Immune Effective Score as a Predictor of Response to Neoadjuvant Trastuzumab Therapy and a Prognostic Indicator for HER2-Positive Breast Cancer

Round 1

Reviewer 1 Report

This is an interesting study to reveal the significant immune signatures associated with the therapeutic response to anti-HER2 were identified based on the weighted correlation network analysis method. They established an immune effective score of 557 tumors in four cohorts from patients with confirmed HER2-positive breast cancer, and found immune effective score to be a predictive factor in response to neoadjuvant trastuzumab therapy and an independent prognostic biomarker. Albeit, I consider these findings to provide insight into breast cancer research, I still have some minor suggestions.

 

1, All images are highly professional, however, I suggest the authors can guide the readers to the meaning of the images appropriately; otherwise, it is likely to cause misunderstandings. For example, the author need to explain what is 2,3,4,,5,6,7,8,9,10,12,14,,16,18,20 in Fig1A. For Fig2-3, please explain the meaning of the solid line, dashed line, dash-dotted line, dotted line…etc.

 

2, Line 255: The author demonstrated that they did not have any survival information for the GEO cohorts to explore the prognostic value of IES for disease-free survival (DFS) and event-free survival (EFS) in this study. I suggested that the author can use kmplot  (https://kmplot.com/analysis/) to validate these data (PMID: 34527184, 34638387).

 

3, It would be interesting if these data could be correlated in clinical practice, as a summary in the discussion. Therefore, I suggest that the authors can also validate their data via Proteinatlas (PMID: 25613900, 34359286)

Author Response

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Author Response File: Author Response.pdf

Reviewer 2 Report

The objective of the authors was to harness the immune features to develop a prognostic model system and investigate its applicability in predicting the clinical outcomes in HER2-positive breast cancer. The authors have developed immune effective score (IES) model system and investigated its ability in predicting the clinical outcomes using 4 independent cohorts (GSE66305, n=88; GSE130786, n=110; 15 TCGA, n=123; METABRIC, n=236). The authors have reported positive correlation between IES and different immune signatures and have shown patients with higher IES have higher pCR rate than patients with low IES. The authors have shown IES could be used as predictive biomarker to neoadjuvant trastuzumab therapy but not with other neoadjuvant therapies. The authors have also demonstrated the IES model system as an independent prognostic factor for overall survival in the TCGA and METABRIC cohorts. 

The major limitation of this study is the selected cohorts did not have survival information which limits the confidence in prognostic value of IES and requires further validation and the authors have also mentioned it in the manuscript. However it is very interesting data and the manuscript could be considered for publication.

Minor concerns:

1) Please delete redundant word "was" on Ln # 150.

Author Response

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Author Response File: Author Response.pdf

Reviewer 3 Report

 

There are some points of concern in how statistical methods have been reported and authors conclusions have been addressed  based on different datasets.

The statistical methods used should be better described. In fact, in the static analysis paragraph, the authors reports only Wilcoxon test and Kaplan-Meier approach . Greater consistency between methods and results presented would be desirable. A data analysis work flow should be reported.

Moreover, a detailed description of the various databases used (with the number of events, etc. ) would be useful to better understand the paper.

Author Response

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Author Response File: Author Response.pdf

Round 2

Reviewer 3 Report

Authors adressed all my comments.

Please only,chenge the sentence in the statistica methods as:

'The Wilcoxon test  was used to compare two groups of continuous variables'

 

Author Response

Point 1:

Please only,change the sentence in the statistica methods as:

'The Wilcoxon test  was used to compare two groups of continuous variables'

Response 1:

Thank you for the advice. We have made the indicated changes (Line 91).

Again, thanks for your previous constructive comments, which really helped us improve the manuscript.