Cargando…

Upfront Biology-Guided Therapy in Diffuse Intrinsic Pontine Glioma: Therapeutic, Molecular, and Biomarker Outcomes from PNOC003

PURPOSE: PNOC003 is a multicenter precision medicine trial for children and young adults with newly diagnosed diffuse intrinsic pontine glioma (DIPG). PATIENTS AND METHODS: Patients (3–25 years) were enrolled on the basis of imaging consistent with DIPG. Biopsy tissue was collected for whole-exome a...

Descripción completa

Detalles Bibliográficos
Autores principales: Kline, Cassie, Jain, Payal, Kilburn, Lindsay, Bonner, Erin R., Gupta, Nalin, Crawford, John R., Banerjee, Anu, Packer, Roger J., Villanueva-Meyer, Javier, Luks, Tracy, Zhang, Yalan, Kambhampati, Madhuri, Zhang, Jie, Yadavilli, Sridevi, Zhang, Bo, Gaonkar, Krutika S., Rokita, Jo Lynne, Kraya, Adam, Kuhn, John, Liang, Winnie, Byron, Sara, Berens, Michael, Molinaro, Annette, Prados, Michael, Resnick, Adam, Waszak, Sebastian M., Nazarian, Javad, Mueller, Sabine
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for Cancer Research 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9475246/
https://www.ncbi.nlm.nih.gov/pubmed/35852795
http://dx.doi.org/10.1158/1078-0432.CCR-22-0803
_version_ 1784789871207907328
author Kline, Cassie
Jain, Payal
Kilburn, Lindsay
Bonner, Erin R.
Gupta, Nalin
Crawford, John R.
Banerjee, Anu
Packer, Roger J.
Villanueva-Meyer, Javier
Luks, Tracy
Zhang, Yalan
Kambhampati, Madhuri
Zhang, Jie
Yadavilli, Sridevi
Zhang, Bo
Gaonkar, Krutika S.
Rokita, Jo Lynne
Kraya, Adam
Kuhn, John
Liang, Winnie
Byron, Sara
Berens, Michael
Molinaro, Annette
Prados, Michael
Resnick, Adam
Waszak, Sebastian M.
Nazarian, Javad
Mueller, Sabine
author_facet Kline, Cassie
Jain, Payal
Kilburn, Lindsay
Bonner, Erin R.
Gupta, Nalin
Crawford, John R.
Banerjee, Anu
Packer, Roger J.
Villanueva-Meyer, Javier
Luks, Tracy
Zhang, Yalan
Kambhampati, Madhuri
Zhang, Jie
Yadavilli, Sridevi
Zhang, Bo
Gaonkar, Krutika S.
Rokita, Jo Lynne
Kraya, Adam
Kuhn, John
Liang, Winnie
Byron, Sara
Berens, Michael
Molinaro, Annette
Prados, Michael
Resnick, Adam
Waszak, Sebastian M.
Nazarian, Javad
Mueller, Sabine
author_sort Kline, Cassie
collection PubMed
description PURPOSE: PNOC003 is a multicenter precision medicine trial for children and young adults with newly diagnosed diffuse intrinsic pontine glioma (DIPG). PATIENTS AND METHODS: Patients (3–25 years) were enrolled on the basis of imaging consistent with DIPG. Biopsy tissue was collected for whole-exome and mRNA sequencing. After radiotherapy (RT), patients were assigned up to four FDA-approved drugs based on molecular tumor board recommendations. H3K27M-mutant circulating tumor DNA (ctDNA) was longitudinally measured. Tumor tissue and matched primary cell lines were characterized using whole-genome sequencing and DNA methylation profiling. When applicable, results were verified in an independent cohort from the Children's Brain Tumor Network (CBTN). RESULTS: Of 38 patients enrolled, 28 patients (median 6 years, 10 females) were reviewed by the molecular tumor board. Of those, 19 followed treatment recommendations. Median overall survival (OS) was 13.1 months [95% confidence interval (CI), 11.2–18.4] with no difference between patients who followed recommendations and those who did not. H3K27M-mutant ctDNA was detected at baseline in 60% of cases tested and associated with response to RT and survival. Eleven cell lines were established, showing 100% fidelity of key somatic driver gene alterations in the primary tumor. In H3K27-altered DIPGs, TP53 mutations were associated with worse OS (TP53(mut) 11.1 mo; 95% CI, 8.7–14; TP53(wt) 13.3 mo; 95% CI, 11.8–NA; P = 3.4e−2), genome instability (P = 3.1e−3), and RT resistance (P = 6.4e−4). The CBTN cohort confirmed an association between TP53 mutation status, genome instability, and clinical outcome. CONCLUSIONS: Upfront treatment-naïve biopsy provides insight into clinically relevant molecular alterations and prognostic biomarkers for H3K27-altered DIPGs.
