Citations

Abstract Background To protect minors’ future autonomy, professional organizations have historically discouraged returning predictive adult-onset genetic test results and carrier status to children. Recent clinical guidance diverges from this norm, suggesting that when minors have genomic sequencing performed for clinical purposes, parents and children should have the opportunity to learn secondary findings, including for some adult-onset conditions. While parents can currently opt in or out of receiving their child’s secondary findings, the American Society of Human Genetics Workgroup on Pediatric Genetic and Genomic Testing suggests including adolescents in the decision-making process. However, it is not clear what factors young people consider when given the opportunity to learn genetic findings for themselves. We are examining adolescents’, young adults’, and parents’ (if applicable) decisions about learning genomic information for the adolescent. Methods We are enrolling assenting (ages 13–17) adolescents and consenting (ages 18–21) young adults in a prospective genomic screening study to assess the choices they make about receiving individual genomic results. Participants use an online tool to indicate whether they want to learn their personal genetic risk for specific preventable, treatable, and adult-onset conditions, as well as carrier status for autosomal recessive conditions. We are examining 1) how choices differ between adolescent and young adult cohorts (as well as between adolescents/young adults and parents) and 2) decisional conflict and stability across study timepoints. Results are returned based on participants’ choices. Qualitative interviews with a subset of participants explore decisional stability, adolescent/young adult engagement with parents in decision-making, and the impact of learning pathogenic/likely pathogenic and carrier results. Discussion This study explores decision making and decision stability between adolescents and parents (where applicable), as well as the ethical implications and impact of return of clinical-grade genetic research results to adolescents and young adults. The results of this study will contribute empirical evidence to support best practices and guidance on engaging young people in genetic research studies and clinical care that offer return of results. Trial Registration: ClinicalTrials.gov Identifier: NCT04481061. Registered 22 July 2020.

AbstractIntroductionIn evaluating malignant pleural fluid cytology, metastatic adenocarcinomas and mesotheliomas are often differential diagnoses. GATA binding protein 3 (GATA3) has historically been used to confirm metastatic breast carcinomas; however, GATA3 has low specificity if mesothelioma is included in differential diagnoses. Trichorhinophalangeal syndrome type 1 (TRPS1) protein is expressed in all types of breast carcinomas, with reported high specificity and sensitivity. We investigated the performance of TRPS1 immunohistochemistry (IHC) and compared it to GATA3 in pleural fluids diagnosed with metastatic breast carcinoma and mesothelioma.MethodsThirty‐six consecutive ThinPrep pleural fluids and 4 pleural fine needle aspirations (FNAs) with diagnoses of metastatic breast carcinoma (21) and mesothelioma (19) were retrieved, and IHC with TRPS1 and GATA3 was performed on all. Immunoreactivity scores for TRPS1 were calculated by multiplying percentage of immunoreactive cells by staining intensity. Immunoreactivity scores were negative if 0 or 1, low positive if 2, intermediate positive if 3 or 4, or high positive if 6 or 9. Nuclear immunoreactivity of ≥10% with at least moderate intensity was judged GATA3 positive.ResultsGATA3 showed immunoreactivity in all metastatic breast carcinomas and 84% of mesotheliomas. TRPS1 was immunoreactive in all breast carcinoma cases (18 with a score of 9 and 3 with a score of 6). TRPS1 showed low positivity in 5% of mesothelioma cases with all other cases being negative.ConclusionWhen cytomorphologic differential diagnoses of mesothelioma exist, TRPS1 is a more specific marker than GATA3 for confirmation of metastatic breast carcinoma in pleural fluid cytology.

Abstract Background No human rabies post-exposure prophylaxis (PEP) failure has been documented in the United States using modern cell culture–based vaccines. In January 2021, an 84-year-old male died from rabies 6 months after being bitten by a rabid bat despite receiving timely rabies PEP. We investigated the cause of breakthrough infection. Methods We reviewed medical records, laboratory results, and autopsy findings and performed whole-genome sequencing (WGS) to compare patient and bat virus sequences. Storage, administration, and integrity of PEP biologics administered to the patient were assessed; samples from leftover rabies immunoglobulin were evaluated for potency. We conducted risk assessments for persons potentially exposed to the bat and for close patient contacts. Results Rabies virus antibodies present in serum and cerebrospinal fluid were nonneutralizing. Antemortem blood testing revealed that the patient had unrecognized monoclonal gammopathy of unknown significance. Autopsy findings showed rabies meningoencephalitis and metastatic prostatic adenocarcinoma. Rabies virus sequences from the patient and the offending bat were identical by WGS. No deviations were identified in potency, quality control, administration, or storage of administered PEP. Of 332 persons assessed for potential rabies exposure to the case patient, 3 (0.9%) warranted PEP. Conclusions This is the first reported failure of rabies PEP in the Western Hemisphere using a cell culture–based vaccine. Host-mediated primary vaccine failure attributed to previously unrecognized impaired immunity is the most likely explanation for this breakthrough infection. Clinicians should consider measuring rabies neutralizing antibody titers after completion of PEP if there is any suspicion for immunocompromise.

