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Two targets with one arrow: #Immunotherapy as single treatment for synchronous RRD #glioblastoma and #metastatic cancers. [ABSTRACT FROM AUTHOR]

(A) Timeline of first surgery, tumor regrowth, second surgery, initiation of nivolumab, and follow-up. (B) Histopathology confirming glioblastoma and loss of staining of PMS2 and MLH1 in tumor cells only, and retained in normal cells, along with staining retained in tumor cells for MSH2 and MSH6. Pediatric glioblastoma (GBM) accounts for up to 15% of primary CNS neoplasms in children and is the leading cause of death among this group. As family history and clinical phenotypes may be insufficient to uncover RRD in GBM, molecular tumor analysis should be performed in all patients because of the potential therapeutic benefits. [Extracted from the article]

Purpose: Molecular characterization is key to optimally diagnose and manage cancer. The complexity and cost of routine genomic analysis have unfortunately limited its use and denied many patients access to precision medicine. A possible solution is to rationalize use-creating a tiered approach to testing which uses inexpensive techniques for most patients and limits expensive testing to patients with the highest needs. Here, we tested the utility of this approach to molecularly characterize pediatric glioma in a cost- and time-sensitive manner., Methods: We used a tiered testing pipeline of immunohistochemistry (IHC), customized fusion panels or fluorescence in situ hybridization (FISH), and targeted RNA sequencing in pediatric gliomas. Two distinct diagnostic algorithms were used for low- and high-grade gliomas (LGGs and HGGs). The percentage of driver alterations identified, associated testing costs, and turnaround time (TAT) are reported., Results: The tiered approach successfully characterized 96% (95 of 99) of gliomas. For 82 LGGs, IHC, targeted fusion panel or FISH, and targeted RNA sequencing solved 35% (29 of 82), 29% (24 of 82), and 30% (25 of 82) of cases, respectively. A total of 64% (53 of 82) of samples were characterized without targeted RNA sequencing. Of 17 HGG samples, 13 were characterized by IHC and four were characterized by targeted RNA sequencing. The average cost per sample was more affordable when using the tiered approach as compared with up-front targeted RNA sequencing in LGG ($405 US dollars [USD] v $745 USD) and HGGs ($282 USD v $745 USD). The average TAT per sample was also shorter using the tiered approach (10 days for LGG, 5 days for HGG v 14 days for targeted RNA sequencing)., Conclusion: Our tiered approach molecularly characterized 96% of samples in a cost- and time-sensitive manner. Such an approach may be feasible in neuro-oncology centers worldwide, particularly in resource-limited settings.

Purpose: Diagnosis of Mismatch Repair Deficiency (MMRD) is crucial for tumor management and early detection in patients with the cancer predisposition syndrome constitutional mismatch repair deficiency (CMMRD). Current diagnostic tools are cumbersome and inconsistent both in childhood cancers and in determining germline MMRD., Patients and Methods: We developed and analyzed a functional Low-pass Genomic Instability Characterization (LOGIC) assay to detect MMRD. The diagnostic performance of LOGIC was compared with that of current established assays including tumor mutational burden, immunohistochemistry, and the microsatellite instability panel. LOGIC was then applied to various normal tissues of patients with CMMRD with comprehensive clinical data including age of cancer presentation., Results: Overall, LOGIC was 100% sensitive and specific in detecting MMRD in childhood cancers (N = 376). It was more sensitive than the microsatellite instability panel (14%, P = 4.3 × 10 -12 ), immunohistochemistry (86%, P = 4.6 × 10 -3 ), or tumor mutational burden (80%, P = 9.1 × 10 -4 ). LOGIC was able to distinguish CMMRD from other cancer predisposition syndromes using blood and saliva DNA ( P < .0001, n = 277). In normal cells, MMRDness scores differed between tissues (GI > blood > brain), increased over time in the same individual, and revealed genotype-phenotype associations within the mismatch repair genes. Importantly, increased MMRDness score was associated with younger age of first cancer presentation in individuals with CMMRD ( P = 2.2 × 10 -5 )., Conclusion: LOGIC was a robust tool for the diagnosis of MMRD in multiple cancer types and in normal tissues. LOGIC may inform therapeutic cancer decisions, provide rapid diagnosis of germline MMRD, and support tailored surveillance for individuals with CMMRD.

