Early and locally advanced breast cancer: diagnosis and management

Genetic testing for people with early and locally advanced breast cancer

Recommendation 1.1.4 in NICE's guideline on early and locally advanced breast cancer, recommends offering genetic testing for BRCA1 and BRCA2 mutations to women under 50 years with triple‑negative breast cancer, including those with no family history of breast or ovarian cancer. This was based on recommendations on genetic testing in NICE's guideline on familial breast cancer. As there was no evidence review question on genetic testing for NICE's guideline on early and locally advanced breast cancer, evidence on this was not searched for as part of this surveillance review; however, we received feedback from a patient group and topic expert that the recommendation differs from newer guidance from NHS England in 2022 on genetic testing (see NHS England's National genomic test directory). We also identified a 2022 NIHR evidence alert on genetic risk scores for breast cancer not being accurate in some ethnic groups, which found that while genetic tests accurately predict the risk of breast cancer in White Europeans, these risk scores are inaccurate and exaggerate risk in Black, Asian, mixed-race and Ashkenazi Jewish women, so need adapting for use in women from these groups. As recommendation 1.1.4 on genetic testing is out-of-date with the latest guidance from NHS England, an update is required to consider whether the recommendation should be changed. Consideration should also be given to the finding that established genetic risk scores may be overestimating the breast cancer risk of women from Black, Asian, mixed-race and Ashkenazi Jewish backgrounds.

Further surgery after breast-conserving surgery based on tissue margins, invasive cancer (early and locally advanced breast cancer)

Evidence from 1 systematic review indicates that there is a benefit in terms of reducing local and distant recurrence from having further surgery where invasive cancer is present within 2 mm of the radial margins (greater than 0 mm and less than 2 mm). This may change the wording of recommendation 1.3.2 in NICE's guideline on early and locally advanced breast cancer, which says to discuss the benefits and risks of further surgery (re‑excision or mastectomy) to minimise the risk of local recurrence, but does not provide specific information on the benefits of further surgery. The current wording of recommendation 1.3.2 was based on no evidence of a clear and consistent benefit of having tumour-free tissue margins between >0 mm and 2 mm for invasive disease. Because there was not enough evidence to clearly define an optimum margin width between 0 mm and 2 mm to minimise local recurrence rates and minimise further surgery, the committee agreed that this was an important topic for further research, and made a recommendation for research on the optimum tumour-free margin width after surgery to the breast. There appears to now be evidence that could address this recommendation for research.

Two related ongoing trials are being tracked by NICE:

Neoadjuvant chemotherapy for people with HER2‑positive invasive breast cancer and triple‑negative invasive breast cancer (early and locally advanced breast cancer)

New evidence from 2 systematic reviews that undertook network meta-analyses comparing neoadjuvant treatment regimens for HER2-positive early and locally advanced breast cancer found that as well as NICE's technology appraisal guidance on pertuzumab for the neoadjuvant treatment of HER2-positive breast cancer, (see recommendation 1.11.2 in NICE's guideline on early and locally advanced breast cancer), neoadjuvant regimes containing trastuzumab emtansine or carboplatin (a platinum-based chemotherapy drug) are also effective in achieving a pathological complete response in patients with HER2-positive breast cancer. As there are no existing NICE technology appraisals for trastuzumab emtansine or carboplatin-containing regimens as a neoadjuvant treatment in HER2-positive early and locally advanced breast cancer, we are proposing that evidence on this should be considered in an update.

New evidence from 4 systematic reviews that assessed the efficacy and safety of immune checkpoint inhibitors plus neoadjuvant chemotherapy compared with neoadjuvant chemotherapy in people with early-stage triple-negative breast cancer, found that compared with neoadjuvant chemotherapy alone, a combination of immune checkpoint inhibitors plus neoadjuvant chemotherapy resulted in a significant improvement in pathological complete response. However, the randomised control trial (RCT) evidence within the systematic reviews does not meet the inclusion criteria for the evidence review question on the effectiveness of neoadjuvant chemotherapy on which recommendations in NICE's guideline on early and locally advanced breast cancer were made (see evidence review J: neoadjuvant treatment). To be included an RCT had to assess neoadjuvant chemotherapy ± biological therapy compared with no neoadjuvant chemotherapy ± biological therapy, whereas all the evidence in the above systematic reviews had neoadjuvant chemotherapy as the comparator. However as neoadjuvant chemotherapy is now accepted as standard treatment, we think that neoadjuvant chemotherapy should be included as a comparator when assessing evidence on the effectiveness of the addition of immune checkpoint inhibitors to neoadjuvant chemotherapy on outcomes in people with early-stage triple-negative breast cancer.