AbstractLymphangioleiomyomatosis (LAM) is a rare disease with variable presentations. The neoplastic cells in LAM demonstrate a unique and diagnostically important “myomelanocytic” phenotype. Cytologic reports of LAM are infrequent and have not in the past emphasized the floating island pattern in which circumscribed aggregates of lesional cells are rimmed by appliques of flattened endothelium. This case illustrates the cytology of LAM and emphasizes that the floating island cytoarchitectural pattern more classically associated with entities such as hepatocellular carcinomas may be seen in cytological preparations of LAM at unanticipated body sites.

Abstract Background The protective efficacy of prior coronavirus disease 2019 (COVID-19) with or without vaccination remains unknown. This study sought to understand if 2 or more messenger RNA (mRNA) vaccine doses provide additional protection in patients with prior infection, or if infection alone provides comparable protection. Methods We conducted a retrospective cohort study of the risk of COVID-19 from 16 December 2020 through 15 March 2022, among vaccinated and unvaccinated patients of all ages with and without prior infection. A Simon-Makuch hazard plot illustrated the incidence of COVID-19 between groups. Multivariable Cox proportional hazards regression was used to examine the association of demographics, prior infection, and vaccination status with new infection. Results Among 101 941 individuals with at least 1 COVID-19 polymerase chain reaction test prior to 15 March 2022, 72 361 (71.0%) received mRNA vaccination and 5957 (5.8%) were previously infected. The cumulative incidence of COVID-19 was substantially higher throughout the study period for those previously uninfected and unvaccinated, and lowest for those previously infected and vaccinated. After accounting for age, sex, and the interaction between vaccination and prior infection, a reduction in reinfection risk was noted during the Omicron and pre-Omicron phases of 26% (95% confidence interval [CI], 8%–41%; P = .0065) to 36% (95% CI, 10%–54%; P = .0108), respectively, among previously infected and vaccinated individuals, compared to previously infected subjects without vaccination. Conclusions Vaccination was associated with lower risk of COVID-19, including in those with prior infection. Vaccination should be encouraged for all including those with prior infection, especially as new variants emerge and variant-specific booster vaccines become available.

