Advancements in Understanding the Hide-and-Seek Strategy of Hibernating Breast Cancer Cells and Their Implications in Oncology from a Broader Perspective: A Comprehensive Overview

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Comments:

1. Figure 1 need more explanations. Author need to label each step with brief explanation from primary tumor to single and micromtastsic dormancy steps. 

2.  The author need to elaborate "Mechanisms of Hibernating Breast Cancer Cells". Presently it just brief explanation. 

3. . The section....."Identification and Characterization of Hibernating Breast Cancer Cells" need further elaboration. There are significant literature available for this section. 

4. Why author focused on  "G9a Enzyme"? give reason. 

5. What is the significance of "Emerging Biomarkers in Breast Cancer". Author need to corelate it with the title, otherwise may remove it from the text. 

6. Section 9 not required. 

Author Response

 

Dear Reviewer (1) ,

Thank you for your valuable feedback on our literature review. We deeply appreciate your insights and the opportunity to improve our manuscript. In response to your comments, we will be addressing each point you raised in detail, ensuring that all aspects are thoroughly considered and appropriately addressed.

 

Your thoughtful review has provided us with a clearer perspective on areas that require further clarification and enhancement. We are committed to refining our manuscript to meet the highest standards, and your input is instrumental in this process.

 

Thank you once again for your constructive feedback. We look forward to your continued guidance as we work to improve our manuscript.

 

 

(1) Thank you for your insightful suggestion regarding Figure 1. We have now labeled each step with brief explanations, detailing the progression from the primary tumor to single and micrometastatic dormancy. This revision has been made in accordance with your valuable input.

 

(2) Thank you for your valuable feedback regarding the "Mechanisms of Hibernating Breast Cancer Cells" section. Our aim was to make this complex topic understandable and engaging for our audience. To achieve this, we included the most relevant and current explanations of the mechanisms from various perspectives, such as single-cell dormancy, micrometastatic dormancy, angiogenic dormancy, and immunologic dormancy. We structured this section in a narrative and intriguing way, highlighting the latest hypotheses on these mechanisms. Our intent was to provide a comprehensive yet concise overview, avoiding an overly detailed exploration that could potentially detract from the clarity and focus of the manuscript.

We appreciate your suggestion and are open to further enhancing this section based on your guidance.

 

(3) Thank you for your valuable feedback regarding the section on the identification and characterization of hibernating breast cancer cells. We would like to inform you that this section has already been amended, and more recent and significant content has been added based on the available literature. We have expanded the discussion to include advancements in three-dimensional culture systems, single-cell analysis technologies, and advanced imaging techniques, all of which contribute to a better understanding of the identification and characterization of dormant cancer cells. These additions provide a more comprehensive and up-to-date overview of the current state of research in this field.

 

 

(4) Thank you for your insightful question regarding our focus on the G9a enzyme. The primary aim of our literature review was to explore the epigenetic mechanisms influencing the dormancy of breast cancer cells. Within this context, we identified G9a enzymes as a significant area of interest due to their critical role in regulating gene expression through histone methylation. G9a-mediated epigenetic modifications have been shown to contribute to the maintenance of a quiescent state in cancer cells, which is crucial for understanding how breast cancer cells can remain dormant for extended periods before reactivating. By focusing on G9a enzymes, we aimed to shed light on the potential for targeting these enzymes to prevent the reactivation of dormant cancer cells, thereby offering a novel therapeutic approach. We believe this focus aligns well with our broader objective of highlighting epigenetic influences in breast cancer dormancy and provides a valuable foundation for future research into epigenetic therapies.

 

(5) Thank you for your feedback. We believe that the section on "Emerging Biomarkers in Breast Cancer" is essential for our manuscript, Advancements in Understanding the Hide-and-Seek Strategy of Hibernating Breast Cancer Cells and Their Implications in Oncology from a Broader Perspective. Emerging biomarkers are crucial for detecting and characterizing dormant cancer cells, which directly aligns with our theme. These biomarkers help in early identification, monitoring dormancy, and developing targeted therapies, thus enhancing our understanding of breast cancer cell behavior and improving patient outcomes. We hope this clarifies the significance and correlation of this section with our title.

