Progression-free survival and overall survival after BRCA1/2-associated epithelial ovarian cancer: A matched cohort study

Bernadette A. M. Heemskerk-Gerritsen; Antoinette Hollestelle; Christi J. van Asperen; Irma van den Beek; Willemien J. van Driel; Klaartje van Engelen; Encarna B. Gómez Garcia; Joanne A. de Hullu; Marco J. Koudijs; Marian J. E. Mourits; Maartje J. Hooning; Ingrid A. Boere

doi:10.1371/journal.pone.0275015

Peer Review History

Original SubmissionMarch 24, 2022
18 May 2022 Decision Letter - Mohammad R. Akbari, Editor PONE-D-22-08760Progression-free survival and overall survival after BRCA1/2-associated epithelial ovarian cancer: a matched cohort studyPLOS ONE Dear Dr. Heemskerk-Gerritsen, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. Please submit your revised manuscript by Jul 02 2022 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. Please include the following items when submitting your revised manuscript: A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter. If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols. We look forward to receiving your revised manuscript. Kind regards, Mohammad R. Akbari Academic Editor PLOS ONE Journal Requirements: When submitting your revision, we need you to address these additional requirements. 1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf. 2. Please include your full ethics statement in the ‘Methods’ section of your manuscript file. In your statement, please include the full name of the IRB or ethics committee who approved or waived your study, as well as whether or not you obtained informed written or verbal consent. If consent was waived for your study, please include this information in your statement as well. 3. We note that the grant information you provided in the ‘Funding Information’ and ‘Financial Disclosure’ sections do not match. When you resubmit, please ensure that you provide the correct grant numbers for the awards you received for your study in the ‘Funding Information’ section. 4. We note that you have indicated that data from this study are available upon request. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly. For information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions. In your revised cover letter, please address the following prompts: a) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially identifying or sensitive patient information) and who has imposed them (e.g., an ethics committee). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent. b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings as either Supporting Information files or to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. Please see http://www.bmj.com/content/340/bmj.c181.long for guidelines on how to de-identify and prepare clinical data for publication. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories. We will update your Data Availability statement on your behalf to reflect the information you provide. Additional Editor Comments: The two reviewers nicely outlined the issues that need to be addressed in your manuscript before publishing it. Please do your best in addressing their comments and resubmit your revised manuscript for further consideration. [Note: HTML markup is below. Please do not edit.] 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: Yes Reviewer #2: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: Yes ****** 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 ****** 4. 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 ****** 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: Thank you for the opportunity to review this very important analysis aiming to compare survival trajectory of women with ovarian cancer; with and without a germline BRCA mutation. The manuscript is well-written, the methodology is robust, and the analysis is of interest. However, there are a few factors that should be considered that the authors did not describe in detail, address, or account for. Considering the access to the detailed information for such an analysis is available to these authors, I suggest some of the key clinical and treatment variables are included to allow for a more robust analysis. In particular, route and timing of chemo and residual disease status following surgery. Some specific comments include: 1. Introduction: line 69: age-specific recommendations for preventive surgery is based on ages when risks start to increase; not really when childbearing is complete 2. Introduction: line 76: the authors did not include one of the largest, comprehensive analyses on the topic (PMID: 26556769). 3. Methods: line 106: the authors should consider refining the staging as a matching variable. Why were patients not matched by exact stage? 4. Methods; line 108: although clearly addressed in the limitations section of the discussion; this is a major limitation of this study. The sporadic cases were assumed to be negative for BRCA [or other HRD mutations]; which definitely resulted in misclassification of a proportion of these women who were included as the ‘control’ group. 5. Methods: line 134: ‘complete debulking surgery – yes/no’ is not an ideal classification of this very important predictor of prognosis. Ideally, the authors would have had classified this information according to size of residual disease following cytoreductive surgery … unless this indeed means NO or ZERO residual disease. 