The PreQ-20 TRIAL: A prospective cohort study of the oncologic safety, quality of life and cosmetic outcomes of patients undergoing prepectoral breast reconstruction.

BACKGROUND: Mastectomy currently constitutes a necessary surgical procedure in the oncologic setting and in the context of high risk. Prepectoral breast reconstruction (PBR) has been proposed as a surgical alternative to retropectoral techniques by providing less postoperative morbidity and a better cosmetic result. However, there is a lack of prospective studies that have evaluated its safety and patient-reported satisfaction.
METHODS: We conducted a prospective cohort study to assess the safety, quality of life and cosmetic sequelae of PBR in women with breast cancer and high risk. The study's main objective is to assess the safety of PBR in terms of postsurgical complications and the feasibility of reconstruction (loss of implants). The secondary objectives are to evaluate oncologic safety (local relapses, residual glandular tissue) and to identify factors related to quality of life and cosmetic sequelae. The evaluation of residual tissue will be conducted by MRI 12 to 18 months after the surgery, and the quality-of-life assessment will be performed using the Breast-Q questionnaire. An initial patient evaluation will be conducted 12-18 months after the surgery, and a second evaluation will be performed at 5 years. The estimated sample size is 81 patients. DISCUSSION: The PreQ-20 study will analyze the impact of PBR on 3 separate measures: safety, quality of life and cosmetic sequelae. Unlike other studies that analyzed these three measures jointly for women with breast cancer and high risk, this study will individualize the results for these 2 patient groups. This differentiation is necessary from the methodological point of view, given that the 2 patient groups have separate clinical and emotional implications. The assessment of these groups will focus on the following aspects: postoperative complications, local relapses, evaluation of residual glandular tissue and incidence rate of primary tumors in the same, the cosmetic sequelae and the satisfaction and the quality-of-life assessment by the patients. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04642508.

Background

In recent years, mastectomy techniques have evolved towards less aggressive procedures with increased skin preservation, skin-sparing mastectomy (SSM), and skin and nipple-sparing mastectomy (NSM). Reconstructive procedures have changed the placement of implants from the retropectoral position towards the prepectoral location in an attempt to decrease postoperative pain, prevent animation deformity and improve the refilling of the lower pole. Various studies [1-3] published in the past 5 years have shown that the combination of SSM/NSM and prepectoral breast reconstruction (PBR) ensures good results both in the oncologic context and in reducing risk (RR). The meta-analysis by Li et al. [4] analyzed 16 studies that compared retropectoral breast reconstruction (RBP) with PBR and found no significant differences in the safety of the two procedures (in terms of seroma, implant loss, infection, skin necrosis), although PBR showed a lower incidence of capsular contracture, less pain and higher scores on the Breast-Q questionnaire compared with RBP.

Despite these technical improvements, there are still a number of unknowns regarding various clinical aspects related to PBR such as safety, quality of life and the progression of the cosmetic results. First, from the point of view of safety, the rate of postoperative complications needs to be evaluated, as well as local relapses in patients with breast cancer and primary tumors in women with high risk. There are some studies [5] that have analyzed this aspect, however, the level of evidence for these studies was low. Another aspect related to the safety of SSM and NSM is the presence of residual glandular tissue (RGT) because it can facilitate a local relapse in patients with breast cancer or promote the onset of a primary carcinoma, both in patients with cancer and those at high risk. Various studies have analyzed the presence of RGT after mastectomy [6-16]. None of these studies have reported the rate of RGT or the time interval between mastectomy and the MRI study. The identification of this RGT during follow-up facilitates the joint decision-making process with the patient, either for their specific follow-up or extirpation.

The patient-reported satisfaction and quality of life after PBR have been analyzed by several authors; however, only 3 studies have evaluated them prospectively [17-19]. The main limitations of these studies are the lack of differentiation in the results between patients with breast cancer and RRM, the scarce follow-up and the absence of a preoperative assessment in one of the studies [19]. Most of the women with breast reconstruction experienced changes and deterioration of their breast during the follow-up. There are no available prospective studies that have analyzed these changes during the follow-up for RBP or PBR. Some retrospective studies detect a very low incidence of complications, cosmetic deterioration and replacement of implants [20, 21]. In contrast, prospective studies have detected a higher rate of cosmetic sequelae after PBR [18, 19]. These studies highlighted the low breast satisfaction of patients with rippling, especially those who underwent a prepectoral procedure.

Although at this time SSM/NSM with PBR constitutes a necessary surgical procedure in the oncologic setting and in the context of high risk, there is a lack of prospective studies that have evaluated their oncologic safety and patient-reported quality of life. Therefore, the objective of this study will be to assess prospectively and with long-term follow-up the safety of sparing mastectomies with PBR. To do this, we will analyze the safety of the technique in terms of implant loss, polyurethane safety, and surgical complications; oncological safety in terms of RGT, local relapses and new tumors; and the resilience of the reconstruction, assessing cosmetic deterioration, the need for new surgeries and long-term patient satisfaction.

Research hypothesis

Prepectoral breast reconstruction with polyurethane implant after mastectomy is a safe procedure.

Study objectives

Main objective

To evaluate the safety of prepectoral reconstruction in terms of postsurgical complications and the feasibility of reconstruction (implant loss).

Secondary objectives:

To evaluate the safety of sparing mastectomy through the identification of RGT, primary carcinomas and breast cancer relapses (patients operated on for breast cancer).

To assess satisfaction and quality of life after prepectoral reconstruction in women with breast cancer and those with high risk.

To identify factors related to satisfaction and quality of life after prepectoral reconstruction.

To evaluate the cosmetic sequelae after prepectoral reconstruction in women with breast cancer and with high risk.

To identify factors related to the cosmetic sequelae after prepectoral reconstruction.

Study design

Prospective single arm cohort study to evaluate the safety, quality of life and cosmetic sequelae of breast reconstruction using prepectoral implantation in women with breast cancer and those at high risk. The safety of the technique is assessed in terms of loss of implants.

Methods

Study setting

The study will be conduct in the Breast Unit of the University Hospital Complex of A Coruña, Spain.