Purpose: Constitutional mismatch repair deficiency syndrome (CMMRD) is a lethal cancer predisposition syndrome characterized by early-onset synchronous and metachronous multiorgan tumors. We designed a surveillance protocol for early tumor detection in these individuals., Patients and Methods: Data were collected from patients with confirmed CMMRD who were registered in the International Replication Repair Deficiency Consortium. Tumor spectrum, efficacy of the surveillance protocol, and malignant transformation of low-grade lesions were examined for the entire cohort. Survival outcomes were analyzed for patients followed prospectively from the time of surveillance implementation., Results: A total of 193 malignant tumors in 110 patients were identified. Median age of first cancer diagnosis was 9.2 years (range: 1.7-39.5 years). For patients undergoing surveillance, all GI and other solid tumors, and 75% of brain cancers were detected asymptomatically. By contrast, only 16% of hematologic malignancies were detected asymptomatically ( P < .001). Eighty-nine patients were followed prospectively and used for survival analysis. Five-year overall survival (OS) was 90% (95% CI, 78.6 to 100) and 50% (95% CI, 39.2 to 63.7) when cancer was detected asymptomatically and symptomatically, respectively ( P = .001). Patient outcome measured by adherence to the surveillance protocol revealed 4-year OS of 79% (95% CI, 54.8 to 90.9) for patients undergoing full surveillance, 55% (95% CI, 28.5 to 74.5) for partial surveillance, and 15% (95% CI, 5.2 to 28.8) for those not under surveillance ( P < .0001). Of the 64 low-grade tumors detected, the cumulative likelihood of transformation from low-to high-grade was 81% for GI cancers within 8 years and 100% for gliomas in 6 years., Conclusion: Surveillance and early cancer detection are associated with improved OS for individuals with CMMRD., Competing Interests: Hagit N. BarisConsulting or Advisory Role: Sanofi, Igentify LtdSpeakers' Bureau: Sanofi, Takeda, Pfizer Donald BaselHonoraria: BioMarinConsulting or Advisory Role: iQvia Deborah T. BlumenthalConsulting or Advisory Role: AstraZeneca, Novocure, Takeda Miriam BornhorstConsulting or Advisory Role: AstraZeneca/MedImmune Sara RhodeHonoraria: Myriad GeneticsSpeakers' Bureau: Myriad GeneticsTravel, Accommodations, Expenses: Myriad Genetics Roula FarahHonoraria: Novo NordiskConsulting or Advisory Role: Novo Nordisk William D. FoulkesResearch Funding: AstraZeneca David GassEmployment: X4 PharmaceuticalsHonoraria: X4 PharmaceuticalsSpeakers' Bureau: Precisionscientia Heather HampelStock and Other Ownership Interests: Genome MedicalConsulting or Advisory Role: InVitae, Genome Medical, Promega, 23andMe Jordan R. HansfordConsulting or Advisory Role: Bayer Craig HarlosTravel, Accommodations, Expenses: GlaxoSmithKline Nobuko HijiyaHonoraria: NovartisConsulting or Advisory Role: Novartis, IncyteResearch Funding: Pfizer Junne KamiharaStock and Other Ownership Interests: PanTher Therapeutics, ROME Therapeutics, TellBioHonoraria: Pfizer, NanoString Technologies, Third Rock Ventures, Foundation MedicineConsulting or Advisory Role: ROME Therapeutics, Third Rock VenturesResearch Funding: PureTech, Ribon Therapeutics, ACD BiotechnePatents, Royalties, Other Intellectual Property: Patent on drug delivery device licensed to PanTher Therapeutics, Patents on Repeat RNA biomarkers and therapeutics licensed to Rome Therapeutics, Patents on Circulating Tumor Cell Biomarkers Licensed to TellBio Inc Jeffrey KnipsteinEmployment: PRA Health SciencesConsulting or Advisory Role: Atheneum Alvaro LassalettaStock and Other Ownership Interests: Gilead SciencesConsulting or Advisory Role: Shire, Jazz Pharmaceuticals, Roche, ServierTravel, Accommodations, Expenses: Shire, Gilead Sciences Simon C. LingHonoraria: AbbvieResearch Funding: Abbvie, Gilead Sciences Michael P. LinkConsulting or Advisory Role: Incyte, ADC Therapeutics, Lilly, Steba Biotech, Mesoblast, GlaxoSmithKline, SyndaxResearch Funding: Seattle Genetics, Janssen Oncology Rebecca Loret de MolaEmployment: Huron Consulting Maura MassiminoConsulting or Advisory Role: Oncoscience, Novartis Gary MasonEmployment: Janssen Research & Development, MerckStock and Other Ownership Interests: Johnson & Johnson, MerckTravel, Accommodations, Expenses: Janssen Research & Development Kim E. NicholsStock and Other Ownership Interests: IncyteResearch Funding: Incyte/Novartis, Alpine Immune Sciences Enrico OpocherConsulting or Advisory Role: AstraZenecaTravel, Accommodations, Expenses: AstraZeneca Michael OsbornTravel, Accommodations, Expenses: Amgen, Pfizer Benjamin OshrineHonoraria: Mesoblast Alyssa ReddyConsulting or Advisory Role: Novartis, AstraZeneca Lara ReichmanResearch Funding: Illumina Marc RemkeStock and Other Ownership Interests: Bayer, BB Biotech Ventures, BioNTech AG, InVitae, IDEXX Laboratories Kami Wolfe SchneiderOther Relationship: Journal of Genetic Counseling Duncan StearnsConsulting or Advisory Role: AstraZenecaOpen Payments Link: https://openpaymentsdata.cms.gov/physician/792397 Patrick TombocHonoraria: Unicare Health PlanConsulting or Advisory Role: UniCare Health Plan An Van DammeConsulting or Advisory Role: Octapharm, Pfizer, BayerResearch Funding: Johnson & JohnsonTravel, Accommodations, Expenses: Pfizer, Sobi, Shire, Roche Ira WinerResearch Funding: Oncoceutics David S. ZieglerConsulting or Advisory Role: Bayer, AmgenTravel, Accommodations, Expenses: Bayer Cynthia HawkinsConsulting or Advisory Role: BayerPatents, Royalties, Other Intellectual Property: IP for low-grade glioma and sarcoma fusion panels as well as medulloblastoma subgrouping panel David MalkinConsulting or Advisory Role: Bayer Eric BouffetConsulting or Advisory Role: NovartisResearch Funding: Roche, Bristol Myers SquibbNo other potential conflicts of interest were reported.

