Background

Breast cancer affects 54,000 women per year in the United Kingdom (UK) [1], and treatment comprises a combination of loco-regional therapies (surgery and radiotherapy) as well as systemic treatments (chemotherapy, endocrine and biological therapies). Selection of systemic therapies is made at an individual patient level, based on tumour biology, clinicopathological variables and patient fitness and preference.

Randomised trials have shown that systemic chemotherapy is equally effective in both the neoadjuvant and adjuvant settings, in terms of overall and distant disease-free survival [2], [3]. However, the prescription of systemic therapies in the neoadjuvant setting may have some specific advantages over their adjuvant use.

Neoadjuvant therapy facilitates in vivo assessment of tumours’ sensitivity to specific treatments. Attaining a pathological complete response (pCR) following neoadjuvant treatment is an excellent prognostic indicator at an individual patient level [4]. Pathological complete response rates vary according to breast cancer subtype, and may be as high as 60% in the HER2 positive subgroup [5], [6], [7]. Where pCR, is not achieved patients at high risk of relapse may be stratified to additional adjuvant treatments to improve their outcome. Neoadjuvant therapy (NST) may also downsize primary cancers in order to facilitate breast-conserving surgery, where a mastectomy would otherwise have been required. This is an attractive option for many patients who wish to preserve their breast. Notably however a recent meta-analysis demonstrated that the modest gains in breast conservation with the use of NST, are associated with higher local recurrence rates, although this reflects historical patient data who received suboptimal local therapy when compared to today’s standards [8].

Neoadjuvant endocrine therapy has also been utilised in oestrogen receptor (ER) positive breast cancer [9]. Indeed, some studies have suggested that in strongly hormone receptor positive disease, it may be as effective as chemotherapy. In current practice neoadjuvant endocrine therapy tends to be reserved for older, less fit patients [10], [11].

There are limited data about the utilization of NST throughout the UK. A recent study in the Netherlands found wide variance in NST use, with rates ranging from 0-97% in different centres [12]. The UK Mastectomy Decisions Audit (MasDA) highlighted inconsistencies in the utilisation of neoadjuvant treatment across the UK [13]. Many patients with large ER positive or HER2 positive tumours, who were potentially candidates for NST and were likely to benefit most from downstaging, proceeded directly to mastectomy without being offered NST.

Where NST takes place, increasing pCR rates have not been matched by increasing rates of breast conservation [14], [15]. One issue is a lack of consensus in surgical approach to excising the tumour footprint in the breast and axilla, and indeed, whether or not surgery is required at all following apparent complete response. This is an area of ongoing research [16]. Furthermore, there is variation in surgical practice with respect to the timing of SLNB in relation to neoadjuvant therapy, with some centres performing pre-treatment SLNB, and others tailoring axillary treatment to the post-neoadjuvant clinical and radiological picture [17]. There is also substantial variation in methods for reporting response to NST, both in terms of radiological monitoring of response during treatment and assessing clinical response [18]. Finally, the lack of consistency in reporting of pathological treatment response makes the interpretation of clinical trial outcomes and the planning of further treatment or future research difficult given much variability [19].

Therefore, there appears to be considerable variation in the utilization of NST across the UK. There is a need to explore current UK practice through a large-scale, multicentre prospective cohort study, and to use the data generated to define best practice.

Although there are challenges in undertaking such a large-scale, prospective, multicentre cohort study, the trainee research collaborative model has emerged as both a time- and cost-efficient method for delivering high-quality prospective audit and research [20], [21]. These have a proven track record in prospective cohort studies [22], [23], [24], and more recently, this model has been applied successfully in the field of breast surgery through the iBRA and MasDA studies [13], [25], [26], [27]. The NeST (Neoadjuvant Systemic Therapy in breast cancer) study aims to work with the Northern Ireland Surgical Research Collaborative, the Mammary Fold Academic and Research Collaborative and existing networks of enthusiastic breast surgery trainees and MDT consultants to deliver a robust assessment of current practice and a high-quality prospective audit of practice and outcomes of NST across the UK.

Methods and analysis

Discussion

Use of NST in breast cancer clearly has potential advantages for patients, allowing an increase in the use of breast conserving surgery, and giving accurate information regarding tumour response to treatment. This approach has recently been the subject of some controversy, with some commentators suggesting that the use of neoadjuvant therapy be reconsidered [34].

There remains lack of consensus around optimal patient selection for NST, and around the monitoring and reporting of treatment response. The NeST Study is therefore important in improving our understanding of current patterns of care in this situation. This study will generate much needed novel data, concerning rates of access to and utility of NST in breast cancer, facilitate the design of appropriate randomised controlled trials and may inform best practice, allowing the development of appropriate national guidelines.

