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Background: This study evaluated a new mainstream genetic testing pathway for hereditary cancer, with expanded eligibility for early-stage breast cancer patients., Methods: The study compared multigene panel (62 genes) germline testing uptake and results for breast cancer patients at 4 pilot sites (n = 502 patients) and 10 non-pilot sites (n = 1792 patients) within Kaiser Permanente Northern California from December 2020, to June 2021. At the pilot sites, breast care coordinators (BCCs) offered and consented patients for testing, with eligibility expanded to include all patients age 65 years or younger. At the non-pilot sites, eligible patients were referred to genetics for pre-test counseling, ordering, and follow-up evaluation with the standard guideline that included all patients age 45 years or younger., Results: Demographic and disease characteristics were similar at the pilot and non-pilot sites. At the pilot verses non-pilot sites, a higher percentage of patients was tested overall (61.6% vs 31.7%) and across all age groups. The median time from breast biopsy to test result also was reduced (22 vs 33 days, respectively). A higher percentage of patients at the pilot sites was identified as having a pathogenic/likely pathogenic variant (PV/LPV) in a breast cancer-related gene (3.6% vs 1.6%). Although the percentage of total patients tested was nearly twofold higher at the pilot sites than at the non-pilot sites, the percentage of total patients seen by genetics was estimated to be similar (33.7% vs 31.7%)., Conclusion: Mainstream genetic testing of breast cancer patients facilitated by BCCs makes it feasible for a large health care system to expand germline genetic testing to early breast cancer patients age 65 years or younger., Competing Interests: Disclosure: There are no conflicts of interest., (© 2024. The Author(s).)

Competing Interests: Disclosures: None

Purpose: We compared approaches to recruitment of diverse women with breast cancer in a study designed to collect complex social network data., Methods: We recruited 440 women from the Kaiser Permanente Northern California population newly diagnosed with breast cancer, either in person at a clinic, by email, or by mailed letter. In clinic and mail recruitment, women completed a brief 3-page paper survey (epidemiologic data only), and women had the option to complete a separate, longer (30-40 min) personal social network survey online. In email recruitment, we administered epidemiologic and personal social network measures together in a single online survey. In email and mail recruitment, we limited the sample of non-Hispanic white (NHW) women to 30% of their total. We used descriptive analysis and multinomial logistic regression to examine odds of recruitment vs. mailed letter., Results: Women responded to the social network surveys on average 3.7 months post-diagnosis. Mean age was 59.3 (median = 61.0). In-person clinic recruitment was superior with a 52.1% success rate of recruitment compared with 35.6% by mail or 17.3% by email (χ 2  = 65.9, p < 0.001). Email recruitment produced the highest completion rate (82.1%) of personal network data compared with clinic (36.5%) or mail (28.7%), (χ 2  = 114.6, p < 0.001). Despite intentional undersampling of NHW patients, response rates for Asian, Hispanic, and Black women by email were lower. However, we found no significant differences in recruitment rates by race and ethnicity for face-to-face clinic recruitment vs. by letter. Letter recruitment produced the highest overall response., Conclusion: Mailed letter was the best approach to representative recruitment of diverse women with breast cancer and collection of social network data, and further yielded the highest absolute response., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: We aimed to define the clinical and variant spectrum and to provide novel molecular insights into the DHX30-associated neurodevelopmental disorder., Methods: Clinical and genetic data from affected individuals were collected through Facebook-based family support group, GeneMatcher, and our network of collaborators. We investigated the impact of novel missense variants with respect to ATPase and helicase activity, stress granule (SG) formation, global translation, and their effect on embryonic development in zebrafish. SG formation was additionally analyzed in CRISPR/Cas9-mediated DHX30-deficient HEK293T and zebrafish models, along with in vivo behavioral assays., Results: We identified 25 previously unreported individuals, ten of whom carry novel variants, two of which are recurrent, and provide evidence of gonadal mosaicism in one family. All 19 individuals harboring heterozygous missense variants within helicase core motifs (HCMs) have global developmental delay, intellectual disability, severe speech impairment, and gait abnormalities. These variants impair the ATPase and helicase activity of DHX30, trigger SG formation, interfere with global translation, and cause developmental defects in a zebrafish model. Notably, 4 individuals harboring heterozygous variants resulting either in haploinsufficiency or truncated proteins presented with a milder clinical course, similar to an individual harboring a de novo mosaic HCM missense variant. Functionally, we established DHX30 as an ATP-dependent RNA helicase and as an evolutionary conserved factor in SG assembly. Based on the clinical course, the variant location, and type we establish two distinct clinical subtypes. DHX30 loss-of-function variants cause a milder phenotype whereas a severe phenotype is caused by HCM missense variants that, in addition to the loss of ATPase and helicase activity, lead to a detrimental gain-of-function with respect to SG formation. Behavioral characterization of dhx30-deficient zebrafish revealed altered sleep-wake activity and social interaction, partially resembling the human phenotype., Conclusions: Our study highlights the usefulness of social media to define novel Mendelian disorders and exemplifies how functional analyses accompanied by clinical and genetic findings can define clinically distinct subtypes for ultra-rare disorders. Such approaches require close interdisciplinary collaboration between families/legal representatives of the affected individuals, clinicians, molecular genetics diagnostic laboratories, and research laboratories.

