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Background Genetic testing has become more complex with the transition from single gene testing to multi-gene panels and whole-exome sequencing. The adoption of more complex genetic testing and the promise of precision medicine has created a critical and urgent need for longitudinal clinical follow-up with patients who undergo cancer genetic testing given the residual uncertainty. There is an increasing need for multidisciplinary translational research that focuses on how to advance precision medicine discoveries into clinical practice and to capitalize on connectivity (e.g. digital health) interventions in ways that optimize cancer risk reducing behaviors in real-world clinical populations. Methods The overall goal of this Hybrid Type 1 effectiveness-implementation randomized study is to evaluate the effectiveness of the MyCancerGene intervention to improve longitudinal (short-term and long-term) understanding (e.g. knowledge) and reactions to (e.g. anxiety) clinical genetic testing compared to usual care. We hypothesize that access to MyCancerGene will be associated with short-term and post-disclosure increases in knowledge, decreases in distress, increases in communication with relatives and health care providers and performance of risk reducing health behaviors compared to usual care. Equally important, we hypothesize that our implementation process evaluation will inform recommendations for future adaptation and sustainability for other precision medicine applications. Discussion Given the increasing complexity of genetic testing applications (e.g. multi-gene testing, whole exome sequencing) and the need for post-disclosure follow-up, we expect this study to inform evidence-based practice guidelines for delivery of genetic medicine and potentially change the paradigm to include longitudinal care in precision medicine. To address the clinically significant gap in the delivery of genetic medicine, patient and provider stakeholder input have been used to develop a patient and provider informed centered genetic digital health portal to enhance patient understanding of, and affective and behavioral responses to genetic testing, particularly in the era of evolving evidence and risk information. Trial registration This protocol was registered at clinicaltrials.gov (NCT04774445) in February 18, 2021.

Background Background parenchymal enhancement (BPE) on breast magnetic resonance imaging (MRI) may be associated with breast cancer risk, but previous studies of the association are equivocal and limited by incomplete blinding of BPE assessment. In this study, we evaluated the association between BPE and breast cancer based on fully blinded assessments of BPE in the unaffected breast. Methods The Imaging and Epidemiology (IMAGINE) study is a multicenter breast cancer case-control study of women receiving diagnostic, screening, or follow-up breast MRI, recruited from three comprehensive cancer centers in the USA. Cases had a first diagnosis of unilateral breast cancer and controls had no history of or current breast cancer. A single board-certified breast radiologist with 12 years’ experience, blinded to case-control status and clinical information, assessed the unaffected breast for BPE without view of the affected breast of cases (or the corresponding breast laterality of controls). The association between BPE and breast cancer was estimated by multivariable logistic regression separately for premenopausal and postmenopausal women. Results The analytic dataset included 835 cases and 963 controls. Adjusting for fibroglandular tissue (breast density), age, race/ethnicity, BMI, parity, family history of breast cancer, BRCA1 / BRCA2 mutations, and other confounders, moderate/marked BPE (vs minimal/mild BPE) was associated with breast cancer among premenopausal women [odds ratio (OR) 1.49, 95% CI 1.05–2.11; p  = 0.02]. Among postmenopausal women, mild/moderate/marked vs minimal BPE had a similar, but statistically non-significant, association with breast cancer (OR 1.45, 95% CI 0.92–2.27; p  = 0.1). Conclusions BPE is associated with breast cancer in premenopausal women, and possibly postmenopausal women, after adjustment for breast density and confounders. Our results suggest that BPE should be evaluated alongside breast density for inclusion in models predicting breast cancer risk.

