Molecular Profiling of H-MSI/dMMR/for Endometrial Cancer Patients: “New Challenges in Diagnostic Routine Practice”
Round 1
Reviewer 1 Report
Comments and Suggestions for Authors
The manuscript is generally well written. There are quite a few typos that need to be rectified before publication (e.g., page 2). Ideally, the authors should provide a few more figures to better summarize and discuss the mutations in endometrial cancer and the molecular profiling system.
Comments on the Quality of English LanguageNA
Author Response
Reviewer 1
The manuscript is generally well written. There are quite a few typos that need to be rectified before publication (e.g., page 2). Ideally, the authors should provide a few more figures to better summarize and discuss the mutations in endometrial cancer and the molecular profiling system
We really thank the reviewer for the kind appreciation.
There are quite a few typos that need to be rectified before publication (e.g., page 2).
We really thank the reviewer for the kind appreciation. We have modified the latest version of the manuscript rectifying typos, accordingly.
Ideally, the authors should provide a few more figures to better summarize and discuss the mutations in endometrial cancer and the molecular profiling system
We really thank the reviewer for the kind appreciation. We have modified the latest version of the manuscript adding a new figure to summarize endometrial cancer types and the molecular profiling system.
Reviewer 2 Report
Comments and Suggestions for AuthorsDear authors,
Congratulations for your work. The article successfully compiles and compares various commercially available diagnostic assays for MSI/dMMR status in EC patients, including IHC, Pentaplex Bethesda Panel Assay, OncoMate™ MSI Dx Analysis System, LMR MSI Analysis System, EasyPGX® ready MSI Kit, Idylla™ MSI Test, and ddPCR Microsatellite Instability (MSI) Kit. This comprehensive comparison provides valuable insights into the advantages and limitations of each assay, which can aid clinicians and pathologists in choosing the most appropriate test for their patients.
You highlight the importance of molecular profiling in the era of precision medicine, showcasing how molecular diagnostics can guide personalized therapeutic strategies for EC patients. This aligns well with current trends in oncology, emphasizing the importance of a tailored approach to cancer treatment.
The inclusion of Table 1, which outlines the technical evaluation of MSI/dMMR testing strategies, is particularly useful. This table concisely summarizes the analyzed loci, advantages, and disadvantages of each assay, serving as a quick reference for readers.
The discussion reflects on the transition from traditional IHC-based methods to advanced PCR-based assays and the advent of semi-automated and automated systems for MSI testing. This narrative underscores the technological advancements in the field and the ongoing need for optimization and validation of diagnostic tools.
Although the article discusses various diagnostic tools, it also reveals the diversity in methodologies and potential discrepancies in test results. More specific recommendations or guidelines on how to achieve standardization across assays would enhance the article's impact.
While the technical aspects of the assays are thoroughly reviewed, the article could benefit from a deeper discussion on the clinical outcomes associated with the use of these diagnostics, such as patient survival, response to therapy, and overall cost-effectiveness of each method.
The article focuses primarily on existing commercial assays but could explore more on emerging technologies and their potential impact on EC diagnostics. For example, next-generation sequencing (NGS)-based approaches or artificial intelligence (AI) applications in pathology could represent the next frontier in molecular profiling of EC.
Author Response
Reviewer 2
Congratulations for your work. The article successfully compiles and compares various commercially available diagnostic assays for MSI/dMMR status in EC patients, including IHC, Pentaplex Bethesda Panel Assay, OncoMate™ MSI Dx Analysis System, LMR MSI Analysis System, EasyPGX® ready MSI Kit, Idylla™ MSI Test, and ddPCR Microsatellite Instability (MSI) Kit. This comprehensive comparison provides valuable insights into the advantages and limitations of each assay, which can aid clinicians and pathologists in choosing the most appropriate test for their patients.
You highlight the importance of molecular profiling in the era of precision medicine, showcasing how molecular diagnostics can guide personalized therapeutic strategies for EC patients. This aligns well with current trends in oncology, emphasizing the importance of a tailored approach to cancer treatment.
The inclusion of Table 1, which outlines the technical evaluation of MSI/dMMR testing strategies, is particularly useful. This table concisely summarizes the analyzed loci, advantages, and disadvantages of each assay, serving as a quick reference for readers.
The discussion reflects on the transition from traditional IHC-based methods to advanced PCR-based assays and the advent of semi-automated and automated systems for MSI testing. This narrative underscores the technological advancements in the field and the ongoing need for optimization and validation of diagnostic tools.
We really thank the reviewer for the kind appreciation.
Although the article discusses various diagnostic tools, it also reveals the diversity in methodologies and potential discrepancies in test results. More specific recommendations or guidelines on how to achieve standardization across assays would enhance the article's impact.
We really thank the reviewer for the kind appreciation. We have modified the latest version of the manuscript accordingly “At the sight of these critical aspects, College of American Pathologists established a consensus panel able to overcome pre-analytical and analytical bias in H-MSI/dMMR profile evaluation for EC patients. Particularly, EC patients eligible to ICIs in accordance with MSI status, should be tested adopting an integrated workflow based on MMR-IHC MSI by PCR or NGS for the detection of DNA mismatch repair defects”
While the technical aspects of the assays are thoroughly reviewed, the article could benefit from a deeper discussion on the clinical outcomes associated with the use of these diagnostics, such as patient survival, response to therapy, and overall cost-effectiveness of each method.
We really thank the reviewer for the kind appreciation. We have modified the latest version of the manuscript accordingly. “To date, MMR/MSI status has rapidly revolutionized the clinical landscape of EC patients. In this scenario, Dostarlimab (Immune checkpoint inhibitor) was approved to treat H-MSI/d-MMR EC patients thanks to a statistically significant benefit in terms of progression-free survival at 24 months (61.4%, 95% confidence interval [CI], 46.3 to 73.4 versus 15.7% (95% CI, 7.2 to 27.0) and overall survival at 24 months (71.3% (95% CI, 64.5 to 77.1) with dostarlimab compared with 56.0% (95% CI, 48.9 to 62.5) of placebo group. (54) At the sight of these aspects, H-MSI/d-MMR became pivotal in the clinical management of EC patients”
“In terms of saving technical costs, Orellana et al. highlighted that molecular testing strategy arises cost-effective in comparison with no testing approach ($100,000/QALY) including in this statistical evaluation all clinically promising biomarkers for EC patients. Particularly, IHC based approach, routinely adopted in diagnostic routine practice represents a cost-effective testing strategy compared with molecular techniques whereas molecular testing approaches are sustainable setting a willingness-to-pay threshold of $100,000/QALY”
The article focuses primarily on existing commercial assays but could explore more on emerging technologies and their potential impact on EC diagnostics. For example, next-generation sequencing (NGS)-based approaches or artificial intelligence (AI) applications in pathology could represent the next frontier in molecular profiling of EC
We really thank the reviewer for this kind suggestion. We have modified the latest version of the manuscript, accordingly.
“Taking into account technical opening challenges in detecting MSI status, NGS platforms enable simultaneous analysis of several loci potentially reflecting genomic instability among different tumor types. As showed by Bartels et al. a technical sensitivity and specificity of 88.6% and 95.2%, respectively, was calculated on a series of EC patients previously tested with standardized approaches. (70) Although this comprehensive approach allows to detect H-MSI status across several types of histological tumors, optimized bioinformatic pipelines are required to implement NGS based in diagnostic routine practice of EC patients. (71)”