Purpose: We sought to investigate clinical outcomes of relapsed medulloblastoma and to compare molecular features between patient-matched diagnostic and relapsed tumors., Methods: Children and infants enrolled on either SJMB03 (NCT00085202) or SJYC07 (NCT00602667) trials who experienced medulloblastoma relapse were analyzed for clinical outcomes, including anatomic and temporal patterns of relapse and postrelapse survival. A largely independent, paired molecular cohort was analyzed by DNA methylation array and next-generation sequencing., Results: A total of 72 of 329 (22%) SJMB03 and 52 of 79 (66%) SJYC07 patients experienced relapse with significant representation of Group 3 and wingless tumors. Although most patients exhibited some distal disease (79%), 38% of patients with sonic hedgehog tumors experienced isolated local relapse. Time to relapse and postrelapse survival varied by molecular subgroup with longer latencies for patients with Group 4 tumors. Postrelapse radiation therapy among previously nonirradiated SJYC07 patients was associated with long-term survival. Reirradiation was only temporizing for SJMB03 patients. Among 127 patients with patient-matched tumor pairs, 9 (7%) experienced subsequent nonmedulloblastoma CNS malignancies. Subgroup (96%) and subtype (80%) stabilities were largely maintained among the remainder. Rare subgroup divergence was observed from Group 4 to Group 3 tumors, which is coincident with genetic alterations involving MYC , MYCN , and FBXW7 . Subgroup-specific patterns of alteration were identified for driver genes and chromosome arms., Conclusion: Clinical behavior of relapsed medulloblastoma must be contextualized in terms of up-front therapies and molecular classifications. Group 4 tumors exhibit slower biological progression. Utility of radiation at relapse is dependent on patient age and prior treatments. Degree and patterns of molecular conservation at relapse vary by subgroup. Relapse tissue enables verification of molecular targets and identification of occult secondary malignancies.