Eligibility criteria

We will include all older women operated on in the Breast Unit through SSM/NSM (unilateral or bilateral) and immediate reconstruction with prepectoral implantation. The study population will include 2 patient groups:

Women with breast carcinoma. This group consists of patients with a histological diagnosis of in situ or infiltrating breast carcinoma, either primary or metachronic, which requires mastectomy as the surgical treatment.

Women at high risk for breast cancer. This group consists of women evaluated at a high-risk consultation and whose RRM has been approved by the tumor committee of the Breast Unit of University Hospital Complex of A Coruña. For this procedure, the patients should meet at least one of the following criteria:

○ hereditary breast and ovarian cancer syndrome, either by demonstrated genetic mutation or through their family history.

○ histological diagnosis of high-risk lesions (atypical hyperplasia, ductal carcinoma in situ, lobular carcinoma in situ) associated with family history.

○ high-risk criteria (genetic, histological, family) during the breast cancer follow-up.

Exclusion criteria

The following clinical conditions were excluded from the study:

Inability to undergo magnetic resonance imaging during the diagnosis and follow-up.

Inability to fill out the BREAST-Q questionnaire.

Unwillingness by the patient to participate in the study.

Breast sarcomas.

PBR using expanders.

Prepectoral reconstruction with mesh

Interventions

Mastectomy technique

The breast removal will be performed using a mastectomy adapted to the breast and optimizing the preservation of the breast’s original elements (inframammary fold, skin envelope, fat transitions, nipple-areolar complex) according to each patient’s anatomical and oncologic possibilities. To this end, we will employ Carlson type 1, 2, 3 and 4 SSM [22] or NSM through an inframammary incision or vertical pattern.

Reconstruction technique. The reconstruction will be performed by placing a silicone implant coated with polyurethane foam (MicrothaneTM, POLYTECH Health & Aesthetics Dieburg, Germany. https://polytech-health-aesthetics.com) in the prepectoral position.

The authors confirm that all ongoing and related trials for this drug/intervention are registered.

Modification and adherence

Does not apply to the type of study.

Concomitant care

24-hour intravenous antibiotic prophylaxis is performed in all patients. Usually cefazolin. In patients allergic to penicillin, ciprofloxacin should be used.

Outcomes

Primary outcome measures.

Incidence of implant loss (Feasibility of reconstruction). To evaluate the feasibility of prepectoral reconstruction in terms of implant loss the first year after surgery, also during oncological treatment (example: chemotherapy) (Unit of mesure: number of implant loss). Implant loss is defined as the need to remove the prosthesis for any cause such as strusion, infection or necrosis.

Secondary outcome measures.

Incidence of surgical complications—reoperations (Safety). To determine the global incidence of surgical complications, as well as the causes of complications in terms of: postoperative bleeding, skin necrosis, necrosis of the nipple areola complex, seroma and infection.

Postoperative bleeding is defined as the appearance of any amount of bleeding that modifies the course of the first 7 postoperative days. Among these modifications we find: the need to prolong admission due to blood drainage and the need for reoperation due to bleeding or hematoma. Superficial ecchymoses that do not modify the immediate postoperative period are not included

Skin necrosis is defined as the appearance of areas of skin without vascularization that condition cell death. Necrosis that appeared during the first 3 months after surgery that conditioned some action by the surgeon are included.

Within the necrosis of the nipple areola complex, only deep necroses that required some surgical interventions are included.

Seroma is defined as the accumulation of periprosthetic fluid that required maintaining the drain for more than 10 days or placing a new one (ultrasound-guided or at operating room).

An infection is defined as the need for antibiotics in the first 30 postoperative days. The antibiotic prophylaxis used (Cefazolin the first 24 hours) is excluded.

Incidence of residual glandular tissue (Safety). To evaluate the safety of sparing mastectomy through the identification of residual glandular tissue through a magnetic resonance one year after surgery.

Incidence of breast cancer relapse (oncological safety). To evaluate the safety of sparing mastectomy through the identification relapses in the same breast during the follow up.

Incidence of new breast cancer (safety of risk reducing mastectomy). To evaluate the safety of risk reducing sparing mastectomy in high risk for breast cancer patients through the identification of new breast cancer.

Quality of life and satisfaction after a mastectomy with prepectoral reconstruction, using the Breast-Q questionnaire. To assess satisfaction and quality of life after prepectoral reconstruction in women with breast cancer and those with high risk through Breast-Q questionnaire. Also, to identify factors related to satisfaction and quality of life after prepectoral reconstruction (e.g. marital status, psychological illnesses).

Incidence of cosmetic sequelae. To evaluate the cosmetic sequelae after prepectoral reconstruction in women with breast cancer and with high risk and Identify factors related to the cosmetic sequelae after prepectoral reconstruction. The investigators will employ the Clough classification, where type I sequelae identified the patients with breast asymmetry but no deformity, type II sequelae were defined by the presence of a deformity that could be corrected using a breast-conserving procedure, and type III sequelae identified those women whose breast showed a deformity or painful fibrosis that could only be solved through mastectomy. To determine the sequelae, the criteria of the breast surgeon will be used, documented through photos.

Participants’ timeline (see Table 1 and Fig 1)

Preoperative assessment

All patients will be assessed by a surgeon of the unit who will indicate SSM/NSM and assess its feasibility for each patient. Similarly, the decision for the mastectomy will be made in consensus with the multidisciplinary committee. Before the surgery, the patients will undergo a mammography and magnetic resonance imaging to confirm the tumor size and rule out multifocality/multicentricity, as well as an evaluation of the distribution of glandular tissue and transitions between the breast and chest wall.

Breast magnetic resonance imaging

From the clinical standpoint, this diagnostic test is necessary for the follow-up of patients with breast reconstruction for the early diagnosis of relapses and deterioration of the breast implant. This study will employ the first magnetic resonance imaging during the postoperative period (between 12 and 18 months) to assess the residual glandular tissue following the mastectomy.

Breast-Q questionnaire

The Breast-Q questionnaire is aimed at evaluating patient-reported satisfaction and quality of life through the use of breast reconstruction modules. The questionnaires are the intellectual property of the University of Columbia (New York, USA), which freely allows their use for clinical research. The questionnaire is presented in 2 formats: the preoperative format, which is delivered to patients before the surgery, and the postoperative format, which is delivered to them 12–18 months after the surgery. Likewise, we will conduct a second postoperative assessment at 5 years of the surgery. The final score for each module will be calculated according to the Mapi Research Trust criteria [23] and will range from 0 to 100 (the higher the score, the greater the satisfaction and wellbeing).