Background Germline cancer genetic testing has become a standard evidence-based practice, with established risk reduction and screening guidelines for genetic carriers. Access to genetic services is limited in many places, which leaves many genetic carriers unidentified and at risk for late diagnosis of cancers and poor outcomes. This poses a problem for childhood cancer survivors, as this is a population with an increased risk for subsequent malignant neoplasms (SMN) due to cancer therapy or inherited cancer predisposition. The ENG aging and A ctivating cancer survivors in Ge netic services (ENGAGE) study evaluates the effectiveness of an in-home, collaborative PCP model of remote telegenetic services to increase uptake of cancer genetic testing in childhood cancer survivors compared to usual care options for genetic testing. Methods The ENGAGE study is a 3-arm randomized hybrid type 1 effectiveness and implementation study within the Childhood Cancer Survivor Study population which tests a clinical intervention while gathering information on its delivery during the effectiveness trial and its potential for future implementation among 360 participants. Participants are randomized into three arms. Those randomized to Arm A receive genetic services via videoconferencing, those in Arm B receive these services by phone, and those randomized to Arm C will receive usual care services. Discussion With many barriers to accessing genetic services, innovative delivery models are needed to address this gap and increase uptake of genetic services. The ENGAGE study evaluates the effectiveness of an adapted model of remote delivery of genetic services to increase the uptake of recommended genetic testing in childhood cancer survivors. This study assesses the uptake in remote genetic services and identify barriers to uptake to inform future recommendations and a theoretically-informed process evaluation which can inform modifications to enhance dissemination beyond this study population and to realize the benefits of precision medicine. Trial registration This protocol was registered at clinicaltrials.gov (NCT04455698) on July 2, 2020.

Background There is consensus that research participants should be informed about plans for return of genetic research results. However, best practices for return of results in large biobank and cohort studies do not exist currently, and how best to communicate actionable genetic research results remains unclear. While having genetic counselors disclose these results may be ideal to ensure understanding, minimize distress, and optimize medical follow-up, genetic counselor (GC) workforce shortages and costs are barriers. The RESPECT3 study evaluates whether digital delivery alternatives for pre-disclosure education and return of actionable genetic research results is non-inferior to remote telehealth disclosure by a genetic counselor. Methods The RESPECT3 Study is a hybrid type 1 effectiveness-implementation study which evaluates digital alternatives for pre-disclosure education and return of actionable research results in randomized non-inferiority trial. The return of results process in RESPECT3 uses a two-step process. In step one, participants with an actionable result and procedural controls (no actionable result) are invited to digital pre-disclosure education and provided options for opting out of results. In Step 2, those with actionable results who have not opted out are randomized to receive results via a digital disclosure intervention (digital-ROR) or with a GC. Participants include English-speaking adults who enrolled in the Penn Medicine BioBank (PMBB) and have an actionable research result according to the ACMG secondary findings list. The primary outcomes are non-inferiority of knowledge and disease specific distress (cancer and cardiovascular disease) after receipt of research results. Uptake of research results is a secondary non-inferiority outcome. Confirmatory clinical testing is covered by the study and all participants with confirmed results are referred to the appropriate clinical genetic program for clinical recommendations. Discussion The RESPECT3 study is expected to provide critical empiric data on the effectiveness of using digital alternatives for pre-disclosure education and return of genetic research results in a representative clinical population of research participants who enrolled in an institutional biobank where return of results was not the focus of the study. Equally important, our theoretically-informed process evaluation data is expected to inform modifications to identify barriers and facilitators to broader implementation. Trial registration NCT04242667.