6. Methods: line 176 – the fact that there was a lot of missing data for the key prognostic variables is also problematic, in particular, residual disease. 7. Results: Table 1 should include overall survival from diagnosis to death 8. Results: Table 1 there is no information on route of chemotherapy; adjuvant vs. neoadjuvant, etc. 9. Results: Table 1 has no information on stage, histology, etc. 10. Results: although very few women used PARPs, perhaps a sensitivity analysis excluding these patients and running the key models would be a good idea. 11. Results: the inclusion of all stages and subtypes is a key limitation. Analyses should be stratified, at the very least, by stage ¾ OR high grade serous disease. 12. Discussion: the discussion is well done and the limitations are well described. Nevertheless, given there are other publications on the topic that allowed for a more robust statistical analysis on the topic. Reviewer #2: Thank you for this important and well written paper. Though I am no expert on statistics, I thought your analysis was incredibly well thought out and thorough. The paper reads neatly and is easy to understand. My critical feedback is as follows: 1. You mention that none of the sporadic OC specimens were tested for a somatic mutation. I feel the lack of somatic testing will include a number of BRCA positive specimens in the sporadic group, and will confound your results. I would like to see some attention paid to this in the confounders and discussion, as I think it is a major limitation of your study. I also think you should mention that these are germline mutations only in your abstract and introduction, as readers may now be accustomed to having EOC specimens tested and may assume all specimens are correctly classified before reading your statement on gremlin vs somatic testing. 2. The range of follow up includes 0.1 years. Did you consider a minimum amount of follow up time to include in the criteria (0.5y for example) to exclude the patients who died so early in their journey? At minimum did you match for death/recurrence at less than 6 mo as these outcomes are likely not in the spirit of your conclusions, which is to compare longer term outcomes? 3. Could you expand on censoring events in line 128? I am unclear what you mean by “another tumour” and wonder what you include here. Are metastasis included? Benign tumours? 4. Line 135 has a typographic error and should read “not confounding” Thank you again for this excellent work. I look forward to its final acceptance. ****** 6. 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. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review?** For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: No Reviewer #2: No [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0275015.r001
Revision 1
11 Jul 2022 Author Response Journal Requirements: When submitting your revision, we need you to address these additional requirements. 1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf. Response We have checked the manuscript and adjusted if necessary. 2. Please include your full ethics statement in the ‘Methods’ section of your manuscript file. In your statement, please include the full name of the IRB or ethics committee who approved or waived your study, as well as whether or not you obtained informed written or verbal consent. If consent was waived for your study, please include this information in your statement as well. Response We have included our full ethics statement in the ‘Methods’ section of the manuscript file (page 4; lines 96-97. Please note that pages and line numbers refer to the Revised Manuscript with Track Changes). 3. We note that the grant information you provided in the ‘Funding Information’ and ‘Financial Disclosure’ sections do not match. When you resubmit, please ensure that you provide the correct grant numbers for the awards you received for your study in the ‘Funding Information’ section. Response We have compared the ‘Funding Information’ section in the manuscript with the ‘Financial Disclosure’ section and the given information is correct. 4. We note that you have indicated that data from this study are available upon request. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly. For information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#locunacceptable-data-access-restrictions. In your revised cover letter, please address the following prompts: a) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially identifying or sensitive patient information) and who has imposed them (e.g., an ethics committee). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent. b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings as either Supporting Information files or to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. Please see http://www.bmj.com/content/340/bmj.c181.long for guidelines on how to de-identify and prepare clinical data for publication. