EMBR-21_Alberto Delaidelli
EMBR-21 CLINICALLY TRACTABLE OUTCOME PREDICTION OF GROUP 3/4 MEDULLOBLASTOMA BASED ON TPD52 IMMUNOHISTOCHEMISTRY: A MULTICOHORT STUDY
Contact Presenter
Alberto Delaidelli1, Christopher Dunham2, Maria Rita Santi3, Gian Luca Negri1, Joanna Triscott4, Olga Zheludkova5, Andrey Golanov6, Marina Ryzhova6, Konstantin Okonechnikov7, Daniel Schrimpf7, Damian Stichel7, Andreas von Deimling7, Marcel Kool7, Stefan Pfister7, Vijay Ramaswamy8, Andrey Korshunov7, Michael Taylor8, Poul Sorensen1;
1BC Cancer Research Centre, Vancouver, BC, Canada. 2BC Children's Hospital, Vancouver, BC, Canada. 3Children's Hospital of Philadelphia, Philadelphia, PA, USA. 4University of Bern, Bern, Switzerland. 5St Luka’s Clinical Research Center for Children, Moscow, Russian Federation. 6Neurosurgical NN Burdenko Institute, Moscow, Russian Federation. 7German Cancer Research Center (DKFZ), Heidelberg, Germany. 8The Arthur and Sonia Labatt Brain Tumour Research Centre, Toronto, ON, Canada
BACKGROUND: International consensus and the 2021 WHO classification recognize eight molecular subtypes among Group 3/4 medulloblastoma (representing ~60% of tumors). However, very few clinical centers worldwide possess the technical capabilities to determine DNA-methylation patterns or other molecular parameters of high-risk for Group 3/4 tumors. As a result, biomarker-driven risk stratification and therapy assignment constitutes a major challenge in medulloblastoma research. Here, we identify an immunohistochemistry (IHC) marker as a clinically tractable method for improved medulloblastoma risk-stratification. PATIENTS and METHODS: We bioinformatically analyzed published medulloblastoma transcriptomes and proteomes identifying as a potential biomarker TPD52, whose IHC prognostic value was validated across three Group 3/4 medulloblastoma clinical cohorts (n = 387) treated with conventional therapies. Risk stratification and prediction capability were computed utilizing uni- and multivariate survival analysis. Newly developed risk classifiers including TPD52 IHC were compared to state-of-the-art risk stratification schemes in terms of prediction error, area under the time-dependent receiver operating characteristic (ROC) curves and C-statistic. Biomarker-driven prognostic stratification models identified were cross validated in different cohorts. RESULTS: TPD52 IHC positivity represents a significant independent predictor of early relapse and death for Group 3/4 medulloblastoma (HRs between 3.67-26.7 [95% CIs between 1.00-706.23], p = 0.05, 0.017 and 0.0058). Cross-validated survival models incorporating TPD52 IHC with clinical features outperformed existing disease risk-stratification schemes, and reclassified ~50% of patients into more appropriate risk categories. Finally, TPD52 immunopositivity is a predictive indicator of poor response to chemotherapy (HR 12.66 [95% CI 3.53-45.40], p < 0.0001), suggesting important implication for therapeutic choices. CONCLUSION: The current study redefines the approach to risk-stratification in Group 3/4 medulloblastoma. Integration of TPD52 IHC in classification algorithms significantly improves outcome prediction and can be rapidly adopted for risk stratification on a global scale, independently of advanced but technically challenging molecular profiling techniques.
Contact Presenter
Alberto Delaidelli1, Christopher Dunham2, Maria Rita Santi3, Gian Luca Negri1, Joanna Triscott4, Olga Zheludkova5, Andrey Golanov6, Marina Ryzhova6, Konstantin Okonechnikov7, Daniel Schrimpf7, Damian Stichel7, Andreas von Deimling7, Marcel Kool7, Stefan Pfister7, Vijay Ramaswamy8, Andrey Korshunov7, Michael Taylor8, Poul Sorensen1;
1BC Cancer Research Centre, Vancouver, BC, Canada. 2BC Children's Hospital, Vancouver, BC, Canada. 3Children's Hospital of Philadelphia, Philadelphia, PA, USA. 4University of Bern, Bern, Switzerland. 5St Luka’s Clinical Research Center for Children, Moscow, Russian Federation. 6Neurosurgical NN Burdenko Institute, Moscow, Russian Federation. 7German Cancer Research Center (DKFZ), Heidelberg, Germany. 8The Arthur and Sonia Labatt Brain Tumour Research Centre, Toronto, ON, Canada
BACKGROUND: International consensus and the 2021 WHO classification recognize eight molecular subtypes among Group 3/4 medulloblastoma (representing ~60% of tumors). However, very few clinical centers worldwide possess the technical capabilities to determine DNA-methylation patterns or other molecular parameters of high-risk for Group 3/4 tumors. As a result, biomarker-driven risk stratification and therapy assignment constitutes a major challenge in medulloblastoma research. Here, we identify an immunohistochemistry (IHC) marker as a clinically tractable method for improved medulloblastoma risk-stratification. PATIENTS and METHODS: We bioinformatically analyzed published medulloblastoma transcriptomes and proteomes identifying as a potential biomarker TPD52, whose IHC prognostic value was validated across three Group 3/4 medulloblastoma clinical cohorts (n = 387) treated with conventional therapies. Risk stratification and prediction capability were computed utilizing uni- and multivariate survival analysis. Newly developed risk classifiers including TPD52 IHC were compared to state-of-the-art risk stratification schemes in terms of prediction error, area under the time-dependent receiver operating characteristic (ROC) curves and C-statistic. Biomarker-driven prognostic stratification models identified were cross validated in different cohorts. RESULTS: TPD52 IHC positivity represents a significant independent predictor of early relapse and death for Group 3/4 medulloblastoma (HRs between 3.67-26.7 [95% CIs between 1.00-706.23], p = 0.05, 0.017 and 0.0058). Cross-validated survival models incorporating TPD52 IHC with clinical features outperformed existing disease risk-stratification schemes, and reclassified ~50% of patients into more appropriate risk categories. Finally, TPD52 immunopositivity is a predictive indicator of poor response to chemotherapy (HR 12.66 [95% CI 3.53-45.40], p < 0.0001), suggesting important implication for therapeutic choices. CONCLUSION: The current study redefines the approach to risk-stratification in Group 3/4 medulloblastoma. Integration of TPD52 IHC in classification algorithms significantly improves outcome prediction and can be rapidly adopted for risk stratification on a global scale, independently of advanced but technically challenging molecular profiling techniques.