Purpose: Children with pediatric gliomas harboring a BRAF V600E mutation have poor outcomes with current chemoradiotherapy strategies. Our aim was to study the role of targeted BRAF inhibition in these tumors., Patients and Methods: We collected clinical, imaging, molecular, and outcome information from patients with BRAF V600E-mutated glioma treated with BRAF inhibition across 29 centers from multiple countries., Results: Sixty-seven patients were treated with BRAF inhibition (pediatric low-grade gliomas [PLGGs], n = 56; pediatric high-grade gliomas [PHGGs], n = 11) for up to 5.6 years. Objective responses were observed in 80% of PLGGs, compared with 28% observed with conventional chemotherapy ( P < .001). These responses were rapid (median, 4 months) and sustained in 86% of tumors up to 5 years while receiving therapy. After discontinuation of BRAF inhibition, 76.5% (13 of 17) of patients with PLGG experienced rapid progression (median, 2.3 months). However, upon rechallenge with BRAF inhibition, 90% achieved an objective response. Poor prognostic factors in conventional therapies, such as concomitant homozygous deletion of CDKN2A , were not associated with lack of response to BRAF inhibition. In contrast, only 36% of those with PHGG responded to BRAF inhibition, with all but one tumor progressing within 18 months. In PLGG, responses translated to 3-year progression-free survival of 49.6% (95% CI, 35.3% to 69.5%) versus 29.8% (95% CI, 20% to 44.4%) for BRAF inhibition versus chemotherapy, respectively ( P = .02)., Conclusion: Use of BRAF inhibition results in robust and durable responses in BRAF V600E-mutated PLGG. Prospective studies are required to determine long-term survival and functional outcomes with BRAF inhibitor therapy in childhood gliomas., Competing Interests: The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center. Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments). Vijay RamaswamyHonoraria: AstraZenecaMiriam BornhorstConsulting or Advisory Role: AstraZeneca/MedImmuneDaniel R. BoueStock and Other Ownership Interests: Vertex Pharmaceuticals, Intuitive Surgical, IlluminaAdela CaneteConsulting or Advisory Role: EUSA Pharma, Bayer Speakers’ Bureau: EUSA PHarma Research Funding: EUSA Pharma (Inst) Travel, Accommodations, Expenses: EUSA PharmaIra J. DunkelConsulting or Advisory Role: Bayer, Apexigen, Celgene, Roche/Genentech, AstraZeneca Research Funding: Bristol-Myers Squibb (Inst), Genentech (Inst), Novartis (Inst)Karen GauvainEmployment: Iqvia Biotech Consulting or Advisory Role: Bayer, Axiom Health Care SciencesJordan R. HansfordConsulting or Advisory Role: BayerSarah G. InjacResearch Funding: TakedaMatthias KarajannisConsulting or Advisory Role: Bayer, Recursion Pharma Research Funding: Novartis Travel, Accommodations, Expenses: Bayer Uncompensated Relationships: Debiopharm (Inst) Open Payments Link: https://openpaymentsdata.cms.gov/physician/710370/summaryNormand LaperriereHonoraria: Merck/Schering Plough Consulting or Advisory Role: AbbVieAlvaro LassalettaConsulting or Advisory Role: Shire, Jazz Pharmaceuticals, Roche Travel, Accommodations, Expenses: Shire, Gilead SciencesRoger PackerHonoraria: Novartis Consulting or Advisory Role: Novartis, AstraZenecaJaroslav SterbaResearch Funding: Roche/Genentech (Inst) Travel, Accommodations, Expenses: Bristol-Myers SquibbDerek S. TsangOther Relationship: Varian Medical Systems (Inst), Mevion Medical Systems (Inst), Hitachi (Inst), RaySearch Laboratories (Inst), IBA (Inst), ProTom (Inst)Cornelis M. van TilburgConsulting or Advisory Role: Novartis, BayerOlaf WittConsulting or Advisory Role: Novartis, AstraZeneca, Janssen Research & Development, Bristol-Myers Squibb, Roche, BayerEric BouffetResearch Funding: Roche (Inst), Bristol-Myers Squibb (Inst)Cynthia HawkinsConsulting or Advisory Role: Bayer Patents, Royalties, Other Intellectual Property: IP for low-grade glioma and sarcoma fusion panels as well as medulloblastoma subgrouping panel No other potential conflicts of interest were reported., (© 2020 by American Society of Clinical Oncology.)

