Recommendations for NHSScotland
SHTG Council Considerations
Evidence Overview
Background
In patients* with oestrogen receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2-), early-stage breast cancer with 0-3 positive lymph nodes, the use of tumour profiling tests:
• is unlikely to provide additional benefit for decision making about adjuvant chemotherapy for patients who have a low or high clinical risk of distant recurrence, as defined using a validated tool such as PREDICT or the Nottingham Prognostic Index (NPI)
• is recommended as set out in the decision tree on page 2 for patients who have an intermediate risk of distant recurrence, as defined using a validated tool such as PREDICT or the NPI
When tumour profiling tests are indicated, their use should be limited to patients in whom there is uncertainty from both the patient and the clinician as to the benefit of chemotherapy. The tests are intended to be used in addition to existing tools to increase clarity around adjuvant chemotherapy decision making. A shared decision-making discussion should take into account clinical and pathological risk factors alongside patient characteristics and preferences.
There should be ongoing data collection on the impact of using tumour profiling tests on patient outcomes and return on investment in NHSScotland.
NHSScotland is required to consider the Scottish Health Technologies Group (SHTG)
recommendations.
1. The recommendations in the NICE guidance were not split by menopausal status. The SHTG Recommendations have considered pre- and postmenopausal patients separately because several studies, including the three main RCTs, noted a greater treatment effect from adjuvant chemotherapy in younger (premenopausal) women, even with low-risk scores from tumour profiling tests. This benefit may be partly explained by an antioestrogenic effect associated with premature menopause induced by chemotherapy. Until this question has been answered by the evidence, SHTG considered that greater caution around the use
of tumour profiling tests is needed in premenopausal patients. The Council asked a clinical expert about the applicability of the evidence to men with breast cancer. The expert advised that the recommendations could apply to men and application of the decision tree with male patients should be based on clinical expertise.
2. The SHTG Council considered the decision tree (page 2), and noted the justifications given by the SHTG research team for the recommendation in each of the four main patient groups:
2.1. Premenopausal patients with LN- disease
There is insufficient evidence to support the use of EndoPredict® and MammaPrint® in this patient group, and Prosigna® is only indicated for use in postmenopausal patients.
The TAILORx trial suggested that patients aged 50 years and younger who are LN-, with an Oncotype DX® Recurrence Score (RS) of 15 or lower, may be spared chemotherapy. SHTG Council noted concerns about:
- the generalisability of the participants in the TAILORx study
- a general trend in the literature that suggests premenopausal women benefit more from chemotherapy, even when genomic risk scores are low
As a result of these concerns, the recommendation for use in this subset of patients was restricted.
2.2. Premenopausal patients with LN+ disease
There is insufficient evidence to support the use of EndoPredict®, Oncotype DX® and MammaPrint® in this patient group, and Prosigna® is only indicated for use in postmenopausal patients.
The RxPONDER trial, not included in the NICE guidance, evaluated the use of Oncotype DX® in predicting the benefit of adjuvant chemotherapy in women with LN+ disease, and in premenopausal women a chemotherapy benefit was seen across subgroups. This suggests that premenopausal patients may still benefit from chemotherapy, even with a lower Oncotype DX® RS.
2.3. Postmenopausal patients with LN- disease
In this patient group the recommendations from the NICE (2018) guidance for EndoPredict®, Oncotype DX® and Prosigna® still apply to postmenopausal patients. SHTG identified new clinical- and cost-effectiveness evidence that strengthens NICE’s recommendation.
NICE did not recommend the use of MammaPrint® because it was not found to be cost effective. An updated cost-effectiveness model submitted to SHTG by Agendia demonstrated that the MammaPrint® test may be cost effective in LN- patients with intermediate clinical risk. SHTG concluded that MammaPrint® could be recommended
in this patient group because of changes in the availability of the evidence to inform the parameters of the economic model.