Images

The evaluation of the cosmetic sequelae requires taking photographs of the patient’s chest (from the suprasternal notch to navel). Photographs will be taken prior to the surgery (frontal, right and left lateral), then again at 12–18 months and finally at 5 years of the surgery.

Follow-up

The initial follow-up of the patients will be performed by the surgeon. The immediate complications will be assessed during the first 24–48 h in the hospital (postoperative pain and bleeding). The patients will subsequently be followed in the doctor’s Breast Unit office. The first visits will be held at 1 week and at 15 days after the surgery. Visits will subsequently be scheduled at 1 and 3 months of the surgery. If there are any complications and/or incidences, an earlier visit will be scheduled.

The patients will visit the Medical Oncology and Radiation Oncology office to complete their adjuvant therapy. The oncology control tests will be performed according to the Breast Unit’s protocol, this includes a clinical review (surgeon or medical oncologist) every 3–6 months for the first 5 years. In these reviews, a directed physical examination and the corresponding imaging tests will be performed annually. During these consultations, data will be collected regarding local and systemic relapses.

The women at high risk will undergo annual check-ups in the Breast Unit office (surgeon). All study patients will be evaluated at 12–18 months after the surgery to undergo a breast MRI, imaging and to deliver the postoperative Breast-Q questionnaire. Those patients with RGT will be evaluated by surgeon. The decision to remove this tissue will be made between the patient and the surgeon, considering the amount of residual tissue, the vital status of the patient and the risk of a relapse or new tumor. Women with RGT who do not undergo a reoperation will be followed up with an annual ultrasound and / or MRI.

A second assessment will subsequently be conducted at 5 years during which new images will be taken and the postoperative Breast-Q questionnaire will be delivered.

Sample size

According to the meta-analysis by Wagner et al. [1] and the iBRA study [21], the incidence rate of implant loss is 3.3% and 9%, respectively. Our study will therefore assume that a 5% loss of implants would be acceptable and will use this value for calculating the sample size. Therefore, with a 95% confidence level (95% CI), an accuracy of 5% and assuming a 10% of potential losses during follow-up, we estimated that the necessary sample size will be 81 patients.

Recruitment

Recruitment will be done by the surgeons / gynecologists of the breast unit. Every woman diagnosed with breast cancer is referred for surgery. In it, the surgeon will identify the patients who meet the inclusion criteria.

Recruitment began when the Hospital’s ethics committee approved the study. therefore, the registration and publication of the protocol has been carried out later.

Data collection and management

The data sets generated and/or analyzed during the present study will be collected in our center’s Breast Unit database and will not be publicly available due to the data protection law and our center’s standard protocol. However, the datasets might be available through the corresponding author.

The following variables will be collected for all patients:

Epidemiological variables: age, weight (kg), height (m), muscle mass index (kg/m2), smoking habit (yes/no), suprasternal notch-nipple distance (cm)and assessment of high risk.

Healthcare variables: length of stay (days), surgical time (minutes), complications, diagnosis to surgery delay (days), surgery to first adjuvant therapy delay (days), readmission (yes/no), reoperation (yes/no), postsurgical pain at 24–48h and in the first week, measured with the visual analog scale (1 to 10).

Surgical variables: type of mastectomy (Carlson Classification), surgical specimen weight (g), implant type (volume in cc) and lymph node staging (Sentinel lymph node biopsy or axillary lymph node dissection).

Histological variables: histological type, nuclear grade, final grade, lymphovascular invasion, intraductal component, lymph node involvement and number of lymph nodes affected.

Oncologic variables: primary systemic therapy, TNM, final staging, chemotherapy agent, radiotherapy, antihormonal therapy and biological therapy.

Follow-up variables: residual tissue, residual tissue location, tumor recurrence, tumor recurrence location, deformity, deformity location and asymmetry.

Satisfaction and quality of life variables (using the Breast-Q questionnaire): breast satisfaction, satisfaction with the information received, satisfaction with the surgeon, satisfaction with the nurses, satisfaction with the team, social wellbeing, sexual wellbeing and physical wellbeing.

Retention

The assessment and follow-up of the participants included in the study was carried out in the consultations usually scheduled for follow-up and treatment. In this way, patients do not usually leave the study.

Statistical analysis

We will conduct a descriptive analysis of the variables included in the study. All quantitative variables will be expressed with the mean, standard deviation and corresponding 95% confidence interval. Comparison of proportions: The differences between the various qualitative variables will be found using Fisher’s exact test or the chi-squared test (χ2). The qualitative variables will be expressed in proportions and respective confidence intervals. The differences between the quantitative variables will be analyzed using Student’s t-test for independent groups. If the conditions of the t-test are not verified, we will use the Mann-Whitney U test. We will use Kaplan-Meier curves and compare them using the log-rank test to determine those variables related to locoregional relapse and the incidence rate of new tumors, as well as to assess cosmetic deterioration. The statistical analysis will be performed using version 24 of the statistical program IBM SPSS and Epidat 4.1.

Patients with missing data will be exclude for the analysis.

The analysis of the safety of the surgical technique will be performed on the entire sample. Oncological safety and satisfaction assessment will be analyzed by groups: oncological patients and patients with a RRM.

Monitoring

The monitoring committee is made up of medical and radiation oncologists, pathologists, breast surgeons, and radiologists. This committee evaluates the inclusion of each patient in the study. Surgical complications are assessed by the unit’s surgical committee.

Harms

In our study an adverse event will be defined as any untoward medical occurrence in a subject without regard to the possibility of a causal relationship. Adverse events will be collected after the subject has provided consent and enrolled in the study.

Ethics and dissemination

The study has been approved by our hospital’s research ethics committee (Ethics Committee of A Coruña-Ferrol. Spain. Prospectively registered on 20/Jul/2020. Registration code: 2020/95). All included patients will sign a specific informed consent form for the study. This consent form will be delivered by the surgeon in the preoperative consultation during which the patient may ask questions. It is estimated that the preliminary data will be published 2–3 years after the study has begun and that the final data will be divulged at 6–7 years. The data obtained during this study will be published in indexed journals.