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories. We will update your Data Availability statement on your behalf to reflect the information you provide. Response We have addressed the requested prompt in the revised cover letter. Additional Editor Comments: The two reviewers nicely outlined the issues that need to be addressed in your manuscript before publishing it. Please do your best in addressing their comments and resubmit your revised manuscript for further consideration. Response We would like to thank both reviewers for their time and thorough and fair review of our manuscript. Reviewer #1: Thank you for the opportunity to review this very important analysis aiming to compare survival trajectory of women with ovarian cancer; with and without a germline BRCA mutation. The manuscript is well written, the methodology is robust, and the analysis is of interest. However, there are a few factors that should be considered that the authors did not describe in detail, address, or account for. Considering the access to the detailed information for such an analysis is available to these authors, I suggest some of the key clinical and treatment variables are included to allow for a more robust analysis. In particular, route and timing of chemo and residual disease status following surgery. Some specific comments include: 1. Introduction: line 69: age-specific recommendations for preventive surgery is based on ages when risks start to increase; not really when childbearing is complete Response We definitely agree with the reviewer that risk-reducing salpingo-oophorectomy is advised from specific ages, and not based on completeness of childbearing. We have rephrased the sentence on this topic in the Introduction (page 3; lines 69-72. Please note that pages and line numbers refer to the Revised Manuscript with Track Changes). 2. Introduction: line 76: the authors did not include one of the largest, comprehensive analyses on the topic (PMID: 26556769). Response According to the reviewer’s suggestion, we have included the study by Kotsopoulos et al. (reference number 29). 3. Methods: line 106: the authors should consider refining the staging as a matching variable. Why were patients not matched by exact stage? Response Since BRCA1/2-associated ovarian cancer is usually diagnosed at considerable younger age than sporadic ovarian cancer, selecting a sufficient number of sporadic controls was difficult when matching on exact stage. Therefore, in consultation with the medical oncologist and in view of the different treatment indications for patients with lower and higher FIGO stages, we matched on the more rough categories of low (i.e. <= IIA) and high (i.e. >=IIB) FIGO stage. Reassuringly, as can be seen in the table below, there were no import differences between the comparison groups when looking at the exact FIGO stage, neither within the low grade categories nor in the high grade categories. BRCA1 sporadic BRCA2 sporadic N (%) N (%) p-value N (%) N (%) p-value FIGO Low (≤IIA) I 0 (0%) 5 (11%) 0.277 0 (0%) 2 (11%) 0.383 IA 7 (20%) 10 (22%) 5 (32%) 7 (36%) IB 3 (9%) 3 (6%) 2 (12%) 0 (0%) IC 18 (53%) 24 (52%) 7 (44%) 8 (42%) IIA 6 (18%) 4 (9%) 2 (12%) 2 (11%) FIGO High (≥IIB) IIB 20 (6%) 25(8%) 0.053 5 (5%) 5 (6%) 0.086 IIC 25 (8%) 26 (8%) 3 (3%) 8 (9%) III 9 (3%) 6 (2%) 6 (6%) 1 (1%) IIIA 20 (6%) 15 (5%) 5 (5%) 2 (2%) IIIB 45 (14%) 39 (13%) 12 (13%) 16 (18%) IIIC 145 (45%) 168 (54%) 49 (51%) 51 (57%) IV 59 (18%) 31 (10%) 16 (17%) 7 (8%) Unknown 32 33 11 14 For the sake of readability, we omitted these numbers from the table for now, but when desired, we can add them either in the manuscript or as supplementary data. 4. Methods; line 108: although clearly addressed in the limitations section of the discussion; this is a major limitation of this study. The sporadic cases were assumed to be negative for BRCA [or other HRD mutations]; which definitely resulted in misclassification of a proportion of these women who were included as the ‘control’ group. Response We totally agree with the reviewer that the fact that not all sporadic patients were DNA tested is a limitation of the study. In addition to the considerations already addressed in the discussion (page 18; lines 286-294), we might speculate that with the same year of diagnosis and the same age at diagnosis – following from the matching criteria – the indication for DNA testing may have been the same for both groups. This may indicate that for sporadic patients with an indication for testing, indeed no BRCA mutation was found. Furthermore, the sporadic patients were in any case not included in the national Hereditary Breast and Ovarian Cancer Netherlands (HEBON) database, which may indicate at least a lack of family history of breast cancer or ovarian cancer. Still, these arguments do not completely rule out potential misclassification. Unfortunately, due to privacy laws and regulations we cannot retrieve and test tumor tissue of those patients who were not tested before. 5. Methods: line 134: ‘complete debulking surgery – yes/no’ is not an ideal classification of this very important predictor of prognosis. Ideally, the authors would have had classified this information according to size of residual disease following cytoreductive surgery … unless this indeed means NO or ZERO residual disease. Response ‘Complete debulking surgery – yes/no’ indeed means the absence (‘yes’) or presence (‘no’) of any residual disease. For clarification, we have added this specification into the manuscript (page 6; line 136). 