{"product_id":"new-gene-expression-test-predicts-meningioma-outcomes-and-radiotherapy-responses-better-than-current-methods","title":"New Gene Expression Test Predicts Meningioma Outcomes and Radiotherapy Responses Better Than Current Methods","description":"\u003cp\u003eResearchers developed a 34-gene expression biomarker (a molecular test that measures the activity of 34 specific genes) that predicts meningioma outcomes and radiotherapy responses better than current standard methods. In a validation cohort of 1,856 meningiomas from 12 institutions across 3 continents, the biomarker achieved a 5-year area under the curve (AUC, a measure of predictive accuracy) of 0.81 for local recurrence and 0.80 for overall survival, significantly outperforming the World Health Organization (WHO) 2021 grade standard. The biomarker identified patients who benefit from postoperative radiotherapy (hazard ratio 0.54, 95% CI 0.37–0.78, P=0.0001) and suggested that postoperative management could be refined for 29.8% of patients.\u003c\/p\u003e\n\n\u003ch1\u003eNew Gene Expression Test Predicts Meningioma Outcomes and Radiotherapy Responses Better Than Current Methods\u003c\/h1\u003e\n\n\u003ch2\u003eTable of Contents\u003c\/h2\u003e\n\u003cul\u003e\n\u003cli\u003e\u003ca href=\"#ddn-key-points\"\u003eKey Points\u003c\/a\u003e\u003c\/li\u003e\n\n\u003cli\u003e\u003ca href=\"#background\"\u003eBackground: Why This Research Matters\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#methods\"\u003eHow the Research Was Conducted\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#development\"\u003eDeveloping the Gene Expression Biomarker\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#analytical\"\u003eAnalytical Validation: Testing Reliability\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#clinical\"\u003eClinical Validation: Testing Accuracy in Real Patients\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#comparison\"\u003eComparing the Biomarker to Other Classification Systems\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#radiotherapy\"\u003ePredicting Radiotherapy Responses\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#prospective\"\u003eValidation in a Prospective Clinical Trial\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#implications\"\u003eClinical Implications: What This Means for Patients\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#limitations\"\u003eLimitations: What the Study Could Not Prove\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#recommendations\"\u003eRecommendations for Patients\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#ddn-faq\"\u003eFrequently Asked Questions\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#source\"\u003eSource Information\u003c\/a\u003e\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003c!-- ddn:keypoints:start --\u003e\n\u003ch2 id=\"ddn-key-points\"\u003eKey Points\u003c\/h2\u003e\n\u003cul\u003e\n\u003cli\u003eA 34-gene expression biomarker predicted meningioma recurrence and survival better than the WHO 2021 grade standard in a validation cohort of 1,856 tumors from 12 institutions.\u003c\/li\u003e\n\u003cli\u003eIn a multicenter retrospective cohort, 5-year local freedom from recurrence was 92.2% for low risk, 72.6% for intermediate risk, and 19.4% for high risk.\u003c\/li\u003e\n\u003cli\u003eIn that cohort, patients with unfavorable biomarker and surgical features benefited from postoperative radiotherapy (hazard ratio 0.54), while favorable patients did not.\u003c\/li\u003e\n\u003cli\u003eThe biomarker reclassified 52.0% of meningiomas versus clinical criteria and suggested postoperative management could be refined for 29.8% of patients.\u003c\/li\u003e\n\u003cli\u003eThe test is not yet widely available in clinical practice; ask your doctor about molecular testing, radiotherapy decisions, and clinical trials.\u003c\/li\u003e\n\u003c\/ul\u003e\n\u003c!-- ddn:keypoints:end --\u003e\n\n\n\u003ch2 id=\"background\"\u003eBackground: Why This Research Matters\u003c\/h2\u003e\n\n\u003cp\u003eMeningiomas are the most common primary brain tumors, accounting for 39.7% of all primary intracranial tumors (tumors that start in the brain). These tumors are the only brain tumors that are more common in women, Black patients, and elderly patients. These groups are underrepresented in brain tumor clinical trials.\u003c\/p\u003e\n\n\u003cp\u003eTreatment options for meningiomas are largely limited to surgery and radiotherapy (radiation therapy). Systemic therapies (drugs that travel through the bloodstream) remain ineffective or experimental for this type of tumor.\u003c\/p\u003e\n\n\u003cp\u003eHistorically, the World Health Organization (WHO) has graded meningiomas based on how the tumor cells look under a microscope. This grading system looks at features such as mitotic count (the number of cells actively dividing). The grades range from 1 (least aggressive) to 3 (most aggressive).\u003c\/p\u003e\n\n\u003cp\u003eMost WHO grade 1 meningiomas can be effectively treated with surgery or radiotherapy. However, many WHO grade 2 or grade 3 meningiomas resist treatment and cause significant neurological problems and death. Some WHO grade 1 meningiomas recur in ways that cannot be predicted from how they look under a microscope. Some WHO grade 2 or grade 3 meningiomas are unexpectedly well controlled with surgery and radiotherapy.