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  • 1
    Online Resource
    Online Resource
    Early Postoperative Treatment versus Initial Observation in CNS WHO Grade 2 and 3 Oligodendroglioma: Clinical Outcomes and DNA Methylation Patterns
    American Association for Cancer Research (AACR) ; 2022
    In:  Clinical Cancer Research Vol. 28, No. 20 ( 2022-10-14), p. 4565-4573
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 28, No. 20 ( 2022-10-14), p. 4565-4573
    Abstract: The treatment of oligodendroglioma consists of tumor resection and radiochemotherapy. The timing of radiochemotherapy remains unclear, and predictive biomarkers are limited. Experimental Design: Adult patients diagnosed with isocitrate dehydrogenase (IDH)-mutated, 1p/19q-codeleted CNS WHO grade 2 and 3 oligodendroglioma at the Medical University of Vienna and the Kepler University Hospital Linz (Austria) in 1992 to 2019 were included. Progression-free (PFS) and overall survival (OS) between early postoperative treatment and initial observation were compared using propensity score–weighted Cox regression models. DNA methylation analysis of tumor tissue was performed using Illumina MethylationEPIC 850k microarrays. Results: One hundred thirty-one out of 201 (65.2%) patients with CNS WHO grade 2 and 70 of 201 (34.8%) with grade 3 oligodendroglioma were identified. Eighty-three of 201 (41.3%) patients underwent early postoperative treatment, of whom 56 of 83 (67.5%) received radiochemotherapy, 15 of 84 (18.1%) radiotherapy (RT) only and 12 of 83 (14.5%) chemotherapy only. Temozolomide-based treatment was administered to 64 of 68 (94.1%) patients, whereas RT + procarbazine, lomustine (CCNU), and vincristine (PCV) were applied in 2 of 69 (3.5%) patients. Early treatment was not associated with PFS [adjusted hazard ratio (HR) 0.74; 95% CI, 0.33–1.65, P = 0.459] or OS (adjusted HR: 2.07; 95% CI, 0.52–8.21, P = 0.302) improvement. Unsupervised clustering analysis of DNA methylation profiles from patients receiving early treatment revealed two methylation clusters correlating with PFS, whereas no association of clustering with O6-methylguanine methyltransferase (MGMT) promoter methylation, CNS WHO grade, extent of resection, and treating center could be observed. Conclusions: In this retrospective study, early postoperative treatment was not associated with improved PFS/OS in oligodendroglioma. The potentially predictive value of whole-genome methylation profiling should be validated in prospective trials.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-22-1133
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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    detail.hit.zdb_id: 2036787-9
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  • 2
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    DNA methylation profiling in patients with head and neck squamous cell carcinoma treated with immune checkpoint inhibitors.
    American Society of Clinical Oncology (ASCO) ; 2020
    In:  Journal of Clinical Oncology Vol. 38, No. 15_suppl ( 2020-05-20), p. e18527-e18527
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 38, No. 15_suppl ( 2020-05-20), p. e18527-e18527
    Abstract: e18527 Background: Biomarkers for response prediction to immune checkpoint inhibitors in head and neck squamous cell carcinoma (HNSCC) patients are needed for a personalized therapy regimen. Therefore, we investigated the predictive potential of inflammatory biomarkers and DNA methylation. Methods: We profiled the methylation status of 850.000 CpG sites in formalin-fixed, paraffin-embedded primary HNSCC samples collected before ICI therapy start using Infinium Methylation EPIC microarrays. Tumor-infiltrating lymphocytes (TILs) and programmed cell death ligand 1 (PD-L1) expression were analyzed employing immunohistochemistry staining. Methylation profile, TIL density and PD-L1 expression were correlated with best radiological response to ICI treatment. Results: 29 patients (median age of 61; range 28-80) years; 8 (27.6%) females, 21 (72.4%) males) with HNSCC were included. Median number of prior systemic therapies was 1 (range 0-3). Median number of ICI applications was 6 (range 1-45). 2/29 (6.9%) patients achieved an objective response (complete response or partial response) under anti-PD-1 therapy. Median progression-free survival (PFS) and median overall survival (OS) were 3.3 months (range 0-28.8) and 7.2 months (range 0-29.4), respectively. 7/29 (24.1%) patients were still alive and one of these patients was still on ICI therapy at data cut-off. Methylation analyses revealed a combination of methylation changes (both hypo- and hypermethylation) that was predictive for response to ICI. 11/27 (40.7%) patients had PD-L1 expressing tumor cells ( 〉 1% PD-L1 expression). Median density of CD8+ TILs was 423.49 cells/mm 2 tumor (range 5.71-11528.43 cells/mm 2 ) and median density of CD3+ TILs was 794.82 cells/mm 2 tumor (range 1.68-8811.74 cells/mm 2 ). There was no correlation of PD-L1 expression, density of CD8+ or CD3+ TILs with response or disease control (p 〉 0.05). Conclusions: In contrast to PD-L1 expression and TIL density, methylation profiles were associated with response to ICI treatment in HNSCC patients.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2020.38.15_suppl.e18527
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2020
    detail.hit.zdb_id: 2005181-5
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  • 3
    Online Resource
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    Correlation of DNA methylation signatures with response to immune checkpoint inhibitors in metastatic melanoma.
