PONE-D-21-17137The clinicopathology and survival characteristics of patients with POLE proofreading mutations in endometrial carcinoma: A systematic review and meta-analysis.PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

Reviewer #2: Yes

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: No

Reviewer #2: Yes

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3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: General comments: The authors present a systematic review and meta-analysis of the prevalence of POLE mutations in endometrial cancer, survival outcomes, and clinical/pathologic associations. This is an expansion upon a prior meta-analysis by the same authors, and though multiple meta-analyses on the same or similar topic have been performed, this does appear to have the highest number of patients with POLE mutated endometrial cancer in a meta-analysis to date.

- Previously published meta-analyses include those mentioned by the authors as well as the recently published McAlpine JN, Chiu DS, Nout RA, et al. Evaluation of treatment effects in patients with endometrial cancer and POLE mutations: An individual patient data meta-analysis, published in Cancer earlier this year.

Reviewer comments:

Major:

1. Starting in line 13 and throughout the paper, there are multiple comments regarding “improved survival” or “improved overall survival”; however, this 95% confidence interval crosses 1.

a. Also in line 313, 327.

2. Starting in line 18 (“invasion of the myometrium is curtailed,” citing only the significant p-value) and throughout the paper, the results regarding myometrial invasion seem to be overstated. While the OR for myometrial invasion <50% is 1.765 (95% CI 1.28-2.44, p=0.001), the OR for myometrial invasion >50% is 0.83 (95% CI 0.56-1.22, p=0.34), with a 95% CI crossing 1 and a p-value indicating a lack of significance, indicated that there is not (at least significantly) lower odds of deep (>50%) myometrial invasion with POLE mutations.

a. Another example of this is lines 243-245.

b. Also in line 328.

c. Also in line 360: “remain localized in the endometrium”

3. The association of POLE-mutant EC with endometrioid histology is reported as “significant”; however, the 95% CI crosses 1 and the p value is >0.05 (0.073). What are you using as your cut off for a significant p-value?

4. Lines 53-62: Citation 7 is cited when referring to your own prior meta-analysis, but also in sentences referring to other meta-analyses or results (at least some of which I can not find in your prior paper). Please cite the appropriate primary literature. Similarly, in lines 61-62, citation 7 is cited regarding depth of invasion; however, if this is referring to your prior meta-analysis, the 95% CI crosses 1.

5. Line 222 and forward: ORs should not be expressed as a “%.”

Minor:

1. Line 14-17: The way the data regarding stage and grade reads throughout the paper is confusing and needs to be rephrased. E.g. “Compared to wild type, POLE mutant tumors were significantly more likely to present at an early stage (stage I-II, OR=2.96, p<0.001) and high grade (grade 3, OR=1.72, p=0.003).”

a. Line 235-236: Another example. E.g. “POLE mutant EC are significantly more likely to present at an early stage (stage I-II) and high grade (grade 3) compared to wild type POLE EC.”

b. Lines 304-305 as well.

2. Line 51-52: There are papers regarding this subject. Please cite.

3. Line 71: Move “(2)” before “confirm.”

4. Would recommend having the paper reviewed for both grammar and spelling errors. There are many sentences that do not make sense as well as run-on and incomplete sentences.

5. Line 165: In multiple locations throughout the paper, where I believe you are intending to write “PFS” for progression free survival, there are typos such as “PFR” and “PFF.” Please correct.

6. Throughout: Consistently include a space between “95%” and “CI.”

7. Line 195, Table 3: Please clarify in the table legend that for the first line (overall POLE mutation), the denominator is all patients with EC; whereas for subsequent lines, the denominator is limited to patients with POLE mutated EC.

a. Also note typo/misspelling of “endometrioid” in the table.

8. Line 200: Adding “the proportion of” between “A subgroup analysis of” and “POLE mutant EC” will clarify this sentence.

9. Consider limiting decimal places to 2 as 3 can be bulky to read.

10. Lines 241-245: Rephrase for readability – and include p-values. E.g. “The odds ratio of MI in POLE mutant EC to MI in wild type POLE EC is 1.765 (95% CI: 1.28-2.44, p=0.001) for MI<50%, but 0.83 (95% CI: 0.56-1.22, p=0.34) for MI>50%.”

11. Line 248-249: “On the other hand” does not make sense here.

12. Lines 256 forward: The term “negatively involved lymph nodes” does not make sense to me. I would change this to negative lymph nodes and positive lymph nodes.

a. “The pooled proportion of positive lymph nodes in POLE mutant EC is 1.28% (95% CI: 0.24-3.84), while that for negative lymph notdes is 74.33% (95% CI: 61.79-85.11).

13. Line 258 and elsewhere: “odd ratio” should be changed to “odds ratio.”

14. Line 264: Insert “EC” between “type” and “in.”

15. Line 268: I would recommend deleting the word “great.”

16. Lines 278-295: This background information seems more appropriate for the introduction than the discussion.

17. Discussion: I would recommend decreasing the use of exact numbers as these have been presented in the results section, with a focus on a broader summary of the results and discussion of the implications. Would also not refer to tables in the discussion.

18. Line 309: Please clarify whether you are referring to your own previous results.

19. Line 316: What is the “main series of EC studies” referring to?

20. Lines 325-328: The flow from one sentence to the other makes it sound as though you have verified this reasoning/mechanism behind differences in survival outcomes.

21. Line 328-330: May want to discuss the published study(ies) regarding analysis of differences in treatment groups within the POLE mutant ECs.

22. Line 360: Recommend specifying lymph node metastases.

Reviewer #2: This is a well written meta-analysis that follows PRISMA guidelines.

The study aimed to: (1) resolve the reported clinicopathology variations of POLE-mutant endometrial carcinoma and confirm (2) the prognostic benefit of the POLE (exonuclease domain mutant) subtype using survival analysis of the expanded cohort of studies.

Specific suggestions:

Remove the word "fortunately" from line 88

Line 189- define the countries included, rather than "western countries"

ESMO risk stratification is not universally used and should be definted

It would be interesting to also report on tumor size, as that has always been linked to prognosis

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Reviewer #1: No

Reviewer #2: No

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The clinicopathology and survival characteristics of patients with POLE proofreading mutations in endometrial carcinoma: A systematic review and meta-analysis.

PONE-D-21-17137R1

Dear Dr. McAllister

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

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Kind regards,

Manish S. Patankar, Ph.D.

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

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5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Congratulation for completing this important manuscript. All my comments have been addressed and manuscript appear much improved and ready for publication.

Reviewer #2: Thank you for incorporating the suggested feedback. This article is fit for publication. Well done.

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7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

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Reviewer #1: No

Reviewer #2: No