Consent or assent

Consent will be given to the patient during the second consultation with the surgical specialist. In this consultation the intervention and the possibilities of participating in the study will be explained. in the same way, the doubts that the patient may have will be clarified. Later, the patient will talk with the nurse case manager, who will also explain the surgical technique and the results.

After this consultation, if the patient decides to participate in the study, she will sign the informed consent.

The patients are free to leave the study at any time, for this they will only have to request the consent of revocation.

Confidentiality

All study-related information will be stored securely at the study site. All participant information will be stored in locked file cabinets in areas with limited access. All laboratory specimens, reports, data collection, process, and administrative forms will be identified by a coded ID [identification] number only to maintain participant confidentiality. All records that contain names or other personal identifiers, such as locator forms and informed consent forms, will be stored separately from study records identified by code number. All local databases will be secured with password-protected access systems. Forms, lists, logbooks, appointment books, and any other listings that link participant ID numbers to other identifying information will be stored in a separate, locked file in an area with limited access.

Ancillary and post-trial care

The patients will continue to be followed up in the breast unit and the optimal treatment indicated at all times will be provided.

Trial results

The first results will be published 3 months after including the last patient in the study, so we can assess the main result.

Authorship

The main investigators and all surgeons who have included patients in the study will be included in the publications.

Reproducible research

In the first publication we will present our surgical technique and the study protocol. in this way the study can be reproduced.

Discussion

The PreQ-20 study will analyze the impact of PBR on 3 separate measures: safety, quality of life and cosmetic sequelae. Unlike other studies that analyzed these 3 measures jointly for women with breast cancer and RRM, our study will individualize the results for each of these 2 patient groups. This differentiation is necessary from the methodological point of view, given that the 2 patient groups have separate characteristics that modify the results and its interpretation, especially in 4 contexts of the research. The first is in regard to the assessment of RGT, given that various studies have shown that its incidence is higher in RRM due to it being a more conservative mastectomy. The second context refers to the incidence of primary tumors in RGT. This fact requires differentiation between patients with cancer and those with a high risk because the latter have a higher likelihood of a primary carcinoma, especially carriers of the BRCA1 mutation. Third, the satisfaction and quality of life requires an independent assessment for each group because women at high risk are healthy, and therefore their expectations and experiences are very different from women with a diagnosis and treatment for breast cancer. Additionally, the physical and sexual wellbeing of patients with cancer is determined by the effects of the adjuvant therapy (hormone therapy, chemotherapy, radiation therapy) and are therefore experienced in different conditions and connotations compared with women at high risk. Lastly, there is a fourth differentiating element between the two groups that focuses on cosmetic sequelae. It is foreseeable that patients with cancer experience a higher incidence of cosmetic sequelae given that the implementation of radiation adjuvant therapy or salvage surgery (nipple excision, subcutaneous fat excision) result in a higher likelihood of cosmetic deterioration. These differences determine that the results of the PBR assessment should be differentiated for these 2 patient groups.

The safety assessment of PBR in women with breast cancer requires a minimum follow-up of 5 years. These results will therefore be published 6–7 years after the start of the study. Another secondary objective of the PreQ-20 study is the identification of risk factors for local recurrence after PBR and especially their link with ductal carcinoma in situ and the tumor’s biological profile. Another objective will be to detect the onset of primary carcinoma in women with RRM, especially in carriers of the BRCA1 mutation. In our community, 45% of patients with the BRCA1 mutation have an ancestral mutation characteristic of Spain (R71G BRCA1) [24], which has shown greater lethality by promoting a high incidence of triple-negative tumors.

The assessment of RGT with MRI at 1 year of surgery helps determine the incidence rate while simultaneously providing information on the criteria for its assessment and the decision-making process for its follow-up or excision. This new modality for postmastectomy assessment starts a new culture in controlling and following-up sparing mastectomies aimed at the search for RGT.

The quality-of-life assessment in the PreQ-20 study will be conducted using a preoperative survey and 2 postoperative surveys (1 and 5 years after surgery). This methodology differs from most previous studies that only performed 1 postoperative assessment. The comparison between the preoperative and postoperative surveys will help identify those patients who specifically improve or worsen in their satisfaction and wellbeing, which will enable the identification of patient profiles with a higher likelihood of expected improvement or worsening in their satisfaction or wellbeing. By this method, individualized information processes can be established for patients to improve the joint decision-making process. This type of study has already been employed by the authors with women who underwent oncoplastic surgery to identify groups with a greater or lesser benefit for oncoreductive mammoplasty [25].

Lastly, the assessment of cosmetic sequelae will be performed through clinical examinations during the patients’ follow-up in the doctor’s office. Most of these sequelae will occur during the first 2 years. The PreQ-20 study will analyze their incidence, origin and, especially, the decisions taken to improve them. The study’s prospective design will allow for a more specific assessment of these sequelae, given that the patients will be reviewed in the doctor’s office over the course of at least 5 years.

Conclusion

The PreQ-20 study’s main objective is to assess the safety of PBR in terms of postsurgical complications and loss of implants. The results of this study will be differentiated for the groups of women with breast cancer and women with RRM. This differentiation will allow us to analyze the impact of this procedure independently in the contexts of cancer and risk reduction. The secondary objectives of the PreQ-20 study are focused on the analysis of risk factors for local recurrence in women with breast cancer and on identifying the patient profiles with foreseeable changes in their postoperative satisfaction and wellbeing.

SPIRIT 2013 checklist: Recommended items to address in a clinical trial protocol and related documents*.

(DOCX)

Click here for additional data file.

(DOCX)

Click here for additional data file.

14 Oct 2021

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,

Joon Jeong

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 additional information regarding the survey or questionnaire used in the study and ensure that you have provided sufficient details that others could replicate the analyses. For instance, if you developed a questionnaire as part of this study and it is not under a copyright more restrictive than CC-BY, please include a copy, in both the original language and English, as Supporting Information.

3. Thank you for submitting your clinical trial to PLOS ONE and for providing the name of the registry and the registration number. The information in the registry entry suggests that your trial was registered after patient recruitment began. PLOS ONE strongly encourages authors to register all trials before recruiting the first participant in a study.

