The Role of Genomics and Transcriptomics in Characterizing and Predicting Patient Response to Treatment in Triple Negative Breast Cancer (TNBC)

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Thank you for submitting this outstanding review regarding the predictive biomarkers and response to  the currently used therapies for triple negative breast cancer patients .  the article was well written, clear and easy to read.  The topic was  important and would significantly add to our knowledge.  However; I would like to suggest the following to increase the impact of the study:

- Discuss in more details the limitations and challenges of the study and how the authors combated them.

- Highlight the novelty and strength the article.

Author Response

• Comment 1: Please add.
  This should be written in one paragraph before the Abstract in layman’s terms, to ex-plain why the research is being suggested, what the authors aim to achieve, and how the findings from this research may impact the research community. Please use as few abbreviations as possible and do not cite references in the Simple Summary. The Simple Summary should not exceed 150 words. Submissions without a simple summary will be returned directly. An example can be found at https://www.mdpi.com/2072-6694/12/9/2424.
• Response 1: Simple summary added.
• Comment 2: Please confirm there is no Copyright issue in all tables and figures in the manuscript. 
• Response 2: No copyright issues in any tables or figures. 
• Comment 3: For research articles with several authors, a short paragraph specifying their individual contributions must be provided. The following statements should be used “Conceptualization, X.X. and Y.Y.; methodology, X.X.; software, X.X.; validation, X.X., Y.Y. and Z.Z.; formal analysis, X.X.; investigation, X.X.; resources, X.X.; data curation, X.X.; writing—original draft preparation, X.X.; writing—review and editing, X.X.; visualization, X.X.; supervision, X.X.; project administration, X.X.; funding acquisition, Y.Y. All authors have read and agreed to the published version of the manuscript.” Please turn to the CRediT taxonomy for the term explanation. Authorship must be limited to those who have contributed substantially to the work reported. Please add: “This research received no external funding” or “This research was funded by NAME OF FUNDER, grant number XXX” and “The APC was funded by XXX”. Check carefully that the details given are accurate and use the standard spelling of funding agency names at https://search.crossref.org/funding. Any errors may affect your future funding. In this section, you should add the Institutional Review Board Statement and approval number, if relevant to your study. You might choose to exclude this statement if the study did not require ethical approval. Please note that the Editorial Office might ask you for further information. Please add “The study was conducted in accordance with the Declaration of Helsinki, and approved by the Institutional Review Board (or Ethics Committee) of NAME OF INSTITUTE (protocol code XXX and date of approval).” for studies involving humans. OR “The animal study protocol was approved by the Institutional Review Board (or Ethics Committee) of NAME OF INSTITUTE (protocol code XXX and date of approval).” for studies involving animals. OR “Ethical review and approval were waived for this study due to REASON (please provide a detailed justification).” OR “Not applicable” for studies not involving humans or animals. In this section, you should add the Institutional Review Board Statement and approval number, if relevant to your study. You might choose to exclude this statement if the study did not require ethical approval. Please note that the Editorial Office might ask you for further information. Please add “The study was conducted in accordance with the Declaration of Helsinki, and approved by the Institutional Review Board (or Ethics Committee) of NAME OF INSTITUTE (protocol code XXX and date of approval).” for studies involving humans. OR “The animal study protocol was approved by the Institutional Review Board (or Ethics Committee) of NAME OF INSTITUTE (protocol code XXX and date of approval).” for studies involving animals. OR “Ethical review and approval were waived for this study due to REASON (please provide a detailed justification).” OR “Not applicable” for studies not involving humans or animals. We encourage all authors of articles published in MDPI journals to share their research data. In this section, please provide details regarding where data supporting reported results can be found, including links to publicly archived datasets analyzed or generated during the study. Where no new data were created, or where data is unavailable due to privacy or ethical restrictions, a statement is still required. Suggested Data Availability Statements are available in section “MDPI Research Data Policies” at https://www.mdpi.com/ethics. In this section, you can acknowledge any support given which is not covered by the author contribution or funding sections. This may include administrative and technical support, or donations in kind (e.g., materials used for experiments). Declare conflicts of interest or state “The authors declare no conflicts of interest.” Authors must identify and declare any personal circumstances or interest that may be perceived as inappropriately influencing the representation or interpretation of reported research results. Any role of the funders in the design of the study; in the collection, analyses or interpretation of data; in the writing of the manuscript; or in the decision to publish the results must be declared in this section. If there is no role, please state “The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results”. Declare conflicts of interest or state “The authors declare no conflicts of interest.” Authors must identify and declare any personal circumstances or interest that may be perceived as inappropriately influencing the representation or interpretation of reported research results. Any role of the funders in the design of the study; in the collection, analyses or interpretation of data; in the writing of the manuscript; or in the decision to publish the results must be declared in this section. If there is no role, please state “The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results”. 
• Response 3: All statements added with appropriate information.