One ongoing study is being tracked by NICE:

Platinum-based neoadjuvant chemotherapy regimens for people with triple‑negative invasive early and locally advanced breast cancer

New evidence from 2 systematic reviews is consistent with the content of recommendation 1.11.4 in NICE's guideline on early and locally advanced breast cancer to consider a neoadjuvant chemotherapy regimen that contains both a platinum and an anthracycline for people with triple‑negative invasive breast cancer as it provides further evidence that, compared with anthracycline ± taxanes-based neoadjuvant chemotherapy, platinum‑containing neoadjuvant chemotherapy regimens improve pathological complete response rate in people with triple-negative breast cancer. As this represents further supportive evidence, the committee may want to assess whether the strength of the recommendation wording should change from a consider to offer recommendation (see section 9.2 wording the recommendations in developing NICE guidelines: the manual for further information on wording reflecting the strength of evidence).

The evidence from 2 systematic reviews also indicates that the addition of platinum to anthracycline ± taxanes-based neoadjuvant chemotherapy is associated with a significant increase in disease-free survival, and possibly overall survival, at least for carboplatin-based neoadjuvant chemotherapy, in people with invasive triple-negative cancer. Recommendation 1.11.5 in NICE's guideline on early and locally advanced breast cancer says to discuss the benefits and risks (listed in table 6) of adding a platinum to an anthracycline‑containing neoadjuvant chemotherapy regimen. Table 6 says that there is no increase in overall survival with platinum‑based chemotherapy, however new evidence indicates that there may be a survival benefit. It is therefore proposed that evidence on survival outcomes is considered in an update.

There are currently no recommendations in NICE's guideline on early and locally advanced breast cancer on neoadjuvant chemotherapy regimens for people with the BRCA germ line mutation subgroup as no evidence was available. We identified a systematic review which indicates that there is available RCT data for this subgroup. An update should therefore also include a check for new evidence on the relationship between BRCA status in people with triple-negative breast cancer and pathological complete response rates with platinum-based neoadjuvant chemotherapy compared with neoadjuvant chemotherapy alone.

Evidence on homologous recombination deficiency (HRD) has not been reported in this surveillance review as this was not considered within evidence review J. For information, homologous recombination 'is a multistep DNA repair process involving several mediators, most notably BRCA1 and BRCA2. Alteration in HR genes is prevalent among many cancer types (13% to 17%), especially breast, ovarian, and pancreatic cancers. BRCA1 and BRCA2 are the most altered HR genes, with germline pathogenic variants (PVs) found in 2% to 3% of unselected tumours in several pan-cancer analyses' (Toh and Ngeow 2021). We are aware, from our literature search, of a small body of evidence which indicates that HRD status may play a role in mediating the effectiveness of platinum-based neoadjuvant chemotherapy in people with triple-negative cancer (Chai et al. 2022 and Zhang et al. 2022). As part of the evidence review development process for the update on platinum-based neoadjuvant chemotherapy regimens for people with triple‑negative invasive early and locally advanced breast cancer, whether a review of the evidence on whether HRD impact the efficacy of platinum-based neoadjuvant chemotherapy is currently appropriate should be considered (see breast cancer committee feedback).

A Cochrane review on platinum-based chemotherapy for early-stage triple-negative breast cancer is expected in 2022/2023; and 6 ongoing studies are being tracked by NICE:

Chemotherapy for advanced breast cancer

Recommendations on chemotherapy for people with advanced breast cancer have not been updated since 2009. Topic experts highlighted that chemotherapy for advanced breast cancer recommendations require an update and cumulative evidence from surveillance indicates that this should now be undertaken. There are also several relevant NICE technology appraisals that should be cross-referenced.

The 2018 surveillance review found various studies on platinum-based chemotherapy for people with advanced breast cancer, but reported that results on efficacy were inconclusive and did not have an impact on the generic recommendations 1.3.8 and 1.3.9 in NICE's guideline on advanced breast cancer, which state on disease progression, offer systemic sequential therapy to the majority of patients with advanced breast cancer who have decided to be treated with chemotherapy, and consider using combination chemotherapy to treat patients with advanced breast cancer for whom a greater probability of response is important and who understand and are likely to tolerate the additional toxicity. We identified new evidence from a Cochrane review and 2 systematic reviews which indicate that a platinum containing chemotherapy regime for women with triple-negative metastatic breast cancer leads to significant improvements in progression free survival, but not for overall survival.

Evidence was also identified from 1 Cochrane review and 2 systematic reviews which indicate that capecitabine combination chemotherapy could improve the survival rate of patients with advanced breast cancer, whereas recommendation 1.3.10 in NICE's guideline on advanced breast cancer only recommends capecitabine monotherapy as either a second- or third-line chemotherapy treatment. We propose that an update is conducted in this area to assess whether capecitabine combination therapy is preferential to the currently recommended monotherapies.

New evidence, from a Cochrane review and systematic review was identified which indicates that taxanes could be considered as a first line treatment.