\u003c\/p\u003e\n\n\u003cp\u003eThis uncertainty has created controversy around how to classify meningioma risk and how to treat these tumors. Two Phase III clinical trials — NRG BN-003 and EORTC 1308 — are currently randomizing patients with primary WHO grade 2 meningiomas. The trials are randomizing patients to either postoperative surveillance (watchful waiting) or postoperative radiotherapy after gross total resection (complete tumor removal).\u003c\/p\u003e\n\n\u003cp\u003eThe only multicenter prospective studies of meningioma radiotherapy that have reported data are RTOG 0539 and EORTC 22042. These Phase II clinical trials provide safety data and non-randomized results based on clinical criteria. These criteria do not predict radiotherapy responses in most retrospective studies (studies that look back at past patient data).\u003c\/p\u003e\n\n\u003cp\u003eIn 2021, the WHO revised meningioma grading criteria. The new criteria incorporate rare hotspot TERT promoter mutations (specific genetic changes). The new criteria incorporate homozygous deletion of CDKN2A\/B (loss of both copies of a specific gene). The new criteria incorporate these alongside traditional microscopic features. This update reflects a growing understanding of the molecular landscape of meningiomas from diverse bioinformatic studies.\u003c\/p\u003e\n\n\u003cp\u003eResearchers have used several molecular approaches to classify meningiomas. These include DNA sequencing. These include copy number variant (CNV) analyses (which look at gains or losses of chromosome segments). These include RNA sequencing. These include DNA methylation profiling (which looks at chemical tags on DNA that affect gene activity). Integrated systems have been proposed that combine CNVs, CDKN2A\/B status, DNA methylation, and microscopic features.\u003c\/p\u003e\n\n\u003cp\u003eIt was unknown which of these diverse classification systems might best optimize risk stratification or predict postoperative radiotherapy responses for patients with meningiomas.\u003c\/p\u003e\n\n\u003cp\u003eKnowledge of biological pathways underlying diverse cancers has generated robust targeted gene expression biomarkers. These biomarkers are recommended for risk stratification and prediction of treatment response by the National Comprehensive Cancer Network (NCCN). A small pilot study suggested that targeted gene expression profiling may be useful for meningioma risk stratification. However, an optimized gene expression biomarker — as well as its analytical validity, clinical validity, generalizability, and potential impact on postoperative meningioma management — was unknown.\u003c\/p\u003e\n\n\u003ch2 id=\"methods\"\u003eHow the Research Was Conducted\u003c\/h2\u003e\n\n\u003cp\u003eThe researchers used knowledge of biological pathways underlying meningiomas from previous bioinformatic studies. They developed a 34-gene expression biomarker that is prognostic for clinical outcomes in a single-institution discovery cohort (a group of patients used to develop the test).\u003c\/p\u003e\n\n\u003cp\u003eThe researchers then performed clinical and analytical validation of the gene expression biomarker using independent meningiomas from a large multicenter retrospective cohort. They compared biomarker performance across contemporary meningioma classification systems and clinical contexts using a total of 4,898 bioinformatic assays.\u003c\/p\u003e\n\n\u003cp\u003eThe study included several key groups:\u003c\/p\u003e\n\n\u003cul\u003e\n\u003cli\u003e\n\u003cstrong\u003eDiscovery cohort:\u003c\/strong\u003e 173 meningiomas used to develop the 34-gene expression biomarker and risk score\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eAnalytical validation cohort:\u003c\/strong\u003e 1,219 meningiomas from 8 institutions, used to test reproducibility and reliability\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eMulticenter retrospective clinical validation cohort:\u003c\/strong\u003e 866 meningiomas from 6 institutions (572 frozen samples, 294 FFPE samples)\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eProspective clinical trial cohort:\u003c\/strong\u003e 103 meningiomas from patients enrolled on the RTOG 0539 clinical trial\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eThe researchers also provided investigator-blinded, independent validation of the gene expression biomarker. This means the researchers analyzing the samples did not know the patients' clinical outcomes, preventing bias.\u003c\/p\u003e\n\n\u003ch2 id=\"development\"\u003eDeveloping the Gene Expression Biomarker\u003c\/h2\u003e\n\n\u003cp\u003eTargeted gene expression profiling of 173 meningiomas in the discovery cohort resulted in a 34-gene expression biomarker. This biomarker produces a continuous risk score between 0 and 1. The researchers converted this continuous score into discrete low, intermediate, and high risk groups for Kaplan Meier analyses (a statistical method for measuring survival over time).