The advancement of immune-therapeutics in cancer treatment has proven to be promising in various malignant diseases. However, in castration resistant prostate cancer (mCRPC) major Phase III trials ...have been unexpectedly disappointing. To contribute to a broader understanding of the role and use of immune-therapeutics in mCRPC, we conducted a systematic review. We searched the websites ClinicalTrials.gov, PubMed and ASCO Meeting Library for clinical trials employing immune checkpoint inhibitors in mCRPC. This article not only describes the rationale of individual trials, but it also summarizes the current status of the field and sheds light on strategies for future success.
Abstract
BACKGROUND
Diffuse gliomas show considerable heterogeneity in terms of survival. The WHO classifications of 2016 and 2021 improved prognostic stratification due to the definition of ...biologically and clinically homogeneous tumor entities. However, further prognostic models considering clinical and molecular factors are needed to balance survival benefit with adverse treatment-related long-term effects in therapeutic decisions.
MATERIALS AND METHODS
Patients with diffuse gliomas of WHO grades 2 and 3 diagnosed in 2000 - 2019 have been included. Long term survivors (LTS) were defined as patients with an overall survival (OS) of >10 years after radiological diagnosis, whereas short-term survivors (STS) had an OS of <1 year. Histological diagnosis was performed by a board-certified neuropathologist. DNA methylation analysis of formalin-fixed, paraffin-embedded tumor tissue was conducted using the Illumina EPIC 850k platform. The Heidelberg Methylation Classifier was applied to obtain methylation-based diagnoses.
RESULTS
Of 697 patients with WHO grade 2 and 3 glioma, 182 (26.1%) were LTS, and 42 (6.0%) were STS. LTS were younger than STS (median age: 36 vs. 59.5; p<0.001) and had a higher Karnofsky Performance Score at diagnosis (median: 90% vs. 80%; p<0.001). LTS more frequently presented with epileptic seizures (p<0.001), while more STS had motoric (p<0.001), sensory (p=0.021), and visual deficits (p=0.027) as well as aphasia (p<0.001) and behavioral changes (p=0.009). Histological diagnoses (including pre-2016) showed astrocytic histology in 117 (70.9% LTS, 29.1% STS), oligodendroglial in 61 (93.4% LTS, 6.6% STS), oligo-astroglial in 43 (97.7% LTS, 2.3% STS) and not otherwise specified in 3 (all STS; p<0.001). Molecular reclassification of pre-2016 diagnoses (n = 143) yielded divergent entities in 46 (32.2%) cases. Overall, integrated molecular diagnoses included astrocytoma (isocitrate dehydrogenase IDH-mutant in 65 patients (95.4% LTS and 4.6% STS), oligodendroglioma (IDH-mutant, 1p/19q-codeleted) in 64 patients (98.4% LTS and 1.6% STS), IDH-wildtype gliomas in 24 patients (100% STS), anaplastic pilocytic astrocytoma in 2 STS, diffuse midline glioma (H3K27-altered) in 1 STS, and dysembryoplastic neuroepithelial tumor in 1 LTS, while not otherwise specified diagnoses were found in 4 patients (75% LTS, 25% STS; p<0.001). Unsupervised clustering based on DNA methylation profiling revealed two major clusters consisting of IDH-wildtype STS (cluster A) and IDH-mutant patients (cluster B; 94.6% LTS, 5.4% STS). In cluster B, one subcluster (n = 8) contained 3/4 IDH-mt STS. Further analyses of these cases including validation with publicly available DNA methylation data are ongoing.
CONCLUSION
LTS and STS show distinct clinical and molecular features. Further profiling of cases with divergent survival could provide more refined prognostic stratification.
Abstract
Background
Immunotherapy (IO) has changed the treatment landscape of metastatic cancer patients, however, treatment resistance is frequent. We aimed to characterize the inflammatory tumor ...microenvironment in brain metastases (BM) after IO to gain a deeper understanding of immunologic escape mechanisms.
Material and Methods
Solid cancer patients who had BM resection after IO progression (IO cohort) were retrospectively identified. We analyzed tumor-infiltrating immune cell subsets (CD3, CD8, CD45RO, FOXP3) and expression of immune checkpoint molecules (PD-L1, PD-1, LAG-3) by immunohistochemistry. A control cohort of BM tissue samples without prior IO served for comparison (no immunotherapy cohort, NIO).