Nineteen ongoing trials are being tracked by NICE looking at chemotherapy in combination with biological and/or endocrine therapy.

Biological therapy for advanced breast cancer

Topic experts and a patient group said that an update needs to be made in the area of recommendation 1.3.12 in NICE's guideline on advanced breast cancer as it is the only recommendation on the use of trastuzumab for advanced breast cancer. However, there are a number of biological therapeutic agents, beyond trastuzumab, which are now available on the NHS, for which there are relevant NICE technology appraisals, including on immune checkpoint inhibitor drugs; bevacizumab; trastuzumab emtansine; pertuzumab with trastuzumab and docetaxel; tucatinib with trastuzumab and capecitabine.

It is planned that the future guideline will be organised to ensure that the relevant NICE technology appraisals are within the recommendation section on biological therapy for advanced breast cancer.

New evidence from 4 systematic reviews was also identified that found survival benefits from anti-HER2 antibody treatment regimens and second-line therapies, following trastuzumab based treatments for women with HER2 positive metastatic breast cancer, which may be considered in an update if they add additional treatment options/regimes beyond those recommended within current and planned NICE technology appraisals.

There is a large volume of ongoing research looking at biological therapy in combination with chemotherapy and/or endocrine therapy, however much of this is for treatments covered by existing NICE technology appraisals.

Ovarian function suppression for premenopausal and perimenopausal women with oestrogen receptor‑positive early, locally advanced and advanced breast cancer

The findings from a Cochrane review and 2 systematic reviews are consistent with recommendation 1.7.4 in NICE's guideline on early and locally advanced breast cancer to consider ovarian function suppression in addition to endocrine therapy for premenopausal women with oestrogen receptor‑positive early and locally advanced invasive breast cancer.

Evidence from 3 systematic reviews indicated that ovarian function suppression with an aromatase inhibitor is a suitable, or potentially better, alternative to ovarian function suppression with tamoxifen in premenopausal women with oestrogen receptor-positive early and locally advanced invasive breast cancer, due to better outcomes for local and distant disease recurrence in those on ovarian function suppression with an aromatase inhibitor compared with ovarian function suppression with tamoxifen. Tamoxifen is recommended as the first-line choice for endocrine therapy for this population (see recommendation 1.7.2 in NICE's guideline on early and locally advanced breast cancer), whereas an aromatase inhibitor is only recommended for postmenopausal women with oestrogen receptor‑positive invasive breast cancer (see recommendation 1.7.3 in NICE's guideline on early and locally advanced breast cancer).

While recommendation 1.7.4 does not name tamoxifen as the endocrine therapy of choice, the rationale and impact section on ovarian function suppression only discusses tamoxifen, as only evidence on tamoxifen was assessed. An update should therefore consider evidence on the comparative effectiveness of ovarian function suppression with tamoxifen and ovarian function suppression with an aromatase inhibitor (also see breast cancer committee feedback).

No evidence was identified that was relevant to recommendations 1.3.5 and 1.3.6 in NICE's guideline on advanced breast cancer on offering tamoxifen and ovarian function suppression to premenopausal and perimenopausal women with oestrogen receptor-positive advanced breast cancer. However system intelligence indicates that these recommendations are out-of-date. It is therefore proposed that the update also considers whether there is any relevant RCT evidence for this population that can inform recommendations.

Three ongoing studies are being tracked by NICE:

Psychological support for all people with breast cancer

Looking at recommendation 1.2.3 in NICE's guideline on early and locally advanced breast cancer, recommends offering all people with breast cancer prompt access to specialist psychological support and, where appropriate, psychiatric services. While this recommendation remains valid, a large body of evidence from Cochrane reviews and systematic reviews was identified which supports the development of recommendations on effective strategies to prevent and manage psychological distress in patients with early-stage breast cancer. The evidence is also potentially relevant to patients with locally advanced or advanced breast cancer as the abstracts of most systematic reviews have not specified the breast cancer stage within study samples.

The evidence supports the use of specific interventions to prevent and manage psychological distress in patients with breast cancer. This included evidence from 2 Cochrane reviews and 9 systematic reviews on the beneficial effects of psychological interventions based on cognitive behavioural therapy, mindfulness and/or acceptance strategies and/or supportive-expressive group psychotherapy. There was also evidence from 1 Cochrane review and 11 systematic reviews that physical activity and/or mind-body interventions may lead to reductions in anxiety and depression and improve other outcomes related to positive mental health. There was a small body of evidence identified in 1 systematic review on appearance care interventions, which indicated that these may lead to improvements in anxiety and depression in breast cancer patients; and there was mixed evidence from 2 systematic reviews concerning the effectiveness of acupuncture on depression in patients with breast cancer. There was also evidence from 2 Cochrane reviews and 6 systematic reviews on mode of delivery of interventions that aim to support the psychological needs of patients with breast cancer and breast cancer survivors, which could be considered as part of an update.