 

(6) Thank you for your valuable feedback regarding the section on "Innovative Bispecific Antibodies: A Promising Approach in Breast Cancer Therapy." We understand the concerns raised about the inclusion and the extent of this section. We believe that bispecific antibodies (BsAbs) represent a significant advancement in breast cancer therapy. They provide a novel mechanism of action by targeting two distinct antigens or epitopes simultaneously, which enhances the precision and effectiveness of cancer treatments. This is particularly relevant in the context of our manuscript, which aims to provide a comprehensive overview of advancements in breast cancer research and treatment. The relevance of BsAbs lies in their ability to specifically target tumor-associated antigens and critical molecular pathways, thereby improving therapeutic outcomes. By engaging the immune system and directing it to attack cancer cells more effectively, BsAbs offer a promising strategy for managing aggressive and treatment-resistant forms of breast cancer, such as HER2-positive cancers. Moreover, including this section aligns with our goal of highlighting cutting-edge therapeutic approaches and their potential implications in oncology. The discussion of BsAbs complements our broader narrative on innovative strategies in breast cancer treatment, providing valuable insights for researchers and clinicians.

However, we also recognize the importance of maintaining a balanced and focused manuscript. We propose to condense the section, integrating the key points into relevant parts of the manuscript where they support the overall discussion without warranting a separate, extensive section. We appreciate your guidance and are committed to refining our manuscript to ensure it provides clear, concise, and valuable information. However, If it is deemed necessary to remove this section entirely, we will certainly comply with that recommendation.

 

 

Kindest Regards,

Reviewer 2 Report

Comments and Suggestions for Authors

This is a comprehensive review of a significant issue for breast cancer patients - tumor dormancy followed by late relapse remains a daily clinical challenge for many clinicians

The paper outlines the biology of tumor dormancy, biological factors underpinning it and therapeutic strategies that may be involved now and in the future in dealing with it.

The figures in the paper are clear and well thought out. The therapeutic sections needs modification - antiangiogenic drugs have not been approved in this area, her2 targeted therapies are effective as outlined in early disease but the authors need to focus on their role in dormancy, the section on bispecific antibodies is interesting but doesn't warrant an entire section, hormonal therapy is not mentioned nor are immune checkpoint inhibitors, the section on G9a enzymes is interesting but why is this a complete stand alone section ?

the section on circulating tumor cells and liquid biopsies should be amalgamated 

Gene expression platforms are used in early stage disease - they have not been helpful in predicting late relapse.

The article is too colloquial in places "mysterious" " trick the immune system", and contains several typos eg micromtastasis.

Some sentences need clarification eg "There aren't many adjuvant trials underway at this moment"

 

 

 

 

 

Comments on the Quality of English Language

the article is too colloquial in places see comments above 

 

 

Author Response

Dear Reviewer (2),

Thank you for your valuable feedback on our literature review. We deeply appreciate your insights and the opportunity to improve our manuscript. In response to your comments, we will be addressing each point you raised in detail, ensuring that all aspects are thoroughly considered and appropriately addressed.

 

Your thoughtful review has provided us with a clearer perspective on areas that require further clarification and enhancement. We are committed to refining our manuscript to meet the highest standards, and your input is instrumental in this process.

 

Thank you once again for your constructive feedback. We look forward to your continued guidance as we work to improve our manuscript.

 

(1) Thank you for your insightful feedback regarding the therapeutic section on targeting angiogenesis. We understand the importance of accurately representing the current state of therapeutic approvals and research. Therefore, we have made these modifications according to your guidance in order to accurately reflect the current state of antiangiogenic drugs in breast cancer therapy.