6. Methods: line 176 – the fact that there was a lot of missing data for the key prognostic variables is also problematic, in particular, residual disease. Response We totally agree with the reviewer that missing data on residual disease is a limitation of the study. However, as mentioned in the Discussion (page 19; lines 312-315), and as can be found in Table1 , we observed no differences between the comparison groups in the percentages of patients with residual disease for those patients with available data. As there seems no association for this variable with the exposure (i.e. carrying a germline BRCA pathogenic variant) in the current study population, the variable is no confounder according to the classical definition for confounders (i.e. being associated with the exposure and the outcome without being an intermediate factor), and therefore the variable does not have to be included in the multivariable model. In addition, although we realize we cannot be absolutely sure of this, we cannot think of a plausible reason to expect this distribution would be different among the patients with missing data, especially since the percentage of these patients is approximately the same in all groups (~30%). Therefore, we expect no influence on the estimated HRs by adjusting for the presence or absence of residual disease 7. Results: Table 1 should include overall survival from diagnosis to death Response We thank the reviewer for this suggestion and added the data into Table 1 and into Supplementary Table S1. 8. Results: Table 1 there is no information on route of chemotherapy; adjuvant vs. neoadjuvant, etc. Response We thank the reviewer for this suggestion and added the data into Table 1 and into Supplementary Table S1. 9. Results: Table 1 has no information on stage, histology, etc. Response Information on stage can be found above in our response on comment 3. As mentioned there, we omitted these numbers from the table for the sake of readability, but when desired, we can add them in. Following the reviewer’s suggestion, we have added the information on histology into Table 1 and into Supplementary Table S1. 10. Results: although very few women used PARPs, perhaps a sensitivity analysis excluding these patients and running the key models would be a good idea. Response Indeed, only a few women in this cohort were treated with PARP inhibitors (PARPi), and if so this was only done in the recurrent setting. Therefore, there is in our opinion no rationale to exclude patients who received PARPi after recurrent disease from the PFS analyses. Following the reviewer’s suggestion, we performed subgroup analyses for OS excluding patients who were treated with PARPi in the recurrent setting and their matched counterparts. The results can be found in the table below. The subgroup analyses for OS revealed similar results as the original analyses. We have added a few sentences regarding the subgroup analyses for OS to the Discussion (page 17; lines 261-265). 11. Results: the inclusion of all stages and subtypes is a key limitation. Analyses should be stratified, at the very least, by stage 3-4 OR high grade serous disease. Response In our opinion, the inclusion of all stages and subtypes is no limitation but rather a reflection of reality. In addition, since the distribution of low and high FIGO stages is not different between the comparison groups (due to the matching procedure), there is no need to adjust for this variable in the multivariable analyses. To inform the reviewer, we performed subgroup analyses including only those patients and their matched counterparts with FIGO stage 3 or 4. The results can be found in the table below. The proportional hazard assumption was violated only for the overall survival analysis comparing BRCA1 gPV carriers with sporadic patients. For the other analyses, stratification by time was not necessary and survival was in favor of the BRCA gPV carriers during the whole observation period. As one can see, the results point in the same direction as the original analyses, with slightly stronger hazard ratios. HR (95% CI) BRCA1 versus sporadic BRCA2 versus sporadic Progression-free survival 0.75 (0.61-0.92) 0.46 (0.31-0.67) Overall survival 0.65 (0.53-0.81) 0.42 (0.28-0.62) Observation period < 5.1 years 0.56 (0.44-0.72) Observation >= 5.1 years 0.98 (0.64-1.49) 12. Discussion: the discussion is well done and the limitations are well described. Nevertheless, given there are other publications on the topic that allowed for a more robust statistical analysis on the topic. Response We thank the reviewer for the kind words regarding the discussion. Indeed, there are other publications on the topic, although only a few have stratified the analyses by observation time or performed separate BRCA1 and BRCA2 analyses. Reviewer #2: Thank you for this important and well written paper. Though I am no expert on statistics, I thought your analysis was incredibly well thought out and thorough. The paper reads neatly and is easy to understand. My critical feedback is as follows: 1. You mention that none of the sporadic OC specimens were tested for a somatic mutation. I feel the lack of somatic testing will include a number of BRCA positive specimens in the sporadic group, and