• Comment 4: Please revise the reference format and keep the self-citation rate to <15%:

  For documents co-authored by =<10 authors, all of the authors should be cited; For documents co-authored by more than 10 authors, you can cite the first ten authors, then add a semicolon and add ‘et al.’ at the end: "Author 1; Author 2; Author 3; Author 4; Author 5; Author 6; Author 7; Author 8; Author 9; Author 10; et al."

• Response 4: Self citation kept to a minimum and citation changes made.
• Comment 5: Discuss in more details the limitations and challenges of the study and how the authors combated them. Highlight the novelty and strength the article.
• Response 5: Additional paragraph added in the conclusions to discuss limitations and strengths as well as to introduce clinical trials as how to overcome limitations.

Reviewer 2 Report

Comments and Suggestions for Authors

Dear authors, please find my comments below: 

Figure 1. You have MES and MSL in the same category, would you consider splitting them, as MSL originates same as MES, but at molecular level it has low levels of claudin? Or anyways, you should debate the classification, as currently the scientific community is trying to offer the best alternative for TNBC classification which may help for a better diagnosis and therapeutical approach. Please check this reference https://www.nature.com/articles/s41523-020-00197-2 

For chemotherapy and drug conjugates, a figure would be useful. Describing the molecular pathways that are triggered by the therapy. 

In table titles you should provide the title, without discussions what Song and Shao said...or others. 

Same issue for all tables. 

The conclusion section should contain the conclusion remarks, without other details.

Move table 4 in another chapter, make another chapter if needed. 

References. 

The literature for TNBC is complex and contains a lot of published papers on the topic. For a review paper is not acceptable to add only 44 reference, on a topic like TNBC. 

Please revise the manuscript, which has potential, and resubmit it. 

Author Response

• Comment 1: Figure 1. You have MES and MSL in the same category, would you consider splitting them, as MSL originates same as MES, but at molecular level it has low levels of claudin? Or anyways, you should debate the classification, as currently the scientific community is trying to offer the best alternative for TNBC classification which may help for a better diagnosis and therapeutical approach. Please check this reference https://www.nature.com/articles/s41523-020-00197-2 
• Response 1: Discussion on the variability and effect that tumor heterogeneity has on the division of these subtypes has been included as well as the source contributed by the reviewer.
• Comment 2: For chemotherapy and drug conjugates, a figure would be useful. Describing the molecular pathways that are triggered by the therapy. 
• Response 2: Added.
• Comment 3: In table titles you should provide the title, without discussions what Song and Shao said...or others. Same issue for all tables. 
• Response 3: Table captions edited to only incorporate table titles.
• Comment 4: The conclusion section should contain the conclusion remarks, without other details.
• Response 4: Previous "Conclusions" section renamed to "Discussion" and formal "Conclusions" section created.
• Comment 5: Move table 4 in another chapter, make another chapter if needed. 
• Response 5: The authors believe that the inclusion of Table 3 in the manuscript versus the supplement should be left to the discretion of the journal.
• Comment 6: The literature for TNBC is complex and contains a lot of published papers on the topic. For a review paper is not acceptable to add only 44 reference, on a topic like TNBC. 
• Response 6: Another reference was added. We agree with this reviewer that this is a complex topic and we can expand to include more references but that will make the whole manuscript more extensive. 

