Early and locally advanced breast cancer: diagnosis and management

Search strategy

We searched for new evidence related to the whole of both guidelines; however the following areas were not considered within this surveillance review as they were the subject of recent exceptional surveillance reviews for NICE's guideline on early and locally advanced breast cancer:

We found 5,706 studies in a search for systematic review evidence published between 1 January 2020 and 25 August 2022 and Cochrane reviews published between 1 January 2015 and 26 June 2022.

Eighty-one systematic reviews were included for NICE's guideline on early and locally advanced breast cancer and 29 systematic reviews for NICE's guideline on advanced breast cancer.

We also included:

From all sources, we considered 131 studies to be relevant to the guidelines.

See appendix A for details of all evidence considered.

Selecting relevant studies

Studies were considered for inclusion using criteria defined by the guideline review protocols contained in the evidence reviews for NICE's guideline on early and locally advanced breast cancer (see evidence reviews – July 2018) and the evidence review – February 2009 for 2009 recommendations not updated in 2018. For NICE's guideline on advanced breast cancer, see full guideline, evidence review.

In certain circumstances evidence was included if it answered a review question but differed slightly from inclusion criteria (for example, a different comparator was used than originally included). Where this was done, a full explanation has been given for why it was included (see appendix A).

Some 2009 recommendations within NICE's guideline on advanced breast cancer were not clearly linked to a review question, so evidence was considered relevant if it addressed a recommendation, even when there was no linked review question (see appendix A for explanations).

Topic experts

We considered the views of topic experts who had been members of the committees that developed either or both of NICE's guidelines on breast cancer and topic experts who were recruited to the NICE Centre for Guidelines Expert Advisers Panel to represent their specialty. For this surveillance review, topic experts completed a questionnaire about developments in evidence, policy, practice, and services related to the guidelines.

We received 6 questionnaire responses from topic experts: 2 consultant clinical oncologists, a consultant histopathologist, a specialist breast cancer pharmacist, an advanced nurse practitioner and a GP principle and associate medical director with special interest in primary care oncology and palliative care.

Patient groups

Six patient groups were contacted for their views on developments in evidence, policy, practice, and services related to the guidelines and the need to update recommendations. We received a response from 1 patient group. The patient group highlighted a number of relevant NICE technology appraisals and other NICE guidance that is of direct relevance to breast cancer. It is planned that this guidance be presented alongside the relevant recommendations from both NICE guidelines on breast cancer as part of NICE's digital living guidelines ambition. See appendix A for all other feedback and its impact.

External reference group for breast cancer

We received feedback on the implementation of recommendations within the NICE guidelines on breast cancer from an external reference group who were established to advise on the key sources of, and support the interpretation, of system intelligence affecting implementation in the context of digital living guidelines. Membership includes policy, clinical, quality improvement and patient representatives alongside the chair of the guideline development group and NICE clinical adviser.

System intelligence

This describes feedback received from NICE internal teams. We received feedback from a NICE clinical expert, publishing team, field team, and medicines prescribing team at various stages of the surveillance process.

Other sources of information

We considered all other external correspondence received since the guideline was published.

Surveillance proposal, areas for update

The 20 members of the breast cancer standing committee were asked to provide feedback on the proposed surveillance decisions which were provided as a draft report and the details provided in appendix A. This was done by an electronic survey, with findings discussed at a breast cancer committee meeting on 25 November 2022. Seventeen responses to the survey were received, these were from 9 lay members, 3 breast surgeons, 2 radiologists, 1 therapeutic radiographer, 1 physiotherapist and 1 clinical oncologist.

There was agreement for all areas proposed for update, with only 1 person expressing disagreement with the proposal to update recommendations on the prevention and management of lymphoedema. They disagreed with the update proposal based on their experience that treatments are not available, and that there are difficulties with accessing lymphoedema specialists. They thought that people need to learn how to manage after node removal and have quicker access to clinics. They also said that GPs need more training on lymphoedema prevention and management. Implementation issues with current recommendations are not considered a reason for not undertaking an update on areas that may improve outcomes.

