrial or ovarian cancer, 1.1% met criteria for hereditary nonpolyposis colon cancer.ConclusionsWe provide population-based prevalence estimates for moderate and strong familial risk for five common cancers and hereditary breast-ovarian cancer and hereditary nonpolyposis colon cancer. Such estimates are helpful in planning and evaluation of genetic services and prevention programs, and assessment of cancer surveillance and prevention strategies.     

Time to prophylactic surgery in BRCA1/2 carriers depends on psychological and other characteristics

PurposeTo investigate the medical and psychosocial factors determining the time to prophylactic surgery of unaffected women carriers of a deleterious BRCA1/2 mutation.MethodsProspective study on a French national cohort of unaffected BRCA1/2 carriers (N = 244); multivariate Cox proportional hazard modeling.ResultsMedian follow-up time was 2.33 years (range, 0.04–6.84 years). Time to surgery was shorter when the psychological impact of BRCA1/2 result disclosure was stated to be higher (P ≤ 0.01). Those who intended to opt for prophylactic surgery before being tested did so faster and more frequently after test disclosure than those who were undecided/opposed. The older the women were, the faster their uptake of risk-reducing salpingo-oophorectomy (adjusted hazard ratio >2.95; P < 0.001) was; the uptake of those with at least two children was also faster (adjusted hazard ratio = 2.51; [1.38–4.55]). Those who opted most quickly for risk-reducing mastectomy more frequently had a younger child at the time of testing (adjusted hazard ratio = 4.63 [1.56–13.74]). Time to surgery was shorter when there was a first-degree relative with ovarian/breast cancer (P ≤ 0.01).ConclusionTime to prophylactic surgery depends on the stated psychological impact of disclosure and on women's cognitive anticipation of surgery after adjusting on sociodemographic characteristics.     

An intervention strategy to improve genetic testing for dilated cardiomyopathy in a heart failure clinic

PurposeDespite its clinical implications in screening and therapy, genetic testing in dilated cardiomyopathy (DCM) is underused. This study evaluated implementing a practice intervention in a heart failure clinic to automate and streamline the process of genetic testing.MethodsEligible patients with DCM were compared for frequency of pretest genetic education and testing during pre- and postintervention periods. The intervention comprised automated prescheduling of a cardiovascular genomics e-consult that served as a placeholder for downstream, pretest education, testing, and post-test review of genetic results.ResultsPatients with DCM were more likely to undergo pretest genetic education after intervention than before intervention (33.5% vs 14.8%, P < .0001). Similarly, patients with DCM were more likely to undergo genetic testing after intervention than before intervention (27.3% vs 13.0%, P = .0006). The number of patients who were diagnosed to have likely pathogenic or pathogenic genetic variants were 2 of 21 (9.5%) and 6 of 53 (11.1%) before and after intervention, respectively, and variants were present in the following genes: FLNC, TTN, DES, LMNA, PLN, and TNNT2.ConclusionAn intervention strategy in a heart failure clinic to increase the rates of pretest genetic education and testing in eligible patients with DCM was feasible and efficacious and may have important implications for the management of DCM.     

Genotype–phenotype associations among panel-based TP53+ subjects

PurposePanel testing has led to the identification of TP53 pathogenic/likely pathogenic (P/LP) variant carriers (TP53+) who exhibit a broad range of phenotypes. We sought to evaluate and compare genotype–phenotype associations among TP53+ panel-ascertained subjects.MethodsBetween 2012 and 2017, 317 TP53+ subjects (279 females and 38 males) identified through panel testing at one testing laboratory were found to have evaluable clinical histories and molecular results. Subject cancer histories were obtained from test requisition forms. P/LP variants were categorized by type and were examined in relation to phenotype.ResultsLoss-of-function (LOF) variants were associated with the earliest age at first cancer, with a median age of 30.5 years (P = 0.014); increased frequency of a sarcoma diagnosis(P = 0.016); and more often meeting classic LFS testing and Chompret 2015 criteria (P = 0.004 and 0.002 respectively), as compared with dominant-negative missense, other missense, or miscellaneous (splice or in-frame deletion) P/LP variant categories.ConclusionLoss-of-function variants were more often associated with characteristic LFS cancer histories than other variant categories in TP53+ carriers ascertained through multigene panel testing. These findings require validation in other TP53+ cohorts. Genetic counseling for panel-ascertainedTP53+ individuals should reflect the dynamic expansion of the Li–Fraumeni syndrome phenotype.     

Impact of a printed decision aid on patients’ intention to undergo prostate cancer screening: a multicentre,pragmatic randomised controlled trial in primary care

BackgroundDespite recommendations against systematic screening for prostate cancer, 70% of patients still request prostate-specific antigen testing.AimTo assess the impact of a decision aid on patients’ intention to undergo prostate cancer screening.MethodMales aged 50–75 years were randomised to receive either the decision aid (intervention group) or usual care (control group). The primary outcome was the proportion of patients’ intending to undergo prostate cancer screening, assessed immediately after reading the decision aid. The reasons underlying their choice were elicited and the proportion of patients citing each reason to undergo, or not undergo, prostate cancer screening were compared between the two arms.ResultsA total of 1170 patients were randomised (588 in the intervention arm) from November 2012 to February 2013. The proportion of patients who intended to be tested for prostate cancer in the intervention arm (123 patients [20.9%]) was significantly reduced compared with the control arm (57 patients [9.8%]) (difference 11.1%, 95% confidence interval [CI] = 7.0 to 15.2, P<0.0001). In the intervention group, a lower proportion of individuals expressed that cancer screening would protect them from the disease, compared with the control group (P<0.0001), while a greater proportion of individuals stated that prostate cancer screening would not benefit their health (P<0.0001) and may involve procedures with harmful side effects (P = 0.0005).ConclusionThe decision aid improved participants’ informed decision making and reduced their intent to undergo prostate cancer screening.     

Cost-effectiveness of long-term clinical management of BRCA pathogenic variant carriers

PurposeWomen who inherit a BRCA1 or BRCA2 pathogenic variant are at high risk of developing breast and ovarian cancer. Evidence for the effectiveness and cost-effectiveness of long-term management in clinical practice is lacking. The purpose of this study was to evaluate the real-world cost-effectiveness of BRCA carrier management within a structured clinical program.MethodsLifetime health outcomes and costs of clinical management for female unaffected BRCA carriers aged 20 were measured using a microsimulation model. For the intervention, women could attend a high-risk clinic, undergo risk-reducing surgery, and receive annual breast screening. Input data for the model was from a clinical database of 983 BRCA carriers. The comparator was no risk management. Outcomes were discounted at 5%.ResultsThe incremental cost-effectiveness ratio for the program was $32,359 to $48,263 per quality-adjusted life-year (QALY). Limiting uptake of risk-reducing salpingo-oophorectomy to <50% of carriers decreased cost-effectiveness by $7000–8000 per QALY. Achieving perfect adherence to guidelines was less cost-effective for BRCA2 due to increased risk-reducing mastectomy costs with smaller incremental health benefit.ConclusionLong-term management of BRCA carriers within a structured clinical program is cost-effective. Suboptimal adherence to risk management guidelines can substantially affect outcomes and is an important consideration for future studies.