Lim, Sanghee

Abstract OBJECTIVE To demonstrate that Prostate-specific membrane antigen (PSMA) PET imaging, though primarily used in prostate cancer surveillance, can reveal PSMA uptake in non-prostatic tumors due to neovascular PSMA expression. BACKGROUND PSMA PET imaging is increasingly used for staging and monitoring prostate cancer. However, PSMA uptake is not exclusive to prostate carcinoma and may be observed in non-prostatic malignancies, including glioblastoma, due to neovascular expression. CASE REPORT We present a 67-year-old gentleman with metastatic prostate carcinoma, diagnosed in 2014 and treated with neoadjuvant Lupron, prostatectomy, and salvage radiation. In 2019, he developed nodal recurrence in retroperitoneal and bilateral iliac chain nodes, treated with lymphadenopathy, six cycles of Taxotere-based chemotherapy, and consolidative proton beam radiation (56.25 Gy/25 fractions). He later developed progression to the right proximal humerus and left coracoid process, treated with stereotactic body radiation therapy (25Gy/5 fractions). Follow-up PSMA PET/CT revealed no systemic abnormalities but showed a new PSMA-avid lesion in the right medial temporal lobe. Brain MRI confirmed a 3.5 x 1.7 x 2.5 cm ring-enhancing, intra-axial lesion with edema. The patient was asymptomatic. PSA was undetectable on abiraterone/prednisone and leuprolide. He underwent right frontotemporal craniotomy and resection. Pathology confirmed Glioblastoma, IDH-wildtype, CNS WHO Grade 4 with focal epithelioid features and positive MGMT promoter methylation. He received standard-of-care treatment with radiation, temozolomide, and TTF device. Surveillance PSMA PET and MRI showed no residual brain avidity or progression. Discussion: PSMA is a type II transmembrane glycoprotein expressed by prostatic and various non-prostatic tissues. In healthy brain parenchyma, PSMA expression is typically absent but is overexpressed in neovasculature of high-grade gliomas, including glioblastoma, IDH-wildtype, allowing for radiotracer uptake, as seen in this case. CONCLUSION This case illustrates the potential role of PSMA as a diagnostic tool, as it allows for easy identification of glioblastoma neovasculature, as demonstrated in our case report.

Abstract BACKGROUND Tumor Treating Field (TTF) therapy exerts antineoplastic effects through application of alternating electrical fields that disrupt mitotic machinery and induce DNA damage and activation of cell cycle checkpoints. However, despite extensive utilization in clinical practice for the management of glioblastoma, molecular markers for TTF sensitivity have proven elusive. METHODS To assess impact of molecular alterations on TTF response, we evaluated our institutional cohort of IDH wild type glioblastomas (n=449) for whom chromosomal microarray data was available. RESULTS A total of 142 patients were found to have undergone TTF treatment (31.6%) with improved overall survival (OS) (p=0.0049, univariate analysis). We assessed TTF treatment responses when stratified by alterations in the MDM2/4-TP53 axis, as well as the CDK4/6-RB1 axis, given well-described roles for these pathways on cellular responses to DNA damage and mitotic stressors. On univariate analysis, MDM2/4 amplified tumors treated with TTFs demonstrated significantly improved OS compared to untreated tumors (p=0.0012), and while MDM2/4-unaltered, TP53 intact tumors showed OS benefit from TTFs (p=0.0192), TP53-altered tumors did not demonstrate such benefit (p=0.6591). We confirmed these findings with multivariate Cox regression after adjusting for age and sex, where TTF therapy improved OS in MDM2/4 amplified tumors (HR 0.3881, p=0.0062) and a signal towards improved OS was seen in TP53 intact tumors (HR 0.7552, p=0.0509) but no such benefit was seen in TP53-altered tumors (HR 1.0025, p=0.9916). TTF therapy appeared to demonstrate improved OS in CDK4/6 amplified tumors (p=0.0116) on univariate analysis, with continued signal towards this effect on multivariate Cox regression (HR 0.5975, p=0.0870). CONCLUSIONS TP53 intact status and MDM2/4 amplification may represent previously unappreciated molecular markers for sensitivity to TTF therapy in IDH wild type glioblastoma. Confirmatory work with multi-institutional collaborations and evaluation of other potential prognostic factors are currently underway.

Abstract BACKGROUND Chromosomal instability is a well-recognized hallmark of tumorigenesis. However, it is not known how markers for chromosomal instability, such as total distance of DNA altered or total copy number variations (CNV), affect survival, particularly in IDH wild type glioblastoma. Additionally, whether alterations in pathways that impact cellular responses to chromosomal instability, such as the TP53 or RB1 axis, influence survival, similarly remain poorly understood. METHODS To better characterize potential prognostic impact of markers of chromosomal instability on patient outcomes, we assessed the Mayo Clinic cohort of IDH wild type glioblastomas (n=449) for whom chromosomal microarray data was available. RESULTS We found that while total distance of DNA altered on microarray analysis was not associated with overall survival (OS) (p=0.4030, univariate analysis), the least altered tumors (stratified by quartiles) when assessed by numbers of CNVs demonstrated improved OS (p=0.0057, univariate analysis). We next evaluated alterations in the MDM2/4-TP53 signaling axis, as well as the CDKN2A/B-CDK4/6-RB1 axis, as both amplifications and losses impacting these pathways have been well characterized in adult diffuse gliomas. While TP53 status was not predictive of OS (p=0.1504, univariate analysis), amplification of MDM2 or MDM4 was predictive of decreased OS (p=0.0071, univariate analysis). We also found that tumors without alterations in the CDKN2A/B-CDK4/6-RB1 axis had improved OS when compared to altered tumors (p<0.0001, univariate analysis). Multivariate Cox regression analysis, adjusting for age and sex, confirmed prognostic impact of MDM2/4 amplification status (HR 1.4090, p=0.0370) and CNV status (HR 0.6798, p=0.00312) on OS. CONCLUSIONS CNV status and MDM2/4 amplification represent previously unappreciated molecular markers for prognostication in IDH wild type glioblastoma. Further work is underway to confirm our findings through multi-institutional collaborations and to account for additional potential prognostic factors.