Reviewer 3 Report

Comments and Suggestions for Authors

Review on the manuscript titled “The Role of Genomics and Transcriptomics In Characterizing and Predicting Patient Response to Treatment in Triple Negative Breast Cancer (TNBC)” by Corea-Dilbert and Afzal, 2025.

                In their review, the authors address possible targets in BC most malign type TNBC due to the current absence of obvious target in TNBC therapy. Based on auxiliary genetic data, the authors aimed at outlining possible targets in TNBC.

                In the comprehensive introduction, the authors present three current BC types and their targets (Fig. 1), further outlining TNBC subtypes: BL-1, BL-2, MES/MSL, IM, LAR.

                The chapter “2. Molecular Subtypes of TNBC” elaborates on the current etiologies/gene mutations of specific TNBC types, corresponded in Table 1.

3. Chemotherapy and Antibody Drug Conjugates.

                This chapter addresses the specifics of treatment in TNBC in subchapters:

3.1. Chemotherapy – overview of chemotherapy specifics, including effectiveness of toxic agents’ assessment and other points in TNBC therapy based on current publications.

3.2. Antibody-Drug Conjugates chapter is devoted to combined approach for efficient drug delivery review.

Next follows the chapter:

4. Immunotherapy which address several modern treatments, namely:

4.1. Pembrolizumab treatment with an explicit description of its targets and genes networks.

   Notably, here is Table 2, which is directly connected with “Genomics and Trancriptomics” claim in the review’s title. It’s not immediately clear whether this table is connected with Pembrolizumab. It is a list of genes associated with the TNBC outcome based on the recent study (Song and Shao, 2024).

4.2. Atezolizumab – “Atezolizumab binds to PD-L1 on cancer cells to interfere with the PD-1/PD-L1 binding.” Herein, the authors listed several statements/conclusions from several papers, but it’s better providing some sort of table/scheme.

The chapter 5. “Targeted Therapy outlines several basic factors/targets in cancer therapy” contains several corresponding subchapters, namely:

5.1. PARP Inhibitors

5.2. PIK3/AKT/mTOR Inhibitors

5.3. Other Targeted Therapies (CDK4/6 inhibitor, etc)

The final chapter: “6. Conclusions and Future Directions”, contains some concluding remarks and outlining Table 3, devoted to current ongoing projects on applying/testing different drugs/methods in the TNBC therapy (apparently).

To my opinion, the major conclusion statement the authors made is: “In the age of personalized medicine, these studies are crucial not just for the clinician to guide therapy, but for the patient to be able to make the most informed decision on their care as possible”

While the subject is of definite importance, the authors should revise manuscript to be more transparent and structured, the conclusive remarks should be added in certain sites for the clarity. Some notes are listed below.

• “Table 2. Song and Shao found 12 differently expressed genes that have been associated as protective and unfavorable prognostic factors within TNBC across subtypes.” – This title is noncompliant with ‘subtypes’ since no subtypes are mentioned in the Table. Also, it says nothing on Pembrolizumab which is the chapter the table located in. Please make it more comprehensive.
• Table 3 should be outsourced in the Supplement. Also, the source of the data should be denoted at the table header.
• The manuscript doesn’t contain any elaboration/chapter on “Genomics and Transcriptomics” statement claimed in the Review title. Please address it. I consider the genomics and transcriptomics is relevant for mutation hotspots identification, but I’m sure the authors implied more meaning for that to be specified in a separate chapter. Either the authors should change it to ‘genetic background’ term. There is some data listed in table 2, probably it should be moved to this chapter.

