Review Reports

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

General comments

-  The review titled “PD‑L1‑Guided Chemo‑Immunotherapy in Advanced Triple‑Negative Breast Cancer: A Meta‑Analysis of Survival Benefits and Toxicity Profiles” presents a thoroughly developed and well‑structured analysis. The introduction is clearly articulated, and the authors demonstrate a solid grasp of the existing literature. Their search strategy is systematic and transparent, the analytical methods are rigorously applied, and the discussion thoughtfully synthesizes the findings. The supplementary materials are extensive, evidence‑rich, and contribute significantly to the credibility of the study. Overall, the review offers a comprehensive selection and evaluation of relevant studies, effectively consolidating current knowledge on the added value of combining immunotherapy with chemotherapy in advanced TNBC. The findings highlight particularly strong benefits in patients with PD‑L1–positive tumors, offering meaningful clinical insights. These results not only enhance understanding of treatment efficacy but also provide a valuable foundation for clinicians and researchers seeking to design future investigations and optimize therapeutic strategies for triple‑negative breast cancer.

- There is no specific comments

Comments on the Quality of English Language

The English language is fine

Author Response

We sincerely appreciate the reviewer’s highly positive feedback and thorough evaluation of our manuscript. We are grateful for the recognition of our systematic search strategy, rigorous analytical methods, comprehensive data synthesis, and the clinical value of our findings in PD-L1-guided chemo-immunotherapy for advanced triple-negative breast cancer. Given that no specific concerns or revisions were proposed, we have maintained the original content of the manuscript in its current form. We hope this revised version continues to meet the high standards of Frontiers in Immunology. Thank you again for your professional assessment and valuable support of our work.

Reviewer 2 Report

Comments and Suggestions for Authors

cancers-4240496

The presented systematic review is devoted to the summarization of the outcomes of the PD-L1-based immunotherapy in combination with chemotherapy in case of triple negative breast cancer. Authors analyzed data from PubMed, Embase, and the Cochrane Libraries focusing on randomized clinical trials. They pooled together both data on therapeutic outcomes (progression-free survival, overall survival) and on adverse effects. The review seems to be relevant to the scope of the journal and the amount of the analyzed data is sufficient for publication. Concerning the methodology, the review was prepared appropriately according to PRISMA guidelines for systematic reviews. However, there are several issues to be addressed before the publication:

1. The moderate English editing is needed. The text is too wordy and should be edited to be more concise.

2.  In Figures 2-4 brief description of the methodology should be provided in the Figure Legends.

3.  Brief comparison with the similar meta-analyses should be made to ensure the novelty of the conclusions provided.

4.  The conclusion could be strengthened with the potential of optimization of the analyzed approach to cancer treatment (research and preclinical studies)

Comments on the Quality of English Language

The moderate English editing is needed. The text is too wordy and should be edited to be more concise.

Author Response

Reviewer 2 - Comment 1 We greatly appreciate the reviewer’s constructive suggestion. We have carefully revised the entire manuscript to streamline redundant expressions, optimize sentence structure, and improve overall readability. All wordy descriptions have been simplified to ensure clarity and conciseness. We sincerely thank the reviewer for helping us improve the quality of this work. Reviewer 2 - Comment 2 Brief methodological descriptions have been formally supplemented to the legends of Figures 2–4, including the type of pooled effect measures, the selection criteria of fixed-effect or random-effect models based on heterogeneity assessment (I² statistic), and key statistical processing details, to ensure the transparency and standardization of the methodological description. Reviewer 2 - Comment 3 A new dedicated paragraph has been added in the Discussion section to systematically compare the present findings with previously published meta-analyses from 2023 to 2025. We have clearly illustrated the novelty and additional value of the current study, including the inclusion of the latest published trial evidence, clearer stratification and separation of the ITT population and PD-L1-positive subgroups, as well as a more comprehensive and detailed synthesis of safety outcomes. Reviewer 2 - Comment 4 The Conclusion section has been comprehensively strengthened and expanded with a forward‑looking translational perspective. We have further highlighted the necessity of assay harmonization and standardization, the optimization of steroid‑sparing and immunogenic chemotherapy regimens, and the development of novel predictive biomarkers beyond PD-L1, which enhances the translational potential and clinical guiding value of the study for cancer immunotherapy optimization. We sincerely appreciate the valuable comments on the English language quality. We have conducted moderate English editing throughout the manuscript, streamlined the wordy and redundant expressions, and revised the text to be more concise and fluent. The language quality and readability of the manuscript have been significantly improved.

Reviewer 3 Report

Comments and Suggestions for Authors

General Comments

This manuscript presents a systematic review and meta-analysis evaluating chemotherapy combined with immune checkpoint inhibitors in locally recurrent unresectable or metastatic triple-negative breast cancer. The topic is clinically important and timely, particularly given conflicting evidence from major trials. The study includes key randomized controlled trials and applies appropriate meta-analytic methods. The manuscript is generally well structured and provides useful clinical insights. However, several important issues related to data consistency, interpretation, and heterogeneity need to be addressed before the manuscript can be considered for publication.