Additional questions

The breast cancer committee were also asked some additional questions on areas proposed for update to gather detailed information specific to the proposed updates and to inform potential future work. This information will be shared with the NICE breast cancer digital living guideline team for consideration.

The breast cancer committee were asked whether the current evidence review question for ovarian function suppression: what is the effectiveness of ovarian suppression in addition to endocrine therapy in premenopausal women with oestrogen-positive breast cancer? and protocol (see evidence review D: endocrine therapy for invasive disease) should be amended to include progesterone receptor-positive breast cancer that is considered oestrogen receptor-negative (this would also involve considering the threshold score to define a cancer as oestrogen receptor-positive). This was asked in response to topic expert feedback that data from the Suppression of ovarian function trial suggested a broader population of premenopausal patients benefit from ovarian suppression, for example, not just those who have oestrogen‑positive invasive breast cancer as the trial included oestrogen receptor and/or progesterone receptor positive-breast cancer. It is known that there are a small group of people with oestrogen receptor-negative and progesterone receptor positive-breast cancer, and benefits from endocrine therapies are less certain for this population.

Five committee members said they were not able to provide feedback, but 9 did agree with amending the review question and protocol to include evidence on the effectiveness of ovarian suppression in addition to endocrine therapy in premenopausal women with progesterone receptor-positive breast cancer that is considered oestrogen receptor-negative. Feedback highlighted that patients often ask about the implications of progesterone receptor-positive breast cancer, but that there is only limited information that can be provided to them. Other committee members agreed in principle if oncologists agreed with the proposal. The clinical oncologist agreed with including evidence on progesterone receptor status in an update. Of the 3 who disagreed, 1 questioned whether there would be sufficient evidence on progesterone receptor-positive breast cancer that is considered oestrogen receptor-negative; and another said that progesterone receptor status has no impact on the efficacy of hormonal therapy. In support of their statement, they cited Early Breast Cancer Trialists' Collaborative Group 2011, which reported that 5 years of adjuvant tamoxifen safely reduced the 15-year risk of breast cancer recurrence and death, with oestrogen receptor status the only recorded factor importantly predictive of the proportional reductions; and that in oestrogen receptor-positive disease, relative risk was approximately independent of progesterone receptor status (or level).

The breast cancer committee were also asked whether the evidence review question for ovarian function suppression and protocol should be amended to include aromatase inhibitors as an intervention and comparator (for example, as well as endocrine therapy without ovarian suppression, include endocrine therapy with an alternative ovarian suppression as comparator). This was asked because studies included in evidence review D only compared ovarian function suppression plus endocrine therapy with endocrine therapy alone (and did not include evidence on aromatase inhibitors); whereas we identified evidence comparing the efficacy of ovarian function suppression with different endocrine therapy regimes against one another (for example, ovarian function suppression plus an aromatase inhibitor compared with ovarian function suppression plus tamoxifen). Results of the latter comparisons indicated that ovarian function suppression with an aromatase inhibitor may result in better outcomes for local and distant disease recurrence when compared with ovarian function suppression plus tamoxifen in premenopausal women with hormone receptor-positive breast cancer.

Five committee members said they were not able to provide feedback, 11 agreed with amending the protocol and there was only 1 disagreement. The committee member who disagreed said that aromatase inhibitors should be included, but not as a comparator and said that most women get ovarian suppression and aromatase inhibitor, not tamoxifen. As recommendations 1.7.4 and 1.7.5 in NICE's guideline on early and locally advanced breast cancer do not explicitly name aromatase inhibitor as an option, it is considered important to include evidence on ovarian function suppression plus an aromatase inhibitor, and consider its relative efficacy compared with ovarian function suppression plus tamoxifen so that recommendations can be made about both options.