As per the journal’s editorial policy, please include in the Methods section of your paper:

1) your reasons for your delay in registering this study (after enrolment of participants started);

2) confirmation that all related trials are registered by stating: “The authors confirm that all ongoing and related trials for this drug/intervention are registered”.

4. Thank you for stating the following financial disclosure:

N/A

At this time, please address the following queries:

a) Please clarify the sources of funding (financial or material support) for your study. List the grants or organizations that supported your study, including funding received from your institution.

b) State what role the funders took in the study. If the funders had no role in your study, please state: “The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.”

c) If any authors received a salary from any of your funders, please state which authors and which funders.

d) If you did not receive any funding for this study, please state: “The authors received no specific funding for this work.”

Please include your amended statements within your cover letter; we will change the online submission form on your behalf.

5. We note that you have stated that you will provide repository information for your data at acceptance. Should your manuscript be accepted for publication, we will hold it until you provide the relevant accession numbers or DOIs necessary to access your data. If you wish to make changes to your Data Availability statement, please describe these changes in your cover letter and we will update your Data Availability statement to reflect the information you provide.

6. Please amend your authorship list in your manuscript file to include author Lourdes García Jiménez.

7. Please amend your list of authors on the manuscript to ensure that each author is linked to an affiliation. Authors’ affiliations should reflect the institution where the work was done (if authors moved subsequently, you can also list the new affiliation stating “current affiliation:….” as necessary).

8. Please amend your manuscript to include your abstract after the title page.

[Note: HTML markup is below. Please do not edit.]

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: Partly

Reviewer #2: No

**********

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: Partly

Reviewer #2: Partly

**********

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: No

**********

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

**********

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 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: The PreQ-20 Trial is designed as a prospective cohort (a single arm) study to evaluate the safety (postoperative and oncologic safety, quality of life, and cosmetic outcomes of prepectoral breast reconstruction in patients who will receive skin-sparing mastectomy or nipple-sparing mastectomy. However, I have some concerns regarding the Study protocol and will be grateful if the authors could clarify these.

Abstract

Methods

1) The authors calculated the sample size based on the loss of implant. Therefore, only “loss of implant” is considered a primary endpoint, and the remaining postoperative complications should be considered secondary endpoints.

2) Please describe the statistical method for calculating the sample size.

3) Please clarify that this is a single-arm study.

Discussion

4) Isn’t “PreQ-20” right instead of “BreastQ-20”?

Manuscript

p.3 Table

5) Key inclusion and exclusion criteria: Patients who need a mastectomy for breast cancer or reducing risk: I would recommend changing “mastectomy” to “Skin-sparing mastectomy / Nipple-sparing mastectomy

Introduction

6) The introduction is redundant and needs to be revised more smoothly. In addition, it is necessary to clarify the purpose for which this study should be conducted.

Methods

7) Eligibility criteria: Women at high risk for breast cancer are included in this study. Is it correct to include benign breast tumors in the exclusion criteria?

8) Please clarify the definition of post-operative complications, including loss of implant, postoperative bleeding, skin necrosis, necrosis of the nipple-areola complex, seroma. and infection. Please describe how to evaluate these outcomes.

9) If there is residual glandular tissue on follow-up breast MRI, is it surgically removed or followed? Please clarify this.

10) Most of the results are measured at baseline, 12-18 months after surgery, and 5 years after surgery. Is there no follow-up between 12-18 months after surgery and 5 years after surgery? It needs to be clarified on this.

11) Please provide the criteria for “drop out” and enrollment/follow-up period.

Discussion

12) The authors said that the strength of this study is to evaluate safety in high risk for cancer/cancer groups separately. Is it enrolling 80 participants per group? If there are 80 people in total, is the ratio of the two groups preset?

13) QoL is measured at baseline, 12-18 months, and 60 months after surgery, but this is evaluated at different time points within one PBR group. It is thought that it is more important to compare with RBR or non-reconstruction populations, and it is necessary to discuss this.

Reviewer #2: 1. The authors introduced a new prospective study protocol(PreQ-20 Trial) for the oncologic safety, QoL, and aesthetic outcomes of prepectoral breast reconstruction. The followings are comments and criticisms.

2. First of all, it is not clear what the purpose of this study is. Is this a study comparing the differences in safety and patient satisfaction between the PBR and the RBR? Or is it a comparison of the results of the PBR between the cancer patients and the high-risk patients? If the purpose of this study is the former, this study should be re-designed with the RBR patient group as a control group. This might be a critical issue of this study. If the main purpose is the latter, the title should be changed as follows; “The PreQ-20 Trial, a prospective cohort study of the oncologic safety, quality of life and cosmetic outcomes of Patients WITH BREAST CANCER AND HIGH RISK undergoing prepectoral breast reconstruction”.

3. The authors included both SSM and NSM as study subjects. However, there is inevitably a big difference between patient satisfaction and cosmetic sequelae in SSM and NSM. No matter how good the symmetry of volume and shape is, the presence or absence of papilla has no choice but to influence satisfaction significantly. If both SSM and NSM are included, both methods should be equally assigned to the cancer patient and the high-risk groups through stratification. In addition, if the stratified extraction method is applied, the overall sample size should be larger than now.

4. Post-mastectomy radiation therapy(PMRT) and chemotherapy are performed only in cancer patients. PMRT is known to increase the rate of implant loss and capsular contracture, and chemotherapy is known to increase the incidence of postoperative infection or seroma. Therefore, the difference in outcome between cancer patients and high-risk patients is inevitably significant.

5. As for the implant type, the polyurethane(PU) implant is a very controversial prosthesis. The PU implant was taken off the worldwide market in 1991 but was later reintroduced. Studies have shown potential toxicity with polyurethane, and our studies have shown that it tends to disintegrate. Because polyurethane implants have the CE mark (the European Union stamp of approval), they can be marketed in the European Union.

The PU implants have not been reintroduced in the US since their discontinuation in 1991. They have not been used in North America, including Canada, these days. Also, they are not welcomed by the Ibero-Latin American Plastic Surgeons(FILACP), and the percentage of use of the implants is less than 5%. (Cir. Plást. Iberolatinoam. 46(2), 2020, 125-140). PU implant is also low in use in Asia and has been taken off from the market in several countries, including South Korea.

