Background
Since 2002 NICE has recommended that women at intermediate or high risk of recurrence who have not had neoadjuvant chemotherapy should normally be offered a multiagent chemotherapy
that includes anthracyclines.28 Chemotherapy is defined as the use of cytotoxic medications
with the intention of preventing cancer recurrence in patients. It should be noted that, for the purposes of this assessment, chemotherapy does not include other forms of systemic therapy such as endocrine treatments or targeted biological therapy (trastuzumab).
Meta-analyses of randomised controlled trials (RCTs) by the EBCTCG have indicated that the use of adjuvant chemotherapy (chemotherapy following surgery) is associated with a reduction in
TABLE 7 Expanded IHC tests
IHC4 NPI+ Mammostrat
Function Risk of recurrence Subtyping and risk of recurrence Subtyping and risk of recurrence Technology Combines four IHC tests and clinical
parameters to derive prognostic score Uses 10 biomarkers to derive prognostic score (plus others – to be defined)
Uses five biomarkers to derive risk score
Location of testing Local? (but quality assurance issues
need to be addressed) Not known Central Type of sample FFPE FFPE FFPE
Staining material Resection/core biopsy Resection/core biopsy Resection/core biopsy Population Postmenopausal, ER+, LN– All women, age 18–79 years ER+, LN–, tamoxifen treated Key output of test Continuous IHC4 score Not yet finalised. To include biological
class and projected survival Risk index and risk group Presentation of results IHC4 risk score Not yet finalised. Likely to be similar
to Adjuvant! Online Risk groups: high, moderate and low Commercially available
in the UK Algorithm available. Quality assurance issues to be addressed No No
the risk of relapse and death in women with early-stage breast cancer.29 Although chemotherapy
can reduce the likelihood of cancer recurrence and death for women with breast cancer, it has considerable adverse effects. Short-term and long-term adverse events will affect a proportion of patients receiving chemotherapy, imposing costs and reducing quality of life. Short-term adverse events that occur during chemotherapy are usually temporary and reversible. The most common side effects include nausea, vomiting, mouth soreness, diarrhoea, tiredness, hair loss and
temporary lowering of the blood counts. Long-term side effects such as damage to the heart and a small increase in the risk of leukaemia are not reversible. Although chemotherapy may prevent relapse in some, not all women with early-stage breast cancer will benefit and many women remain recurrence free at 10 years without chemotherapy. However, a subset of patients with a ‘good’ prognosis may still develop recurrence after curative surgery and adjuvant therapy. This presents a great challenge to clinicians in estimating prognosis and making the most appropriate therapeutic decisions relating to whether or not to use adjuvant chemotherapy in women with early-stage breast cancer.
Recommendations about which patients should receive chemotherapy are typically based on estimations of recurrence risk and expected benefit of therapy. Historically, clinicopathological factors, such as patient age, tumour size, nodal involvement, histological grade, ER expression, HER2 overexpression and comorbidities, have been assessed and considered alongside patient preference. In the UK, guidelines based on NPI and Adjuvant! Online have been developed to assist decision-making relating to adjuvant chemotherapy. These guidelines assist clinicians in deciding the benefits of prescribing chemotherapy for a particular patient. NPI provides information about prognosis that is largely based on pathological parameters (e.g. tumour size, grade and lymph node status), with the addition of ER receptor status, age and comorbidity for Adjuvant! Online. However, these clinicopathological tools are imperfect; different guidelines can give different results and it has been suggested that a proportion of women with early-stage breast cancer are over- or undertreated. This may result in unnecessary use of toxic and expensive chemotherapy for women who derive little or no benefit, or avoidable deaths in women for whom chemotherapy was withheld.
Role of new tests
Gene expression profiling and expanded IHC tests aim to improve the targeting of chemotherapy in breast cancer by improving the stratification and identification of patients who will gain most benefit from chemotherapy. The new tests will provide an indication of the risk of recurrence of patients (based on the results of an algorithm to estimate risk of recurrence or indirectly by identifying the cancer subtype). This is based on the knowledge that certain biological features of cancers may indicate an increased likelihood of rapid growth and metastatic potential. The management of these patients, that is, the decision whether or not to prescribe chemotherapy, will be influenced by the test results, and this may result in a change of management of patients compared with current practice (a decision made based on NPI and/or Adjuvant Online). By more accurately guiding the selection of patients to receive adjuvant chemotherapy in early breast cancer management, the use of GEP or expanded IHC tests in patients with early-stage breast cancer may improve health outcomes and quality of life compared with currently used decision-making protocols.
Comparators
The comparator is standard UK practice. This varies between trusts and encompasses the use of Adjuvant! Online and/or guidelines based on NPI to guide decisions on which patients with early breast cancer should be offered adjuvant chemotherapy.
Identification of important subgroups
The NICE scope25 identifies the population under assessment as people diagnosed with early
breast cancer. However, many of the GEP and expanded IHC tests have been developed for use in a specific subpopulation or currently have evidence of efficacy only within a specific subpopulation. For tests providing a risk of recurrence output, the majority of evidence relates to populations with ER+, LN– early breast cancer. Some of these tests also have more limited evidence in LN+ populations (for patients with one to three nodes involved) and in patients with ER– disease.
These tests will have an impact on the health of patients only if they lead to changes in patient management. This is most likely to happen in populations in which the decision on whether or not to offer chemotherapy is currently uncertain. One such group is patients with ER–, LN–, HER2– early breast cancer for whom prognostic factors suggest that they are at intermediate risk. The definition of this ‘intermediate group’ is not clear-cut. Clinical advice suggests that patients
with a NPI score of ≤ 3.4 are typically considered at low risk either using current prognostic tools
(except for a few very young women with aggressive early breast cancer) or based on the new tests and are unlikely to receive chemotherapy; therefore, their management is unlikely to change.
Few patients with ER–, LN–, HER2– early breast cancer will have a NPI score > 5.4 and therefore
those with a NPI score > 3.4 can be considered as being at intermediate risk.
Current treatment protocols indicate that women with HER2+, ER– early breast cancer or with several positive nodes are likely to receive chemotherapy in most centres in England and Wales. Although the use of GEP or expanded IHC tests might be able to spare chemotherapy in a proportion of these patients, the evidence base for the use of these tests in this population is more limited and clinical opinion therefore considered the assessment of these tests in this population to be a lower priority.
Patients with ER+ LN–, HER2– early breast cancer are therefore considered to be an important population in which to assess these tests, given the current evidence base. Within this population those at intermediate risk for whom the decision about whether or not to offer chemotherapy is not clear cut are considered to be an important subgroup.
Outcomes
The clinical effectiveness review will consider the clinical effectiveness of the tests in relation to:
■ Analytical validity (i.e. the ability of the test to accurately and reliably measure the expression
of mRNA or proteins by breast cancer tumour cells).
■ Clinical validity (i.e. the degree to which the test could accurately predict the risk of an
outcome such as disease recurrence and discriminate patients with different outcomes). This relates to the prognostic ability of the test.
■ Clinical utility (i.e. the ability of the test to discriminate between those who will have more
or less benefit from a therapeutic intervention). This includes evidence relating to how the tests will influence decision-making in terms of which patients will be offered chemotherapy and evidence relating to the predictive ability of the test, that is, the extent to which the test identifies those patients who will benefit most in terms of the relative reduction in the risk of recurrence from treatment.
The outcomes of interest for the economic evaluation are the morbidity and mortality associated with invasive breast cancer and its treatment. Outcomes from the model are expressed in terms of cost per quality-adjusted life-year (QALY).