Universal Tumor DNA BRCA1/2 Testing of Ovarian Cancer: Prescreening PARPi Treatment and Genetic Predisposition.

BACKGROUND: Women with epithelial ovarian cancer (OC) have a higher chance to benefit from poly (ADP-ribose) polymerase inhibitor (PARPi) therapy if their tumor has a somatic or hereditary BRCA1/2 pathogenic variant. Current guidelines advise BRCA1/2 genetic predisposition testing for all OC patients, though this does not detect somatic variants. We assessed the feasibility of a workflow for universal tumor DNA BRCA1/2 testing of all newly diagnosed OC patients as a prescreen for PARPi treatment and cancer predisposition testing. METHODS: Formalin-fixed paraffin-embedded tissue was obtained from OC patients in seven hospitals immediately after diagnosis or primary surgery. DNA was extracted, and universal tumor BRCA1/2 testing was then performed in a single site. Diagnostic yield, uptake, referral rates for genetic predisposition testing, and experiences of patients and gynecologists were evaluated. RESULTS: Tumor BRCA1/2 testing was performed for 315 (77.6%) of the 406 eligible OC samples, of which 305 (96.8%) were successful. In 51 of these patients, pathogenic variants were detected (16.7%). Most patients (88.2%) went on to have a genetic predisposition test. BRCA1/2 pathogenic variants were shown to be hereditary in 56.8% and somatic in 43.2% of patients. Participating gynecologists and patients were overwhelmingly positive about the workflow. CONCLUSIONS: Universal tumor BRCA1/2 testing in all newly diagnosed OC patients is feasible, effective, and appreciated by patients and gynecologists. Because many variants cannot be detected in DNA from blood, testing tumor DNA as the first step can double the identification rate of patients who stand to benefit most from PARP inhibitors.

Surveillance of Women with the BRCA1 or BRCA2 Mutation by Using Biannual Automated Breast US, MR Imaging, and Mammography.

Purpose To evaluate a multimodal surveillance regimen including yearly full-field digital (FFD) mammography, dynamic contrast agent-enhanced (DCE) magnetic resonance (MR) imaging, and biannual automated breast (AB) ultrasonography (US) in women with BRCA1 and BRCA2 mutations. Materials and Methods This prospective multicenter trial enrolled 296 carriers of the BRCA mutation (153 BRCA1 and 128 BRCA2 carriers, and 15 women with first-degree untested relatives) between September 2010 and November 2012, with follow-up until November 2015. Participants underwent 2 years of intensified surveillance including biannual AB US, and routine yearly DCE MR imaging and FFD mammography. The surveillance performance for each modality and possible combinations were determined. Results Breast cancer was screening-detected in 16 women (age range, 33-58 years). Three interval cancers were detected by self-examination, all in carriers of the BRCA1 mutation under age 43 years. One cancer was detected in a carrier of the BRCA1 mutation with a palpable abnormality in the contralateral breast. One incidental breast cancer was detected in a prophylactic mastectomy specimen. Respectively, sensitivity of DCE MR imaging, FFD mammography, and AB US was 68.1% (14 of 21; 95% confidence interval [CI]: 42.9%, 85.8%), 37.2% (eight of 21; 95% CI: 19.8%, 58.7%), and 32.1% (seven of 21; 95% CI: 16.1%, 53.8%); specificity was 95.0% (643 of 682; 95% CI: 92.7%, 96.5%), 98.1% (638 of 652; 95% CI: 96.7%, 98.9%), and 95.1% (1030 of 1088; 95% CI: 93.5%, 96.3%); cancer detection rate was 2.0% (14 of 702), 1.2% (eight of 671), and 1.0% (seven of 711) per 100 women-years; and positive predictive value was 25.2% (14 of 54), 33.7% (nine of 23), and 9.5% (seven of 68). DCE MR imaging and FFD mammography combined yielded the highest sensitivity of 76.3% (16 of 21; 95% CI: 53.8%, 89.9%) and specificity of 93.6% (643 of 691; 95% CI: 91.3%, 95.3%). AB US did not depict additional cancers. FFD mammography yielded no additional cancers in women younger than 43 years, the mean age at diagnosis. In carriers of the BRCA2 mutation, sensitivity of FFD mammography with DCE MR imaging surveillance was 90.9% (10 of 11; 95% CI: 72.7%, 100%) and 60.0% (six of 10; 95% CI: 30.0%, 90.0%) in carriers of the BRCA1 mutation because of the high interval cancer rate in carriers of the BRCA1 mutation. Conclusion AB US may not be of added value to yearly FFD mammography and DCE MR imaging surveillance of carriers of the BRCA mutation. Study results suggest that carriers of the BRCA mutation younger than 40 years may not benefit from FFD mammography surveillance in addition to DCE MR imaging. © RSNA, 2017 Online supplemental material is available for this article.

Peer support and additional information in group medical consultations (GMCs) for BRCA1/2 mutation carriers: A randomized controlled trial.