The PU implant's association with a rare malignant tumor called BIA-ALCL has also been reported. (Aesthet Surg J 39(S1);2019, S49–S54/ Aesthet Surg J 40(8);2020, 838-846 / Plast Reconstr Surg 143; 2019, 30S-40S.) Therefore, their use is no longer recommended in Australia and New Zealand.

Of course, there might be reflections, but I don't think it's appropriate for the PU implant to be used for safety assessment after breast cancer surgery.

**********

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: 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.

13 Nov 2021

Journal Requirements:

As per the journal’s editorial policy, please include in the Methods section of your paper:

1) your reasons for your delay in registering this study (after enrolment of participants started)

The study began when the ethics committee of the Hospital made the preliminary approval of the study. However, we had to wait for the final approval report from the committee. Additionally, we first registered on the clinicaltrials.gov website.

Finally, we have managed the publication of the protocol in your journal.

We add a phrase in methods.

2) confirmation that all related trials are registered by stating: “The authors confirm that all ongoing and related trials for this drug/intervention are registered”.

We add the phrase in methods.

a) Please clarify the sources of funding (financial or material support) for your study. List the grants or organizations that supported your study, including funding received from your institution.

Our study has no funding. The Breast Unit is located in a Public Hospital and all the materials used in the surgery are financed by the public health.

b) State what role the funders took in the study. If the funders had no role in your study, please state: “The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.”

We do not have funders.

c) If any authors received a salary from any of your funders, please state which authors and which funders.

No authors received any salary from funders.

d) If you did not receive any funding for this study, please state: “The authors received no specific funding for this work.”

We add this phrase at protocol.

5. We note that you have stated that you will provide repository information for your data at acceptance. Should your manuscript be accepted for publication, we will hold it until you provide the relevant accession numbers or DOIs necessary to access your data. If you wish to make changes to your Data Availability statement, please describe these changes in your cover letter and we will update your Data Availability statement to reflect the information you provide.

The authors believe that this means that they will provide payment information once the article is accepted.

6. Please amend your authorship list in your manuscript file to include author Lourdes García Jiménez.

We add the author.

7. Please amend your list of authors on the manuscript to ensure that each author is linked to an affiliation. Authors’ affiliations should reflect the institution where the work was done (if authors moved subsequently, you can also list the new affiliation stating “current affiliation:….” as necessary).

We add the affiliation.

8. Please amend your manuscript to include your abstract after the title page.

We add an abstract.

Reviewers' comments:

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: Partly

Reviewer #2: No

________________________________________

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: Partly

Reviewer #2: Partly

________________________________________

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: No

________________________________________

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

________________________________________

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 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: The PreQ-20 Trial is designed as a prospective cohort (a single arm) study to evaluate the safety (postoperative and oncologic safety, quality of life, and cosmetic outcomes of prepectoral breast reconstruction in patients who will receive skin-sparing mastectomy or nipple-sparing mastectomy. However, I have some concerns regarding the Study protocol and will be grateful if the authors could clarify these.

Abstract

Methods

1) The authors calculated the sample size based on the loss of implant. Therefore, only “loss of implant” is considered a primary endpoint, and the remaining postoperative complications should be considered secondary endpoints.

The reviewer makes an approach that we consider correct. Our main endpoint, from which the sample size has been calculated, is the loss of implants. Therefore, we accept the reviewer's suggestion and put the rest of the complications as secondary endpoints.

2) Please describe the statistical method for calculating the sample size.

We use the sample size calculation formula for proportions. Our population is 250 thousand inhabitants. We assume that we can loss 10% of patient during follow-up. Our study will assume a 5% loss of implants. Therefore, with a 95% confidence level (95% CI), an accuracy of 5%, we need 81 mastectomies.

3) Please clarify that this is a single-arm study.

Yes, our study is a prospective single-arm study, in which all women included in the analysis will undergo a mastectomy with immediate reconstruction with a polyurethane implant in the prepectoral location. We add the phrase "single arm" in the study design section to improve the reader's understanding of our study

Discussion

4) Isn’t “PreQ-20” right instead of “BreastQ-20”?

We agree with the reviewer. We correct in the discussion, changing BreastQ 20 for PreQ 20.

Manuscript

p.3 Table

5) Key inclusion and exclusion criteria: Patients who need a mastectomy for breast cancer or reducing risk: I would recommend changing “mastectomy” to “Skin-sparing mastectomy / Nipple-sparing mastectomy

We accept the recommendation and make the modification in the text.

Introduction

6) The introduction is redundant and needs to be revised more smoothly. In addition, it is necessary to clarify the purpose for which this study should be conducted.

Thanks to the suggestion of the reviewer, we have optimized the introduction. We have summarized the points with incomplete analysis about the conservative mastectomies with immediate prepectoral reconstruction that motivated us to carry out this study. We consider that the literature published to date lacks long-term follow-up to assess the safety of the technique in terms of surgical complications and oncological safety. Furthermore, we do not know the evolution of the reconstruction over time. That is why we carried out this prospective study in which we intend to analyze these aspects with a long-term follow-up.

Methods

7) Eligibility criteria: Women at high risk for breast cancer are included in this study. Is it correct to include benign breast tumors in the exclusion criteria?

We understand the question postured by the reviewer, since cancer patients have different clinical and psychological characteristics from women who underwent a risk-reducing mastectomy. However, as our main objective is to determine the safety of the surgical technique in terms of implant losses, we consider the joint analysis of both patients is adequate. For this section we will analyze whether cancer treatments (chemotherapy and / or radiotherapy) increase the risk of surgical complications and loss of implants. Similarly, for the analysis of residual glandular tissue, the risk reduction and oncological groups can be grouped, since the amount of residual tissue assesses the quality of the mastectomy and the experience of the surgeon regardless of the diagnosis for which the mastectomy was performed. Subsequently, for the assessment of oncological safety and satisfaction of the surgery, an analysis by groups will be carried out, since these variables could be influenced by the criterion by which the mastectomy is performed.

To explain this, and avoid confusion for the reader, we add in the statistical analysis section the phrase: “The analysis of the safety of the surgical technique will be performed on the entire sample. Oncological safety and satisfaction assessment will be analyzed by groups: oncological patients and patients with a risk-reducing mastectomy.”

The reviewer's opinion of benign breast tumors is adequate. Therefore, we decided to remove this from the exclusion criteria.