INTRODUCTION Disclosing Alzheimer's disease (AD) genetic and biomarker information is becoming increasingly common but often resource‐intensive, requiring a clinician to return results. As results become relevant for clinical care and more people want to learn their results, scalable approaches to disclosure are needed. Here, we describe the design of a decentralized, randomized, non‐inferiority clinical trial (eSMARTER) to evaluate self‐directed scalable digital methods for returning APOE and plasma pTau‐217 results. METHODS Participants (n ≈ 600) aged 60–80 years are randomized to receive their apolipoprotein E (APOE) and pTau‐217 results via either a clinician‐mediated telehealth videoconference (usual care) or a self‐mediated eHealth platform. The primary hypothesis is that self‐mediated APOE disclosure will result in non‐inferior outcomes compared to clinician‐mediated disclosure. The three primary outcomes are changes in anxiety, AD‐related knowledge, and disease‐specific distress. For the three primary analyses, we will apply non‐inferiority tests to examine if self‐mediated disclosure provides equivalent or improved outcomes compared to usual care. Our secondary hypothesis is that learning APOE and pTau‐217 results will affect participants’ mood, self‐perception of disease risk, and quality of life. We hypothesize participants who learn results indicating more risk will report increased, but not clinically significant psychological distress and increased disease risk. We hypothesize there will not be changes in quality of life. We will examine change scores of the validated mood, self‐perception of disease risk, and quality of life measures from pre‐ to post‐disclosure. RESULTS Data collection is ongoing. Results will allow for non‐inferiority comparisons between clinician‐ and self‐mediated disclosure of APOE results and initial characterization of the impact of learning pTau‐217 results. DISCUSSION The eSMARTER Study represents an important step towards meeting expected increases in demand for learning AD genetic and biomarker information. The digital platforms developed for this study will be made available to support clinicians and investigators returning genetic and/or biomarker results. Highlights Novel, scalable design for self‐mediated disclosure of APOE and pTau‐217. Non‐inferiority trial examining self‐mediated versus clinician‐mediated disclosure. All materials, methods, data, and samples will be shared publicly.

Background Exome and genome sequencing are routinely used in clinical care and research. These technologies allow for the detection of pathogenic/likely pathogenic variants in clinically actionable genes. However, fueled in part by a lack of empirical evidence, controversy surrounds the provision of genetic results for adult-onset conditions to minors and their parents. We have designed a mixed-methods, longitudinal cohort study to collect empirical evidence to advance this debate. Methods Pediatric participants in the Geisinger MyCode® Community Health Initiative with available exome sequence data will have their variant files assessed for pathogenic/likely pathogenic variants in 60 genes designated as actionable by MyCode. Eight of these genes are associated with adult-onset conditions (Hereditary Breast and Ovarian Cancer Syndrome (HBOC), Lynch syndrome, MUTYH -associated polyposis, HFE- Associated Hereditary Hemochromatosis), while the remaining genes have pediatric onset. Prior to clinical confirmation of results, pediatric MyCode participants and their parents/legal guardians will be categorized into three study groups: 1) those with an apparent pathogenic/likely pathogenic variant in a gene associated with adult-onset disease, 2) those with an apparent pathogenic/likely pathogenic variant in a gene associated with pediatric-onset disease or with risk reduction interventions that begin in childhood, and 3) those with no apparent genomic result who are sex- and age-matched to Groups 1 and 2. Validated and published quantitative measures, semi-structured interviews, and a review of electronic health record data conducted over a 12-month period following disclosure of results will allow for comparison of psychosocial and behavioral outcomes among parents of minors (ages 0–17) and adolescents (ages 11–17) in each group. Discussion These data will provide guidance about the risks and benefits of informing minors and their family members about clinically actionable, adult-onset genetic conditions and, in turn, help to ensure these patients receive care that promotes physical and psychosocial health. Trial registration ClinicalTrials.gov Identifier: NCT03832985 . Registered 6 February 2019