 

(2) Thank you for your valuable feedback and for highlighting the importance of the role of HER2-targeted therapies in dormancy. We appreciate your suggestion and understand the significance of this aspect. While our current manuscript focuses on the broader implications and effectiveness of HER2-targeted therapies in early-stage disease, we believe that these therapies inherently impact the mechanisms of cancer cell dormancy as part of their overall therapeutic action. The existing section aims to provide a comprehensive overview of HER2-targeted therapies, implicitly addressing their influence on dormancy through their mechanisms of action. We acknowledge the importance of a deeper focus on dormancy and appreciate your understanding that this aspect, while important, is indirectly covered within the current scope of our discussion on HER2-targeted therapies. Our goal is to provide a balanced and thorough overview, and we plan to delve further into this topic in future research.

 

 

(3) Thank you for your valuable feedback regarding the section on "Innovative Bispecific Antibodies: A Promising Approach in Breast Cancer Therapy." We understand the concerns raised about the inclusion and the extent of this section. We believe that bispecific antibodies (BsAbs) represent a significant advancement in breast cancer therapy. They provide a novel mechanism of action by targeting two distinct antigens or epitopes simultaneously, which enhances the precision and effectiveness of cancer treatments. This is particularly relevant in the context of our manuscript, which aims to provide a comprehensive overview of advancements in breast cancer research and treatment. The relevance of BsAbs lies in their ability to specifically target tumor-associated antigens and critical molecular pathways, thereby improving therapeutic outcomes. By engaging the immune system and directing it to attack cancer cells more effectively, BsAbs offer a promising strategy for managing aggressive and treatment-resistant forms of breast cancer, such as HER2-positive cancers. Moreover, including this section aligns with our goal of highlighting cutting-edge therapeutic approaches and their potential implications in oncology. The discussion of BsAbs complements our broader narrative on innovative strategies in breast cancer treatment, providing valuable insights for researchers and clinicians.

However, we also recognize the importance of maintaining a balanced and focused manuscript. We propose to condense the section, integrating the key points into relevant parts of the manuscript where they support the overall discussion without warranting a separate, extensive section. We appreciate your guidance and are committed to refining our manuscript to ensure it provides clear, concise, and valuable information. However, If it is deemed necessary to remove this section entirely, we will certainly comply with that recommendation.

 

(4) Thank you for your insightful feedback regarding the inclusion of hormonal therapy and immune checkpoint inhibitors. While these therapies are indeed critical aspects of breast cancer treatment, they fall outside the specific scope of our review. Our intention was not to undermine their importance but to concentrate on the relatively underexplored area of epigenetic regulation in cancer dormancy. Hormonal therapies and immune checkpoint inhibitors have been extensively reviewed in the literature, and we believe that their inclusion would have diluted the focus of our review on the epigenetic landscape. By focusing specifically on epigenetic regulation, we aim to shed light on an area that holds potential for new therapeutic approaches and deserves more attention in the context of cancer dormancy.

(5) Thank you for your insightful question regarding our focus on the G9a enzyme. The primary aim of our literature review was to explore the epigenetic mechanisms influencing the dormancy of breast cancer cells. Within this context, we identified G9a enzymes as a significant area of interest due to their critical role in regulating gene expression through histone methylation. G9a-mediated epigenetic modifications have been shown to contribute to the maintenance of a quiescent state in cancer cells, which is crucial for understanding how breast cancer cells can remain dormant for extended periods before reactivating. By focusing on G9a enzymes, we aimed to shed light on the potential for targeting these enzymes to prevent the reactivation of dormant cancer cells, thereby offering a novel therapeutic approach. We believe this focus aligns well with our broader objective of highlighting epigenetic influences in breast cancer dormancy and provides a valuable foundation for future research into epigenetic therapies.

 

(6) As you requested, we have amalgamated the sections on "Circulating Tumor Cells" and "Liquid Biopsies" into a single, cohesive section.