Purpose BRAF V600E is a potentially highly targetable mutation detected in a subset of pediatric low-grade gliomas (PLGGs). Its biologic and clinical effect within this diverse group of tumors remains unknown. Patients and Methods A combined clinical and genetic institutional study of patients with PLGGs with long-term follow-up was performed (N = 510). Clinical and treatment data of patients with BRAF V600E mutated PLGG (n = 99) were compared with a large international independent cohort of patients with BRAF V600E mutated-PLGG (n = 180). Results BRAF V600E mutation was detected in 69 of 405 patients (17%) with PLGG across a broad spectrum of histologies and sites, including midline locations, which are not often routinely biopsied in clinical practice. Patients with BRAF V600E PLGG exhibited poor outcomes after chemotherapy and radiation therapies that resulted in a 10-year progression-free survival of 27% (95% CI, 12.1% to 41.9%) and 60.2% (95% CI, 53.3% to 67.1%) for BRAF V600E and wild-type PLGG, respectively ( P < .001). Additional multivariable clinical and molecular stratification revealed that the extent of resection and CDKN2A deletion contributed independently to poor outcome in BRAF V600E PLGG. A similar independent role for CDKN2A and resection on outcome were observed in the independent cohort. Quantitative imaging analysis revealed progressive disease and a lack of response to conventional chemotherapy in most patients with BRAF V600E PLGG. Conclusion BRAF V600E PLGG constitutes a distinct entity with poor prognosis when treated with current adjuvant therapy.

Purpose: Posterior fossa ependymoma comprises two distinct molecular variants termed EPN&#95;PFA and EPN&#95;PFB that have a distinct biology and natural history. The therapeutic value of cytoreductive surgery and radiation therapy for posterior fossa ependymoma after accounting for molecular subgroup is not known., Methods: Four independent nonoverlapping retrospective cohorts of posterior fossa ependymomas (n = 820) were profiled using genome-wide methylation arrays. Risk stratification models were designed based on known clinical and newly described molecular biomarkers identified by multivariable Cox proportional hazards analyses., Results: Molecular subgroup is a powerful independent predictor of outcome even when accounting for age or treatment regimen. Incompletely resected EPN&#95;PFA ependymomas have a dismal prognosis, with a 5-year progression-free survival ranging from 26.1% to 56.8% across all four cohorts. Although first-line (adjuvant) radiation is clearly beneficial for completely resected EPN&#95;PFA, a substantial proportion of patients with EPN&#95;PFB can be cured with surgery alone, and patients with relapsed EPN&#95;PFB can often be treated successfully with delayed external-beam irradiation., Conclusion: The most impactful biomarker for posterior fossa ependymoma is molecular subgroup affiliation, independent of other demographic or treatment variables. However, both EPN&#95;PFA and EPN&#95;PFB still benefit from increased extent of resection, with the survival rates being particularly poor for subtotally resected EPN&#95;PFA, even with adjuvant radiation therapy. Patients with EPN&#95;PFB who undergo gross total resection are at lower risk for relapse and should be considered for inclusion in a randomized clinical trial of observation alone with radiation reserved for those who experience recurrence., (© 2016 by American Society of Clinical Oncology.)

Purpose: Recurrent glioblastoma multiforme (GBM) is incurable with current therapies. Biallelic mismatch repair deficiency (bMMRD) is a highly penetrant childhood cancer syndrome often resulting in GBM characterized by a high mutational burden. Evidence suggests that high mutation and neoantigen loads are associated with response to immune checkpoint inhibition., Patients and Methods: We performed exome sequencing and neoantigen prediction on 37 bMMRD cancers and compared them with childhood and adult brain neoplasms. Neoantigen prediction bMMRD GBM was compared with responsive adult cancers from multiple tissues. Two siblings with recurrent multifocal bMMRD GBM were treated with the immune checkpoint inhibitor nivolumab., Results: All malignant tumors (n = 32) were hypermutant. Although bMMRD brain tumors had the highest mutational load because of secondary polymerase mutations (mean, 17,740 ± standard deviation, 7,703), all other high-grade tumors were hypermutant (mean, 1,589 ± standard deviation, 1,043), similar to other cancers that responded favorably to immune checkpoint inhibitors. bMMRD GBM had a significantly higher mutational load than sporadic pediatric and adult gliomas and all other brain tumors (P < .001). bMMRD GBM harbored mean neoantigen loads seven to 16 times higher than those in immunoresponsive melanomas, lung cancers, or microsatellite-unstable GI cancers (P < .001). On the basis of these preclinical data, we treated two bMMRD siblings with recurrent multifocal GBM with the anti-programmed death-1 inhibitor nivolumab, which resulted in clinically significant responses and a profound radiologic response., Conclusion: This report of initial and durable responses of recurrent GBM to immune checkpoint inhibition may have implications for GBM in general and other hypermutant cancers arising from primary (genetic predisposition) or secondary MMRD., (© 2016 by American Society of Clinical Oncology.)

