Targeted and Personalized Therapy for Difficult Benign Brain Tumors: A Review
Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsReviewer Report
- Main Research Question
The manuscript addresses an important and clinically relevant question on how molecular profiling and biomarker-driven stratification can support personalized treatment in difficult benign intracranial tumors beyond conventional histology-based paradigms. The authors primarily focus on meningiomas, schwannomas, NF-related tumors, and PitNETs, using gliomas as a comparator, where biomarker-to-therapy translation is more advanced. The research question is clearly defined and well introduced.
- Originality and Relevance
The review is timely and relevant. A key strength is that it organizes the field around clinical actionability and treatment selection, rather than only listing biomarkers. The synthesis of molecular classification and potential targeted therapies is well presented and aligns well with the goals of precision medicine.
- Contribution to the Field
The manuscript highlights the biological heterogeneity of benign CNS tumors and emphasizes the potential role of molecular profiling and functional testing in guiding personalized treatment. The discussion is balanced and acknowledges that biomarker expression does not always translate into therapeutic dependence, which is an important point.
- Methodological Comments / Suggested Improvements
Overall, this is a solid and well-written review. My suggestions mainly aim to improve completeness.
First, the manuscript could expand the discussion of non-invasive biomarker prediction, particularly in gliomas. Recent studies demonstrate that AI-based radiomics and deep learning models can predict clinically relevant biomarkers, such as MGMT methylation or IDH-related molecular states, from MRI, thereby linking imaging directly to personalized treatment strategies (e.g., 10.3389/fonc.2025.1731258; 10.1038/s41698-025-00884-y). Briefly mentioning this emerging area would strengthen the translational perspective.
Second, the manuscript would benefit from a short discussion of theranostics, which is currently missing and, in my opinion, represents a serious omission given the rigorous methodology and study design the authors implemented for the literature search. This is particularly relevant given the mention of receptor-targeted radionuclide therapy in meningiomas. Framing these approaches within the broader theranostic paradigm would improve conceptual completeness. The authors may consider referencing the recent review on theranostics in neuro-oncology (10.3390/ijms26157396).
Finally, the discussion could briefly emphasize that the field is evolving along three complementary translational directions:
- molecular tumor classification,
- non-invasive imaging/AI biomarker prediction,
- therapy-linked platforms such as functional assays and theranostics.
- Conclusions
The conclusions are appropriate and consistent with the evidence presented. Expanding the discussion to include theranostics and AI-driven biomarker prediction would further strengthen the manuscript's forward-looking perspective.
- References
The reference list is generally appropriate and up to date. However, including recent literature on theranostics in neuro-oncology and on AI-based imaging for predicting actionable glioma biomarkers would improve completeness.
- Tables and Figures
Tables and figures are clear and informative. No major changes are required.
Overall Assessment:
This is a well-structured and clinically meaningful review. I recommend a revision, mainly to incorporate a brief discussion of theranostics and AI-based biomarker prediction approaches relevant to personalized neuro-oncology.
Author Response
Comment: Incorporate Discussion on theranostics in neuro-oncology and on AI-based imaging for predicting actionable glioma biomarkers - mention of receptor-targeted radionuclide therapy in meningiomas. This is particularly relevant given the mention of receptor-targeted radionuclide therapy in meningiomas. Framing these approaches within the broader theranostic paradigm would improve conceptual completeness. The authors may consider referencing the recent review on theranostics in neuro-oncology (10.3390/ijms26157396). Expand the discussion of non-invasive biomarker prediction, particularly in gliomas. Recent studies demonstrate that AI-based radiomics and deep learning models can predict clinically relevant biomarkers, such as MGMT methylation or IDH-related molecular states, from MRI, thereby linking imaging directly to personalized treatment strategies (e.g., 10.3389/fonc.2025.1731258; 10.1038/s41698-025-00884-y)
Response: Reviewer 1 highlighted the relevance of the manuscript while recommending expansion of several novel translational areas. In response, we revised the Discussion to incorporate a dedicated section on radiogenomics, AI-based biomarker prediction, and theranostics (lines 462-483). This addition now addresses the emerging role of non-invasive imaging approaches in personalized neuro-oncology, including recent studies showing that MRI-based radiomics and deep learning models can predict clinically relevant glioma biomarkers. We also added a focused discussion of theranostics in neuro-oncology, particularly to contextualize receptor-targeted radionuclide therapy in meningioma within a broader framework that links molecular imaging with treatment selection. These revisions have strengthened the translational scope of the review to better reflect the novel development in difficult benign tumor management to date.
Reviewer 2 Report
Comments and Suggestions for AuthorsThis article presents a narrative review of the role of molecular profiling and biomarkers in the personalized treatment/target-therapy of “difficult to treat” benign CNS tumors, summarizing novel therapies innovations for different types of tumors: meningiomas, schwannomas, NF-associated lesions, and PitNETs (comparing with low-grade gliomas). To this end, the manuscript revises current evidence on tumor genomics and molecular markers, supported by methylation-based classification, immunohistochemistry, and functional assays, emphasizing current clinical application.
Although the authors present a review for each tumor group, some considerations need to be made regarding the methodology.
