Genomic Landscape of Endometrial, Ovarian, and Cervical Cancers in Japan from the Database in the Center for Cancer Genomics and Advanced Therapeutics

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The present manuscript titled “Genomic landscape of endometrial, ovarian, and cervical cancers in Japan from the database in the Center for Cancer Genomics and Advanced Therapeutics” by Xi et al. is well written. However, even if results are interesting, it remains some critical issue linked to the lack of data from patients without medical insurance. Furthermore, it would useful to analyze the  response to therapy before the deterioration and death of end-stage patients.This  would improve the value of the study.

I have only a few minor comments for the authors:

- Is it possible to add a work-flow of the design of the study?

- Figure 2 is a bit difficult to understand.

- The conclusion sections is poor. The authors should revise this section.

Comments on the Quality of English Language

Good quality of English Language

Author Response

Reply to reviewer 1

• It remains some critical issue linked to the lack of data from patients without medical insurance. Furthermore, it would be useful to analyze the response to therapy before the deterioration and death of end-stage patients. This would improve the value of the study.

Response: We agree with the reviewer that the issues about medical insurance and drug response are important in clinical settings. Therefore, we explained these limitations in “Discussion” section.

Line 439- “In addition, this study lacks data from patients without medical insurance due to the universal health insurance system in Japan. Second, the response to genome-matched therapies was not analyzed in this study because of the low accessibility of the recommended drugs.”

 

• Is it possible to add a work-flow of the design of the study?

Response: Thank you very much for your specific suggestion to add a workflow for the study design. Following your valuable advice, we have added a workflow as Figure 1, which explains the flow of collection of clinical information and genomic datasets from the C-CAT database. This workflow will help our readers to understand how our analysis can be comprehensively performed in gynecological cancers in Japan.

 

• Figure 2 is a bit difficult to understand.

Response: Thank you very much for the kind suggestion. To improve clarity and avoid the confusion, we have deleted several mutated genes, which are less affected in the specific signaling pathways.

 

• The conclusion sections is poor. The authors should revise this section.

Response: We agree with the reviewer and revised the “Conclusion” section with a more comprehensive summary of the manuscript, emphasizing key genetic alterations and their implications in precision oncology.

5. Conclusions

This study uniquely illustrates the genomic landscape of 3 major gynecological cancers in the Japanese cohort. It highlights the necessity of future drug developments in each cancer type, and each histological subtype. Especially, ERBB2, PIK3CA, ARID1A, and KRAS would be key molecular targets in gynecological cancers. Furthermore, the prevalence and correlation between TMB and MSI may influence future immunotherapy, including combination therapies. These insights reinforce the necessity of molecular classification in understanding tumor biology and developing personalized therapies, underlining the potential of genomic profiling in precision oncology.

 

Reviewer 2 Report

Comments and Suggestions for Authors

Work by Xi et al in characterization of the genomic landscape involving endometrial, cervical and ovarian cancer provides an extensive amount of relevant molecular signal expression involving these 3 cancers. Attempt to relate product management to the signal expression however was somewhat lacking. Relevant target therapeutics described in this paper are not covered in sufficient detail with respect to use or use opportunity. A brief explanation should be added to the manuscript providing more therapeutic option discussion for each of the highly expressed target sites. In addition, the amount of text used to explain molecular profiles generated is excessive. I’d reduce repetitive discussion of target expression and try to summarize results better in one table. Figure 1 impressive but display of results appears excessive. Would consider deleting Table 1. This will then better support clinical directed readership.

Comments on the Quality of English Language

Minor editing required.

Author Response

Reply to reviewer 2

• Relevant target therapeutics described in this paper are not covered in sufficient detail with respect to use or use opportunity. A brief explanation should be added to the manuscript providing more therapeutic option discussion for each of the highly expressed target sites.

Response: We agree with the reviewer and emphasized the necessity of drug development in each tumor type. In addition, we have created a “Table 1” summarizing the genetic alterations that can be targeted in gynecological tumors, along with their corresponding clinical treatment opportunities. This table serves as a useful reference for readers seeking a quick overview of the topic.

 

Line 170-: The high frequency of PIK3CA genomic alterations, regardless of the histological types, suggested the need for potential therapies targeting the PI3K pathway (Fig. 3A and Table 1).

Line 362-: Drug development targeting ARID1A and PIK3CA in clear-cell ovarian carcinomas is also warranted.

Line 366-: Targeting the RAS-MAPK pathway should be a key in mucinous carcinomas.

Line 387-: Although pembrolizumab has been approved in any solid cancers with either TMB-H and MSI-H, the combination therapies with immune checkpoint inhibitors may be developed separately, according to the status of TMB and MSI.

 

• Figure 1 impressive but display of results appears excessive. The amount of text used to explain molecular profiles generated is excessive.

Response: We agree with the reviewer that the information of Fig 1 and the text about molecular profiles are excessive. We have made the following revisions:

• We have limited Figure 1 to display up to top 20 genes with the highest mutation rates, ensuring a more focused and less overwhelming presentation of our findings.
• We have also carefully reviewed the “Results” section and reduced the excessive text about molecular profiles throughout the manuscript, aiming to maintain clarity and relevance while eliminating unnecessary details.

 

• Reduce repetitive discussion of target expression and try to summarize results better in one table.

Response. Thank you very much for your thoughtful suggestions. We have made the following revisions:

• We have reduced the repetitive discussions on target expression in the “Results” section to avoid redundancy and ensure a more streamlined presentation of our findings.
• We have created a new "Table 1" to serve as a comprehensive summary of our results, as described above. This table highlights the key targets of our study and provides a clear overview of their expression and corresponding clinical therapeutic options.

 

• Would consider deleting Table 1. This will then better support clinical directed readership.

Response: Thank you very much for your suggestion. We have deleted the Table 1, and instead, have shown the Table as a Supplementary Table (Table S2).

 

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

None.