Author Response

• Comment 1: Notably, here is Table 2, which is directly connected with “Genomics and Trancriptomics” claim in the review’s title. It’s not immediately clear whether this table is connected with Pembrolizumab. It is a list of genes associated with the TNBC outcome based on the recent study (Song and Shao, 2024).
• Response 1: Caption changed to title that reflects purpose of table.
• Comment 2: Herein, the authors listed several statements/conclusions from several papers, but it’s better providing some sort of table/scheme.
• Response 2: New figure made to visualize the various therapies and their targets.
• Comment 3: This title is noncompliant with ‘subtypes’ since no subtypes are mentioned in the Table. Also, it says nothing on Pembrolizumab which is the chapter the table located in. Please make it more comprehensive.
• Response 3: As in Response 1, table captions changed to reflect accurate title of table.
• Comment 4: Table 3 should be outsourced in the Supplement. Also, the source of the data should be denoted at the table header.
• Response 4: We believe the inclusion of Table 3 within the manuscript or the supplement should be left to the discretion of the journal. We took appropriate clinical trials relevant to the review from clinicaltrials.gov and have designated it as a source within the caption.
• Comment 5: The manuscript doesn’t contain any elaboration/chapter on “Genomics and Transcriptomics” statement claimed in the Review title. Please address it. I consider the genomics and transcriptomics is relevant for mutation hotspots identification, but I’m sure the authors implied more meaning for that to be specified in a separate chapter. Either the authors should change it to ‘genetic background’ term. There is some data listed in table 2, probably it should be moved to this chapter.
• Response 5: The authors have contributed the molecular profiles of TNBC, BRCA, PIK3CA and various other genetic markers within the paper to discuss genomics and transcriptomics. We have also created a new chapter to discuss genomic markers that indicate resistance to pembrolizumab. 

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

Table 1 needs references for the information mentioned in. From where did you selected all the data? The most common mutations? Add another column with references.  

Figure 2. Explain the figure. Don't leave it just with figure title. 

Table 2. You mentioned table 2 in chapter 4.1 then the table appears in chapter 4.3. Also, you don't have references. Add references to the table. 

Table 3. You mentioned table 3 in chapter 6, and insert the table in conclusion. This has no logic. 

I believe that making the review more extensive would be in the benefit of all authors (you will gain many more citations) and will help also the journal to increase the quality of its publications. Honestly, I really like this paper and I believe that making it more complex/extensive will help a lot, and it will increase the quality. 

Also the purpose of a review is to synthesize in a comprehensive manner on its topic as much as possible from the literature

Author Response

Comment 1: Table 1 needs references for the information mentioned in. From where did you selected all the data? The most common mutations? Add another column with references.  
Response 1: We extracted these data points from two references. References have been added to captions. 

Comment 2: Figure 2. Explain the figure. Don't leave it just with figure title.
Response 2: Explanation added. The font size has also increased.

Comment 3: Table 2. You mentioned table 2 in chapter 4.1 then the table appears in chapter 4.3. Also, you don't have references. Add references to the table. 
Response 3: Adjusted.

Comment 4: Table 3. You mentioned table 3 in chapter 6, and insert the table in conclusion. This has no logic. 
Response 4: Table 3 has been moved to following Chapter 7 where it is mentioned.

Comment 5: I believe that making the review more extensive would be in the benefit of all authors (you will gain many more citations) and will help also the journal to increase the quality of its publications. Honestly, I really like this paper and I believe that making it more complex/extensive will help a lot, and it will increase the quality. Also the purpose of a review is to synthesize in a comprehensive manner on its topic as much as possible from the literature
Response 5: Thank you for your suggestion. We have added another paragraph to also expand on the role of genomics and transcriptomics and how they are utilized within this setting. As a result, we have added more references.

Reviewer 3 Report

Comments and Suggestions for Authors

The authors addressed my comments sufficiently. One minor point: please enlarge the font size in Fig. 2.

Author Response

Comment 1: The authors addressed my comments sufficiently. One minor point: please enlarge the font size in Fig. 2.
Response 2: Font size has been increased. Thank you for your suggestions.

Round 3

Reviewer 2 Report

Comments and Suggestions for Authors

Dear authors, 

You answered to all my remarks and changed the text according to the suggestions. 

I have no further observations.