    American Society of Clinical Oncology (ASCO) ; 2023
    In:  Journal of Clinical Oncology Vol. 41, No. 16_suppl ( 2023-06-01), p. 9561-9561
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 16_suppl ( 2023-06-01), p. 9561-9561
    Abstract: 9561 Background: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of metastatic melanoma with objective response rates of 40-58%. However, reliable biomarkers to predict treatment response are lacking. Tumor tissue methylation profiles were recently proposed to have predictive value in various solid organ tumor entities. Methods: Patients with metastatic melanoma, American Joint Committee on Cancer (AJCC; 8 th Edition) stage IV, receiving first-line ICI-based therapy, were retrospectively identified and formalin-fixed paraffin-embedded tumor tissue samples (FFPE) prior to ICI therapy were retrieved. We analyzed DNA methylation profiles of 〉 850.000 CpG sites in tumor specimens by Infinium MethylationEPIC microarrays. DNA methylation profiles were then correlated with radiological response (iRECIST). Results: 71 patients with metastatic melanoma (44 (62.0%) male, 27 (38.0%) female) were investigated; median progression free survival (PFS) was 8.5 months (range: 0 – 104.1 months) and median overall survival (OS) was 30.6 months (range: 0 – 104.1 months), respectively. 29 (40.8%) patients achieved an objective response to ICIs. Microarray analyses revealed a methylation signature including mainly hypomethylation, corresponding to the response to ICIs. Based on the 500 mostly differentially methylated genes, a total of 3 clusters were identified with the majority of responders being in cluster 2 (12/12) and 3 (12/22). The predictive performance of the methylation signature was high with 80% sensitivity, 81% specificity, and an AUC of 0.853. Conclusions: Our findings suggest that tumor DNA methylation profiling may be useful to predict response to ICIs in patients with metastatic melanoma.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2023.41.16_suppl.9561
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
    detail.hit.zdb_id: 2005181-5
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  • 4
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    DNA methylation profiles differ in responders versus non-responders to anti-PD-1 immune checkpoint inhibitors in patients with advanced and metastatic head and neck squamous cell carcinoma
    BMJ ; 2022
    In:  Journal for ImmunoTherapy of Cancer Vol. 10, No. 3 ( 2022-03), p. e003420-
    Details
    In: Journal for ImmunoTherapy of Cancer, BMJ, Vol. 10, No. 3 ( 2022-03), p. e003420-
    Abstract: Biomarkers for response prediction to anti-programmed cell death 1 (PD-1) immune checkpoint inhibitors (ICI) in patients with head and neck squamous cell carcinoma (HNSCC) are urgently needed for a personalized therapy approach. We investigated the predictive potential of inflammatory parameters and DNA methylation profiling in patients with HNSCC treated with anti-PD-1 ICI. Methods We identified patients with HNSCC that were treated with anti-PD-1 ICI therapy in the recurrent or metastatic setting after progression to platinum-based chemotherapy in two independent centers. We analyzed DNA methylation profiles of 〉 850.000 CpG sites in tumor specimens of these patients by Infinium MethylationEPIC microarrays, immune cell density in the tumor microenvironment (CD8, CD3, CD45RO, forkhead box P3 (FOXP3), CD68), PD-1 and programmed cell death ligand 1 (PD-L1) expression by immunohistochemistry, and blood inflammation markers (platelet-to-lymphocyte ratio, leucocyte-to-lymphocyte ratio, monocyte-to-lymphocyte ratio, neutrophil-to-lymphocyte ratio). DNA methylation profiles and immunological markers were bioinformatically and statistically correlated with radiological response to