format Online
Article
Text
id pubmed-9475246
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher American Association for Cancer Research
record_format MEDLINE/PubMed
spelling pubmed-94752462023-01-05 Upfront Biology-Guided Therapy in Diffuse Intrinsic Pontine Glioma: Therapeutic, Molecular, and Biomarker Outcomes from PNOC003 Kline, Cassie Jain, Payal Kilburn, Lindsay Bonner, Erin R. Gupta, Nalin Crawford, John R. Banerjee, Anu Packer, Roger J. Villanueva-Meyer, Javier Luks, Tracy Zhang, Yalan Kambhampati, Madhuri Zhang, Jie Yadavilli, Sridevi Zhang, Bo Gaonkar, Krutika S. Rokita, Jo Lynne Kraya, Adam Kuhn, John Liang, Winnie Byron, Sara Berens, Michael Molinaro, Annette Prados, Michael Resnick, Adam Waszak, Sebastian M. Nazarian, Javad Mueller, Sabine Clin Cancer Res Clinical Trials: Targeted Therapy PURPOSE: PNOC003 is a multicenter precision medicine trial for children and young adults with newly diagnosed diffuse intrinsic pontine glioma (DIPG). PATIENTS AND METHODS: Patients (3–25 years) were enrolled on the basis of imaging consistent with DIPG. Biopsy tissue was collected for whole-exome and mRNA sequencing. After radiotherapy (RT), patients were assigned up to four FDA-approved drugs based on molecular tumor board recommendations. H3K27M-mutant circulating tumor DNA (ctDNA) was longitudinally measured. Tumor tissue and matched primary cell lines were characterized using whole-genome sequencing and DNA methylation profiling. When applicable, results were verified in an independent cohort from the Children's Brain Tumor Network (CBTN). RESULTS: Of 38 patients enrolled, 28 patients (median 6 years, 10 females) were reviewed by the molecular tumor board. Of those, 19 followed treatment recommendations. Median overall survival (OS) was 13.1 months [95% confidence interval (CI), 11.2–18.4] with no difference between patients who followed recommendations and those who did not. H3K27M-mutant ctDNA was detected at baseline in 60% of cases tested and associated with response to RT and survival. Eleven cell lines were established, showing 100% fidelity of key somatic driver gene alterations in the primary tumor. In H3K27-altered DIPGs, TP53 mutations were associated with worse OS (TP53(mut) 11.1 mo; 95% CI, 8.7–14; TP53(wt) 13.3 mo; 95% CI, 11.8–NA; P = 3.4e−2), genome instability (P = 3.1e−3), and RT resistance (P = 6.4e−4). The CBTN cohort confirmed an association between TP53 mutation status, genome instability, and clinical outcome. CONCLUSIONS: Upfront treatment-naïve biopsy provides insight into clinically relevant molecular alterations and prognostic biomarkers for H3K27-altered DIPGs. American Association for Cancer Research 2022-09-15 2022-07-19 /pmc/articles/PMC9475246/ /pubmed/35852795 http://dx.doi.org/10.1158/1078-0432.CCR-22-0803 Text en ©2022 The Authors; Published by the American Association for Cancer Research https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license.
spellingShingle Clinical Trials: Targeted Therapy
Kline, Cassie
Jain, Payal
Kilburn, Lindsay
Bonner, Erin R.
Gupta, Nalin
Crawford, John R.
Banerjee, Anu
Packer, Roger J.
Villanueva-Meyer, Javier
Luks, Tracy
Zhang, Yalan
Kambhampati, Madhuri
Zhang, Jie
Yadavilli, Sridevi
Zhang, Bo
Gaonkar, Krutika S.
Rokita, Jo Lynne
Kraya, Adam
Kuhn, John
Liang, Winnie
Byron, Sara
Berens, Michael
Molinaro, Annette
Prados, Michael
Resnick, Adam
Waszak, Sebastian M.