The review question on which recommendation 1.2.3 was developed in 2009 was what are the effective strategies to prevent and manage psychological distress in patients with early-stage breast cancer? The inclusion criteria for this review question were broad: any strategy to treat psychological distress was included; and included outcomes were alleviation of psychological distress. It is proposed that clarification of outcomes of interest are needed, including consideration of outcomes indirectly related to psychological distress such as fatigue, which was reported in a large number of identified studies that also reported on anxiety, depression and quality of life outcomes. While there is no existing review question on strategies to prevent and manage psychological distress in patients with advanced cancer, nor any recommendations within NICE's guideline on advanced breast cancer for psychological support, it is proposed that consideration of psychological support needs for all people with breast cancer should be made in an update given the importance of mental wellbeing for all, and the existing evidence base. However, it is recognised that breast cancer stage and prognosis will have an impact on psychological needs, concerns, timing and potentially mode of delivery, so differences according to whether a person has early, locally advanced or advanced breast cancer will need to be considered during recommendation development.

A Cochrane review update on psychological interventions for women with non-metastatic breast cancer is expected in 2022/2023 and 2 related ongoing trials are being tracked by NICE (for example the impact of findings from these will be considered as soon as possible following publication):

Lymphoedema in all people with breast cancer

Two systematic reviews indicated that a combination of surveillance for breast cancer-related lymphoedema plus early intervention in breast cancer survivors reduces the risk of chronic breast cancer-related lymphoedema. There was also evidence from 2 systematic reviews that vascularised lymph node transfer is an effective intervention for managing breast cancer-related lymphoedema. NICE's guideline on early and locally advanced breast cancer currently only includes recommendations for the prevention of breast cancer-related lymphoedema; and while NICE's guideline on advanced breast cancer has recommendations on managing lymphoedema, it does not make any recommendations concerning surveillance and early intervention or vascularised lymph node transfer.

Given that lymphoedema is known to result in limited physical function and/or adverse psychological and social effects, means by which lymphoedema can be identified and managed as early as possible, would benefit all people with breast cancer who have undergone axillary intervention. It is therefore proposed that the evidence review question for NICE's guideline on early and locally advanced breast cancer is expanded to include management of lymphoedema; and that the prevention and management of lymphoedema is an area for update in both of NICE's guidelines on breast cancer.

Evidence was also identified that indicates the effectiveness of management of lymphoedema by laser therapy (1 systematic review), extracorporeal shockwave therapy (1 systematic review) or manual lymphatic drainage (4 systematic reviews) remains uncertain. There was also evidence from 2 systematic reviews that exercise may decrease breast cancer-related lymphoedema, but this was not sufficient to indicate that exercise should be considered as a strategy for preventing or managing breast cancer-related lymphoedema. The evidence base for these interventions will be monitored.

A Cochrane review on physical therapies for reducing and controlling lymphoedema of the limbs is expected in 2022/2023; and 3 ongoing studies are being tracked by NICE:

Menopausal symptoms in all people with breast cancer

Topic experts provided feedback that the management of menopausal symptoms in breast cancer patients is considered a high priority area. New evidence from 4 systematic reviews indicated that acupuncture may improve menopausal symptoms in women with breast cancer. Although the evidence on effectiveness was mixed there is sufficient evidence to indicate that the use of acupuncture to reduce menopausal symptoms in people with breast cancer should be considered as an area for update. It should be noted that there is an ongoing update considering evidence on the effectiveness of cognitive behavioural therapy in the management of menopausal symptoms in people with breast cancer as part of an update of NICE's guideline on menopause: diagnosis and management. It will therefore be important to ensure that the future breast cancer guidelines link to any new recommendations in NICE's guideline on menopause and that there is consistency between the content in all. There are currently no recommendations within NICE's guideline on advanced breast cancer on managing or preventing menopausal symptoms in women with advanced breast cancer, the needs of this population should also be considered within an update.

Evidence was also identified from a Cochrane review and systematic review which was consistent with recommendations 1.12.9 and 1.12.10 in NICE's guideline on early and locally advanced breast cancer to stop systemic hormone replacement therapy (HRT) in women who are diagnosed with breast cancer, and to not routinely offer HRT to women with menopausal symptoms and a history of breast cancer, and to only offer HRT in exceptional circumstances to women with severe menopausal symptoms and with whom the associated risks have been discussed.

A Cochrane review on non-hormonal pharmacological interventions for hot flushes in women with a history of breast cancer and a Cochrane review on Chinese medicinal herbs to treat the side effects of chemotherapy in women with breast cancer are expected in 2022/2023. No ongoing studies have been identified for monitoring.