\u003c\/p\u003e\n\n\u003cp\u003eThe gene expression biomarker was well distributed across intracranial meningioma locations (locations within the skull) and recurring somatic short variants (genetic mutations found in the tumor). The biomarker was prognostic for local freedom from recurrence (LFFR, meaning the tumor did not come back where it started) and overall survival (OS, meaning how long patients lived).\u003c\/p\u003e\n\n\u003cp\u003eThe gene expression biomarker model, risk score, and cutoffs were locked and applied without alteration to multicenter retrospective and prospective validation cohorts from 12 institutions. Locking the model means the researchers did not change it after seeing the validation results, which prevents bias.\u003c\/p\u003e\n\n\u003cp\u003eThe genes included in the biomarker are involved in several important cellular functions:\u003c\/p\u003e\n\n\u003cul\u003e\n\u003cli\u003e\n\u003cstrong\u003eCell cycle and epigenetic regulation:\u003c\/strong\u003e CDK6, CDKN2A, CDC20, CKS2, CHEK1, EZH2, MYBL1\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eMitotic stability (proper cell division):\u003c\/strong\u003e KIF20A\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eGenes located on recurrent CNVs:\u003c\/strong\u003e LINC02593 on chromosome 1p, TMEM30B on 14q, USF1 on 1q, ARID1B on 6q\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eImmune-related genes:\u003c\/strong\u003e CCL21, CD3E\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003ePreviously identified prognostic markers in meningioma:\u003c\/strong\u003e PGR, IGF2, COL1A1\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eInspection of the genes comprising the biomarker across the cellular architecture of meningiomas from single-cell RNA sequencing revealed that some biomarker genes are enriched in meningioma cells. Other biomarker genes are expressed by the tumor microenvironment (the normal cells and structures surrounding the tumor).\u003c\/p\u003e\n\n\u003ch2 id=\"analytical\"\u003eAnalytical Validation: Testing Reliability\u003c\/h2\u003e\n\n\u003cp\u003eAnalytical validity refers to how reliably a test produces the same results under different conditions. The researchers established analytical validity using the multicenter analytical validation cohort of 1,219 meningiomas from 8 institutions.\u003c\/p\u003e\n\n\u003cp\u003eThe researchers tested several conditions:\u003c\/p\u003e\n\n\u003cul\u003e\n\u003cli\u003e\n\u003cstrong\u003eReproducibility over time:\u003c\/strong\u003e Test-retest conditions generated concordant (agreeing) gene expression risk scores\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eReproducibility across laboratories:\u003c\/strong\u003e Different centers generated concordant gene expression risk scores\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003ePaired frozen and FFPE samples:\u003c\/strong\u003e Frozen and FFPE (formalin-fixed, paraffin-embedded, a common way to preserve tissue) meningiomas generated concordant gene expression risk scores\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eDifferent quantification approaches:\u003c\/strong\u003e Both RNA sequencing and microarray approaches were tractable and discriminatory for meningioma outcomes when used to assess the 34-gene signature\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eWith regard to cross-platform interoperability (whether different testing platforms give the same answer), the researchers found a limitation. DNA methylation profiling was only able to predict the gene expression risk score to a moderate degree. This means DNA methylation testing is not a perfect substitute for the gene expression biomarker.\u003c\/p\u003e\n\n\u003ch2 id=\"clinical\"\u003eClinical Validation: Testing Accuracy in Real Patients\u003c\/h2\u003e\n\n\u003cp\u003eIn the multicenter retrospective clinical validation cohort of 866 meningiomas from 6 institutions, the gene expression biomarker achieved a concordance index (c-index) of 0.78 for LFFR and 0.78 for OS. The c-index measures how well a test predicts outcomes; 0.5 is random chance and 1.0 is perfect prediction.\u003c\/p\u003e\n\n\u003cp\u003eThe gene expression biomarker delineated clinically meaningful low, intermediate, and high risk groups. The 5-year LFFR rates were:\u003c\/p\u003e\n\n\u003cul\u003e\n\u003cli\u003e\n\u003cstrong\u003eLow risk:\u003c\/strong\u003e 92.2% (95% CI 88.3–96.2%)\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eIntermediate risk:\u003c\/strong\u003e 72.6% (95% CI 67.8–77.8%)\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eHigh risk:\u003c\/strong\u003e 19.4% (95% CI 13.5–28.0%)\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eThese results mean that patients in the low risk group had a 92.2% chance of remaining free from local recurrence at 5 years. Patients in the high risk group had only a 19.4% chance of remaining free from local recurrence at 5 years.\u003c\/p\u003e\n\n\u003cp\u003eThe gene expression biomarker remained well-calibrated in meningiomas from individual clinical validation institutions. Well-calibrated means the predicted risk matched the actual observed risk.