Purpose: To uncover the genetic events leading to transformation of pediatric low-grade glioma (PLGG) to secondary high-grade glioma (sHGG)., Patients and Methods: We retrospectively identified patients with sHGG from a population-based cohort of 886 patients with PLGG with long clinical follow-up. Exome sequencing and array CGH were performed on available samples followed by detailed genetic analysis of the entire sHGG cohort. Clinical and outcome data of genetically distinct subgroups were obtained., Results: sHGG was observed in 2.9% of PLGGs (26 of 886 patients). Patients with sHGG had a high frequency of nonsilent somatic mutations compared with patients with primary pediatric high-grade glioma (HGG; median, 25 mutations per exome; P = .0042). Alterations in chromatin-modifying genes and telomere-maintenance pathways were commonly observed, whereas no sHGG harbored the BRAF-KIAA1549 fusion. The most recurrent alterations were BRAF V600E and CDKN2A deletion in 39% and 57% of sHGGs, respectively. Importantly, all BRAF V600E and 80% of CDKN2A alterations could be traced back to their PLGG counterparts. BRAF V600E distinguished sHGG from primary HGG (P = .0023), whereas BRAF and CDKN2A alterations were less commonly observed in PLGG that did not transform (P < .001 and P < .001 respectively). PLGGs with BRAF mutations had longer latency to transformation than wild-type PLGG (median, 6.65 years [range, 3.5 to 20.3 years] v 1.59 years [range, 0.32 to 15.9 years], respectively; P = .0389). Furthermore, 5-year overall survival was 75% ± 15% and 29% ± 12% for children with BRAF mutant and wild-type tumors, respectively (P = .024)., Conclusion: BRAF V600E mutations and CDKN2A deletions constitute a clinically distinct subtype of sHGG. The prolonged course to transformation for BRAF V600E PLGGs provides an opportunity for surgical interventions, surveillance, and targeted therapies to mitigate the outcome of sHGG., (© 2015 by American Society of Clinical Oncology.)

Purpose: Medulloblastoma comprises four distinct molecular subgroups: WNT, SHH, Group 3, and Group 4. Current medulloblastoma protocols stratify patients based on clinical features: patient age, metastatic stage, extent of resection, and histologic variant. Stark prognostic and genetic differences among the four subgroups suggest that subgroup-specific molecular biomarkers could improve patient prognostication., Patients and Methods: Molecular biomarkers were identified from a discovery set of 673 medulloblastomas from 43 cities around the world. Combined risk stratification models were designed based on clinical and cytogenetic biomarkers identified by multivariable Cox proportional hazards analyses. Identified biomarkers were tested using fluorescent in situ hybridization (FISH) on a nonoverlapping medulloblastoma tissue microarray (n = 453), with subsequent validation of the risk stratification models., Results: Subgroup information improves the predictive accuracy of a multivariable survival model compared with clinical biomarkers alone. Most previously published cytogenetic biomarkers are only prognostic within a single medulloblastoma subgroup. Profiling six FISH biomarkers (GLI2, MYC, chromosome 11 [chr11], chr14, 17p, and 17q) on formalin-fixed paraffin-embedded tissues, we can reliably and reproducibly identify very low-risk and very high-risk patients within SHH, Group 3, and Group 4 medulloblastomas., Conclusion: Combining subgroup and cytogenetic biomarkers with established clinical biomarkers substantially improves patient prognostication, even in the context of heterogeneous clinical therapies. The prognostic significance of most molecular biomarkers is restricted to a specific subgroup. We have identified a small panel of cytogenetic biomarkers that reliably identifies very high-risk and very low-risk groups of patients, making it an excellent tool for selecting patients for therapy intensification and therapy de-escalation in future clinical trials.

