PONE-D-23-30937A Randomised Control trial of Pre-Operative Oncotype DX® Testing in early-stage breast cancer  – Study ProtocolPLOS ONE

Dear Dr. Northgraves,

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Academic Editor

PLOS ONE

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"Matthew Northgraves has nothing to disclose.

 Judith Cohen reports a grant from Exact Sciences, during the conduct of the study.

 James Harvey reports a consultancy fee from Genomic Health.

 Chao Huang has nothing to disclose.

 Carlo Palmieri reports grants from Daiichi Sankyo, Gilead, Pfizer, Seagen, consulting fees from  AstraZeneca, Daiichi Sankyo, Eli Lilly, Eisai, Exact Sciences, Gilead, Medac, MSD, Novartis, Pfizer, Roche,  Seagen, honoraria for   presentations/educational events from Pfizer, AZ, Seagen, receipt of equipment from  Pfizer, Seagen, travel and meeting support from Gilead, Roche, Novartis and a role with the NCRI. 

 Sarah Pinder reports honoraria for presentations/educational events, travel support and participation on  advisory boards and workshops for Exact Sciences.

 Pankaj .G. Roy reports personal fees from Exact Sciences, outside the submitted work.

 Sarah Reynia reports employment from, and stock in Exact Sciences.

 Marta Soares has nothing to disclose.

 Henry Cain reports a grant, honoraria for presentations/educational events, and consulting fees from Exact  Sciences."

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?

The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Partly

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2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses?

The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory.

Reviewer #1: Yes

Reviewer #2: Partly

Reviewer #3: Yes

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3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable?

Descriptions of methods and materials in the protocol should be reported in sufficient detail for another researcher to reproduce all experiments and analyses. The protocol should describe the appropriate controls, sample size calculations, and replication needed to ensure that the data are robust and reproducible.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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4. Have the authors described where all data underlying the findings will be made available when the study is complete?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. 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: No

Reviewer #2: Yes

Reviewer #3: 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

Reviewer #3: Yes

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6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics.

You may also provide optional suggestions and comments to authors that they might find helpful in planning their study.

(Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: In this study protocol, a two-arm randomized (2:1) controlled multi-center trial is being proposed which aims to compare the impact on the patient treatment pathway of performing Oncotype DX test on the diagnostic core biopsy pre-operatively (intervention) to the excised invasive carcinoma (control). The primary endpoint is the number of clinical interactions between treating team and patient from initial approach until offer and prescription of the first adjuvant treatment.

Minor revisions:

1- Line 353: Clarify if Cox regression implies Cox proportional hazards regression.

2- Line 357: State the statistical methods that will be used for correlating preoperative staging with postoperative pathological staging.

3- Identify the software that will be used for the statistical analysis.

Reviewer #2: Article review (A Randomised Control trial of Pre-Operative Oncotype DX® Testing in early-stage breast cancer – Study Protocol, PONE-D--23-30937):

Summary

This is a protocol for a randomized control trial comparing the preoperative Oncotype testing of the core biopsy to the postoperative Oncotype testing of the surgical pathology specimen. Primary endpoint is number of clinical touchpoints. Secondary endpoints include time from diagnosis to adjuvant therapy, patient-reported anxiety scores and health cost impact analysis, and number of alterations in treatment sequence from original planned surgical treatment to neoadjuvant therapy.

Comments/Revisions

1. The impact of preopereative Oncotype testing in the management of early-stage breast cancer is worthy investigation and there is merit in conducting the proposed trial

2. The main benefit of preoperative testing would be the reduction in time from diagnosis to adjuvant therapy. Therefore, I feel that time to adjuvant therapy should be the primary endpoint. Number of clinical touchpoints can be one of the secondary endpoints.

3. The agreement between preoperative and postoperative Onctotype should be reported.

4. Professional editing is recommended prior to publication

Recommendation

Major revision

Reviewer #3: I am very grateful to you for giving me the opportunity to review this interesting manuscript where the authors describe a new approach to the treatment of early breast cancer. The authors propose to perform the OncotypeDx on the biopsy sample of patients with surgical indication, instead of surgical specimen, in order to optimize the initiation of adjuvant treatment. However, I have a few concerns about the protocol:

- The decision for adjuvant treatment is typically based on an evaluation of both clinical and genomic risk factors, as detailed by Sparano et al (N Engl J Med 2019; 380:2395-2405). Therefore, it is an interesting strategy to conduct the genomic analysis on the biopsy sample, ensuring that the initiation of adjuvant treatment is not delayed. Nevertheless, there are certain scenarios in which it is unnecessary to utilize the genomic platform to make decisions about adjuvant treatment. This includes cases involving premenopausal patients with positive axillary fine-needle aspiration (FNA) or tumors larger than 3 cm with grade 3. Performing genomic platforms in this context could potentially lead to unnecessary costs for the health system. I kindly suggest to the authors to consider and describe strategies in the protocol that could help minimize such scenarios during the study, with the aim of optimizing resource utilization.

- The authors describe the analysis of the number of contact points between the clinician and the participant as the primary outcome and calculate the sample size based on the reduction from 6 to 5 interactions. I kindly suggest that the authors provide an explanation in the manuscript regarding why this reduction might be considered relevant in the treatment of these patients. Additionally, the authors could discuss how this reduction might impact costs to the healthcare system. Providing such context would enhance the understanding of the significance of the chosen primary outcome and its implications for both patient care and resource utilization.

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Reviewer #1: No

Reviewer #2: Yes: Ioannis Alagkiozidis

Reviewer #3: No

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A Randomised Controlled trial of Pre-Operative Oncotype DX® Testing in early-stage breast cancer (PRE-DX study) – Study Protocol

PONE-D-23-30937R1

Dear Dr. Northgraves,

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.

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Kind regards,

Daniele Ugo Tari, M.D.

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?

The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Partly

**********

2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses?

The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable?

Descriptions of methods and materials in the protocol should be reported in sufficient detail for another researcher to reproduce all experiments and analyses. The protocol should describe the appropriate controls, sample size calculations, and replication needed to ensure that the data are robust and reproducible.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

4. Have the authors described where all data underlying the findings will be made available when the study is complete?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. 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: No

Reviewer #2: Yes

Reviewer #3: 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: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics.

You may also provide optional suggestions and comments to authors that they might find helpful in planning their study.

(Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: All comments have been adequately addressed.

Reviewer #2: Accepted. The authors have addressed the points made at the initial review and their proposed protocol meets standards for publication

Reviewer #3: No modifications have been made to the manuscript according to the comments sent. I consider that the two major comments made are related to the clinical relevance of the study, so from my point of view, not considering them could affect the clinical significance of its results. The authors mention that the points raised have not been considered in the REC approved protocol, so they do not consider it necessary to include them in this manuscript.

At this moment I do not have any other comment to share.

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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.

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: Yes: Ioannis Alagkiozidis

Reviewer #3: No

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