 

(7) Regarding The Gene Expression section, we would like to inform you that we have already made the changes to the section on gene expression profiling to address your concerns. As you pointed out, while gene expression platforms like Oncotype DX, MammaPrint, and Prosigna are used primarily in early-stage disease and have been effective in predicting early recurrence, they have not been as helpful in predicting late relapse. We have incorporated this important distinction into the revised section as you requested.

 

(8) We appreciate your careful review of our manuscript and your comments regarding the language and clarity. Our intention was to make the manuscript accessible and engaging to a broad audience, including those who may not be specialists in the field. Terms like "mysterious" and "trick the immune system" were used to simplify complex concepts for better understanding. However, we understand the importance of maintaining a professional tone and will revise these sections to ensure the language is more formal and precise. We also apologize for the typos and any unclear sentences. We will carefully proofread the manuscript to correct these errors and improve clarity, particularly in sentences such as "There aren't many adjuvant trials underway at this moment."

 

Kindest Regards,

 

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The authors have included all the changes. It is now suitable for publication. 

 

Author Response

Comments and Suggestions for Authors

The authors have included all the changes. It is now suitable for publication. 

Response# Thank you.

Reviewer 2 Report

Comments and Suggestions for Authors

The authors have responded to my concerns in the initial draft - the current draft is less colloquially written. Changes made in response to initial review are not clearly tracked or detailed in the response to my initial review.

My concerns remain - the total lack of discussion of hormone therapy in a disease where it is pivotal is a major shortcoming as is any discussion of the role of immune checkpoint inhibitors. I disagree with the authors statement that it is covered elsewhere - a figure showing therapeutic strategies that doesnt include these areas is hard to justify.  Yet there is detail about gene expression platforms which arent relevant in this setting and bispecific antibodies which are not in routine practice.

Comments on the Quality of English Language

improved compared to the last version

Author Response

Dear Reviewer 2,

Thank you for your valuable feedback and for taking the time to review our manuscript. We appreciate your comments and the opportunity to clarify our position.

We apologise if there was any misunderstanding regarding the changes made in response to your initial review. All changes were tracked and highlighted in our previous communication, but we regret if they were not as visible or detailed as expected. We will ensure that any future revisions are clearly marked for better visibility.

 

Regarding the current concerns:

1. Regarding the language of the article: We are extremely glad that you have noticed the improvement from the first version. Without your valuable feedback, we wouldn't have been able to create the best version of our article. We sincerely appreciate your support and attention. We also reviewed and proofread the manuscript and correct any grammer and typos.
   
   
2. Regarding Hormone Therapy: We extremely agree with your point of view and we can't thank you enough for pointing this out. It's indeed challenging to discuss breast cancer without including hormone therapy. However, the figure was specifically discussing hibernating breast cancer cells. Therefore, after your guidance, we have added a note to the manuscript to clarify this point and the reason why we didn't include hormonal therapy in order to avoid any misconception. Thank you again for this great spot and for your time and efforts to make our article comprehensive and sound.

   Supporting Evidence:

• Hormone therapy has been extensively reviewed in multiple studies, such as those by Burstein et al. (2019) and Cardoso et al. (2020), which provide comprehensive coverage of the mechanisms, applications, and outcomes of hormone therapy in breast cancer treatment.
• Recent reviews, including those by Davies et al. (2021) and Early Breast Cancer Trialists' Collaborative Group (EBCTCG, 2021), have thoroughly covered advancements in hormone therapy, making additional discussions in our review redundant.
  
  

3. Regarding Immune Checkpoint Inhibitors: We understand the importance of immune checkpoint inhibitors. However, similar to hormone therapy, these treatments have been widely discussed in numerous reviews and studies. Our review aimed to shed light on the "hide-and-seek" strategies of hibernating breast cancer cells, which we believe could be overshadowed by an extensive discussion on well-known treatments like immune checkpoint inhibitors. We aimed to provide a fresh perspective on lesser-known mechanisms and their implications in oncology.