Nazarian, Javad
Mueller, Sabine
Upfront Biology-Guided Therapy in Diffuse Intrinsic Pontine Glioma: Therapeutic, Molecular, and Biomarker Outcomes from PNOC003
title Upfront Biology-Guided Therapy in Diffuse Intrinsic Pontine Glioma: Therapeutic, Molecular, and Biomarker Outcomes from PNOC003
title_full Upfront Biology-Guided Therapy in Diffuse Intrinsic Pontine Glioma: Therapeutic, Molecular, and Biomarker Outcomes from PNOC003
title_fullStr Upfront Biology-Guided Therapy in Diffuse Intrinsic Pontine Glioma: Therapeutic, Molecular, and Biomarker Outcomes from PNOC003
title_full_unstemmed Upfront Biology-Guided Therapy in Diffuse Intrinsic Pontine Glioma: Therapeutic, Molecular, and Biomarker Outcomes from PNOC003
title_short Upfront Biology-Guided Therapy in Diffuse Intrinsic Pontine Glioma: Therapeutic, Molecular, and Biomarker Outcomes from PNOC003
title_sort upfront biology-guided therapy in diffuse intrinsic pontine glioma: therapeutic, molecular, and biomarker outcomes from pnoc003
topic Clinical Trials: Targeted Therapy
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9475246/
https://www.ncbi.nlm.nih.gov/pubmed/35852795
http://dx.doi.org/10.1158/1078-0432.CCR-22-0803
work_keys_str_mv AT klinecassie upfrontbiologyguidedtherapyindiffuseintrinsicpontinegliomatherapeuticmolecularandbiomarkeroutcomesfrompnoc003
AT jainpayal upfrontbiologyguidedtherapyindiffuseintrinsicpontinegliomatherapeuticmolecularandbiomarkeroutcomesfrompnoc003
AT kilburnlindsay upfrontbiologyguidedtherapyindiffuseintrinsicpontinegliomatherapeuticmolecularandbiomarkeroutcomesfrompnoc003
AT bonnererinr upfrontbiologyguidedtherapyindiffuseintrinsicpontinegliomatherapeuticmolecularandbiomarkeroutcomesfrompnoc003
AT guptanalin upfrontbiologyguidedtherapyindiffuseintrinsicpontinegliomatherapeuticmolecularandbiomarkeroutcomesfrompnoc003
AT crawfordjohnr upfrontbiologyguidedtherapyindiffuseintrinsicpontinegliomatherapeuticmolecularandbiomarkeroutcomesfrompnoc003
AT banerjeeanu upfrontbiologyguidedtherapyindiffuseintrinsicpontinegliomatherapeuticmolecularandbiomarkeroutcomesfrompnoc003
AT packerrogerj upfrontbiologyguidedtherapyindiffuseintrinsicpontinegliomatherapeuticmolecularandbiomarkeroutcomesfrompnoc003
AT villanuevameyerjavier upfrontbiologyguidedtherapyindiffuseintrinsicpontinegliomatherapeuticmolecularandbiomarkeroutcomesfrompnoc003
AT lukstracy upfrontbiologyguidedtherapyindiffuseintrinsicpontinegliomatherapeuticmolecularandbiomarkeroutcomesfrompnoc003
AT zhangyalan upfrontbiologyguidedtherapyindiffuseintrinsicpontinegliomatherapeuticmolecularandbiomarkeroutcomesfrompnoc003
AT kambhampatimadhuri upfrontbiologyguidedtherapyindiffuseintrinsicpontinegliomatherapeuticmolecularandbiomarkeroutcomesfrompnoc003
AT zhangjie upfrontbiologyguidedtherapyindiffuseintrinsicpontinegliomatherapeuticmolecularandbiomarkeroutcomesfrompnoc003
AT yadavillisridevi upfrontbiologyguidedtherapyindiffuseintrinsicpontinegliomatherapeuticmolecularandbiomarkeroutcomesfrompnoc003
AT zhangbo upfrontbiologyguidedtherapyindiffuseintrinsicpontinegliomatherapeuticmolecularandbiomarkeroutcomesfrompnoc003
AT gaonkarkrutikas upfrontbiologyguidedtherapyindiffuseintrinsicpontinegliomatherapeuticmolecularandbiomarkeroutcomesfrompnoc003
AT rokitajolynne upfrontbiologyguidedtherapyindiffuseintrinsicpontinegliomatherapeuticmolecularandbiomarkeroutcomesfrompnoc003
AT krayaadam upfrontbiologyguidedtherapyindiffuseintrinsicpontinegliomatherapeuticmolecularandbiomarkeroutcomesfrompnoc003
AT kuhnjohn upfrontbiologyguidedtherapyindiffuseintrinsicpontinegliomatherapeuticmolecularandbiomarkeroutcomesfrompnoc003
AT liangwinnie upfrontbiologyguidedtherapyindiffuseintrinsicpontinegliomatherapeuticmolecularandbiomarkeroutcomesfrompnoc003
AT byronsara upfrontbiologyguidedtherapyindiffuseintrinsicpontinegliomatherapeuticmolecularandbiomarkeroutcomesfrompnoc003
AT berensmichael upfrontbiologyguidedtherapyindiffuseintrinsicpontinegliomatherapeuticmolecularandbiomarkeroutcomesfrompnoc003
AT molinaroannette upfrontbiologyguidedtherapyindiffuseintrinsicpontinegliomatherapeuticmolecularandbiomarkeroutcomesfrompnoc003
AT pradosmichael upfrontbiologyguidedtherapyindiffuseintrinsicpontinegliomatherapeuticmolecularandbiomarkeroutcomesfrompnoc003
AT resnickadam upfrontbiologyguidedtherapyindiffuseintrinsicpontinegliomatherapeuticmolecularandbiomarkeroutcomesfrompnoc003
AT waszaksebastianm upfrontbiologyguidedtherapyindiffuseintrinsicpontinegliomatherapeuticmolecularandbiomarkeroutcomesfrompnoc003
AT nazarianjavad upfrontbiologyguidedtherapyindiffuseintrinsicpontinegliomatherapeuticmolecularandbiomarkeroutcomesfrompnoc003
AT muellersabine upfrontbiologyguidedtherapyindiffuseintrinsicpontinegliomatherapeuticmolecularandbiomarkeroutcomesfrompnoc003