Major Comments

1. There is a discrepancy in the reporting of progression-free survival (PFS) between the abstract and the Results section. The abstract reports a stronger effect size compared to the pooled estimate in the intention-to-treat population. It is unclear whether this reflects subgroup analysis (e.g., PD-L1–positive population) or a reporting inconsistency. Clear distinction between ITT and subgroup will result and ensure consistency across all sections (Abstract, Results, Figures).
2. Although OS improvement is statistically significant in the overall population, the effect size is modest and not statistically significant in the PD-L1–positive subgroup. Additionally, heterogeneity in this subgroup is high. Please consider revising statements that suggest definitive survival benefit, particularly in PD-L1–positive patients.
3. The included trials used different PD-L1 assays and scoring systems (e.g., CPS vs IC), which are not interchangeable. This represents a major source of clinical and methodological heterogeneity. Expanding discussion of this limitation and, if feasible, include subgroup or sensitivity analyses stratified by PD-L1 assay methodology.
4. Several subgroup analyses (e.g., race, age, metastatic site) are presented with conclusions that may not be adequately powered. These findings should be clearly described as exploratory and hypothesis-generating rather than definitive.
5. While the manuscript concludes that the safety profile is manageable, the analysis shows increased risks of serious adverse events and immune-related adverse events in the combination group. Providing a more balanced interpretation emphasizing the clinical relevance of these toxicities and the need for monitoring may be beneficial to the manuscript.
6. Given the small number of included studies, statistical tests for publication bias may not be reliable. Please acknowledge this limitation explicitly in the manuscript.

Minor Comments

• Several grammatical and typographical errors are present.
• Some encoding issues (e.g., unusual characters) should be corrected.
• Recommend professional language editing.
• Clarify whether patients were exclusively first-line metastatic or included previously treated populations.
• Ensure consistent use of terms (e.g., Chemo-IO vs chemoimmunotherapy; TRAEs vs TEAEs).

 

Author Response

We greatly appreciate the reviewer’s thorough and constructive comments, which have significantly helped improve the rigor, clarity, and consistency of our meta-analysis. We have addressed all concerns point-by-point as detailed below. Major Comment 1 We sincerely apologize for the discrepancy in progression-free survival (PFS) reporting between the Abstract and Results section. This inconsistency has been fully corrected. The Abstract now clearly and separately reports the pooled PFS hazard ratio (HR) for the intention-to-treat (ITT) population (HR=0.82) and the HR for the PD-L1–positive subgroup (HR=0.68). We have uniformly distinguished ITT population data from subgroup findings across the Abstract, Results, Figures, and Figure legends to ensure full consistency throughout the manuscript. Major Comment 2 We have revised the relevant statements in the Abstract, Results, Discussion, and Conclusion to avoid overstating the survival benefit, especially in the PD-L1–positive subgroup. The manuscript now explicitly clarifies that although overall survival (OS) was significantly improved in the overall population, the OS benefit in the PD-L1–positive subgroup was non-significant with a modest effect size and high heterogeneity. All conclusions implying a definitive OS benefit in PD-L1–positive patients have been removed or adjusted accordingly. Major Comment 3 We have expanded the Discussion and Limitations sections to emphasize that different PD-L1 assays and scoring systems (CPS vs. IC) are not interchangeable and represent a major source of clinical and methodological heterogeneity. As requested, we further discuss the impact of this heterogeneity on the generalizability of our findings. Due to strong confounding between PD-L1 assay methodology, study design, immunotherapy agent, and chemotherapy backbone, a stratified meta-analysis by assay type was not statistically robust or feasible; this limitation is now clearly stated in the manuscript. Major Comment 4 All subgroup analyses (including race, age, and metastatic site) are now explicitly labeled as exploratory and hypothesis-generating rather than definitive in the Results, Discussion, and Limitations sections. We have revised all interpretive statements to avoid overstatement and clarify that these findings require validation in future large-scale prospective studies. Major Comment 5 We have revised the safety evaluation to provide a more balanced and clinically relevant interpretation. The manuscript now clearly states that while the overall incidence of adverse events (AEs) was comparable between groups, the combination group was associated with increased risks of grade ≥3 AEs, serious AEs (SAEs), and immune-related AEs (irAEs). We emphasize the clinical importance of these toxicities and the necessity for close clinical monitoring, which strengthens the practical value of our safety conclusions. Major Comment 6 We have explicitly added a limitation stating that statistical tests for publication bias have limited reliability owing to the small number of included studies, and that related results should be interpreted with caution. This addresses the reviewer’s concern and improves the transparency of our statistical methods. Minor Comments All grammatical errors, typos, and character encoding issues have been corrected. Professional English language editing was performed to improve fluency and academic writing quality. Terminology was standardized consistently across the manuscript: we used “Chemo-IO” and “treatment-emergent adverse events (TEAEs)” uniformly. The patient eligibility criteria were clarified: most included trials enrolled first-line metastatic patients, while only the IMpassion132 trial included patients with early-relapsing disease after prior curative-intent therapy. We believe these revisions have thoroughly addressed all reviewer concerns and greatly enhanced the quality of our manuscript.