Results
Twenty-eight IO patients (12/28, 42.9% females; 16/28, 57.1% males; median 61 years; 14/28, 50% lung cancer; 5/28, 17.9% melanoma; 4/28, 14.3% renal cell carcinoma; 1/28, 3.6% breast cancer; 4/28, 14.3% other cancer entities) and 57 NIO patients (28/57, 49.1% females; 29/57, 50.9% males; median 58 years; 35/57, 61.4% lung cancer; 9/57, 15.8% breast cancer; 4/57, 7.0% melanoma; 3/57, 5.3% renal cell carcinoma; 6/57, 10.5% other cancer entities) were included. IO patients had a median of one (range 0-4) systemic therapy line prior to IO. Median time from last IO application until BM resection was 5.6 months (range 0.2-49.8 months). Patients received a median number of 7 (range 1-56) IO applications (14/28, 50% PD-1-targeting IO; 8/28, 28.6% PD-L1; 2/28, 7.1% CTLA4; 4/28, 14.3% CTLA4+PD-1; 3/28, 10.7% IO+chemotherapy). No statistically significant differences in the densities of investigated TILs or PD-L1 expression between the IO and the NIO cohort were observed. Patients of the IO cohort showed higher PD-L1 expression compared to the NIO cohort (57.1 vs. 42.1%, Chi-square, p>0.05). Overall survival (OS) was similar in both cohorts, with a median OS of 11.0 months (range 5.0-17.0) in the IO cohort and 11.0 months (range 5.5-16.5) in the NIO cohort.
Conclusion
Our findings show an upregulation of PD-L1 in BM occurring after prior IO therapy in the absence of other overt changes in the inflammatory microenvironment. Ongoing analyses in this cohort are investigating possible molecular driver of resistance by analyzing DNA methylation profiles of pre-and post-IO tissue samples of the IO cohort to potentially gain insights on inflammatory IO resistance mechanisms in BM patients.
Abstract
Background
Oligodendrogliomas are glial tumors with a relatively favorable survival prognosis of >10 years. While immediate postoperative treatment prolongs survival, long-term toxicities of ...adjuvant radio-chemotherapy remain a concern. Predictive biomarkers guiding postoperative treatment decisions are limited.
Material and Methods
In this retrospective study, we included patients treated for a newly diagnosed oligodendroglioma (isocitrate dehydrogenase (IDH)-mutated, 1p/19q-codeleted, CNS WHO grades 2 and 3) in 1992 - 2019 at the Medical University of Vienna or the Kepler University Hospital Linz (Austria). Early treatment was defined as radiotherapy, chemotherapy, or both within 6 months after resection, whereas benefit from early treatment was defined as progression-free survival (PFS) above the median in the overall cohort. DNA methylation analysis was performed using Illumina MethylationEPIC 850k microarrays.
Results
Of all 201 eligible patients, sufficient tumor tissue for DNA methylation analysis was available in 46 patients. Of these, 25/46 (54.3%) were diagnosed with CNS WHO grade 2 and 21/46 (45.6%) with grade 3 oligodendroglioma. Median age at diagnosis was 41 years (range: 23-70). In total, 21/46 (45.6%) patients received early treatment, of whom 13/21 (61.9%) received radio-chemotherapy, 6/21 (28.6%) radiotherapy only and 2/21 (9.5%) chemotherapy only. Median PFS was 134.0 months (95%CI: 78.3 - not reached) in patients receiving early treatment versus 87.2 months (95%CI: 66.8 - 150) in patients who did not. In patients receiving early treatment, differences in DNA methylation profiles could be detected between patients who drew benefit from postoperative treatment (group 1) versus those who did not (group 2). Based on the top 1000 differentially methylated CpG sites between both groups, two clusters were detected which comprised either patients of group 1 or 2. Clustering was independent from gender, WHO grade, extent of resection, type of postoperative treatment, treating center, and O6-methylguanine-methyltransferease (MGMT) promoter methylation status. Gene set enrichment analysis of the top 1000 differentially methylated gene sites mapped to 694 genes showed differential methylation in genes involved in fibroblast growth receptor 1 (FGFR1) signaling, Wnt signaling, integrin signaling, and actin cytoskeleton regulation. Conversely, in patients not receiving early treatment, PFS did neither correlate with DNA methylation clustering nor with MGMT promoter methylation.
Conclusion
In our cohort, whole genome DNA methylation was associated with PFS in patients who received early postoperative treatment, suggesting a predictive but not prognostic role. As the predictive value of MGMT promoter methylation is limited in oligodendroglioma, whole genome DNA methylation should be considered in future clinical trials.
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