The use of multigene panels has significantly increased the likelihood that genetic testing will leave patients with uncertainties regarding test interpretation, implications, and recommendations, which will change over time. Effective longitudinal care models are needed to provide patients with updated information and to obtain patient and family history updates. To bridge this gap, we aimed to develop a patient- and genetic provider-informed digital genetic health portal (GHP), MyCancerGene, to improve longitudinal patient understanding of and responses to genetic testing. We used a 5-step process to develop MyCancerGene. To better understand their interest in and willingness to use a digital GHP, we surveyed 307 patients who completed genetic testing (step 1). We completed qualitative interviews with 10 patients and a focus group with 17 genetic providers to inform the content and function of MyCancerGene (step 2). Next, we developed initial intervention content (step 3) and completed user testing of intervention content with 25 providers and 28 patients (step 4). After developing the prototype intervention, we completed usability testing with 8 patients for their feedback on the final content, functions, and ease of use (step 5). In surveys conducted in step 1, 90% of patients with positive results reported interest in a digital GHP, and over 75% of participants with variants of uncertain significance or uninformative negative results reported similar interest. The most frequently reported advantages among patients were increasing accessibility, convenience, and efficiency (103/224, 46%); keeping genetic information organized (54/224, 24.1%); and increasing or maintaining patient understanding of the information (38/224, 17%). In qualitative interviews (step 2), both patients and genetic providers endorsed the benefit of the tool for updating personal and family history and for providers to share new risk information, test interpretation, or other medical changes. Patient and provider input informed eight key components of the tool: (1) Landing Page, (2) Summary of Care page, (3) My Genetic Test Results page, (4) My Family History page, (5) Provide an Update page, (6) Review an Update page, (7) Resources page, and (8) the Screenings Tracker. They also recommended key functions, including the ability to download and print materials and the inclusion of reminders and engagement functions. Potential challenges identified by patients included privacy and security concerns (67/206, 32.5%) and the potential for electronic information to generate distress (20/206, 9.7%). While patients were comfortable with updates (ie, even variant reclassification upgrades or clinically significant results), 44% (11/25) of genetic providers were uncomfortable sharing variant reclassification upgrades through MyCancerGene. MyCancerGene, a patient-centered digital GHP, was developed with extensive patient and genetic provider feedback and designed to enhance longitudinal patient understanding of and affective and behavioral responses to genetic testing, particularly in the era of evolving evidence and risk information.

Background Pubertal milestones, such as onset of breast development and menstruation, play an important role in breast cancer etiology. It is unclear if these milestones are different in girls with a first- or second-degree breast cancer family history (BCFH). Methods In the LEGACY Girls Study ( n  = 1040), we examined whether three mother/guardian-reported pubertal milestones (having reached Tanner Stage 2 or higher (T2+) for breast and pubic hair development, and having started menstruation) differed by BCFH. We also examined whether associations between body size and race/ethnicity and pubertal milestones were modified by BCFH. We used mother/guardian reports as the primary measure of pubertal milestones, but also conducted sensitivity analyses using clinical Tanner measurements available for a subcohort ( n  = 204). We analyzed cross-sectional baseline data with logistic regression models for the entire cohort, and longitudinal data with Weibull survival models for the subcohort of girls that were aged 5–7 years at baseline ( n  = 258). Results BCFH was modestly, but not statistically significantly, associated with Breast T2+ (odds ratio (OR) = 1.36, 95% confidence interval (CI) = 0.88–2.10), with a stronger association seen in the subcohort of girls with clinical breast Tanner staging (OR = 2.20, 95% CI = 0.91–5.32). In a longitudinal analysis of girls who were aged 5–7 years at baseline, BCFH was associated with a 50% increased rate of having early breast development (hazard ratio (HR) = 1.49, 95% CI = 1.0–2.21). This association increased to twofold in girls who were not overweight at baseline (HR = 2.04, 95% CI = 1.29–3.21). BCFH was not associated with pubic hair development and post-menarche status. The median interval between onset of breast development and menarche was longer for BCFH+ than BCFH– girls (2.3 versus 1.7 years), suggesting a slower developmental tempo for BCFH+ girls. Associations between pubertal milestones and body size and race/ethnicity were similar in girls with or without a BCFH. For example, weight was positively associated with Breast T2+ in both girls with (OR = 1.06 per 1 kg, 95% CI = 1.03–1.10) and without (OR = 1.14 per 1 kg, 95% CI = 1.04–1.24) a BCFH. Conclusions These results suggest that BCFH may be related to earlier breast development and slower pubertal tempo independent of body size and race/ethnicity.

