Pretest Video Education Versus Genetic Counseling for Patients With Prostate Cancer: ProGen, A Multisite Randomized Controlled Trial.

PURPOSE: Germline genetic testing (GT) is recommended for men with prostate cancer (PC), but testing through traditional models is limited. The ProGen study examined a novel model aimed at providing access to GT while promoting education and informed consent. METHODS: Men with potentially lethal PC (metastatic, localized with a Gleason score of ≥8, persistent prostate-specific antigen after local therapy), diagnosis age ≤55 years, previous malignancy, and family history suggestive of a pathogenic variant (PV) and/or at oncologist's discretion were randomly assigned 3:1 to video education (VE) or in-person genetic counseling (GC). Participants had 67 genes analyzed (Ambry), with results disclosed via telephone by a genetic counselor. Outcomes included GT consent, GT completion, PV prevalence, and survey measures of satisfaction, psychological impact, genetics knowledge, and family communication. Two-sided Fisher's exact tests were used for between-arm comparisons. RESULTS: Over a 2-year period, 662 participants at three sites were randomly assigned and pretest VE (n = 498) or GC (n = 164) was completed by 604 participants (VE, 93.1%; GC, 88.8%), of whom 596 participants (VE, 98.9%; GC, 97.9%) consented to GT and 591 participants completed GT (VE, 99.3%; GC, 98.6%). These differences were not statistically significant although subtle differences in satisfaction and psychological impact were. Notably, 84 PVs were identified in 78 participants (13.2%), with BRCA1/2 PV comprising 32% of participants with a positive result (BRCA2 n = 21, BRCA1 n = 4). CONCLUSION: Both VE and traditional GC yielded high GT uptake without significant differences in outcome measures of completion, GT uptake, genetics knowledge, and family communication. The increased demand for GT with limited genetics resources supports consideration of pretest VE for patients with PC.

NCCN Guidelines® Insights: Prostate Cancer Early Detection, Version 1.2023.

The NCCN Guidelines for Prostate Cancer Early Detection provide recommendations for individuals with a prostate who opt to participate in an early detection program after receiving the appropriate counseling on the pros and cons. These NCCN Guidelines Insights provide a summary of recent updates to the NCCN Guidelines with regard to the testing protocol, use of multiparametric MRI, and management of negative biopsy results to optimize the detection of clinically significant prostate cancer and minimize the detection of indolent disease.

Genetic variants with discordant classifications: An assessment of genetic counselor attitudes and practices.

Discordant variant classifications (DVCs) can impact patient care and pose challenges for clinicians. A survey-based study was conducted to examine genetic counselor (GC) attitudes and practices related to DVCs. Most GCs (202/229, 88%) in the study provide direct patient care across clinical specialties; review patients' genetic test results to determine if reported genetic variants have DVCs (176/202, 88%); and inform patients of known DVCs that impact medical management (165/202, 82%). DVC review, which takes 41 min (range: 5-240) on average per week, is typically prompted by the identification of a variant of uncertain significance (VUS) (160/176, 90%) and is primarily conducted using public databases (176/176, 100%). While most GCs felt it would not be ethical to knowingly provide different medical management recommendations to patients with the same genetic variant (152/229, 66%), they also stated they would rely on the variant classification on the test report (141/229, 61%) and/or the patient's personal/family history (188/229, 82%) to determine which classification to follow if a DVC is identified. Both factors are patient-specific and, inherently, could lead to differing recommendations. When posed with a hypothetical scenario in which two patients have the same genetic variant, but test reports show a DVC (pathogenic vs VUS), most GCs (179/229, 78.2%) stated they would make the same recommendation for both patients regardless of management guidelines. One-third (52/179, 29.1%) cited patient-specific factors, such as personal/family history, would impact their recommendations. Disagreements about whether the pathogenic or VUS classification should be used to make medical management recommendations were noted. Differing practices and opinions on how to manage patients with DVCs, as well as the fact that most GCs (209/229, 91.3%) have consulted with colleagues on this matter, highlight the need for more professional guidance to ensure equitable patient care.

Distinct NSCLC EGFR Variants in a Family With Li-Fraumeni Syndrome: Case Report.

Introduction: Heritable lung cancer may occur in the context of germline TP53 mutations (Li-Fraumeni syndrome). Limited cases of intrafamily tumor genomic characteristics have been reported. Main concerns Important Clinical Findings Primary Diagnoses Interventions Outcomes: A 40-year-old woman with no smoking history or known environmental exposure risk was incidentally found to have stage II (T2N1) NSCLC harboring an EGFR exon 19 p.Glu746_Ala750 deletion. Family history was notable for an identical twin sister with colorectal cancer (diagnosed at age 31 y) and a mother with stage I NSCLC harboring an EGFR exon 21 c.2573T>G (p.Leu858Arg) mutation (diagnosed at age 69 y). Genetic testing revealed a germline TP53 c.542G>A (p.Arg181His) mutation in the patient, her mother, and her sister, consistent with Li-Fraumeni syndrome. No germline EGFR mutations were detected. Conclusion: Shared germline TP53 mutations may be associated with distinct NSCLC somatic EGFR mutations within families with Li-Fraumeni syndrome. Further understanding of the association between genetic cancer syndromes and lung cancer risk may improve early lung cancer detection in populations not otherwise meeting screening eligibility.

Downstream Revenue Generated by a Cancer Genetic Counselor.