2.4. Postmenopausal patients with LN+ disease
SHTG Council concluded that there was insufficient evidence to support the use of tumour profiling tests in postmenopausal patients with LN+ disease. Until more research is available, routine use of tumour profiling tests cannot be recommended in this patient group.
SHTG Council considered the RxPONDER trial and acknowledged the finding that there was no chemotherapy benefit in patients with LN+ disease who had an Oncotype DX® RS of 0-25. SHTG Council expressed the following concerns.
- The majority of participants had cancer that had spread to one lymph node only (65.3%). Only 9% of participants had cancer that had spread to three lymph nodes, meaning the trial mainly reflected the ‘lower risk’ LN+ patients.
- NICE in 2018 raised concerns that, based on the OPTIMA Prelim study, there was a lack of agreement between the tests in risk categorising the groups with LN+ disease and limited their recommendations to LN- populations. No evidence was identified
to alleviate this concern.
3. SHTG Council acknowledged that the evidence base in this area is rapidly evolving and this SHTG Recommendation may change as more evidence and health technology assessments (HTAs) become available. The OPTIMA trial was highlighted as having the potential to address gaps in the evidence.
4. SHTG Council noted that the genes that are mapped by the four tests varied considerably, suggesting that the different tests capture different aspects of prognostic drivers. This would suggest that future improvements and refinements in the tests remain possible.
5. The Council heard from a clinical expert who talked about the use of these tests in NHSScotland, noting current variation in practice. The clinical expert reiterated that tumour profiling tests should not replace existing prognostic tools, but be used alongside them. The
Council noted that every patient has different experiences and preferences, which will influence the value of tumour profiling tests to them.
6. The Council heard from Breast Cancer Now about the devastating impact a breast cancer diagnosis can have on a person and the people close to them. When discussing the impact of tumour profiling tests on patients, the Council agreed that timeliness is important.
Waiting for test results not only prolongs anxiety for patients, but may also delay chemotherapy. This is a factor that should be considered when deciding which test should be used in NHSScotland.
Key points from the evidence
1. This SHTG Recommendation considers the evidence on the use of tumour profiling tests (Endopredict®, MammaPrint®, Oncotype DX® and Prosigna®) in patients with ER+, HER2-early-stage breast cancer with 0-3 positive lymph nodes. Most patients with this type of
breast cancer will be offered surgery as their first-line treatment. Adjuvant therapies, including chemotherapy and endocrine therapy, may be needed following surgery to reduce the risk of recurrence and/or metastases. Chemotherapy may be associated with
adverse events, and not all patients will benefit from it. Prognostic tools are available that can help facilitate the decision on whether or not to have chemotherapy. Where uncertainty remains, tumour profiling tests are intended to be used alongside these
prognostic tools to help patients and clinicians with adjuvant chemotherapy decision making.
2. In 2018, The National Institute for Health and Care Excellence (NICE) published diagnostic guidance (DG34) on the use of tumour profiling tests to guide adjuvant chemotherapy decisions in patients with ER+, HER2-, early breast cancer. The Molecular Pathology Consortium in Scotland endorsed this guidance for NHSScotland. New evidence has become available since 2018 and clinical experts have advised that variation in practice remains in NHSScotland. This SHTG Recommendation updates the evidence review and recommendations from the NICE guidance.
Clinical-effectiveness evidence
3. The RxPONDER randomised controlled trial (RCT) was published after the NICE guidance. The RxPONDER trial evaluated the use of Oncotype DX® in predicting the benefit of adjuvant chemotherapy in women with lymph node positive (LN+) disease. In addition, updated results (median follow up of 8.7 years) of an RCT, which evaluated the clinical utility of MammaPrint® in women with early-stage breast cancer (the MINDACT trial) were published after the NICE guidance.
4. The collective evidence suggests that all four tumour profiling tests provide prognostic information on a patient’s future risk of cancer recurrence and/or survival. The tests add prognostic value over other prognostic clinical and pathological information available to
clinicians and patients. The evidence is weaker and more variable in patients with LN+ disease, compared with those who have LN- disease.