The breast cancer committee were also asked whether the update on platinum-based neoadjuvant chemotherapy regimens for people with triple‑negative early and locally advanced breast cancer should include how HRD may impact the efficacy of platinum-based neoadjuvant chemotherapy. Three committee members said they were not able to provide feedback on this question, 12 agreed based on evidence provided, but highlighted this was an area requiring specialist input; and 2 disagreed. One committee member disagreed on the basis that they were unsure whether there is currently sufficient evidence to support conclusions in this area; and another said that HRD should only be considered if there is a plan/clinical capacity/consensus and quality assurance to determine and report HRD status in routine clinical histopathology labs - that histopathology input and advice is required to see if it is feasible and possible to test for HRD in the UK setting.

The breast cancer committee were also asked about potentially updating recommendations 1.8.1 to 1.8.3 in NICE's guideline on early and locally advanced breast cancer on adjuvant chemotherapy for invasive breast cancer in order to provide recommendations on:

Half of the committee did not feel able to respond to these questions.

In response to needing recommendations on dose-dense anthracycline and taxane-based chemotherapy, 1 committee member said this was not needed as they considered it to be accommodated by the existing recommendations. Two of 7 who responded that recommendations were needed, said that dose-dense anthracycline and taxane-based chemotherapy is increasingly being offered to patients, so it would be good to have clarification on this within recommendations, while others were more circumspect and felt that oncology input on the decision would be needed – clinical oncologist feedback was that a medical oncologist or clinical oncologist whose practice includes systemic treatment is needed to provide feedback on this.

Three committee members thought it was not necessary to have recommendations on 5-fluorouracil as it is not used, which was also said by some of the 7 who agreed with adding information, but they thought it would be useful to provide clarity in order to reduce variation in practice.

With regards to de-escalation of chemotherapy in lower risk disease, 8 committee members thought this should be an area for update as it is important to consider de-escalation where evidence suggests it is safe to do so, as this can avoid unnecessary additional toxicity. One committee member did not think recommendations were needed as individual clinicians can choose to alter traditional regimens if necessary, depending on patient comorbidities and other relevant factors.

The NICE breast cancer digital living guideline team should consider the above committee feedback as part of the continual update process for breast cancer guidance.

Surveillance proposal, withdrawing recommendations

We also proposed withdrawing recommendation 1.13.4 in NICE's guideline on early and locally advanced breast cancer on clinical follow-up for people with early and locally advanced breast cancer as there is an expectation that since 2019 all trusts have a follow-up pathway after breast cancer treatment that suits the needs of patients, and ensures they can get rapid access to clinical support where they are worried that their cancer may have recurred (see NHS long term plan). And in NICE's strategic pillar 2 to develop dynamic, living guideline recommendations, the focus is on topic areas that represent key priorities and where NICE is uniquely and best placed to use our skills to add value, ensuring we maintain the right portfolio with the greatest impact on health and on reducing health inequalities (see the NICE strategy 2021 to 2026). As part of the work to meet the strategy ambitions, we are considering standing down recommendations that are service model and good practice recommendations that duplicate and/or overlap with other national policy or guidance. It was therefore proposed that the recommendation on clinical follow-up be withdrawn.

All 9 lay members and 2 other committee members disagreed with the proposal to withdraw the recommendation on clinical follow-up. Some said that they strongly disagreed, with reasons being that the recommendation provides useful information for patients as it identifies what follow-up to expect; and means that they can challenge services if they are not receiving the expected follow-up care. Concerns were also raised that recommended practice is not being followed, with some saying that there is geographical variation in the follow-up patients receive. There were also concerns that if NICE completely removes mention of clinical follow-up that this may be interpreted by users as meaning this is not considered important. Some who disagreed with withdrawing the recommendation, and others who agreed with the proposal, thought that if the recommendation is withdrawn, that there should remain some mention of clinical follow-up, which could include cross-referencing to relevant guidance such as the NHS long term plan. Of the 5 committee members who agreed with withdrawing recommendation 1.13.4 on clinical follow-up, 2 said that all centres provide follow-up and 2 said that they agreed with the rationale for withdrawing the recommendation.

Additional areas for update

The committee members were also asked whether they thought there were any other areas relevant to early, locally advanced and advanced breast cancer that should be updated now or in the future.