BACKGROUND: Group medical consultations (GMCs) provide individual medical visits in the presence of ≤ 7 peer- patients. This study evaluated the efficacy of GMCs in the yearly breast cancer surveillance of BRCA mutation carriers. MATERIAL AND METHODS: This randomized controlled trial compared GMCs (intervention group, n = 63) with individual medical visits (control group, n = 59). Between-group differences on the primary outcomes distress and empowerment, were analyzed one week and three months after the visit. Feasibility is evaluated in terms of demand, acceptability and practicability. RESULTS: No between-group differences were found on primary outcomes. More themes were discussed in GMCs. Seventy-five percent of GMC-participants experienced peer support. Carriers reported significantly higher satisfaction with individual visits. GMCs were less time-efficient. CONCLUSION: This is the first GMC study which reports results in favor of individual visits. The hereditary nature of the condition differentiates our study population from earlier studied GMC groups. Even though most participants experienced peer support and received more information, the lower patient satisfaction may be explained by the lack of individual time with the clinician and disruption of normal surveillance routines. As the need for peer support and additional information is present in a substantial part of carriers, future research should study the process of peer support.

Effect of maternal and treatment-related factors on the prevalence of birth defects after PESA-ICSI and TESE-ICSI: a retrospective cohort study.

INTRODUCTION: We performed a retrospective cohort study with the aim to evaluate the effect of maternal and treatment-related factors on the prevalence of birth defects after intracytoplasmic sperm injection (ICSI) using percutaneous epididymal sperm aspiration (PESA) and testicular sperm extraction (TESE). MATERIAL AND METHODS: 643 newborns born after PESA-ICSI (n = 406) and TESE-ICSI (n = 237) in Radboud University Medical Center, after a gestational age of 12 weeks, 1 January 2002-1 January 2011 and 1 March-1 November 2014, respectively, were included in this study. Three sources of data were used for analysis: questionnaires, national obstetrics registration forms, and a lab-database of all ICSI treatments. Data were analyzed using generalized estimating equations and logistic regression analysis. RESULTS: The prevalence of major birth defects in newborns born after PESA-ICSI was 6.9% and after TESE-ICSI was 5.9% (odds ratio 0.89, 95% confidence interval 0.46-1.75). No significant association was found between maternal or treatment-related factors and the prevalence of birth defects. CONCLUSIONS: We found a similar overall prevalence of birth defects in newborns born after PESA-ICSI and TESE-ICSI. The maternal and treatment-related factors investigated did not show a significantly increased cumulative risk of birth defects.

Survival benefit in women with BRCA1 mutation or familial risk in the MRI screening study (MRISC).

Adding MRI to annual mammography screening improves early breast cancer detection in women with familial risk or BRCA1/2 mutation, but breast cancer specific metastasis free survival (MFS) remains unknown. We compared MFS of patients from the largest prospective MRI Screening Study (MRISC) with 1:1 matched controls. Controls, unscreened if<50 years, and screened with biennial mammography if ≥50 years, were matched on risk category (BRCA1, BRCA2, familial risk), year and age of diagnosis. Of 2,308 MRISC participants, breast cancer was detected in 93 (97 breast cancers), who received MRI <2 years before breast cancer diagnosis; 33 BRCA1 mutation carriers, 18 BRCA2 mutation carriers, and 42 with familial risk. MRISC patients had smaller (87% vs. 52%

The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and a review of the literature.

Two proα1(IV) chains, encoded by COL4A1, form trimers that contain, in addition, a proα2(IV) chain encoded by COL4A2 and are the major component of the basement membrane in many tissues. Since 2005, COL4A1 mutations have been known as an autosomal dominant cause of hereditary porencephaly. COL4A1 and COL4A2 mutations have been reported with a broader spectrum of cerebrovascular, renal, ophthalmological, cardiac, and muscular abnormalities, indicated as "COL4A1 mutation-related disorders." Genetic counseling is challenging because of broad phenotypic variation and reduced penetrance. At the Erasmus University Medical Center, diagnostic DNA analysis of both COL4A1 and COL4A2 in 183 index patients was performed between 2005 and 2013. In total, 21 COL4A1 and 3 COL4A2 mutations were identified, mostly in children with porencephaly or other patterns of parenchymal hemorrhage, with a high de novo mutation rate of 40% (10/24). The observations in 13 novel families harboring either COL4A1 or COL4A2 mutations prompted us to review the clinical spectrum. We observed recognizable phenotypic patterns and propose a screening protocol at diagnosis. Our data underscore the importance of COL4A1 and COL4A2 mutations in cerebrovascular disease, also in sporadic patients. Follow-up data on symptomatic and asymptomatic mutation carriers are needed for prognosis and appropriate surveillance.

Weight of in vitro fertilization and intracytoplasmic sperm injection singletons in early childhood.

Birth weight and longitudinal growth in the first 4 years of life of term singletons conceived with the use of IVF and intracytoplasmic sperm injection (ICSI) were compared with those of naturally conceived singletons. Although IVF and ICSI singletons had a statistically significantly lower birth weight than naturally conceived singletons, the average individual weight curves showed that this difference was lost before the age of 4 years in all subgroups: IVF, ICSI, boys, and girls.

Chat about what matters most: an analysis of chat contributions posted to an outpatient fertility website.

A content analysis of chat utterances generated by in vitro fertilization (IVF) patients and healthcare professionals revealed that most chat is about the treatment itself and not about childlessness; 56% discloses psychological aspects, 27% physical aspects, and 17% social aspects of the treatment; and that accounts of both external and internal coping behaviors could be identified.