Background: Familial hypercholesterolemia (FH) is an autosomal dominant genetic disorder that causes markedly elevated risk for early onset coronary artery disease. Despite availability of effective therapy, only 5-10% of affected individuals worldwide are diagnosed., Objective: To develop and evaluate a novel approach for identifying and managing patients with FH in a large integrated health system with a diverse patient population, using inexpensive methods., Methods: Using Make Early Diagnosis/Prevent Early Death (MEDPED) criteria, we created a method for identifying patients at high risk for FH within the Kaiser Permanente Northern California electronic medical record. This led to a pragmatic workflow for contacting patients, establishing a diagnosis in a dedicated FH clinic, and initiating management. We prospectively collected data on the first 100 patients to assess implementation effectiveness., Results: Ninety-three (93.0%, 95%CI: 86.1%-97.1%) of the first 100 evaluated patients were diagnosed with FH (median age = 38 years) of whom only 5% were previously recognized; 48% were taking no lipid-lowering therapy, and 7% had acute coronary symptoms. 82 underwent successful genetic testing of whom 55 (67.1%; 95%CI: 55.8%-77.1%) had a pathogenic mutation. Following clinic evaluation, 83 of 85 (97.6%) medication-eligible patients were prescribed combination lipid-lowering therapy. 20 family members in the healthcare system were diagnosed with FH through cascade testing., Conclusions: This novel approach was effective for identifying and managing patients with undiagnosed FH. Care gaps in providing appropriate lipid-lowering therapy were successfully addressed. Further development and dissemination of integrated approaches to FH care are warranted., (Copyright © 2021 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Purpose: In 2016, Kaiser Permanente Northern California began regionalizing testicular cancer care using population-based tumor board review. This mixed methods evaluation describes implementation outcomes and learnings., Methods: We conducted in-depth interviews with key stakeholders, administered surveys to local oncologists and urologists, and used clinical data to evaluate changes in care delivery during 2015-2018., Results: An average of 135 patients with testicular cancer were diagnosed each year. Interviews with 16 key stakeholders provided several insights. Implementation resulted in high levels of satisfaction, was dependent on leadership and staff at various levels, and required technology and consulting solutions aligned to user agreements and clinical workflows. Of 123 local oncologists and urologists who completed surveys, 97% understood why care was regionalized and 89% agreed that tumor board review improved treatment decisions. Among 177 patients with stage I seminoma, the percentage appropriately observed rather than treated with adjuvant chemotherapy or radiation therapy increased from 48% (95% CI, 35 to 62) in 2015 to 87% (75 to 99) in 2018. Review altered care based on pathology and radiology re-review in 14.5 % of cases., Conclusion: Regionalization was feasible and effective.

Purpose: Half of US states mandate women be notified if they have dense breasts on their mammogram, yet guidelines and data on supplemental screening modalities are limited. Breast density (BD) refers to the extent that breast tissue appears radiographically dense on mammograms. High BD reduces the sensitivity of screening mammography and increases breast cancer risk. The aim of this study was to determine the potential impact of California's 2013 BD notification legislation on breast cancer screening patterns., Methods: We conducted a cohort study of women aged 40 to 74 years who were members of a large Northern California integrated health plan (approximately 3.9 million members) in 2011-2015. We calculated pre- and post-legislation rates of screening mammography and magnetic resonance imaging (MRI). We also examined whether women with dense breasts (defined as BI-RADS density c or d) had higher MRI rates than women with nondense breasts (defined as BI-RADS density a or b)., Results: After adjustment for race/ethnicity, age, body mass index, medical facility, neighborhood median income, and cancer history, there was a relative 6.6% decrease (relative risk [RR] 0.934, confidence interval [CI] 0.92-0.95) in the rate of screening mammography, largely driven by a decrease among women <50 years. While infrequent, there was a relative 16% increase (RR 1.16, CI 1.07-1.25) in the rate of screening MRI, with the greatest increase among the youngest women. In the postlegislation period, women with extremely dense breasts (BI-RADS d) had 2.77 times (CI 1.93-3.95) the odds of a MRI within 9 months of a screening mammogram compared with women with nondense breasts (BI-RADS b)., Conclusions: In this setting, MRI rates increased in the postlegislation period. In addition, women with higher BD were more likely to have supplementary MRI. The decrease in mammography rates seen primarily among younger women may have been due to changes in national screening guidelines.