anti-PD-1 ICI. Results 37 patients with HNSCC (median age of 62 years; range 49–83; 8 (21.6%) women, 29 (78.4%) men) were included (Center 1 N=26, 70.3%; Center 2 N=11, 29.7%). Median number of prior systemic therapies was 1 (range 1–4). Five out of 37 (13.5%) patients achieved an objective response to ICI. Median progression-free survival and median overall survival times were 3.7 months (range 0–22.9) and 9.0 months (range 0–38.8), respectively. Microarray analyses revealed a methylation signature including both hypomethylation and hypermethylation which was predictive for response to ICI and included several genes involved in cancer-related molecular pathways. Over-represented differentially methylated genes between responders and non-responders were associated with ‘Axon guidance’, ‘Hippo signaling’, ‘Pathways in cancer’ and ‘MAPK signaling’. A statistically significant correlation of PD-L1 expression and response was present (p=0.0498). Conclusions Our findings suggest that tumor DNA methylation profiling may be useful to predict response to ICI in patients with HNSCC.
    Type of Medium: Online Resource
    ISSN: 2051-1426
    URL: Article
    DOI: 10.1136/jitc-2021-003420
    Language: English
    Publisher: BMJ
    Publication Date: 2022
    detail.hit.zdb_id: 2719863-7
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  • 5
    Online Resource
    Online Resource
    Frequent Overexpression of HER3 in Brain Metastases from Breast and Lung Cancer
    American Association for Cancer Research (AACR) ; 2023
    In:  Clinical Cancer Research Vol. 29, No. 16 ( 2023-08-15), p. 3225-3236
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 29, No. 16 ( 2023-08-15), p. 3225-3236
    Abstract: HER3 belongs to a family of receptor tyrosine kinases with oncogenic properties and is targeted by a variety of novel anticancer agents. There is a huge unmet medical need for systemic treatment options in patients with brain metastases (BM). Therefore, we aimed to investigate HER3 expression in BM of breast (BCa) and non–small cell lung cancer (NSCLC) as the basis for future clinical trial design. Experimental Design: We analyzed 180 BM samples of breast cancer or NSCLC and 47 corresponding NSCLC extracranial tissue. IHC was performed to evaluate protein expression of HER3, and immune cells based on CD3, CD8, and CD68. To identify dysregulated pathways based on differential DNA methylation patterns, we used Infinium MethylationEPIC microarrays. Results: A total of 99/132 (75.0%) of BCa-BM and 35/48 (72.9%) of NSCLC-BM presented with HER3 expression. Among breast cancer, HER2-positive and HER2-low BM showed significantly higher rates of HER3 coexpression than HER2-negative BM (87.1%/85.7% vs. 61.0%, P = 0.004). Among NSCLC, HER3 was more abundantly expressed in BM than in matched extracranial samples (72.9% vs. 41.3%, P = 0.003). No correlation of HER3 expression and intratumoral immune cell density was observed. HER3 expression did not correlate with overall survival from BM diagnosis. Methylation signatures differed according to HER3 status in BCa-BM samples. Pathway analysis revealed subtype-specific differences, such as TrkB and Wnt signaling pathways dysregulated in HER2-positive and triple-negative breast cancer BM, respectively. Conclusions: HER3 is highly abundant in BM of breast cancer and NSCLC. Given the promising results of antibody–drug conjugates in extracranial disease, BM-specific trials that target HER3 are warranted. See related commentary by Kabraji and Lin, p. 2961
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-23-0020
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
    detail.hit.zdb_id: 1225457-5
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  • 6
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    Online Resource