8) Please clarify the definition of post-operative complications, including loss of implant, postoperative bleeding, skin necrosis, necrosis of the nipple-areola complex, seroma and infection. Please describe how to evaluate these outcomes.

At the reviewer's suggestion, these definitions are included in the outcomes section.

- Implant loss is defined as the need to remove the prosthesis for any cause such as strusion, infection or necrosis.

- Postoperative bleeding is defined as the appearance of any amount of bleeding that modifies the course of the first 7 postoperative days. Among these modifications we find: the need to prolong admission due to blood drainage and the need for reoperation due to bleeding or hematoma. Superficial ecchymoses that do not modify the immediate postoperative period are not included

- Skin necrosis is defined as the appearance of areas of skin without vascularization that condition cell death. Necrosis that appeared during the first 3 months after surgery that conditioned some action by the surgeon are included.

- Within the necrosis of the nipple areola complex, only deep necroses that required some surgical interventions are included.

- Seroma is defined as the accumulation of periprosthetic fluid that required maintaining the drain for more than 10 days or placing a new one (ultrasound-guided or at operating room).

- An infection is defined as the need for antibiotics in the first 30 postoperative days. The antibiotic prophylaxis used (Cefazolin the first 24 hours) is excluded.

9) If there is residual glandular tissue on follow-up breast MRI, is it surgically removed or followed? Please clarify this.

The decision to remove the residual glandular tissue will be made jointly between the patient and the surgeon, considering the amount of residual tissue, the vital status of the patient and the risk of a relapse or new tumor. Women with residual glandular tissue who do not undergo a reoperation will be followed up with an annual ultrasound and / or MRI. We add a sentence with this clarification in the section Participants' timeline.

10) Most of the results are measured at baseline, 12-18 months after surgery, and 5 years after surgery. Is there no follow-up between 12-18 months after surgery and 5 years after surgery? It needs to be clarified on this.

All patients with breast cancer will be followed up in the Breast Unit, both by the surgeon and by the medical oncologist, every 3-6 months. Patients with a risk-reducing mastectomy will be evaluated annually by the surgeon. In these reviews, oncological and cosmetic events will be evaluated. However, the postoperative breast Q will only be delivered one year and 5 years after completing the treatments. We add this clarification in the Participant's timeline section.

11) Please provide the criteria for “drop out” and enrollment/follow-up period.

With the phrase "drop out" we mean that by coordinating the study visits with the visits scheduled in the consultation for the follow-up of their disease, patients do not usually leave the study. We understand that the expression can be confusing, so we modify it by: “…patients do not usually leave the study”.

Discussion

12) The authors said that the strength of this study is to evaluate safety in high risk for cancer/cancer groups separately. Is it enrolling 80 participants per group? If there are 80 people in total, is the ratio of the two groups preset?

The sample size was calculated to determine the incidence of implant loss after a mastectomy with prepectoral reconstruction. For this, we include in the analysis all the mastectomies performed, regardless of the reason for which the mastectomy is performed (cancer or risk reduction). There are parts of the study (satisfaction for example) in which we will carry out the analysis separated by groups. We understand that this is a limitation of our study, since the precision of the results to analyze these data in which the sample size may be small is inadequate. That is why, once we complete the sample size, we intend to continue including patients in the study to later propose the analysis of these variables with greater precision and power. For future studies we will calculate the sample size according to each group.

13) QoL is measured at baseline, 12-18 months, and 60 months after surgery, but this is evaluated at different time points within one PBR group. It is thought that it is more important to compare with RBR or non-reconstruction populations, and it is necessary to discuss this.

As the reviewer comments, the study will carry out the satisfaction questionnaire (Breast Q) before the intervention, one year after finishing the treatments and after 5 years. The preoperative questionnaire allows us to know the baseline characteristics of the patients and thus be able to establish improvements or worsening after the intervention. The purpose of obtaining the questionnaire again at 5 years is to assess the deterioration of reconstruction over time and the impact it has on women's satisfaction. Furthermore, the authors believe that the psychology of women after the treatments or 5 years later is different, and therefore, the assessment of reconstruction may be different.

We agree with the reviewer that comparing patient satisfaction with another type of reconstruction (retropectoral for example) is an interesting study, however it is not the objective of this study, which aims to describe and analyze the characteristics, complications and evolution of the most used reconstruction currently in our unit.

In future studies the authors could perform a comparative analysis of both types of reconstruction. In the discussion of our results, we will make comparisons with other series with different types of reconstruction.

Reviewer #2: 1. The authors introduced a new prospective study protocol (PreQ-20 Trial) for the oncologic safety, QoL, and aesthetic outcomes of prepectoral breast reconstruction. The followings are comments and criticisms.

2. First of all, it is not clear what the purpose of this study is. Is this a study comparing the differences in safety and patient satisfaction between the PBR and the RBR? Or is it a comparison of the results of the PBR between the cancer patients and the high-risk patients? If the purpose of this study is the former, this study should be re-designed with the RBR patient group as a control group. This might be a critical issue of this study. If the main purpose is the latter, the title should be changed as follows; “The PreQ-20 Trial, a prospective cohort study of the oncologic safety, quality of life and cosmetic outcomes of Patients WITH BREAST CANCER AND HIGH RISK undergoing prepectoral breast reconstruction”.

PREQ-20 TRIAL is a prospective study that aims to describe and analyze the safety of the surgical technique, oncological safety and the satisfaction of women. PREQ-20 TRIAL is not a clinical trial or a comparative study. Therefore, we do not have two groups to compare. The main analysis, from which the sample size has been calculated, is to determine the safety of the technique in terms of implant loss. For the oncological safety and satisfaction analysis, we will analyze the risk reduction and oncological groups separately, but the main intention is not to compare these groups.

The authors believe that it is very appropriate to carry out a comparative study with other reconstructive techniques such as the retropectoral, but currently in the breast unit, the retropectoral technique is limited to a few selected cases, so we could not carry out a comparative prospective study. However, as we have commented to the other reviewer, in the future we could carry out a comparative study with other techniques.