Germline BRCA1 and BRCA2 testing is a standard evidence-based practice, with established risk reduction and cancer screening guidelines for genetic carriers. With Food and Drug Administration approval for poly (adenosine diphosphate ribose) polymerase (PARP) inhibitors in patients with metastatic breast, ovarian, pancreatic, and prostate cancer, there is an additional therapeutic rationale for testing all patients with these cancers for germline BRCA1 and BRCA2 mutations. However, many at-risk patients do not have access to genetic services, leaving many genetic carriers unidentified. The eREACH (A Randomized Study of an eHealth Delivery Alternative for Cancer Genetic Testing for Hereditary Predisposition in Metastatic Breast, Ovarian, Prostate, and Pancreatic Cancer Patients) study evaluates the effectiveness of a theoretically and stakeholder-informed eHealth (eg, digital) delivery alternative to traditional genetic counseling for patients with metastatic breast or prostate cancer or advanced or metastatic ovarian or pancreatic cancer referred for genetic testing to determine whether they are candidates for a PARP inhibitor. The eREACH study is a randomized noninferiority study using a 2 × 2 design to test a self-directed digital intervention to deliver clinical genetic testing for patients with metastatic cancers. The traditional standard-of-care pretest (visit 1) and posttest (visit 2-disclosure) counseling delivered by a genetic counselor is replaced with our patient-informed digital intervention. The four arms were as follows: arm A, genetic counselor for visits 1 and 2; arm B, genetic counselor for visit 1 and digital intervention for visit 2; arm C, digital intervention for visit 1 and genetic counselor for visit 2; and arm D, digital intervention for both visits. Participants were adults with advanced or metastatic breast, ovarian, pancreatic, and prostate cancer. The primary outcomes of this study were change in genetic knowledge and anxiety from baseline to postdisclosure assessment. We will test whether the digital intervention is noninferior to standard-of-care counseling with a genetic counselor using a modified noninferiority ANOVA of the posttest disclosure minus baseline change scores. In secondary analyses, we will test pairwise differences among the 4 groups. As of January 2025, we have completed enrollment of 229 participants. Data analysis is ongoing, and we expect the results to be published in 2025. Increasing indications for BRCA1 and BRCA2 testing create a pressing need to evaluate alternative delivery models to increase access and uptake of these tests while maintaining adequate patient cognitive, affective, and behavioral outcomes. The eREACH study evaluates the effectiveness of an interactive, patient-centered digital intervention to deliver clinical genetic testing to patients with metastatic cancers. We expect that this work will inform evidence-based guidelines and the standard of care for delivery of genetic testing, and it is designed to be broadly applicable and easily adaptable for other populations and settings even beyond oncology. ClinicalTrials.gov NCT04353973; https://clinicaltrials.gov/study/NCT04353973. DERR1-10.2196/72515.

Background Younger age at onset of breast development, which has been declining in recent decades, is associated with increased breast cancer risk independent of age at menarche. Given the need to study the drivers of these trends, it is essential to validate methods to assess breast onset that can be used in large-scale studies when direct clinical assessment of breast onset is not feasible. Methods Breast development is usually measured by Tanner stages (TSs), assessed either by physical examination or by mother’s report using a picture-based Sexual Maturation Scale (SMS). As an alternative, a mother-reported Pubertal Development Scale (PDS) without pictures has been used in some studies. We compared agreement of SMS and PDS with each other ( n = 1022) and the accuracy of PDS with clinical TS as a gold standard for the subset of girls with this measure ( n = 282) using the LEGACY cohort. We further compared prediction of breast onset using ROC curves and tested whether adding urinary estrone 1-glucuronide (E1G) improved the AUC. Results The agreement of PDS with SMS was high (kappa = 0.80). The sensitivity of PDS vs clinical TS was 86.6%. The AUCs for PDS alone and SMS alone were 0.88 and 0.79, respectively. Including E1G concentrations improved the AUC for both methods (0.91 and 0.86 for PDS and SMS, respectively). Conclusions The PDS without pictures is a highly accurate, sensitive, and specific method for assessing breast onset, especially in settings where clinical TS is not feasible. In addition, it is comparable to SMS methods with pictures and thus easier to implement in large-scale studies, particularly phone-based interviews where pictures may not be available. Urinary E1G can improve accuracy over than PDS or SMS alone.