The Ethics of Genetic Testing for Inherited Cancer-Predisposing Genes.

Once an individual has been identified as a carrier of an inherited cancer-predisposing gene or pathogenic germline variant (PGV), there are measures that have been proven to prevent and diagnose the associated cancers at an earlier, more curable stage. Consequently, patients who are offered and undergo testing are afforded opportunities and health-care information that profoundly affect their lives and the lives of their family members who choose to be tested as well. For years, the debate over the controversial topic of whether all patients should be offered germline testing for cancer-predisposing PGVs centered around questions of the analytical sensitivity of the assays (i.e., the ability of the test to correctly identify those who carry a PGV), legal implications for those identified as PGV carriers, cost to the health-care system, and the uncertain management implications of test results. Currently, the standard of care is to offer testing to individuals where the anticipated benefits of testing outweigh the harms. Here, the ethical question of whether all patients have the right to testing for PGVs is considered.

Defining the Role of the Advanced Practice Provider Within the National Cancer Institute Community Oncology Research Program.

PURPOSE: Oncology advanced practice providers (APPs), including nurse practitioners, clinical nurse specialists, physician assistants, and clinical pharmacists, contribute significantly to quality cancer care. Understanding the research-related roles of APPs in the National Cancer Institute's (NCI) Community Oncology Research Program (NCORP) could lead to enhanced protocol development, trial conduct, and accrual. METHODS: The 2022 NCORP Landscape Assessment Survey asked two questions about the utilization and roles of APPs in the NCORP. RESULTS: A total of 271 practice groups completed the 2022 survey, with a response rate of 90%. Of the 259 nonpediatric exclusive practice groups analyzed in this study, 92% used APPs for clinical care activities and 73% used APPs for research activities. APPs most often provided clinical care for patients enrolled in trials (97%), followed by assistance with coordination (65%), presenting/explaining clinical trials (59%), screening patients (49%), ordering investigational drugs (37%), and consenting participants (24%). Some groups reported APPs as an enrolling investigator (18%) and/or participating in institutional oversight/selection of trials (15%). Only 5% of NCORP sites reported APPs as a site primary investigator for trials, and very few (3%) reported APPs participating in protocol development. CONCLUSION: Practice groups report involving APPs in clinical research within the NCORP network; however, opportunities for growth exists. As team-based care has enhanced clinical practice in oncology, this same approach can be used to enhance successful research. Suggested strategies include supporting APP research-related time, recognition, and education. The findings of this survey and subsequent recommendations may be applied to all adult oncology practices that participate in clinical research.

PTCH1 mutant small cell glioblastoma in a patient with Gorlin syndrome: A case report.

Gorlin syndrome or nevoid basal cell carcinoma syndrome is a rare genetic disease characterized by predisposition to congenital defects, basal cell carcinomas and medulloblastoma. The syndrome results from a heritable mutation in PATCHED1 (PTCH1), causing constitutive activation of the Hedgehog pathway. The present study described a patient with Gorlin syndrome who presented early in life with characteristic basal cell carcinomas and later developed a small cell glioblastoma (GBM), World Health Organization grade IV, associated with a Patched 1 (PTCH1) N97fs*43 mutation. Comprehensive genomic profiling of GBM tissues also revealed multiple co-occurring alterations including cyclin-dependent kinase 4 (CDK4) amplification, receptor tyrosine-protein kinase 3 (ERBB3) amplification, a fibroblast growth factor receptor 1 and transforming acidic coiled-coil containing protein 1 (FGFR1-TACC1) fusion, zinc finger protein (GLI1) amplification, E3 ubiquitin-protein ligase (MDM2) amplification and spectrin α chain, erythrocytic 1 (SPTA1) T1151fs*24. After the biopsy, imaging revealed extensive leptomeningeal enhancement intracranially and around the cervical spinal cord due to leptomeningeal disease. The patient underwent craniospinal radiation followed by 6 months of adjuvant temozolomide (150 mg/m2) with good response. She was then treated with vismodegib for 11 months, first combined with temozolomide and then with bevacizumab, until disease progression was noted on MRI, with no significant toxicities associated with the combination therapy. She received additional therapies but ultimately succumbed to the disease four months later. The current study presents the first documentation in the literature of a primary (non-radiation induced) glioblastoma secondary to Gorlin syndrome. Based on this clinical experience, vismodegib should be considered in combination with standard-of-care therapies for patients with known Gorlin syndrome-associated glioblastomas and sonic hedgehog pathway mutations.

Clinical Experience using Osimertinib in Patients with Recurrent Malignant Gliomas Containing EGFR Alterations.

Background: EGFR alterations are commonly observed in malignant gliomas (MG). Osimertinib, an irreversible EGFR-tyrosine kinase inhibitor, effectively penetrates the blood brain barrier and achieves therapeutic concentrations in brain tissue. Materials and Methods: This retrospective chart review identified six patients with recurrent MG and EGFR alterations who received osimertinib. Results: Four patients were assessed for response. One patient had a partial response, two patients achieved stable disease and one was refractory. One patient with an EGFR vIII rearrangement remained on treatment for 236 days and a second patient with an EGFR vIII mutation remained on treatment for 294 days and continued on treatment at the time of analysis. Thrombocytopenia occurred in two patients, one patient developed grade 1 diarrhea and pneumonia, and another patient developed grade 1 mucositis. Conclusion: Osimertinib had a tolerable safety profile in this heavily pretreated brain tumor population. Osimertinib may benefit select patients with recurrent MG containing EGFR alterations.

An automated system for detecting nonadherence in laboratory testing and monitoring for myelosuppression in patients receiving self-administered oral chemotherapy.

INTRODUCTION: Patient compliance with routine monitoring for self-administered chemotherapy is problematic. We sought to assess monitoring lapses and incidents of myelosuppression in patients undergoing self-administered chemotherapy for glioblastoma, as well as test software designed to detect and alert clinicians to lapses in monitoring. PATIENTS AND METHODS: A retrospective analysis was conducted to identify patients (N=117) who received standard oral temozolomide for glioblastoma at our institution from 2003 to 2010. Gaps in monitoring were classified as minor (10 to 12 days) or major (13 to 28 days), and adverse events were graded using standard criteria. During the prospective portion of the study, we tested a software-based system that alerted clinicians of monitoring lapses and adverse events among patients receiving self-administered temozolomide for glioblastoma (n=37). RESULTS: Our retrospective review found that 34 of 117 patients experienced monitoring gaps during treatment. No association between gaps and risk of myelosuppression were found. Patients with gaps were more likely to be male (P=.04). Patients monitored prospectively with the software experienced no major gaps in monitoring (P=.007 compared with retrospective patients). CONCLUSION: Our retrospective review demonstrated that monitoring nonadherence was occurring at a substantial rate. Our computerized system eliminated major gaps in monitoring in the prospective portion of our study. Although there is no association between monitoring gaps and the occurrence of adverse events, when they do coincide, continuing oral chemotherapy during an unrecognized adverse event may worsen the patient's condition. Automated systems are justified and serve a function not currently being addressed.