PURPOSE: Enhanced cancer risk reduction measures are recommended for patients with hereditary predispositions to cancer. Providing these services within a healthcare institution (HI) generates downstream revenue (DSR). We evaluated the DSR for our institution after patients were identified to have a pathogenic variant by a genetic counselor (GC). METHODS: Retrospective chart review identified patients with hereditary breast and ovarian cancer (HBOC) and Lynch syndrome (LS) seen in the UT Southwestern Medical Center Cancer Genetics Clinic between November 1, 2009, and January 31, 2019. All billable encounters were recorded. Total revenue and work relative value units were calculated after patients met with a GC. RESULTS: Four hundred twenty-five patients with HBOC and LS had financial data available for analysis. After GC visit, DSR totaled $32,798,000 in US dollars (USD). Patients unaffected with cancer (n = 176) generated $8,453,000 (USD). Patients (n = 96) whose first visit to the institution were for GC consultation (naïve patients) generated $5,933,000 (USD). Unaffected, naïve patients (n = 64) generated $3,190,000 (USD) in DSR. The 425 total patients generated 73,957 work relative value units at the institution after their appointment with a GC. CONCLUSION: GCs bring in substantial DSR for their HI by identifying patients with HBOC or LS. Institution naïve and unaffected patients who continue care at the institution provide additional opportunities to generate DSR. If applied to additional pathogenic variant carriers, GCs can further increase DSR for an HI.

De novo SDHB gene mutation in a family with extra-adrenal paraganglioma.

A 14-year-old male presented with abdominal pain. Imaging illustrated a left-sided adrenal mass; he underwent a left nephrectomy, confirming an extra-adrenal PGL. Germline genetic testing revealed a heterozygous, likely pathogenic mutation in the SDHB gene. The patient's family subsequently underwent genetic testing; his mother and sister were both positive for the familial SDHB mutation. Cascade testing for the proband's maternal aunt and maternal grandparents was negative for the familial mutation. SNP genotyping was used to confirm relationships. This is the second reported case of a de novo SDHB gene mutation and the first reported case of a confirmed de novo mutation in a patient who was not the initial proband. As SDHB-associated PGLs and PCCs are expected to be more aggressive and malignant, it is imperative to identify patients with SDHB mutations early. Given that many patients with germline mutations have no family history of PGL of PCC, the possibility of de novo mutations must be considered. Further studies are needed to determine the rate of de novo mutation in SDHB and other SDH-complex genes. Up to 41% of patients with paragangliomas (PGL) or pheochromocytomas (PCC) have an identifiable hereditary cancer predisposition syndrome. Mutations in 12 genes are known to increase the risk of PGL and/or PCC; however, the de novo rate is mostly unknown. Only one case report exists of a de novo SDHB mutation. We present the second case of a family with a de novo SDHB mutation.

Connecting the Dots From Fever of Unknown Origin to Myelodysplastic Syndrome: GATA2 Haploinsufficiency.

Leukemia-predisposing conditions, such as GATA2 haploinsufficiency, are known for their high penetrance and expressivity profiles. These disorders pose a difficult diagnostic challenge to even the most experienced clinician when they first present. We describe the case of a 17-year-old male presenting with features of nontuberculous mycobacterial infection, pulmonary fibrinoid granulomatous vasculitis, and myelodysplasia in the setting of a pathogenic GATA2 frameshift mutation confirmed by next-generation sequencing. The broad differential for GATA2 haploinsufficiency requires prompt recognition of key clinical features and laboratory abnormalities towards directing diagnosis and guiding appropriate and perhaps life-saving therapy.

Family still matters: Counseling patients with complex family histories of colon and endometrial cancers.

BACKGROUND: There are no national guidelines for the management of patients with a family history consistent with Lynch syndrome (LS) but a negative genetic test. To determine current management practices, genetic counselors' (GCs) recommendations were assessed. METHODS: A survey of GCs using five hypothetical pedigrees was posted to National Society of Genetic Counselors (NSGC) discussion forums. Descriptive statistics were used. RESULTS: One-hundred and fifteen surveys were completed. A pedigree with a first-degree relative (FDR) with early-onset colorectal cancer (CRC) and a family history of CRC and endometrial cancer (EC) prompted 83% (n = 95) of respondents to recommend early and frequent colonoscopies, based on family history. When the CRCs and ECs occurred in family members removed from the proband, 96% (n = 110) of GCs said they would screen based on family history. However, only 52% (n = 60) suggested CRC screening should begin earlier and occur more often, and 43% (n = 50) suggested CRC screening should follow standard age and frequency guidelines. CONCLUSION: Concordance of opinion among GCs for the management of patients with negative genetic test results exists when FDRs are affected. However, when affected relatives are more distant, GCs disagreed on screening recommendations. These data suggest a need for guidelines for patients with a family history of cancer and a negative genetic test.

Brainstem Glioblastoma Multiforme in a Patient with NF1.

This case report presents the first known case of a brainstem glioblastoma multiforme (GBM) in a patient with neurofibromatosis type 1 (NF1). While research has proposed that larger germ-line mutations in NF1 may be the driving factor that predisposes patients with NF1 to high-grade astrocytomas, this patient had a nonsense mutation in the NF1 gene, suggesting a variant tumorigenesis. Limited data on targeted immunotherapy for NF1 patients with a GBM have been reported and more data are required before targeted therapies could be proven as second-line treatment options.