CDK4/6 as a Therapeutic Target in HR+/HER2− Breast Cancer Cells—Current Treatment Status
, Anna Liszcz-Tymoszuk 1, Natalia Czerw 1, Aleksandra Czerw 2,3, Katarzyna Sygit 4, Remigiusz Kozłowski 5, Andrzej Deptała 6 and Anna Badowska-Kozakiewicz 6
Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsComment 1: Line 103: The term intracellular control role is not clear please rephrase it.
Comment 2: Too much information in figure 1, if possible please make simple figure, authors can also split it into two. Please correct the typo for Histone.
Comment 3: Please replace "which high absorption".
Author Response
Thank you for your comments. We have carefully revised and supplemented the article according to your opinion.
Comment 1: Line 103: The term intracellular control role is not clear please rephrase it.
Response 1: We corrected “intracellular control role” to make it clearer.
Comment 2: Too much information in figure 1, if possible please make simple figure, authors can also split it into two. Please correct the typo for Histone.
Response 2: We edited the Figure 1 by splitting it into two figures and corrected the word “Histone.”
Comment 3: Please replace "which high absorption".
Response 3: We made a correction for the phrase “which high absorption”.
We hope that the article meets all the requirements. Thank you again for all your comments and valuable suggestions.
Reviewer 2 Report
Comments and Suggestions for AuthorsFirst of all, I would like to thank the Editors for giving me the opportunity to review this paper. This is a narrative review on the current state of CDK4/6 inhibitor therapy in breast cancer, providing an overview of all past and present trials. I would like to congratulate the Authors on the excellent work done. However, I have some minor revisions to suggest:
- The introduction (lines 46–54) should be expanded to include more than just references to incidence and mortality aspects.
- In Table 1, remove the row "Histological subtypes": it is redundant and not entirely clear.
- In Table 3, delineate the subdivision of trials for each drug more clearly.
Author Response
Thank you for your comments. We have carefully revised and supplemented the article according to your opinion.
Comments 1: The introduction (lines 46–54) should be expanded to include more than just references to incidence and mortality aspects.
Response 1: The introduction has been expanded to include a discussion of breast cancer risk factors in addition to incidence and mortality aspects.
Comments 2: In Table 1, remove the row "Histological subtypes": it is redundant and not entirely clear.
Response 2: The row "Histological subtypes" was removed.
Comments 3: In Table 3, delineate the subdivision of trials for each drug more clearly.
Response 3: Table 3 has been revised to improve the clarity of the subdivision of trials.
We hope that the article meets all the requirements. Thank you again for all your comments and valuable suggestions.
Reviewer 3 Report
Comments and Suggestions for AuthorsThe article discusses the contribution of cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors in the treatment of hormone receptor-positive (HR+)/HER2-negative (HER2-) breast cancer. The medications palbociclib, ribociclib, and abemaciclib have been major contributors to the treatment of the disease. The article presents the variations in efficacy, dosing, and toxicity of the medications based on critically analyzed findings of clinical trials such as PALOMA, MONALEESA, and MONARCH. Ongoing trials, including MonarchE and NATALEE, examining their use in the adjuvant setting are evaluated alongside the possibility of incorporating dalpiciclib into the treatment of HR+/HER2- breast cancer.
The research, as I comprehend, is of paramount significance due to its addressal of the application of CDK4/6 inhibitors, which have changed the therapeutic strategy for HR+/HER2- breast cancer by enhancing patient survival and quality of life. It provides an overview of the clinical application of these drugs while comparing their efficacy, thus offering imperative information for clinicians who participate in treatment planning. The mention of adverse effects also assists in the individualization of treatment management and enhancing tolerance of drugs by patients.
The article can be published if some major issues are corrected.
1. The significance of CDK4/6 inhibitors in the treatment of HR+/HER2- breast cancer is reiterated multiple times within the introduction and elsewhere in the text. Minimizing these redundancies enhances the conciseness of the document without diminishing the substance of the analysis.
2. The discussion of clinical trials is detailed, but the presentation can be made more integrated by covering the information in a more orderly manner. For instance, the difference between first-line treatment studies and adjuvant treatment studies can be clarified.
3. While the article provides data regarding the side effects associated with each CDK4/6 inhibitor, a more systematic comparison would be of greater benefit to the discussion. The variation in toxicities like the hematologic toxicity for palbociclib versus the gastrointestinal toxicity associated with abemaciclib could be more clearly outlined on a table for easy understanding.