\u003c\/p\u003e\n\n\u003cp\u003eThe gene expression biomarker was prognostic for LFFR and OS in several clinical situations:\u003c\/p\u003e\n\n\u003cul\u003e\n\u003cli\u003eAmong meningiomas presenting in primary or recurrent settings\u003c\/li\u003e\n\u003cli\u003eAfter gross total resection (GTR, complete removal) or subtotal resection (STR, partial removal)\u003c\/li\u003e\n\u003cli\u003eAcross WHO grades using histological criteria (WHO 2016) or histological and molecular criteria (WHO 2021)\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eThe gene expression biomarker remained independently prognostic on multivariate analysis. Multivariate analysis is a statistical method that accounts for multiple factors at once. The analysis incorporated meningioma setting (primary or recurrent), extent of resection, and WHO grade.\u003c\/p\u003e\n\n\u003cp\u003eThe gene expression biomarker was also prognostic for LFFR and OS within strata from other meningioma molecular classification systems. These systems are based on DNA methylation probes, groups, subgroups, or families, or based on gene expression types, integrated score, or integrated grade. The gene expression biomarker remained independently prognostic on multivariate analyses incorporating each of the 9 other meningioma classification systems.\u003c\/p\u003e\n\n\u003ch2 id=\"comparison\"\u003eComparing the Biomarker to Other Classification Systems\u003c\/h2\u003e\n\n\u003cp\u003eThe researchers compared the gene expression biomarker to 9 other meningioma classification systems. These systems are based on molecular criteria, molecular and histological criteria, or WHO criteria. The researchers used pairwise model combinations for this comparison.\u003c\/p\u003e\n\n\u003cp\u003eThe gene expression biomarker provided additional prognostic information for LFFR and OS in combination with each of the 9 other systems tested. No other meningioma classification system provided additional prognostic information for LFFR in combination with the gene expression biomarker. Only WHO 2021 grade provided additional prognostic information for OS.\u003c\/p\u003e\n\n\u003cp\u003eThe gene expression biomarker achieved the lowest Brier error score over time for LFFR across meningioma classification systems. The Brier score measures the accuracy of probabilistic predictions; a lower score means better accuracy. The gene expression biomarker had an error score comparable to WHO 2021 grade and integrated grade over time for OS.\u003c\/p\u003e\n\n\u003cp\u003eThe gene expression biomarker achieved the highest 5-year area under the curve (AUC) for LFFR (0.81) and OS (0.80) across meningioma classification systems. The AUC is a measure of how well a test can distinguish between patients who will and will not have a specific outcome.\u003c\/p\u003e\n\n\u003cp\u003eThe improvement in AUC compared to the next best performing system (integrated grade) was +0.07 for LFFR (95% CI 0.02–0.12, P\u0026lt;0.001). The improvement compared to the current standard of care (WHO 2021 grade) was +0.11 for LFFR (95% CI 0.07–0.17, P\u0026lt;0.001). A P value less than 0.001 means there is less than a 0.1% chance that this result occurred by random chance.\u003c\/p\u003e\n\n\u003cp\u003eTo translate these findings into clinical practice, the researchers generated nomograms. Nomograms are visual tools that predict the probability of a specific outcome. These nomograms predict 5-year LFFR or OS based on meningioma gene expression risk score, setting (primary or recurrent), extent of resection, and WHO grade.\u003c\/p\u003e\n\n\u003ch2 id=\"radiotherapy\"\u003ePredicting Radiotherapy Responses\u003c\/h2\u003e\n\n\u003cp\u003eThe researchers sought to incorporate the gene expression biomarker into a clinical framework consistent with contemporary NCCN and European Association of Neuro-Oncology (EANO) guidelines. The researchers stratified meningiomas treated with surgical monotherapy (surgery alone). The researchers stratified meningiomas in the multicenter retrospective clinical validation cohort. They stratified by extent of resection and gene expression risk score.\u003c\/p\u003e\n\n\u003cp\u003eThis stratification resulted in a range of clinical subgroups spanning the spectrum of recurrence risk. The 5-year LFFR ranged from 96.1% for gene expression low risk meningiomas with GTR (complete removal) to 9.8% for gene expression high risk meningiomas with STR (partial removal).\u003c\/p\u003e\n\n\u003cp\u003eBased on these combined biomarker and surgical strata, the researchers distinguished favorable and unfavorable meningiomas:\u003c\/p\u003e\n\n\u003cul\u003e\n\u003cli\u003e\n\u003cstrong\u003eFavorable:\u003c\/strong\u003e Gene expression low risk with any resection, or gene expression intermediate risk with GTR\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eUnfavorable:\u003c\/strong\u003e Gene expression intermediate risk with STR, or gene expression high risk with any resection\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eIn clinical practice, meningiomas with unfavorable histological features or STR are often treated with postoperative radiotherapy based on retrospective data. NRG BN-003 and EORTC 1308 represent important prospective studies of radiotherapy for meningioma. However, these trials were initiated before the development of biomarkers for meningioma risk stratification. These trials do not incorporate biomarkers that could potentially elucidate postoperative radiotherapy responses.