Purpose: Reports detailing the prognostic impact of TP53 mutations in medulloblastoma offer conflicting conclusions. We resolve this issue through the inclusion of molecular subgroup profiles., Patients and Methods: We determined subgroup affiliation, TP53 mutation status, and clinical outcome in a discovery cohort of 397 medulloblastomas. We subsequently validated our results on an independent cohort of 156 medulloblastomas., Results: TP53 mutations are enriched in wingless (WNT; 16%) and sonic hedgehog (SHH; 21%) medulloblastomas and are virtually absent in subgroups 3 and 4 tumors (P < .001). Patients with SHH/TP53 mutant tumors are almost exclusively between ages 5 and 18 years, dramatically different from the general SHH distribution (P < .001). Children with SHH/TP53 mutant tumors harbor 56% germline TP53 mutations, which are not observed in children with WNT/TP53 mutant tumors. Five-year overall survival (OS; ± SE) was 41% ± 9% and 81% ± 5% for patients with SHH medulloblastomas with and without TP53 mutations, respectively (P < .001). Furthermore, TP53 mutations accounted for 72% of deaths in children older than 5 years with SHH medulloblastomas. In contrast, 5-year OS rates were 90% ± 9% and 97% ± 3% for patients with WNT tumors with and without TP53 mutations (P = .21). Multivariate analysis revealed that TP53 status was the most important risk factor for SHH medulloblastoma. Survival rates in the validation cohort mimicked the discovery results, revealing that poor survival of TP53 mutations is restricted to patients with SHH medulloblastomas (P = .012) and not WNT tumors., Conclusion: Subgroup-specific analysis reconciles prior conflicting publications and confirms that TP53 mutations are enriched among SHH medulloblastomas, in which they portend poor outcome and account for a large proportion of treatment failures in these patients.

Purpose: Recent genomic approaches have suggested the existence of multiple distinct subtypes of medulloblastoma. We studied a large cohort of medulloblastomas to determine how many subgroups of the disease exist, how they differ, and the extent of overlap between subgroups., Methods: We determined gene expression profiles and DNA copy number aberrations for 103 primary medulloblastomas. Bioinformatic tools were used for class discovery of medulloblastoma subgroups based on the most informative genes in the data set. Immunohistochemistry for subgroup-specific signature genes was used to determine subgroup affiliation for 294 nonoverlapping medulloblastomas on two independent tissue microarrays., Results: Multiple unsupervised analyses of transcriptional profiles identified the following four distinct, nonoverlapping molecular variants: WNT, SHH, group C, and group D. Supervised analysis of these four subgroups revealed significant subgroup-specific demographics, histology, metastatic status, and DNA copy number aberrations. Immunohistochemistry for DKK1 (WNT), SFRP1 (SHH), NPR3 (group C), and KCNA1 (group D) could reliably and uniquely classify formalin-fixed medulloblastomas in approximately 98% of patients. Group C patients (NPR3-positive tumors) exhibited a significantly diminished progression-free and overall survival irrespective of their metastatic status., Conclusion: Our integrative genomics approach to a large cohort of medulloblastomas has identified four disparate subgroups with distinct demographics, clinical presentation, transcriptional profiles, genetic abnormalities, and clinical outcome. Medulloblastomas can be reliably assigned to subgroups through immunohistochemistry, thereby making medulloblastoma subclassification widely available. Future research on medulloblastoma and the development of clinical trials should take into consideration these four distinct types of medulloblastoma.

PURPOSE Choroid plexus carcinomas are pediatric tumors with poor survival rates and a strong, but poorly understood, association with Li-Fraumeni syndrome (LFS). Currently, with lack of biologic predictors, most children are treated with aggressive chemoradiation protocols. PATIENTS AND METHODS We established a multi-institutional tissue and clinical database, which enabled the analysis of specific alterations of the TP53 tumor suppressor and its modifiers in choroid plexus tumors (CPTs). We conducted high-resolution copy-number analysis to correlate these genetic parameters with family history and outcome. Results We studied 64 patients with CPTs. All individuals with germline TP53 mutations fulfilled LFS criteria, whereas all patients not meeting these criteria harbored wild-type TP53 (P < .001). TP53 mutations were found in 50% of choroid plexus carcinomas (CPCs). Additionally, two sequence variants known to confer TP53 dysfunction, TP53 codon72 and MDM2 SNP309, coexisted in the majority of TP53 wild-type CPCs (92%) and not in TP53 mutated CPC (P = .04), which suggests a complementary mechanism of TP53 dysfunction in the absence of a TP53 mutation. High-resolution single nucleotide polymorphism (SNP) array analysis revealed extremely high total structural variation (TSV) in TP53-mutated CPC tumor genomes compared with TP53 wild-type tumors and choroid plexus papillomas (CPPs; P = .006 and .004, respectively). Moreover, high TSV was associated with significant risk of progression (P < .001). Five-year survival rates for patients with TP53-immunopositive and -immunonegative CPCs were 0% and 82 (+/- 9%), respectively (P < .001). Furthermore, 14 of 16 patients with TP53 wild-type CPCs are alive without having received radiation therapy. CONCLUSION Patients with CPC who have low tumor TSV and absence of TP53 dysfunction have a favorable prognosis and can be successfully treated without radiation therapy.