4. The paper reports on ongoing clinical trials of novel applications of CDK4/6 inhibitors, yet the future research recommendations are general. There could be more in-depth discussion of what patient groups would gain most from these medications or in what ways they might be combined with immunotherapy.
5. The paper concentrates chiefly on the effectiveness of the therapies but devotes minimal space to cost considerations or cost-effectiveness studies, even though such factors are significant in clinical decisions. Incorporating a concise analysis of the economic considerations associated with CDK4/6 inhibitor therapy and their accessibility in various health systems would make the article more complete.
Author Response
The article discusses the contribution of cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors in the treatment of hormone receptor-positive (HR+)/HER2-negative (HER2-) breast cancer. The medications palbociclib, ribociclib, and abemaciclib have been major contributors to the treatment of the disease. The article presents the variations in efficacy, dosing, and toxicity of the medications based on critically analyzed findings of clinical trials such as PALOMA, MONALEESA, and MONARCH. Ongoing trials, including MonarchE and NATALEE, examining their use in the adjuvant setting are evaluated alongside the possibility of incorporating dalpiciclib into the treatment of HR+/HER2- breast cancer.
The research, as I comprehend, is of paramount significance due to its addressal of the application of CDK4/6 inhibitors, which have changed the therapeutic strategy for HR+/HER2- breast cancer by enhancing patient survival and quality of life. It provides an overview of the clinical application of these drugs while comparing their efficacy, thus offering imperative information for clinicians who participate in treatment planning. The mention of adverse effects also assists in the individualization of treatment management and enhancing tolerance of drugs by patients.
The article can be published if some major issues are corrected.
Thank you for your comments. We have carefully revised and supplemented the article according to your opinion.
Comments 1: The significance of CDK4/6 inhibitors in the treatment of HR+/HER2- breast cancer is reiterated multiple times within the introduction and elsewhere in the text. Minimizing these redundancies enhances the conciseness of the document without diminishing the substance of the analysis.
Response 1: The repeated mention of the significance of CDK4/6 inhibitors in the treatment of HR+/HER2- breast cancer has been minimized. The introduction now succinctly presents their role, ensuring that the main points are conveyed without unnecessary repetition throughout the text.
Comments 2: The discussion of clinical trials is detailed, but the presentation can be made more integrated by covering the information in a more orderly manner. For instance, the difference between first-line treatment studies and adjuvant treatment studies can be clarified.
Response 2: The discussion of clinical trials has been restructured to present a more coherent flow. In Table 3 the trials have been categorized into neoadjuvant and adjuvant treatment studies, and by the stage of breast cancer to improve clarity.
Comments 3: While the article provides data regarding the side effects associated with each CDK4/6 inhibitor, a more systematic comparison would be of greater benefit to the discussion. The variation in toxicities like the hematologic toxicity for palbociclib versus the gastrointestinal toxicity associated with abemaciclib could be more clearly outlined on a table for easy understanding.
Response 3: A new Table 4 has been added that systematically compares the side effects of the different CDK4/6 inhibitors. This table highlights key differences, such as: hematologic toxicity, especially neutropenia, gastrointestinal toxicity, including diarrhea, cardiotoxicity, including QT prolongation.
Comments 4: The paper reports on ongoing clinical trials of novel applications of CDK4/6 inhibitors, yet the future research recommendations are general. There could be more in-depth discussion of what patient groups would gain most from these medications or in what ways they might be combined with immunotherapy.
Response 4: The discussion on ongoing clinical trials has been expanded to second-line therapy (section 11) and usage of CDK4/6 inhibitors in HER2-positive tumors (section 13). Specific recommendations have been included regarding their potential combination with immunotherapy and the necessity for biomarker-driven patient selection.
Comments 5: The paper concentrates chiefly on the effectiveness of the therapies but devotes minimal space to cost considerations or cost-effectiveness studies, even though such factors are significant in clinical decisions. Incorporating a concise analysis of the economic considerations associated with CDK4/6 inhibitor therapy and their accessibility in various health systems would make the article more complete.
Response 5: A section addressing the cost considerations and cost-effectiveness of CDK4/6 inhibitors has been incorporated in the new section 14.
We hope that the article meets all the requirements. Thank you again for all your comments and valuable suggestions.
Round 2
Reviewer 3 Report
Comments and Suggestions for AuthorsThe authors have revised the manuscript in accordance with the suggestions provided. I recommend the publication of the article.