In addition, the study will strengthen the existing research collaborative network in breast surgery, created through the iBRA study, and establish new collaborative networks in medical and clinical oncology, radiology and pathology. This will allow the development of multidisciplinary research networks to support future collaborative projects in breast cancer.

The potential challenges for this project warrant consideration. The proposed datasets are complex and there is potential for incomplete data. In order to minimise this, the datasets have been piloted prior to study initiation to ensure they are not cumbersome and to streamline the flow through the online data capture sheets. This also allows the removal of any redundant or ambiguous questions. In addition, REDCap allows the use of logic to ensure that only the appropriate fields relevant to the procedure or indication are displayed during data capture.

There is the possibility that participation will be biased towards the most motivated centres, and that this may not provide a truly representative picture of practice nationwide. To address this, we would seek in future to combine NeST data with additional information from linkage to routinely collected NHS national datasets such as the Systemic Anti-Cancer Therapy Dataset (www.chemodataset.nhs.uk) to give a wider picture of UK practice. Furthermore, the NeST Study does not plan to capture information on all cancers diagnosed in participating units during the time frame of the study, meaning that absolute rates of NST usage cannot be calculated. It is accepted that this is a limitation of this study, but determining rates of usage of NST is not the primary aim of NeST.

Finally, although the project will allow the collection of valuable data around treatment access and selection, surgical decision making and short-term outcomes, it will not provide any information regarding the long-term outcomes of NST in these patients. If long-term data is required, proportional ethical approval will be sought centrally by the NeST team to facilitate the central collection of the locally maintained spreadsheets linking study ID to NHS number from participating centres. Only centres with appropriate ethical approval will be able to contribute data at this stage.

Ethics and dissemination

The proposed study will not affect clinical care. Research ethics approval is not required and has been confirmed by the Health Research Authority online decision tool (http://www.hra-decisiontools.org.uk/research/). A Trainee Lead will be identified at each participating unit, who will in turn identify a named supervising consultant to act as the principal investigator for registration purposes. The study lead, in consultation with the principal investigator, will be required to register the audit and obtain local audit approvals for study participation prior to commencing patient recruitment. A copy of local approval will be forwarded to the NeST study team. Patient consent is not required, as no patient identifiable data are being recorded and there is no risk to patients.

If long-term data are required, proportional ethical approval will be sought centrally by the NeST team to facilitate the central collection of the locally maintained spreadsheets linking study ID to NHS number from participating centres. Only centres with appropriate ethical approval will be able to contribute data at this stage.

This protocol will be disseminated through the Mammary Fold Academic Research Collaborative (MFAC), the Reconstructive Surgery Trials Network, the Association of Breast Surgery, the British Association of Plastic, Reconstructive and Aesthetic Surgeons and others. Participating units will have access to their own data and information from individual units will be fed back with a comparison to the national data. National results will be fed back to the appropriate professional associations. Collective results will be analysed and the results presented at relevant scientific meetings and published in appropriate peer-reviewed journals. Results will also be made available to relevant patient advocacy groups such as Independent Cancer Patients’ Voice. Thus, results will be available to aid in the decision-making for women considering NST.

Research registration unique identifying number (UIN)

• 1.  Name of the registry: ISRCTN
• 2.  Unique Identifying number or registration ID: ISRCTN11160072
• 3.  Hyperlink to the registration (must be publicly accessible): https://www.isrctn.com/ISRCTN11160072?q=&filters=conditionCategory:Cancer&sort=&offset=2&totalResults=2133&page=1&pageSize=10&searchType=basic-search

Guarantor

The corresponding author, Stuart McIntosh, is the guarantor for this study.

Funding

This work was funded by a grant from the Association of Breast Surgery of Great Britain and Ireland.

Ethical statement

Ethical approval was not required for this study, as per the Health Regulatory Authority online decision tool. Institutional approval for participation will be required from each participating hospital.

Author contribution

GI wrote the first draft of the manuscript.

GI, CEC, EC, TIC, RVD, MG, CH SI, COB, ROC, CP, AS, NS, JS and IW all contributed to study design, including design of the data collection instruments, and to the writing and editing of the protocol. FB contributed to study design, methodology and the statistical analysis plan. GI, ROC, SP and IW undertook piloting of the data collection instruments. SMcI and SP were responsible for the conception of the project, and contributed to the design of the project, and to the writing and editing of the protocol.

All authors have read and approved the final version of the manuscript.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.