\u003c\/p\u003e\n\n\u003cp\u003eIn the multicenter retrospective clinical validation cohort, the gene expression biomarker remained prognostic for primary meningioma outcomes among patients receiving fractionated postoperative radiotherapy. Fractionated radiotherapy means the radiation is given in multiple smaller doses rather than one large dose. The biomarker was also prognostic among patients with primary WHO grade 2 meningiomas with GTR who may have been eligible for NRG BN-003 or EORTC 1308.\u003c\/p\u003e\n\n\u003cp\u003eHowever, in the absence of biomarker stratification, primary WHO grade 2 meningiomas with GTR did not benefit from postoperative radiotherapy in the multicenter retrospective clinical validation cohort. This means that without the biomarker, doctors could not tell which patients would benefit from radiotherapy.\u003c\/p\u003e\n\n\u003cp\u003eTo determine if the gene expression biomarker could predict meningioma radiotherapy responses, the researchers stratified primary WHO grade 2 meningiomas based on favorable versus unfavorable biomarker and surgical criteria. The results showed:\u003c\/p\u003e\n\n\u003cul\u003e\n\u003cli\u003e\n\u003cstrong\u003eUnfavorable primary WHO grade 2 meningiomas:\u003c\/strong\u003e Benefited from postoperative radiotherapy (HR 0.33, 95% CI 0.14–0.76, P=0.009)\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eFavorable primary WHO grade 2 meningiomas:\u003c\/strong\u003e Did not benefit from postoperative radiotherapy (P=0.88)\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eA hazard ratio (HR) of 0.33 means that patients in the unfavorable group who received radiotherapy had a 67% lower risk of recurrence compared to those who did not receive radiotherapy.\u003c\/p\u003e\n\n\u003cp\u003eThe researchers then applied the same biomarker and surgical strata across all WHO grades in the multicenter retrospective clinical validation cohort. They used propensity matching based on gene expression risk score, extent of resection, and WHO grade. Propensity matching is a statistical technique that creates comparable groups of patients. The results showed:\u003c\/p\u003e\n\n\u003cul\u003e\n\u003cli\u003e\n\u003cstrong\u003eUnfavorable meningiomas:\u003c\/strong\u003e Benefited from postoperative radiotherapy (HR 0.54, 95% CI 0.37–0.78, P=0.0001)\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eFavorable meningiomas:\u003c\/strong\u003e Did not benefit from postoperative radiotherapy (P=0.42)\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eRTOG 0539 was a Phase II multicenter prospective trial that enrolled patients with meningiomas from 78 institutions. The trial assigned patients into 3 clinical risk groups:\u003c\/p\u003e\n\n\u003col\u003e\n\u003cli\u003e\n\u003cstrong\u003eLow clinical risk:\u003c\/strong\u003e Primary WHO grade 1 meningiomas after any resection\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eIntermediate clinical risk:\u003c\/strong\u003e Recurrent WHO grade 1 meningiomas after any resection, or primary WHO grade 2 meningiomas after GTR\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eHigh clinical risk:\u003c\/strong\u003e WHO grade 3 meningiomas after any resection, recurrent WHO grade 2 meningiomas after any resection, and primary WHO grade 2 meningiomas after STR\u003c\/li\u003e\n\u003c\/ol\u003e\n\n\u003cp\u003eIntermediate and high clinical risk patients enrolled on RTOG 0539 received postoperative radiotherapy. Low clinical risk patients underwent postoperative surveillance (watchful waiting).\u003c\/p\u003e\n\n\u003cp\u003eTo determine how the gene expression biomarker could potentially refine postoperative management, the researchers assigned meningiomas in the multicenter retrospective clinical validation cohort to RTOG 0539 clinical risk groups. They then compared these assignments to gene expression biomarker risk groups.\u003c\/p\u003e\n\n\u003cp\u003eThe gene expression biomarker improved discrimination of meningioma outcomes across clinical groups used for postoperative radiotherapy stratification in RTOG 0539. The biomarker re-classified 52.0% of meningiomas compared to clinical criteria. This included downstaging 21.3% of intermediate clinical risk patients who would have received postoperative radiotherapy on RTOG 0539. Downstaging means the biomarker identified these patients as lower risk than the clinical criteria suggested.\u003c\/p\u003e\n\n\u003cp\u003eThe researchers used favorable versus unfavorable biomarker and surgical strata that predict radiotherapy responses. These data suggest that postoperative management could have been refined for 29.8% of patients in the multicenter retrospective clinical validation cohort. This is compared to clinical criteria from RTOG 0539.