will confound your results. I would like to see some attention paid to this in the confounders and discussion, as I think it is a major limitation of your study. I also think you should mention that these are germline mutations only in your abstract and introduction, as readers may now be accustomed to having EOC specimens tested and may assume all specimens are correctly classified before reading your statement on germline vs somatic testing. Response We agree with the reviewer that due to the lack of somatic testing the sporadic group may contain a number of BRCA positive specimens. Indeed, this may have influenced the results, although we think this influence will be limited, as about only 5% of EOCs have a somatic BRCA pathogenic variant. In addition, under the assumption that survival benefit will also apply to EOCs with a somatic BRCA pathogenic variant, potential misclassification of these EOCs in the sporadic group would led to an underestimation of the observed survival benefit rather than an overestimation. Therefore, although we agree that the lack of data on somatic testing may be a deficiency in the study, in our opinion this may play a minor role. We have added a paragraph in the Discussion on this topic (pages 18-19; lines 298-305). To clarify more that the BRCA-deficient groups contain only patients with a germline pathogenic variant, we have mentioned this more specific in the abstract and the manuscript (page 2; lines 36, 41 & 55. page 4; line 87. Page 14; line 220. Page 15; line 225). Furthermore, to make this even more clear, we have replaced the abbreviation PV with gPV throughout the manuscript. 2. The range of follow up includes 0.1 years. Did you consider a minimum amount of follow up time to include in the criteria (0.5y for example) to exclude the patients who died so early in their journey? At minimum did you match for death/recurrence at less than 6 mo as these outcomes are likely not in the spirit of your conclusions, which is to compare longer term outcomes? Response As previous studies reported different short-term and long-term survival rates for gPV carriers, we were highly interested whether this also applied for our cohort. For this reason, we deliberately included patients who died early after diagnosis. Exclusion or matching these patients would have biased the survival rates for the short-term analyses. 3. Could you expand on censoring events in line 128? I am unclear what you mean by “another tumour” and wonder what you include here. Are metastasis included? Benign tumours? Response We considered only malignant tumors as another tumor. The date of the first recurrence defines the endpoint of the PFS analysis, and therefore metastases are not considered as censoring events nor as another tumor. To clarify the definition of the censoring events, we rephrased ‘another tumor’ into ‘a new primary malignant tumor’ (page 6; line 131). 4. Line 135 has a typographic error and should read “not confounding” Response We have corrected the typographic error (page 6; line 138). Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0275015.r002
9 Sep 2022 Decision Letter - Mohammad R. Akbari, Editor Progression-free survival and overall survival after BRCA1/2-associated epithelial ovarian cancer: a matched cohort study PONE-D-22-08760R1 Dear Dr. Heemskerk-Gerritsen, 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. Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication. An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org. If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. Kind regards, Mohammad R. Akbari 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 ******** 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 ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: 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 ****** 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: (No Response) ****** 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: (No Response) ****** 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. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: No ******** https://doi.org/10.1371/journal.pone.0275015.r003
Formally Accepted
13 Sep 2022 Acceptance Letter - Mohammad R. Akbari, Editor PONE-D-22-08760R1 Progression-free survival and overall survival after BRCA1/2-associated epithelial ovarian cancer: a matched cohort study Dear Dr. Heemskerk-Gerritsen: I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org. If we can help with anything else, please email us at plosone@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Mohammad R. Akbari Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0275015.r004

Open letter on the publication of peer review reports

PLOS recognizes the benefits of transparency in the peer review process. Therefore, we enable the publication of all of the content of peer review and author responses alongside final, published articles. Reviewers remain anonymous, unless they choose to reveal their names.

We encourage other journals to join us in this initiative. We hope that our action inspires the community, including researchers, research funders, and research institutions, to recognize the benefits of published peer review reports for all parts of the research system.

Learn more at ASAPbio .