Purpose: Medulloblastoma is the prototype of treatment success in modern pediatric neuro-oncology. Unfortunately, 20% to 30% of tumors recur despite maximal resection and multimodal therapy. Multiple biologic prognostic markers have been investigated to predict recurrences, but controversy remains regarding their clinical utility. Because p53 immunopositivity is an adverse prognostic marker in pediatric medulloblastoma and TP53 mutations are associated with chemotherapy and radiation therapy resistance, we aimed to determine the extent and role of TP53 mutations in pediatric medulloblastoma treatment failure., Patients and Methods: One hundred eight of 111 consecutive patients diagnosed with medulloblastoma in our institution from 1995 to 2007 were included. Median follow-up time was 5.3 years in survivors. All samples were immunostained for p53 and erbB-2. Histologic grade and immunostaining were scored by two blinded reviewers. For 49 patients, frozen material was available for TP53 sequencing. The main outcome measures were overall and progression-free survival., Results: Sixteen percent of sequenced medulloblastomas harbored a TP53 mutation. As a screening test, p53 immunohistochemistry was 100% sensitive and 83% specific for a TP53 mutation. Strikingly, all mutated tumors recurred early, and 5-year survival for average-risk patients was 0% for TP53-mutated medulloblastoma compared with 74% +/- 8% for wild-type medulloblastoma (P < .0001). Furthermore, 75% of recurrences in average-risk patients were associated with TP53 mutations. On multivariate analysis, TP53 mutation status was the strongest adverse prognostic factor (hazard ratio = 10.4, P = .003)., Conclusion: Lack of long-term survival in TP53-mutated medulloblastomas highlights the role of TP53 mutations in medulloblastoma resistance to conventional therapies and the need for alternative treatments, and prospective validation of these findings is needed.

Purpose: Pediatric intracranial ependymomas are a heterogeneous group of neoplasms with unpredictable clinical and biologic behavior. As part of ongoing studies to identify potential biologic and therapeutic markers, we analyzed the role of human telomere reverse transcriptase (hTERT; the catalytic subunit of telomerase) expression as a prognostic marker for this disease., Patients and Methods: Primary intracranial ependymomas that were resected at our institution between 1986 and 2004 were identified through the pathology and oncology databases. A tissue array was constructed from the patient samples and hTERT expression was evaluated by immunohistochemistry. Twenty-one samples were also analyzed for telomerase activity (telomerase repeat amplification protocol assay)., Results: Eighty-seven tumors from 65 patients were analyzed. Five-year progression-free survival was 57% (SEM, 12%) and 21% (SEM, 8%) for hTERT-negative and hTERT-positive tumors, respectively (P = .002). Five-year overall survival was 84% (SEM, 7%) and 41% (SEM, 7%) for hTERT-negative and hTERT-positive tumors, respectively (P = .001). There was good correlation between telomerase activity and hTERT expression (kappa = 0.637). Multivariate analysis revealed hTERT expression to be the single most important predictor of survival of all known pathologic, clinical, and treatment factors (hazard ratio, 60.4; 95% CI, 6.4 to 561). All four patients with hTERT-negative tumors at relapse are still alive, with median follow-up of 11.2 years., Conclusion: In this study, hTERT expression was the strongest predictor of outcome and was independent of other clinical and pathologic prognostic markers. It represents a simple and reliable biologic prognostic factor for intracranial ependymomas. These results should be confirmed in larger prospective trials.