\u003c\/p\u003e\n\n\u003ch2 id=\"prospective\"\u003eValidation in a Prospective Clinical Trial\u003c\/h2\u003e\n\n\u003cp\u003eThe researchers performed investigator-blinded, independent validation of the gene expression biomarker using meningiomas and clinical data that were prospectively collected from patients enrolled on RTOG 0539 itself. This prospective cohort included 103 patients.\u003c\/p\u003e\n\n\u003cp\u003eIn comparison to clinical risk groups used to allocate patients to postoperative radiotherapy or postoperative surveillance on this study, the gene expression biomarker re-classified 39.8% of meningiomas from RTOG 0539. This included downstaging 30.3% of intermediate clinical risk patients who received postoperative radiotherapy.\u003c\/p\u003e\n\n\u003cp\u003eThe gene expression biomarker was prognostic for progression free survival (PFS, meaning the time before the tumor grew or came back) and overall survival (OS) in patients from RTOG 0539. The biomarker was well calibrated with 5-year PFS rates of:\u003c\/p\u003e\n\n\u003cul\u003e\n\u003cli\u003e\n\u003cstrong\u003eLow risk:\u003c\/strong\u003e 92.0%\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eIntermediate risk:\u003c\/strong\u003e 76.5%\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eHigh risk:\u003c\/strong\u003e 38.6%\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eMoreover, the gene expression biomarker remained independently prognostic on multivariate analysis incorporating meningioma setting (primary or recurrent), extent of resection, and WHO grade using data from RTOG 0539.\u003c\/p\u003e\n\n\u003ch2 id=\"implications\"\u003eClinical Implications: What This Means for Patients\u003c\/h2\u003e\n\n\u003cp\u003eThe researchers used targeted gene expression profiling to develop and validate a polygenic biomarker (a test that looks at multiple genes). The polygenic biomarker provides additional information for meningioma outcomes compared to other classification systems. This includes prediction of postoperative radiotherapy responses.\u003c\/p\u003e\n\n\u003cp\u003eThe gene expression biomarker is independently prognostic across all clinical, histological, and molecular contexts tested. This includes WHO 2021 grade, the current standard of care.\u003c\/p\u003e\n\n\u003cp\u003eWhen incorporated into clinical risk groups defined by contemporary trials that are consistent with consensus NCCN and EANO guidelines, the gene expression biomarker potentially refines postoperative management for 29.8% of patients.\u003c\/p\u003e\n\n\u003cp\u003eDNA methylation profiling, CNV analysis, DNA sequencing, and RNA sequencing have improved understanding of meningioma biology. Unsupervised bioinformatic analyses paired with mechanistic and functional approaches have identified molecular groups and subgroups of meningiomas with distinct biologic drivers, therapeutic vulnerabilities, and clinical outcomes. Supervised bioinformatic models incorporating clinical endpoints have refined risk stratification for meningioma local recurrence.\u003c\/p\u003e\n\n\u003cp\u003eThe gene expression biomarker reported here provides additional prognostic information for local recurrence and overall survival when combined with all unsupervised or supervised meningioma molecular classification systems tested. These findings are concordant with pan-cancer analyses examining gene expression, CNV, DNA methylation, protein expression, and DNA sequencing data in 10,884 patients. These pan-cancer analyses suggest gene expression encodes the greatest prognostic information across cancer types.\u003c\/p\u003e\n\n\u003cp\u003eEfforts to reduce molecular classification of meningioma to one or several immunohistochemical stains (tests that detect specific proteins in tissue) have thus far not been reproducible. Such qualitative or semi-quantitative protein expression biomarkers may not fully capture the quantitative signal of a gene expression-based continuous risk score.\u003c\/p\u003e\n\n\u003cp\u003eCurrent indications for postoperative radiotherapy for patients with meningiomas are controversial. This is particularly true for patients with primary WHO grade 2 meningiomas who are randomized to postoperative surveillance or postoperative radiotherapy on NRG BN-003 and EORTC 1308 after GTR.\u003c\/p\u003e\n\n\u003cp\u003eConflicting retrospective series have variably reported a benefit or no benefit from radiotherapy in this setting. This has fueled debate and inspired these international Phase III clinical trials of radiotherapy for patients with meningiomas.\u003c\/p\u003e\n\n\u003cp\u003eThe gene expression biomarker reported here improves risk stratification for primary WHO grade 2 meningiomas. The biomarker may identify favorable WHO grade 2 meningiomas where postoperative radiotherapy could be safely omitted in favor of close surveillance.\u003c\/p\u003e\n\n\u003cp\u003eThe gene expression biomarker also identifies primary WHO grade 1 meningiomas with elevated risk of recurrence. Most meningiomas are WHO grade 1 and are often considered benign. However, the researchers found that 6.4% of primary WHO grade 1 meningiomas in the multicenter retrospective clinical validation cohort were classified as gene expression high risk.