1. Gliomas (or adult-type diffuse gliomas) should not be categorized as benign diseases, as they are a group of great genetic/epigenetic complexity—even considering recent advances in the treatment of IDH-mutated gliomas. I believe that including infiltrative/intra-axial tumors together with extra-axial tumors makes understanding the purpose of the article more confusing.
2. Meningiomas and schwannomas are predominantly surgical tumors. The role of emerging/individualized therapies is in controlling residual disease, in WHO grade 2 or 3 tumors (in this case, atypical or anaplastic meningiomas, respectively, in which the risk of recurrence is much higher) or in patients with syndromes such as NF type 1 and 2, in which there is the presence/appearance of several tumors over time. Tables 2, 3, and 4, summarizing the findings and impacts of studies, are very concise beyond SOC.
3. In the discussion: "personalized therapy for difficult benign brain tumors is feasible when biomarkers are treated as decision-making fundamentals, and therapies are aligned with pathogenic dependencies to maximise patient benefit." This is a very coherent statement—but it is necessary to point out that localized treatments (surgery, radiation) are still responsible for improving the outcome in most cases. A better understanding of molecular markers helps to further stratify the risk of progression/recurrence and, therefore, suggest the selection/recruitment of a patient for research/clinical study.
4. 5th edition of the WHO classification of CNS tumors (2021) recommends describing the grade with numbers rather than Roman numerals.
Author Response
Comment 1: 5th edition of the WHO classification of CNS tumors (2021) recommends describing the grade with numbers rather than Roman numerals.
Response 1: In accordance with Reviewer 2’s terminology recommendation, we revised the manuscript throughout to use Arabic numerals for tumor grades in keeping with the 2021 WHO CNS classification convention.
Comment 2: Meningiomas and schwannomas are predominantly surgical tumors. The role of emerging/individualized therapies is in controlling residual disease, in WHO grade 2 or 3 tumors (in this case, atypical or anaplastic meningiomas, respectively, in which the risk of recurrence is much higher) or in patients with syndromes such as NF type 1 and 2, in which there is the presence/appearance of several tumors over time. In the discussion: "personalized therapy for difficult benign brain tumors is feasible when biomarkers are treated as decision-making fundamentals, and therapies are aligned with pathogenic dependencies to maximise patient benefit." - Necessary to point out that localized treatments (surgery, radiation) are still responsible for improving the outcome in most cases. A better understanding of molecular markers helps to further stratify the risk of progression/recurrence and, therefore, suggest the selection/recruitment of a patient for research/clinical study.
Response 2: We addressed Reviewer 2’s emphasis that meningiomas and schwannomas remain predominantly surgical tumors, with radiotherapy and biomarker methodology being used primarily as an adjuncts. In response, we strengthened this clinical framing throughout the Introduction (Lines 62-69), tumor-specific sections (Lines 180-183 and 271-275), and Discussion (Lines 432-436). The revised manuscript now states more clearly that biomarker-informed and individualized therapies presently have a predominantly adjunctive role, particularly in residual, recurrent, refractory, or biologically higher-risk disease, including WHO grade 2 and 3 meningiomas and syndromic conditions such as NF1 and NF2. Additionally, we revised the Discussion to emphasize that the most immediate clinical value of molecular profiling lies in refining diagnosis, stratifying recurrence risk, informing radiotherapeutic planning, and identifying patients appropriate for biomarker-defined clinical trials when standard local therapies are insufficient. As well, we revised the manuscript to more clearly state that surgery and radiotherapy remain the principal modalities underlying outcome improvement in most patients with difficult benign brain tumors, with personalized therapies being complements, rather than replacements for standard local management.
Comment 3: Gliomas should not be categorized as benign diseases, as they are a group of great genetic/epigenetic complexity—even considering recent advances in the treatment of IDH-mutated gliomas. I believe that including infiltrative/intra-axial tumors together with extra-axial tumors makes understanding the purpose of the article more confusing.
Response 3: We have addressed the comment on glioma categorization by reviewer 2 and greatly appreciate their feedback. With all due respect to the reviewer, we found it pertinent to discuss gliomas as a comparator in our review, as their biomarker-guided classifications are currently more mature and provide a useful reference point for the broader discussion of difficult benign intracranial tumors, and therefore feel it provides useful context to out review. We recognized that the original wording could create conceptual ambiguity by placing infiltrative intra-axial tumors too close to the extra-axial tumors that constitute the primary focus of the review and have added content on lines 49 and 139 to further clarify gliomas’ relevance. However, if upon further revision the reviewer wishes for us to remove gliomas from the review entirely, please let us know and we would be happy to do so.
Comment 4: Tables 2, 3, and 4, summarizing the findings and impacts of studies, are very concise beyond SOC.
Response 4: We thank reviewer 2 for his/her feedback, but do not fully understand if the comment “Tables 2, 3, and 4, summarizing the findings and impacts of studies, are very concise beyond SOC” is a compliment or a request for change. The tables (tables 1-5) were intended to be focused summaries of biomarker-informed findings and emerging treatments most relevant to the research question, rather than comprehensive reviews of standard clinical care.
Round 2
Reviewer 1 Report
Comments and Suggestions for AuthorsThank you for addressing all my concerns