Several committee members raised concerns about the accuracy of mammography in detecting breast cancer in dense breasts. While screening options after a negative mammography in women with dense breasts was raised as an area for update, the content of the national breast cancer screening programme is not within NICE's remit as this is the responsibility of the Breast Cancer UK National Screening Committee. Imaging during preoperative assessment and follow-up is within the scope of the breast cancer guidelines, and recommendation 1.1.2 in NICE's guideline on early and locally advanced breast cancer does say to offer MRI of the breast to people with invasive breast cancer, if breast density precludes accurate mammographic assessment. However, the recommendations on follow-up imaging do not mention imaging options for dense breasts. We have proposed that there is a cross-reference to recommendations on surveillance and strategies for early detection of breast cancer in NICE's guideline on familial breast cancer, which do highlight the possibility that mammography might miss a cancer in dense breasts, and that having dense breasts will increase the likelihood of further investigations, with the option of having an MRI (see appendix A). However, these recommendations are only for people with or without a personal history of breast cancer who also have a family history of breast, ovarian or another related (prostate or pancreatic) cancer. There is therefore a potential gap in recommendations on imaging follow-up for those with early or locally advanced breast cancer who have dense breasts and no family history of cancer. It is also important to note that younger women naturally have more dense breast tissue (see equalities). The breast cancer committee said that breast cancer patients with dense breasts do express concerns about only having mammography follow-up; and decisions around whether or not MRI is offered come down to clinician choice, with no consensus on when alternative imaging techniques to mammography should be offered to those with dense breasts. The committee also highlighted that other countries such as America and Germany recommend MRI follow-up in people with dense breasts and a history of breast cancer. We did not find any evidence that supports the use of MRI for dense breasts (see appendix A), and it is our understanding that while it is recognised that mammography is less accurate for detecting cancer within dense compared with normal breast tissue, that there is not currently sufficient evidence on the diagnostic accuracy of alternative imaging procedures in this population. Given the uncertainties in imaging follow-up for people with a history of breast cancer and dense breasts, and patient concerns about receiving appropriate follow-up, it is recommended that this is an area for which evidence is monitored and considered for a future update.

Some committee members also said that screening for lobular carcinoma in situ (LCIS) should be included in the breast cancer guidelines, however the content of the NHS breast screening (BSP) programme is not within NICE's remit; and LCIS is not cancer, even though it does indicate an increased risk of developing breast cancer (LCIS was excluded from NICE's guideline on early and locally advanced breast cancer).

Feedback was also received that invasive lobular breast cancer should have separate recommendations on preoperative assessment, follow-up imaging and treatment options. Invasive lobular breast cancer is included within NICE's guideline on early and locally advanced breast cancer, and if relevant evidence identified, separate recommendations would be made. Recommendation 1.1.2 in NICE's guideline on early and locally advanced breast cancer does say to offer MRI of the breast to people with invasive breast cancer, to assess the tumour size if breast‑conserving surgery is being considered for invasive lobular cancer but invasive lobular breast cancer is not mentioned in recommendations on follow-up. During the surveillance review, no systematic review evidence was identified specific to invasive lobular breast cancer.

The breast cancer committee also raised concerns around geographical differences in the provision of immediate breast reconstruction and the applicability of recommendations to male breast cancer patients. These are discussed in the equalities section.

Feedback was also received on lack of information (due to evidence gaps) on appropriate surgical and treatment options for people with specific genetic profiles. The issue of how care can keep up with the rapidly evolving field of breast cancer genetics/genomics was identified as a gap and future area for update. Other areas where there are gaps in recommendations: imaging modalities such as use of contrast mammography instead of MRI; radiotherapy techniques such as irradiating the internal mammary chain for high-risk disease; liquid biopsy; prehabilitation (a programme of support and advice to support getting ready for cancer treatment before it starts); and prevention and management of breast and chest wall lymphoedema in breast cancer patients. All feedback will be shared with the NICE breast cancer digital living guideline team for consideration.