\u003c\/p\u003e\n\n\u003ch2 id=\"limitations\"\u003eLimitations: What the Study Could Not Prove\u003c\/h2\u003e\n\n\u003cp\u003eThe functional interactions among the genes included in the biomarker are incompletely understood. The biomarker includes a long non-coding RNA (a type of RNA that does not code for proteins). The interactions among the cell types in meningiomas are also incompletely understood. The relationships of these genes to meningioma histological variants are not fully known.\u003c\/p\u003e\n\n\u003cp\u003eThe study was primarily retrospective, meaning it looked back at past patient data. The prospective validation was limited to 103 patients from RTOG 0539. Larger prospective studies are needed to confirm the findings.\u003c\/p\u003e\n\n\u003cp\u003eThe researchers note that DNA methylation profiling was only able to predict the gene expression risk score to a moderate degree. This means DNA methylation testing is not a perfect substitute for the gene expression biomarker.\u003c\/p\u003e\n\n\u003cp\u003eThe study did not directly compare the gene expression biomarker to the current standard of care in a prospective randomized trial. Such a trial would be needed to definitively prove that using the biomarker improves patient outcomes.\u003c\/p\u003e\n\n\u003ch2 id=\"recommendations\"\u003eRecommendations for Patients\u003c\/h2\u003e\n\n\u003cp\u003eIf you or a loved one has been diagnosed with a meningioma, here are key points to discuss with your medical team:\u003c\/p\u003e\n\n\u003col\u003e\n\u003cli\u003e\n\u003cstrong\u003eAsk about molecular testing:\u003c\/strong\u003e The gene expression biomarker described in this study is not yet widely available in clinical practice. Ask your doctor whether molecular testing of your tumor could provide useful information for your treatment plan.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eDiscuss radiotherapy decisions:\u003c\/strong\u003e If you have a WHO grade 2 meningioma that was completely removed, ask your doctor about the risks and benefits of postoperative radiotherapy versus close surveillance. This study suggests that some patients may benefit from radiotherapy while others may not.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eSeek specialized care:\u003c\/strong\u003e Meningiomas are complex tumors. Consider seeking care at a center with expertise in brain tumors and access to clinical trials.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eAsk about clinical trials:\u003c\/strong\u003e The NRG BN-003 and EORTC 1308 trials are ongoing. Ask your doctor if you might be eligible for these or other clinical trials.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eUnderstand your risk group:\u003c\/strong\u003e If molecular testing is available, ask your doctor to explain which risk group your tumor falls into and what that means for your prognosis and treatment options.\u003c\/li\u003e\n\u003c\/ol\u003e\n\n\u003cp\u003eThe gene expression biomarker is not yet part of routine clinical care. However, this research represents an important step toward more personalized treatment for patients with meningiomas. The ability to predict which patients will benefit from radiotherapy could spare some patients from unnecessary treatment and its side effects, while ensuring that others receive the treatment they need.\u003c\/p\u003e\n\n\u003c!-- ddn:faq:start --\u003e\n\u003ch2 id=\"ddn-faq\"\u003eFrequently Asked Questions\u003c\/h2\u003e\n\u003ch3\u003eWhat is a 34-gene expression biomarker for meningioma?\u003c\/h3\u003e\n\u003cp\u003eIt is a molecular test that measures the activity of 34 specific genes in a meningioma sample. In a validation cohort of 1,856 meningiomas from 12 institutions across 3 continents, it predicted 5-year local recurrence and overall survival better than the World Health Organization 2021 grade standard. It is not yet widely available in routine clinical care.\u003c\/p\u003e\n\u003ch3\u003eHow accurate is this gene expression test for predicting meningioma recurrence?\u003c\/h3\u003e\n\u003cp\u003eIn a validation cohort of 1,856 meningiomas from 12 institutions, the test achieved a 5-year area under the curve of 0.81 for local recurrence and 0.80 for overall survival. An area under the curve of 0.5 is random chance and 1.0 is perfect prediction. It outperformed the World Health Organization 2021 grade standard.\u003c\/p\u003e\n\u003ch3\u003eCan this test tell whether I will benefit from radiotherapy after meningioma surgery?\u003c\/h3\u003e\n\u003cp\u003eIn a multicenter retrospective cohort, patients with unfavorable biomarker and surgical features benefited from postoperative radiotherapy (hazard ratio 0.54, 95% CI 0.37–0.78, P=0.0001), while those with favorable features did not (P=0.42). The test is not yet part of routine care, so discuss radiotherapy decisions with your doctor.\u003c\/p\u003e\n\u003ch3\u003eWhat do the low, intermediate, and high risk groups mean for my prognosis?\u003c\/h3\u003e\n\u003cp\u003eIn a multicenter retrospective cohort of 866 meningiomas, 5-year local freedom from recurrence was 92.2% for low risk, 72.6% for intermediate risk, and 19.4% for high risk. This means patients in the low risk group had a 92.2% chance of remaining free from local recurrence at 5 years, while high risk patients had a 19.4% chance.