5. Predictive ability relates to the ability of the tests to identify those patients who are most likely to benefit from chemotherapy. Three of the tests are indicated for predictive use (Oncotype DX®, MammaPrint® and EndoPredict®), but there is considerable
uncertainty within the evidence that the tests are predictive of improved outcomes with chemotherapy.
Patient and social aspects
6. A qualitative study published after the NICE guidance explored ways in which women in the UK interpret and discuss the Oncotype DX® test. In addition, a patient organisation submission was received from Breast Cancer Now.
7. Patients generally view tumour profiling tests positively, as they are perceived as providing ‘personalised’ information, which is seen as more reliable and informative than risk scores calculated from online algorithms. Low- and high-risk scores from the tumour profiling tests are generally viewed as providing more clarity around the decision to have or forgo chemotherapy, compared with intermediate-risk scores. Waiting for test results prolongs patient anxiety, and so the results of tumour profiling tests should be made available to patients in a timely manner.
Cost-effectiveness evidence
8. SHTG’s updated literature review of the cost-effectiveness evidence highlighted six economic evaluations that were published after the NICE guidance, though these were more limited than the analyses presented by NICE at addressing the decision problem
faced by NHSScotland.
9. The manufacturers of the four tests were invited to submit economic evaluations, and were received from the manufacturers of MammaPrint®, Oncotype DX® and Prosigna®. The results of economic analyses submitted by test manufacturers strengthened the conclusions of the NICE recommendation from 2018, that tumour profiling tests (Oncotype DX®, Prosigna® and EndoPredict®) are likely cost effective in patients with LNdisease who have an intermediate risk of recurrence using a validated algorithm. The
MammaPrint® test is also likely cost effective in this population. Cost effectiveness in this subgroup is driven by the avoidance of unnecessary chemotherapy and reducing distant recurrence.
10. Tumour profiling tests are unlikely to be cost effective for patients with LN- disease and a low risk of recurrence based on a validated algorithm as this subgroup have low rates of chemotherapy in current clinical practice without a test.
11. While three of the tumour profiling tests under consideration (EndoPredict®, MammaPrint® and Oncotype DX®) may be cost effective in patients with LN+ (1-3 nodes) disease, these results should be treated with caution because of uncertainty in the clinical
evidence base for tumour profiling tests in this subgroup.
What were we asked to look at?
We were asked by the Scottish Cancer Network to look at the clinical and cost effectiveness, and patient and clinical experience, of tumour profiling tests for guiding chemotherapy decisions for patients with ER+, HER2-, early-stage breast cancer with 0-3 positive lymph nodes.
Why is this important?
The Scottish Cancer Strategy (2023) states that allied to systemic anticancer therapy delivery, and in order to maximise the opportunities of precision medicine, comprehensive genomic tests should be offered as appropriate to people with cancer at an earlier stage in their clinical pathway.
In Scotland, breast cancer is the most common cancer in women and accounts for 28% of all cancers diagnosed in women, excluding non-melanoma skin cancer. Incidence of breast cancer is increasing over time with 4,297 new cases being diagnosed in 2020 in women in Scotland. The incidence of ER+, HER2- breast cancer is rare in men, but it does occur. While the studies reported were undertaken in women, there is no reason to believe that these tests would be any less useful in men and this guidance should apply to all patients with ER+, HER2-, early-stage breast cancer with 0-3 positive lymph nodes, regardless of sex or gender.
In most types of breast cancer, surgery is the first-line treatment. Adjuvant therapy, including chemotherapy, may be needed following surgery to reduce risk of recurrence and/or metastasis. While chemotherapy can reduce risk of recurrence, not all patients with early-stage breast cancer require it. Chemotherapy can cause short- and long-term adverse events, and it is important to take this into account. Clinicopathological factors such as tumour size, disease stage and age are used to guide choices on the most appropriate treatment strategy. Tumour profiling tests may be used alongside these factors to inform adjuvant chemotherapy decisions.