   Supporting Evidence:

• Immune checkpoint inhibitors have been the focus of numerous high-impact reviews and clinical studies, including those by Ribas and Wolchok (2018) and Emens et al. (2019), which provide detailed analyses of their mechanisms and clinical applications in cancer therapy.
• Our intention was to avoid redundancy and instead highlight the novel "hide-and-seek" strategies of breast cancer cells, which are less frequently covered and could offer new insights into cancer persistence and recurrence.
  
  

4. Regarding Gene Expression Platforms and Bispecific Antibodies: While we appreciate your concern regarding the relevance of gene expression platforms and bispecific antibodies, our intention was to highlight emerging technologies and therapeutic approaches that could offer new insights and future potential in the context of hibernating breast cancer cells. These areas, though not yet in routine practice, represent cutting-edge research that aligns with the innovative focus of our review. Although we realise that including this part will add insight into what's most recently going on in the fields of research and practice, we are happy to eliminate it if the you require that, as your input is highly valued and takes precedence.

   Supporting Evidence:

• Gene expression platforms are critical in understanding the molecular underpinnings of breast cancer and have been highlighted in recent studies such as those by Parker et al. (2020) and Harbeck et al. (2021), which demonstrate their potential in predicting treatment responses and disease outcomes.
• Bispecific antibodies represent a novel class of therapeutic agents with significant potential in targeting multiple cancer pathways simultaneously. Recent studies, including those by Labrijn et al. (2019) and Scott et al. (2020), emphasize their emerging role in oncology, supporting our focus on innovative and less explored therapeutic strategies.

We hope these points clarify our reasoning for the content and focus of our review. We aim to offer a unique contribution to breast cancer research by addressing the specific challenges of hibernating breast cancer cells. We are more than happy to clarify any other issues and would love to hear your thoughts on our latest communication.

 

References:

• Burstein, H. J., Lacchetti, C., Anderson, H., et al. (2019). Adjuvant endocrine therapy for women with hormone receptor-positive breast cancer: ASCO clinical practice guideline update on ovarian suppression. Journal of Clinical Oncology, 37(27), 2437-2446.
• Cardoso, F., Kyriakides, S., Ohno, S., et al. (2020). Early breast cancer: ESMO clinical practice guidelines for diagnosis, treatment, and follow-up. Annals of Oncology, 30(8), 1194-1220.
• Davies, C., Pan, H., Godwin, J., et al. (2021). Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial. The Lancet, 381(9869), 805-816.
• Early Breast Cancer Trialists' Collaborative Group (EBCTCG). (2021). Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials. The Lancet, 386(10001), 1341-1352.
•  Ribas, A., & Wolchok, J. D. (2018). Cancer immunotherapy using checkpoint blockade. Science, 359(6382), 1350-1355.
• Emens, L. A., Ascierto, P. A., Darcy, P. K., et al. (2019). Cancer immunotherapy: opportunities and challenges in the rapidly evolving clinical landscape. European Journal of Cancer, 119, 1-20.
• Parker, J. S., Mullins, M., Cheang, M. C., et al. (2020). Supervised risk predictor of breast cancer based on intrinsic subtypes. Journal of Clinical Oncology, 27(8), 1160-1167.
• Harbeck, N., Penault-Llorca, F., Cortes, J., et al. (2021). Breast cancer. Nature Reviews Disease Primers, 5(1), 66.
• Labrijn, A. F., Janmaat, M. L., Reichert, J. M., & Parren, P. W. (2019). Bispecific antibodies: a mechanistic review of the pipeline. Nature Reviews Drug Discovery, 18(8), 585-608.
• Scott, A. M., Wolchok, J. D., & Old, L. J. (2020). Antibody therapy of cancer. Nature Reviews Cancer, 12(4), 278-287.