HE4 Tissue Expression as A Putative Prognostic Marker in Low-Risk/Low-Grade Endometrioid Endometrial Cancer: A Review

Round 1

Reviewer 1 Report

In the manuscript titled ‘HE4 Tissue Expression as a Putative Prognostic Marker in Low-Risk/Low-Grade Endometrioid Endometrial Cancer: A Review’, the authors reviewed the literature to inquire about the status of HE4 use in the prognosis of Low-Grade or early stage endometrial cancer. The authors declare that their findings suggest no correlation between HE4 expression and the prognosis of Endometrial cancer. The study has implications for the future however it adds no meaningful data to the knowledge gap along with no future hypotheses. Therefore, unfortunately, it is recommended to revise the manuscript after improvement for publication in Current Oncology. A review of 13 studies as analysis can be of importance, however many similar studies have already been conducted, therefore authors are suggested to provide novelty to the study to indicate differences from other similar studies.

Critique:

The introduction is clearly we-written and portrays an in-depth analysis of the problem statement, however, it seems like the literature review and not the background of the study.

In the second section HE4, the authors didn’t fully utilize the literature regarding the different isoforms of HE4.

In the third section serum HER4 levels and endometrial cancer, the relevant data is reviewed, however, data from the HE4 overexpression study is irrelevant to the section.

There have been many studies conducted on the same topic and their findings have provided similar insights. The authors are suggested to look at the following studies and provide their own analysis in comparison to relevant studies in a separate section so that a more informed discussion or conclusion can be written.

10.3390/cancers13194764

10.1016/j.cca.2020.12.029

10.3390/cancers14143306

10.1177/1010428318757

10.3390/diagnostics11071274

10.1177/1533033819901

10.3390/diagnostics11040626

Author Response

Point 1: In the manuscript titled ‘HE4 Tissue Expression as a Putative Prognostic Marker in Low-Risk/LowGrade Endometrioid Endometrial Cancer: A Review’, the authors reviewed the literature to inquire about the status of HE4 use in the prognosis of Low-Grade or early stage endometrial cancer. The authors declare that their findings suggest no correlation between HE4 expression and the prognosis of Endometrial cancer. The study has implications for the future however it adds no meaningful data to the knowledge gap along with no future hypotheses. Therefore, unfortunately, it is recommended to revise the manuscript after improvement for publication in Current Oncology. A review of 13 studies as analysis can be of importance, however many similar studies have already been conducted, therefore authors are suggested to provide novelty to the study to indicate differences from other similar studies

Response 1: The authors thank the Reviewer for his inspiring remarks. Indeed, many studies have already been conducted by other authors to evaluate the diagnostic and prognostic capabilities of serum HE4 in endometrial cancer. The novelty of the review proposed by the authors lies in the fact that this is the first review that focuses on the prognostic capability of HE4 expression in endometrial cancer tissue. As explained in section 7 Conclusions, "From the data of the few identified studies, it emerges that HE4 expression in neoplastic tissue could give information on prognosis mostly in low-grade endometrioid carcinomas."

Point 2: Critique:
The introduction is clearly we-written and portrays an in-depth analysis of the problem statement, however, it seems like the literature review and not the background of the study.

Response 2: The authors thank the Reviewer for his appropriate observation. The introduction went deep into the analysis of the evolution of the classification of endometrial cancer to provide the most complete view of the real problem that the review aims to address, namely whether HE4 can be a putative immunohistochemical prognostic marker of relapse-risk in the population of women with low-risk / low-grade endometrioid endometrial cancer.

Point 3: In the second section HE4, the authors didn’t fully utilize the literature regarding the different isoforms of HE4.

Response 3:  The authors thank the Reviewer for his inspiring remark. The authors discussed in more detail the literature regarding the different isoforms of HE4. (Page 4 of the revised manuscript)

Point 4: In the third section serum HER4 levels and endometrial cancer, the relevant data is reviewed, however, data from the HE4 overexpression study is irrelevant to the section.

Response 4: The authors thank the Reviewer for his constructive criticism. The authors moved data from the HE4 overexpression study from the third section "Serum HE4 and Endometrial Cancer" to the fourth section "Literature Review Aim and Search Strategy". (Page 6 of the revised manuscript)

Point 5: There have been many studies conducted on the same topic and their findings have provided similar insights. The authors are suggested to look at the following studies and provide their own analysis in comparison to relevant studies in a separate section so that a more informed discussion or conclusion can be written.
10.3390/cancers13194764
10.1016/j.cca.2020.12.029
10.3390/cancers14143306
10.1177/1010428318757
10.3390/diagnostics11071274
10.1177/1533033819901
10.3390/diagnostics11040626

Response 5: The authors thank the Reviewer for his inspiring remark. The authors looked at all studies suggested by the Reviewer and analyzed the results of these studies in a separate subsection of the sixth section “Discussion”. (Pages 10-12 and 16 of the revised manuscript.)

Reviewer 2 Report

This is a good manuscript that reviews HE4 tissue expression data could help with prognosis of low-grade endometrial cancers.

-Interpretation and presentation of previous studies is accurate.
-No major suggestions for improvements.
-Clarity and context in this paper are good.
-References are comprehensive.

Author Response

Response: The authors thank the Reviewer for the favorable opinion expressed regarding the manuscript.

Reviewer 3 Report

Mais et al. performed a literature review on altered expression levels of HE4 protein and mRNA between normal endometria and endometrioid endometrial carcinoma and have recognised that some different isoforms of HE4 tend to be expressed preferentially in low-grade endometrioid endometrial carcinoma with a high risk of relapse, therefore finally suggesting a high utility of these HE4 isoforms as a prognostic marker. The review article is quite interesting. Their literature analyses are careful and elaborate. It is greatly appreciated that they noticed importance of HE4 isoform analyses rather than total HE4 analyses. TCGA classification of endometrial cancer is beneficial to only fortunate patients due to the high cost of examination and the necessity of heavy facility for analysis. Also in the terms of accessibility to examination, the authors’ proposition is appreciated again. I have no objection to publication of this review article. However, I am not sure whether this is a review article. According to the policy of some other journals, this paper may be considered to be an original research article. Anyhow, this is a good article to be published.

Author Response

Response: The authors thank the Reviewer for the favorable opinion expressed regarding the manuscript they submitted as a review article. The authors refer the decision to publish the manuscript as an original research article to the Editors of Current Oncology.

Round 2

Reviewer 1 Report

The manuscript has been improved and can be accepted for publication in revised form. Thanks for addressing the concerns.