3. The authors included both SSM and NSM as study subjects. However, there is inevitably a big difference between patient satisfaction and cosmetic sequelae in SSM and NSM. No matter how good the symmetry of volume and shape is, the presence or absence of papilla has no choice but to influence satisfaction significantly. If both SSM and NSM are included, both methods should be equally assigned to the cancer patient and the high-risk groups through stratification. In addition, if the stratified extraction method is applied, the overall sample size should be larger than now.

Some studies have compared satisfaction between SSM and NSM. This aspect will be analyzed in our study, in order to confirm whether women who preserve the nipple really have greater satisfaction with its reconstruction. Women in whom the nipple has not been preserved are offered to reconstruct it through outpatient surgery. Those in whom the areola has been removed, the tattoo of it is offered.

The reviewer proposes stratification according to nipple preservation. The authors believe that this is not possible. In the first place, because the main objective is to assess the safety of the technique in terms of implant loss. Therefore, satisfaction according to the preservation of the nipple will simply be a variable to be analyzed. On the other hand, the decision to preserve the nipple depends on 2 fundamental aspects that make its stratification difficult. In cancer patients, the nipple can only be preserved in those who her nipple is not invaded by cancer. The other aspect is that the decision on the type of incision (type IV, inframammary fold) will depend on the volume and ptosis of the breast.

Our study will provide data on the satisfaction of those women who preserved the nipple in each group (risk reduction and cancer), but they do not be stratified.

4. Post-mastectomy radiation therapy (PMRT) and chemotherapy are performed only in cancer patients. PMRT is known to increase the rate of implant loss and capsular contracture, and chemotherapy is known to increase the incidence of postoperative infection or seroma. Therefore, the difference in outcome between cancer patients and high-risk patients is inevitably significant.

We agree with the reviewer that some studies had proven that radiation and chemotherapy could increase complications related with implant. However, there are no studies that have confirmed these data with polyurethane implants in the prepectoral position. That is why the authors want to analyze whether these treatments influence post-surgical complications.

5. As for the implant type, the polyurethane(PU) implant is a very controversial prosthesis. The PU implant was taken off the worldwide market in 1991 but was later reintroduced. Studies have shown potential toxicity with polyurethane, and our studies have shown that it tends to disintegrate. Because polyurethane implants have the CE mark (the European Union stamp of approval), they can be marketed in the European Union.

The PU implants have not been reintroduced in the US since their discontinuation in 1991. They have not been used in North America, including Canada, these days. Also, they are not welcomed by the Ibero-Latin American Plastic Surgeons(FILACP), and the percentage of use of the implants is less than 5%. (Cir. Plást. Iberolatinoam. 46(2), 2020, 125-140). PU implant is also low in use in Asia and has been taken off from the market in several countries, including South Korea.

The PU implant's association with a rare malignant tumor called BIA-ALCL has also been reported. (Aesthet Surg J 39(S1);2019, S49–S54/ Aesthet Surg J 40(8);2020, 838-846 / Plast Reconstr Surg 143; 2019, 30S-40S.) Therefore, their use is no longer recommended in Australia and New Zealand.

Of course, there might be reflections, but I don't think it's appropriate for the PU implant to be used for safety assessment after breast cancer surgery.

The reflection made by the reviewer is very interesting. As he says, in the 90s there was a campaign against polyurethane implants and in fact the FDA banned their use. However, this alert was removed as they failed to confirm the association between polyurethane and cancer. In fact, some experimental studies confirmed that the amount of the carcinogenic metabolite generated from the degradation of polyurethane is not capable of producing cancer in humans (Hester TR et al. Plas Reconstr Surg. 1997)

However, one of the main motivations for this study is to confirm the safety of polyurethane, since currently in Spain and a large part of Europe are the most widely used implants for prepectoral reconstruction.

We welcome the reviewer's comment and we will do a long-term, comprehensive follow-up to determine the safety of these implants in our patients.

________________________________________

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: 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.

Submitted filename: Response to Reviewer.docx

Click here for additional data file.

23 Dec 2021

11 Jan 2022

Comments to the Author

Reviewer #1:

The authors faithfully responded to the reviewer's comments and revised the manuscript. However, it is necessary to change the "Breast Q-20 trial" to the "PreQ-20 trial" in the discussion of Abstract.

We appreciate the reviewer's comment. We apologize for the mistake in the abstract discussion, and we correct it.

Reviewer #2:

There are still some points that are difficult to agree with, but there seems to be no problem conducting clinical trials to assess the safety of the prepectoral implant based breast reconstruction as the current protocol.

Thanks for the reviewer's comments. We also appreciate that the reviewer accepts the approach of the protocol.

________________________________________

Submitted filename: Comments to the Author 2.docx

Click here for additional data file.

20 May 2022

The PreQ-20 TRIAL, a prospective cohort study of the oncologic safety, quality of life and cosmetic outcomes of patients undergoing prepectoral breast reconstruction

PONE-D-21-20755R2

Dear Dr. García Novoa,

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,

Yann Benetreau, PhD

Division Editor (staff 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

**********

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

**********

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

**********

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: Yes

Reviewer #2: 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

**********

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: The authors faithfully responded to the reviewer's comments and revised the manuscript. There seems to be no problem conducting clinical trial.

Reviewer #2: No additional comment this time except for the implant issue(polyurethane coated implant which is not widely accepted in the world)

**********

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: No

13 Jun 2022

PONE-D-21-20755R2

The PreQ-20 TRIAL: a prospective cohort study of the oncologic safety, quality of life and cosmetic outcomes of patients undergoing prepectoral breast reconstruction

Dear Dr. García Novoa:

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. Yann Benetreau

Staff Editor

PLOS ONE

Table 1

Schedule for patient assessment in the PreQ-20 study.

	STUDY PERIOD
	Enrolment	Allocation	Post-allocation			Close-out
TIMEPOINT**	-t 1	0	t 1 3 months	t 2 1 year	t 3 5 years	t x
ENROLMENT:
Eligibility screen	X
Informed consent	X
MRI+ Picture + Breast Qpre		X
Allocation/Inclusion		X
INTERVENTIONS:
[Mastectomy and Prepectoral reconstruction]			X
[Annual Control -MRI+ BreastQ post]				X
[Long Term Follow up + BreastQ post]					X
ASSESSMENTS:
[List baseline variables]	X	X
[List outcome variables]			X	X	X	X
[List other data variables]			X	X	X	X

MRI: magnetic resonance image