This study gives an overview of the stated practice in the use of neoadjuvant systemic therapy for breast cancer in the UK, confirming that wide variation in such practice exists. All 39 participating centres in the first phase of the NeST Study offer NACT, although it appears that a relatively small proportion of patients (median 10%, range 5-60%) are recommended this treatment strategy. There is wide variation reported in the frequency with which NACT is recommended in UK MDTs, although we showed no difference in stated rates of use between teaching hospitals and DGHs, albeit in a relatively small number of hospitals using self-reported data. When considering the findings of studies such as MasDA, and considering the potential benefits for patients of using NST (both in terms of surgical downstaging and the utility of treatment response as a prognostic biomarker) , it is likely that there is under-utilisation of this approach across the UK (15). Furthermore, the variation in usage of NACT between MDTs appears too wide to be accounted for by variation in patient populations between units, although it is known that the age structure of the UK population varies by local area, and that use of both NACT and NET may consequently vary with age (21). Individual patient-level data for patients being treated with NeST was not collected in the National Practice Questionnaire; however, the prospective audit phase of NeST will seek to explore this aspect of neoadjuvant therapy usage in more detail (18).
It remains clear that surgical downstaging is a primary indication for the use of NACT in many MDTs. However, it is equally clear that other indications for recommending NACT are emerging, in line with disease biology. Response to treatment has been shown to be a valuable predictor of long-term outcome following neoadjuvant chemotherapy (22). However, it is also increasingly clear that pathological response to treatment can be utilised as a functional biomarker, to guide the use of subsequent adjuvant therapies where patients have an incomplete response to treatment, particularly in the context of certain disease subtypes, such as HER2+ or triple negative disease (5, 6).
Around two thirds of MDTs in this survey are using NET. However, this approach tends to be offered only to a small proportion of patients (a median of 4% in this study), and appears to be primarily used in the UK where disease is considered to be locally advanced or inoperable, to facilitate surgical treatment, with a relatively small proportion of centres employing this approach to downstage disease to reduce the extent of surgery. Similarly low usage of NET was seen in the MasDA study, although many post-menopausal women with ER-positive breast cancer were recommended mastectomy due to a large tumour to breast size ratio, and could potentially have benefitted from NET (15). A 2016 metanalysis suggests that NET with aromatase inhibitors is comparable to NACT in terms of radiological and clinical response rates, with similar rates of breast conserving surgery, (11). In this meta-analysis it is noted that 90% of published studies of NET include post-menopausal women, and that there is little data on the use of NET in pre-menopausal women with hormone receptor positive breast cancer. Clearly the role and benefits of NET in such pre-menopausal women is yet to be established, and the prospective audit phase of NET will determine the age distribution and menopausal status of women in the UK being treatment with NET (18). However, this data, taken together with the MasDA findings show that there remains a clear reluctance to utilise this approach routinely in clinical practice within the UK despite the low pCR reported with NACT in this group. The reasons for this remain unclear, but may relate to a perceived lack of evidence regarding the long-term oncological outcomes of this approach. While genomic assays may be of value here and increase clinician confidence in decision-making, there remains a need for further high-quality clinical trial data to guide the management of this patient group.
It is also clear from this data that there is a wide variation in radiological monitoring and pathological reporting during and after neoadjuvant therapy, with no consensus on the optimal radiological method of monitoring response. With respect to pathological reporting, several reporting systems are available, and current UK pathology guidelines do not recommend a particular system (23). Although the Residual Cancer Burden system is increasingly regarded as the gold standard for reporting pathological response following neoadjuvant chemotherapy and is the system recommended for neoadjuvant trials, only around one quarter of units are using this reporting system routinely, with around 20% of units issuing descriptive reports only (24).
Although surgical downstaging was noted to be a key indication for recommending NAC in this study, around 25% of centres stated that following treatment, the surgical goal remained removal of the original tumour footprint, regardless of response. This is in contrast to the St Gallen consensus guidance, which recommended that excision of the initial tumour bed was not required (25). It seems likely, therefore, that the opportunity to de-escalate breast surgery following NACT is not being fully utilised in some patients.
Management of the axilla following NACT has been a controversial area, although subsequent to this survey, UK multidisciplinary recommendations have been produced to guide treatment (26). At the time of this study, the majority of patients diagnosed with clinically node negative breast cancer receiving NACT were undergoing post-treatment SLNB. However, in patients presenting with node-positive disease, the majority of centres were performing axillary node clearance, with only a small number of centres carrying out axillary reassessment and response-guided treatment of the axilla. It appears likely, therefore, that a proportion of patients may not have the opportunity for de-escalation of axillary surgery following NACT, although the impact of the published guidance remains to be seen.
Clearly, there are some limitations to the data provided by this questionnaire. Only 39 of 144 breast units (27%) in the UK participated in the study, and consequently there may be selection bias as these units may not be representative of UK practice more broadly. Although this data has been supplied by all members of the MDT and therefore should represent an accurate reflection of multidisciplinary perspectives, we accept that this study is based on reported rather than actual practice of MDTs. We note that the self-reported range of NACT use is from 5-60%, with the upper limit appearing surpriginly high. While this may reflect genuine variation in NACT use (and that some centres, including specialist tertiary referral centres are high users of this treatment approach), it is possible that self-reported data may not be entirely reflective of actual patterns of care. Consequently the data may be reflective of perceived rather than actual practice, as studies (albeit in other specialties) have demonstrated there to be a difference between these (27). Furthermore, units were not specifically asked about compliance with national and international guidelines regarding the use of NeST such as UK NICE guidance or the St Gallen guidelines (7, 8). However, the prospective audit phase of the NeST study will provide valuable insight into decision-making on an individual patient basis across UK MDTs(18).
In spite of these limitations, to our knowledge this is the first UK study to broadly examine real-world stated practice in terms of the use of neoadjuvant systemic therapy. It is clear that there is wide variety in perceived indications for and use of neoadjuvant systemic therapy in the UK, as well as a lack of consensus on the optimal methods for monitoring and reporting response and on the surgical management of the primary tumour following systemic therapy. Although NICE guidance outlines potential indications of the use of NST in breast cancer, this study indicates a clear need for both further research and the development of multidisciplinary guidance with respect to monitoring of response, pathological reporting and surgical decision-making, to ensure optimal outcomes for breast cancer patients treated with neoadjuvant therapies. We await the prospective phase of the NeST study, which will allow the corroboration of these results with the real-world use of neoadjuvant systemic therapy for breast cancer in the UK (18).