3 Clinical need and practice
3.1 Gene expression profiling and immunohistochemistry tests aim to improve the targeting of chemotherapy in breast cancer by more accurately identifying patients who will gain the most benefit. This rationale is based on the knowledge that certain biological features of cancers may indicate an increased likelihood of rapid growth and metastasis (in particular, distant recurrence). Distant recurrence is the return of detectable cancer in another part of the body. The tests may also identify, in some instances, which patients are most likely to benefit from chemotherapy. Some tools or tests provide mainly prognostic information (such as the Nottingham Prognostic Index [NPI] and Adjuvant! Online). Others may or may not be able to predict the extent to which the patient could benefit from chemotherapy (such as Oncotype DX, MammaPrint, Mammostrat and IHC4). Breast cancer patients face significant emotional and psychological strain when considering chemotherapy. It can be particularly distressing for patients in whom the decision to have chemotherapy is unclear using currently available tools (especially for people with an intermediate risk of distant recurrence). Tools or tests that help people decide whether or not to have chemotherapy are likely to be greatly appreciated by patients. The aim of this evaluation is to determine whether using gene expression profiling and expanded immunohistochemistry tests (MammaPrint, Oncotype DX, IHC4 and Mammostrat), in conjunction with current decision-making protocols (including tools such as the NPI and Adjuvant! Online) to guide the use of adjuvant chemotherapy, cost-effectively improves health outcomes and quality of life of people with early stage breast cancer, compared with current decision-making protocols alone.
3.2 Breast cancer is the most commonly diagnosed cancer in women in England and Wales, but it can affect both men and women. In 2010 there were approximately 49,600 new cases in women and 400 in men. For both sexes, incidence varies with age. Just over 80% of cases occur in women aged 50 years and over. In England and Wales, 2006–2008 data demonstrate highest incidence rates for women in the 60‑ to 70‑year age range.
3.3 Incidence also varies with family origin. In England, people of Asian, Chinese and black family origin and those with mixed heritage have a lower incidence than those of white family origin. Incidences are 0.65, 0.75, 0.49 and 0.58 that of those of white family origin respectively.
3.4 Breast cancer is the second largest cause of cancer-related death in women after lung cancer, with an age-standardised mortality rate of 24 per 100,000 women. In 2010 this constituted 10,328 deaths for women in England and Wales.
3.5 Overall, 5‑year age-standardised survival rates for breast cancer are around 80%. Breast cancer survival rates have improved over the last 2 decades and now almost 2 out of 3 women with breast cancer survive beyond 20 years. Survival varies with age, stage of disease, family origin, socioeconomic status and tumour characteristics.
3.6 Clinicians currently estimate prognosis using tools such as the NPI (see section 4.10) or Adjuvant! Online (see section 4.11). The NPI takes into account grade as well as size and spread of the tumour, whereas Adjuvant! Online uses age of the patient, tumour size, nodal involvement, hormonal receptor status, histological grade and comorbidities to predict disease course and treatment options. Better prognosis is associated with small tumour size, younger age, lymph node negative (LN−), oestrogen receptor positive (ER+) and progesterone receptor positive (PR+) status. Human epidermal growth factor receptor 2 (HER2) over-expression (also known as HER2+) is associated with a poor prognosis. A tool called PREDICT, which is based on cancer registry data for women treated in England (East Anglia) and includes HER2 and Ki‑67 status, has recently become available to the NHS.
3.7 Some patients considered to have a 'good' prognosis using current tools may still have recurrence after curative surgery and adjuvant therapy. Some patients considered to have a 'poor' prognosis may never develop metastatic disease. It is therefore challenging to decide whether to treat early stage breast cancer with adjuvant chemotherapy.
3.8 The decision whether to offer adjuvant chemotherapy is uncertain in people with ER+, LN− and HER2− early breast cancer. The External Assessment Group and clinical specialists who were consulted advised that the tests being evaluated would most likely be of benefit to the NHS in this patient group. Moreover, the evidence base was most robust for this population. Therefore the economic analysis for this evaluation focused on people with ER+, LN− and HER2− early breast cancer.
3.9 Patients diagnosed with early breast cancer currently follow the diagnosis/treatment pathway described in figure 1.
FISH: fluorescence in situ hybridisation
3.10 For the purposes of this assessment, chemotherapy is defined as the use of cytotoxic drugs with the intention of preventing cancer recurrence and does not include other forms of systemic therapy such as endocrine treatments or targeted biological therapy. Generally, chemotherapy regimens containing anthracyclines are used after cancer surgery (in the adjuvant setting).
3.11 NICE cancer service guidance Improving outcomes in breast cancer recommends that women at intermediate or high risk of recurrence who have not had neoadjuvant chemotherapy should normally be offered multi-agent chemotherapy, which includes anthracyclines.
3.12 Early and locally advanced breast cancer: diagnosis and treatment (NICE clinical guideline 80) recommends that adjuvant therapy should be considered for all patients with early invasive breast cancer after surgery, based on assessment of the prognostic and predictive factors, and the potential benefits and side effects of the treatment. These guidelines do not refer to the use of gene expression profiling and expanded immunohistochemistry tests to aid decision making. NICE clinical guideline 80 recommends that decisions should be made following discussion of these predictive and prognostic factors with the patient and that Adjuvant! Online should be considered to support estimations of individual prognosis and the absolute benefit of adjuvant treatment. The NPI is also commonly used locally to aid decisions about chemotherapy for patients with early stage breast cancer and is discussed in NICE clinical guideline 80.
3.13 In the UK, local guidance based on the NPI and Adjuvant! Online has been developed to help clinicians decide about the benefits of adjuvant chemotherapy for a particular patient. However, it has been suggested that these tools may be imperfect and different local approaches to the use and interpretation of these tools leads to a proportion of people with early stage breast cancer being over- or under-treated. This may result in unnecessary use of expensive chemotherapy with its associated adverse effects for people who derive little or no benefit. In addition, there may be avoidable deaths in people who would have benefitted from chemotherapy had it been offered.