    Tumor DNA methylation profiles correlate with response to anti-PD-1 immune checkpoint inhibitor monotherapy in sarcoma patients
    BMJ ; 2021
    In:  Journal for ImmunoTherapy of Cancer Vol. 9, No. 3 ( 2021-03), p. e001458-
    Details
    In: Journal for ImmunoTherapy of Cancer, BMJ, Vol. 9, No. 3 ( 2021-03), p. e001458-
    Abstract: Some sarcomas respond to immune checkpoint inhibition, but predictive biomarkers are unknown. We analyzed tumor DNA methylation profiles in relation to immunological parameters and response to anti-programmed cell death 1 (anti-PD-1) immune checkpoint inhibitor (ICI) therapy in patients with sarcoma. Patients and methods We retrospectively identified adult patients who had received anti-PD-1 ICI therapy for recurrent sarcoma in two independent centers. We performed (1) blinded radiological response evaluation according to immune response evaluation criteria in solid tumors (iRECIST) ; (2) tumor DNA methylation profiling of 〉 850,000 probes using Infinium MethylationEPIC microarrays; (3) analysis of tumor-infiltrating immune cell subsets (CD3, CD8, CD45RO, FOXP3) and intratumoral expression of immune checkpoint molecules (PD-L1, PD-1, LAG-3) using immunohistochemistry; and (4) evaluation of blood-based systemic inflammation scores (neutrophil-to-lymphocyte ratio, leucocyte-to-lymphocyte ratio, monocyte-to-lymphocyte ratio, platelet-to-lymphocyte ratio). Response to anti-PD-1 ICI therapy was bioinformatically and statistically correlated with DNA methylation profiles and immunological data. Results 35 patients (median age of 50 (23–81) years; 18 females, 17 males; 27 soft tissue sarcomas; 8 osteosarcomas) were included in this study. The objective response rate to anti-PD-1 ICI therapy was 22.9% with complete responses in 3 out of 35 and partial responses in 5 out of 35 patients. Adjustment of DNA methylation data for tumor-infiltrating immune cells resulted in identification of methylation differences between responders and non-responders to anti-PD-1 ICI. 2453 differentially methylated CpG sites (DMPs; 2043 with decreased and 410 with increased methylation) were identified. Clustering of sarcoma samples based on these DMPs revealed two main clusters: methylation cluster 1 (MC1) consisted of 73% responders and methylation cluster 2 (MC2) contained only non-responders to anti-PD-1 ICI. Median progression-free survival from anti-PD-1 therapy start of MC1 and MC2 patients was 16.5 and 1.9 months, respectively (p=0.001). Median overall survival of these patients was 34.4 and 8.0 months, respectively (p=0.029). The most prominent DNA methylation differences were found in pathways implicated in Rap1 signaling, focal adhesion, adherens junction Phosphoinositide 3-kinase (PI3K)-Akt signaling and extracellular matrix (ECM)–receptor interaction. Conclusions Our data demonstrate that tumor DNA methylation profiles may serve as a predictive marker for response to anti-PD-1 ICI therapy in sarcoma.
    Type of Medium: Online Resource
    ISSN: 2051-1426
    URL: Article
    DOI: 10.1136/jitc-2020-001458
    Language: English
    Publisher: BMJ
    Publication Date: 2021
    detail.hit.zdb_id: 2719863-7
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  • 7
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    Immune cell distribution and DNA methylation signatures differ between tumor and stroma enriched compartment in pancreatic ductal adenocarcinoma
    Elsevier BV ; 2024
    In:  Translational Research Vol. 271 ( 2024-09), p. 40-51
    Details
    In: Translational Research, Elsevier BV, Vol. 271 ( 2024-09), p. 40-51
    Type of Medium: Online Resource
    ISSN: 1931-5244
    URL: Article
    DOI: 10.1016/j.trsl.2024.05.005
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2024
    detail.hit.zdb_id: 2252085-5
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