Breast cancer

The keys to successful breast cancer treatment are early detection and treatment and the use of treatments tailored to both the person and the type of cancer. Some cancers are more aggressive than others; some have oestrogen and progesterone receptors that promote their growth in the presence of these hormones; some overexpress HER2/neu; some are more sensitive to chemotherapy and others less so. Breast cancer treatment usually includes a combination of surgery, radiotherapy, chemotherapy, hormone therapy, targeted therapy and sometimes biological therapy.

The types of breast cancer treatment are chosen on the basis of several factors:

Patient’s age and health
Tumour size
Presence or absence of progesterone and/or oestrogen receptors
Presence of HER2/neu overexpression
Grade of the cancer (how normal or abnormal the tumour cells are)
Stage of the cancer – whether it has stayed localised (stages I and II), spread to nearby tissues (stage III) or spread to other organs (stage IV)
Presence of cancer cells in the lymph nodes near the tumour

Patients with small localised tumours that have not spread to the lymph nodes may or may not be treated with specific adjuvant therapies – additional systemic treatments such as chemotherapy and/or tamoxifen (for hormone-sensitive tumours) – to reduce the risk that some cancer cells escape detection and treatment and cause the cancer to come back later. Adjuvant therapies are not effective in all breast cancer patients. Multiparameter gene expression tests are intended mainly to help assess the patient’s prognosis and risk of breast cancer recurrence and, secondly, to give the doctor information about which patients are likely to benefit from adjuvant chemotherapy.

Multiparameter gene expression tests for breast cancer are relatively new. They require a minimum amount of tumour tissue and specific samples to be processed. They are currently intended only for tumours that have not yet spread to the lymph nodes, and each has been developed for use in specific patient populations. They have the potential to help identify patients at higher and lower risk of breast cancer recurrence, but their full clinical usefulness has yet to be established.

Several multiparameter gene expression tests are being developed, but most are still considered mainly research tools. Two of them, Oncotype DX and MammaPrint, have been cleared for use by the Food and Drug Administration.

Oncotype DX was included in the 2007 American Society of Clinical Oncology (ASCO) update on the use of tumour markers in breast cancer and is to be used to predict the risk of recurrence in patients treated with tamoxifen. ASCO considered the MammaPrint test and several other multiparameter gene expression tests, including the Rotterdam Signature and the Breast Cancer Gene Expression Ratio, to be promising but still in need of further clinical data defining their usefulness before ASCO endorses them. The National Comprehensive Cancer Network (NCCN) and the National Breast Cancer Coalition (NBCC) also recognise the potential of these tests but consider that further research is needed to support their clinical use.

Research continues through many large clinical trials, such as TAILORx (Trial Assigning Individualized Options for Treatment), which compares adjuvant hormone therapy with adjuvant chemo-hormonal therapy in women with an intermediate Oncotype DX recurrence score, and MINDACT (Microarray In Node-Negative Disease may Avoid Chemotherapy), which compares the MammaPrint test with clinical and pathological criteria for assigning patients to chemotherapy. These trials will further clarify the clinical usefulness of these tests and assess their ability to guide breast cancer treatment, but it will be a number of years before the results are available.

Intended use
Assesses the likelihood of breast cancer recurrence and the benefit of adjuvant chemotherapy

Patient/tumour type
Newly diagnosed stage I and II patients with oestrogen receptor-positive, lymph node-negative tumours who will be treated with tamoxifen

Sample type
Formalin-fixed, paraffin-embedded tumour tissue

Method
Quantitative real-time PCR

Results
The calculated results give a “Recurrence Score” between 0 and 100, with <18 defined as low risk of distant recurrence at 10 years, >31 high risk, and 18-30 intermediate risk. Patients with a high risk score are more likely to benefit from adjuvant chemotherapy.

Test status
FDA-approved, commercially available.

MammaPrint
MammaPrint is a 70-gene expression profile that measures 70 cancer-related genes, in triplicate, as well as reference genes (normalisation genes and negative controls)

Intended use
To predict the risk of breast cancer recurrence at 5 to 10 years.

Patient/tumour type
Newly diagnosed patients under 61 years of age with stage I or II tumours up to 5 cm and negative lymph nodes

Sample type
Frozen tumour sample with at least 30% malignant cells

Method
DNA microarray

Results
Calculation of the MammaPrint index, giving a low- or high-risk prognosis score

Test status
FDA-cleared; commercially available in the Netherlands

Breast Cancer Gene Expression Ratio, 2-gene H/I ratio or HOXB13/IL17BR
The Breast Cancer Gene Expression Ratio is a two-gene expression profile that assesses the H:I expression ratio of the homeobox gene (HOXB13) and the interleukin-17B receptor gene (IL-17BR)

Intended use
To help predict breast cancer recurrence

Patient/tumour type
Newly diagnosed breast cancer patients with oestrogen receptor-positive tumours and negative lymph nodes

Sample type
Formalin-fixed, paraffin-embedded tumour tissue

Method
Quantitative real-time PCR

Results
Assesses the H:I ratio against a 5-year risk of recurrence. The risk increases as the ratio increases

Test status
Commercially available, but ASCO would like more data on its clinical usefulness

Rotterdam Signature 76-gene panel
The Rotterdam Signature test is a 76-gene expression profile. Sixty genes are intended for assessing oestrogen receptor-positive tumours and 16 genes for oestrogen receptor-negative tumours

Intended use
To predict the risk of breast cancer recurrence

Patient/tumour type
Patients with breast cancer and negative lymph nodes

Sample type
Fresh frozen tumour sample

Method
RNA microarray

Results
Risk ratio for recurrence

Test status
Research use, not commercially available