Reviewer 4 Report

Comments and Suggestions for Authors

The present highly detailed review illustrates the discrepancy between major efforts and minor results in clinical trials. It is useful as a signal against hasty conclusions drawn from such trials.

Data from seven randomized clinical trials (RCT) comparing chemotherapy combined with immune check point inhibitors (ICIs ) versus chemotherapy with placebo or control in 3485 versus 1400 patients respectively, with locally recurrent unresectable or metastatic TNBC were pesented in 1Table & 22 Supplementary Tables, added with 4 Figures and 32 Supplementary Figures. The meta-analysis uses recent high-quality randomized controlled trials to address inconsistencies from previous studies ascribed to variables such as chemotherapy backbones, PD-L1 assay methodologies, and patient selection, that led to the withdrawal of the US indication for atezolizumab in metastatic TNBC.

The authors infer that chemo-immuno therapy may significantly improve both PFS, OS, ORR and CBR in the TNBC  ITT poplulation examined (Figures 2 & 3), though various adverse events (AE) need attention (Figure 4).  They emphasize that the effect of methodological differences in PD-L1 assay in patients with PD-L1-positive tumors may significantly influence patient stratification and trial outcomes.

The Conclusion section formulates therapeutic recommendations: Select pembrolizumab plus CT for treatment-naïve patients with CPS >10; avoid paclitaxel requiring higher doses of immunosuppressive corticosteroids.

 

Author Response

We sincerely appreciate the reviewer’s positive and insightful feedback, as well as the thoughtful recognition of our meta-analysis addressing key inconsistencies in clinical trials for metastatic triple-negative breast cancer. In response to the constructive suggestions, we have thoroughly revised the Conclusion section to moderate overly assertive statements, further emphasizing individualized patient selection, rigorous toxicity monitoring, and the critical impact of standardized PD-L1 assay methodology on clinical decision-making. We have also refined the therapeutic recommendations to be more prudent and evidence-based, balancing efficacy data with safety considerations. We believe these revisions have greatly improved the rigor and clinical applicability of our conclusions, and we are grateful for the reviewer’s valuable input to enhance the quality of our work.

Reviewer 5 Report

Comments and Suggestions for Authors

Comments

The work of Nan L., et al. entitled “PD-L1-Guided Chemo-Immunotherapy in Advanced Triple-Negative Breast Cancer: A Meta-Analysis of Survival Benefits and Toxicity Profiles” describes a systematic review of the combination of chemotherapy with immunotherapy to demonstrate the benefits and toxicity of the combination in advanced TNBC. The topic of the work is highly important since there are inconsistencies in the therapeutic protocols of TNBC. Additionally, the management of TNBC is not as effective as with other breast cancer subtypes; thus; large studies on this matter are relevant. It fits into the scope of Cancers.

 

 

Line 182 – Did you perform an analysis by ICI type?

Line 301 – Do you know the level of PD-L1 expression? Do you think that it might be relevant for the outcomes?

Line 312 – Do you have an analysis per metastatic site?

Line 316 – this paragraph is important, but difficult to read owing to its size…

Author Response

We sincerely appreciate the insightful and constructive comments from Reviewer 5, which have greatly helped us improve the clarity and rigor of our manuscript. We have addressed each comment point-by-point as follows: Line 182 We did not perform a formal subgroup analysis stratified by ICI type, owing to the limited number of included studies and substantial confounding between ICI class, chemotherapy backbone, PD-L1 assay methodology, and overall trial design. We have explicitly added this clarification to the Discussion and Limitations sections to enhance transparency. Line 301 We have expanded the Discussion section to clarify that granular subgroup analyses by precise PD-L1 expression level were not feasible, as the included trials employed non-interchangeable PD-L1 detection assays and disparate positivity thresholds (e.g., CPS vs. immune-cell scoring). We have clarified this analytical constraint and its potential impact on interpretation. Line 312 Exploratory analyses stratified by metastatic site were already conducted and are presented in the supplementary material (Table S15 and Figure S8). We have added explicit cross-references to these results in both the Results and Discussion sections for improved accessibility. Line 316 The overly lengthy paragraph has been split into several shorter, well-structured paragraphs to improve readability. We have separately presented the discussions of assay heterogeneity, chemotherapy backbone/corticosteroid effects, exploratory subgroup findings, and safety interpretation to enhance logical flow and clarity.

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

No further comments