\u003c\/p\u003e\n\u003ch3\u003eCould this test spare some patients from unnecessary radiotherapy?\u003c\/h3\u003e\n\u003cp\u003eIn a multicenter retrospective cohort, the biomarker reclassified 52.0% of meningiomas compared to clinical criteria, including downstaging 21.3% of intermediate clinical risk patients who would have received postoperative radiotherapy. The researchers suggested postoperative management could have been refined for 29.8% of patients. The test is not yet part of routine care.\u003c\/p\u003e\n\u003ch3\u003eIs this gene expression test available now for patients with meningioma?\u003c\/h3\u003e\n\u003cp\u003eNo. The gene expression biomarker described is not yet widely available in clinical practice and is not part of routine clinical care. If you have been diagnosed with a meningioma, ask your doctor whether molecular testing of your tumor could provide useful information for your treatment plan, and ask about clinical trials.\u003c\/p\u003e\n\u003ch3\u003eWhat should I discuss with my doctor if I have a WHO grade 2 meningioma that was completely removed?\u003c\/h3\u003e\n\u003cp\u003eAsk your doctor about the risks and benefits of postoperative radiotherapy versus close surveillance. In a multicenter retrospective cohort, primary WHO grade 2 meningiomas with complete removal did not benefit from postoperative radiotherapy without biomarker stratification, but unfavorable biomarker and surgical features identified those who did benefit (hazard ratio 0.33, 95% CI 0.14–0.76, P=0.009).\u003c\/p\u003e\n\u003ch3\u003eI have a WHO grade 2 meningioma that was completely removed — when should I seek a second opinion about whether I need postoperative radiotherapy?\u003c\/h3\u003e\n\u003cp\u003eA 34-gene expression biomarker identifies which meningiomas benefit from postoperative radiotherapy. Unfavorable tumors (intermediate risk with partial removal, or high risk with any removal) benefited (HR 0.54), while favorable tumors did not. Without biomarker stratification, primary WHO grade 2 meningiomas with complete removal showed no radiotherapy benefit, and postoperative management could be refined for 29.8% of patients. Because radiotherapy decisions for completely removed grade 2 meningiomas are controversial, a second opinion can help clarify whether testing and radiotherapy are appropriate. Diagnostic Detectives Network provides independent expert second opinions.\u003c\/p\u003e\n\u003c!-- ddn:faq:end --\u003e\n\n\u003ch2 id=\"source\"\u003eSource Information\u003c\/h2\u003e\n\n\u003cp\u003e\u003cstrong\u003eOriginal article title:\u003c\/strong\u003e Targeted gene expression profiling predicts meningioma outcomes and radiotherapy responses\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eAuthors:\u003c\/strong\u003e William  C. Chen, Abrar Choudhury, Mark W. Youngblood, Mei‐Yin C. Polley, Calixto‐Hope G. Lucas, Kanish Mirchia, et al.\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eJournal:\u003c\/strong\u003e Nature Medicine, 29(12): 3067–3076\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003ePublication date:\u003c\/strong\u003e December 2023\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eDOI:\u003c\/strong\u003e 10.1038\/s41591-023-02586-z\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eCorresponding authors:\u003c\/strong\u003e David R. Raleigh, MD, PhD (University of California, San Francisco); Stephen T. Magill, MD, PhD (Northwestern University); William C. Chen, MD (University of California, San Francisco)\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eInstitutions involved:\u003c\/strong\u003e 12 institutions across 3 continents, including the University of California, San Francisco\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eFunding and disclosures:\u003c\/strong\u003e WCC and DRR are the inventors on patent PCT\/US 21\/70288 describing the use of targeted gene expression profiling to predict meningioma outcomes and radiotherapy responses. MP has received honoraria for lectures, consultation, or advisory board participation from several for-profit companies. The remaining authors declare no competing interests.\u003c\/p\u003e\n\n\u003cp\u003e\u003cem\u003eThis patient-friendly article is based on peer-reviewed research published in Nature Medicine. It is intended for educational purposes and should not replace consultation with a qualified healthcare provider.\u003c\/em\u003e\u003c\/p\u003e","brand":"DiagnosticDetectives.Com","offers":[{"title":"Default Title","offer_id":47797550481564,"sku":null,"price":0.0,"currency_code":"KRW","in_stock":true}],"thumbnail_url":"\/\/cdn.shopify.com\/s\/files\/1\/0599\/5449\/5644\/files\/ddn-medical-article-new-gene-expression-test-predicts-meningioma-outcomes-and-radiotherapy-responses-better-than-current-methods-hero.png?v=1791955269","url":"https:\/\/diagnosticdetectives.kr\/products\/new-gene-expression-test-predicts-meningioma-outcomes-and-radiotherapy-responses-better-than-current-methods","provider":"DiagnosticDetectives.Com","version":"1.0","type":"link"}