Abstract Introduction Breast cancer is uncommon in men. Almost all male breast cancers are hormone receptor-positive, HER2-negative, although the pathogenesis is not always attributable to an endocrine condition. A few studies have compared biological characteristics or molecular signatures with breast cancers in women. We sought to evaluate whether hormone receptor-related gene expression is different in cancers from men compared to equivalent cancers from women. SET2,3 index measures non-proliferative hormone receptor-related transcriptional activity in the cancer (SET-ER/PR index) and adjusts this for a Baseline Prognosis Index (BPI) that combines the measurements of tumor and nodal stage with a 4-gene molecular subtype (ESR1, PGR, ERBB2, and AURKA). Methods We received aliquots of total RNA from male patients with breast cancer included in the retrospective cohort study of the EORTC 10085/BCG/TBCRC/BIG/NCTN International Male Breast Cancer Program (NCT01101425). SET2,3 assay was performed using the QuantiGene assay (Thermo Fisher) using bead-based hybridization and laser spectroscopy (Luminex). The statistical analyses were performed by the EORTC statistician. The primary objective of the study was the assessment of the prognostic value of the SET2,3 index score in patients with early-stage hormone receptor-positive, HER2-negative male breast cancer, treated with endocrine therapy. Clinical outcomes (recurrence-free survival – RFS; overall survival – OS) were estimated by Kaplan-Meier curves and secondarily compared using multivariable Cox models adjusted for continuous SET2,3 index, tumor size, nodal status, age, and chemotherapy and radiotherapy use. An exploratory analysis to compare the SET2,3 index scores distribution in female and male breast cancer patients was also performed using results from the same assay performed on cancers from women selected on the same inclusion criteria. Due to the low numbers of male patients treated with neoadjuvant treatment (N=6), this analysis was restricted to patients treated with adjuvant treatment (n=315 male and 660 female). Results Of the 321 male patients with breast cancer analyzed, treated between 1990 and 2010, 211 (65.7%) were categorized as high SET2,3 index score, reflecting a high endocrine activity in the cancer and low risk of recurrence, and 110 patients (34.3%) categorized as being low score, reflecting low endocrine activity and high risk of recurrence. At 5 years, the RFS was 75.0% (95% CI, 67.4-81.1) in the high SET2,3 group versus 60.7% (95% CI, 49.1-70.5) in the low SET2,3 group (HR univariate, 0.49; 95% CI, 0.34-0.70; P< 0.0001). The 5-year OS rate among patients with a high SET2,3 index was 84.3% (95% CI, 45.5-73.8), in contrast of 67.8% (95% CI, 56.6-76.7) in the low SET2,3 group (HR univariate, 0.44; 95% CI, 0.30-0.65; P< 0.0001). SET2,3 was independently prognostic for OS, but not RFS in multivariable Cox models. In patients classified as low SET2,3, the addition of neo/adjuvant chemotherapy to adjuvant endocrine therapy was associated with 5-year OS of 76.0% (95% CI, 59.5-86.4) and in patients who received endocrine therapy alone the 5-year OS was 61.3% (95% CI, 45.5-73.8), an absolute difference of 14.7 percentage points. Overall, we did not observe a difference in the distributions (median, interquartile range) of SET2,3 index between men (2.4, 1.9–2.6) and women (2.3, 2.0–2.7). Conclusion SET2,3 index measurements of endocrine-related transcriptional activity in male patients with breast cancer were not different from measurements in female patients with breast cancer. SET2,3 was prognostic in male breast cancer and our exploratory analysis suggests that chemotherapy might improve the poor prognosis for men with breast cancer that has low SET2,3 index. This study was funded by the Breast Cancer Research Foundation (BCRF). Citation Format: Danielle B. Zakon, Coralie Poncet, Fatima Cardoso, Neven Anouk, Vicente Valero, Stefan Aebi, Kim Benstead, Oliver Bogler, Lissandra Dal Lago, Judith Fraser, Carmela Caballero, Ingrid A. Hedenfalk, Larissa A. Korde, Barbro Linderholm, John WM Martens, Lavinia P. Middleton, Melissa Murray, Catherine M. Kelly, Cecilia Nilsson, Monika Nowaczyk, Stephanie Peeters, Melanie Beauvois, Peggy Porter, Carolien P. Schroder, Isabel T. Rubio, Kathryn Ruddy, Christi van Asperen, Danielle Van Den Weyngaert, Carolien HM van Deurzen, Elise van Leeuwen-Stok, Joanna M. Vermeij, John MS Bartlett, Antonio C. Wolff, Sharon H. Giordano, W. Fraser Symmans. PD6-11 Evaluation of the Sensitivity to Endocrine Therapy Index (SET2,3) in Early Male Breast Cancer: Results from an analysis in the EORTC 10085/TBCRC/BIG/NCTN International Male Breast Cancer Program [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD6-11.

Heterozygous loss-of-function (LOF) mutations in PIK3R1 (encoding phosphatidylinositol 3-kinase [PI3K] regulatory subunits) cause activated PI3Kδ syndrome 2 (APDS2), which has a similar clinical profile to APDS1, caused by heterozygous gain-of-function (GOF) mutations in PIK3CD (encoding the PI3K p110δ catalytic subunit). While several studies have established how PIK3CD GOF leads to immune dysregulation, less is known about how PIK3R1 LOF mutations alter cellular function. By studying a novel CRISPR/Cas9 mouse model and patients’ immune cells, we determined how PIK3R1 LOF alters cellular function. We observed some overlap in cellular defects in APDS1 and APDS2, including decreased intrinsic B cell class switching and defective Tfh cell function. However, we also identified unique APDS2 phenotypes including defective expansion and affinity maturation of Pik3r1 LOF B cells following immunization, and decreased survival of Pik3r1 LOF pups. Further, we observed clear differences in the way Pik3r1 LOF and Pik3cd GOF altered signaling. Together these results demonstrate crucial differences between these two genetic etiologies.