3 Clinical need and practice
3.1 The intraoperative molecular tests (RD‑100i OSNA system and Metasin test) are used during breast cancer surgery to detect the presence of 1 or 2 biological markers that are associated with metastatic spread in sentinel lymph node samples. The intention is that the test results are available during surgery and may be used to determine if other axillary lymph nodes should be removed at the same time as the initial tumour. This could avoid the need for a second operation and allow subsequent treatments such as chemotherapy to begin earlier.
3.2 The aim of this evaluation is to determine the clinical and cost effectiveness of using the RD‑100i OSNA system and the Metasin test to detect metastases in the sentinel lymph nodes of patients having breast cancer surgery.
3.3 Breast cancer is one of the most common cancers in women in England and Wales; there are about 46,000 new cases diagnosed and 10,900 deaths recorded each year. Around 1 in 9 women develop breast cancer at some stage in their life. Most breast cancers develop in women over 50 years, but they can also occur in younger women and, in rare cases, in men. There are around 260 cases of breast cancer diagnosed and 68 deaths recorded in men in England and Wales each year. Around 11,000 women with newly diagnosed breast cancer need additional surgery to manage the spread of breast cancer to the lymph nodes every year. In a few people, the tumour has spread significantly within the breast or to other organs of the body at initial diagnosis. Also, some people who have been treated with curative intent subsequently develop either a local recurrence or metastases.
3.4 Breast cancer mainly spreads by local spread to nearby tissues, or by regional or distant spread through the circulatory or lymphatic system. Spread through the lymphatic system is of relevance for this evaluation. It occurs when cancer cells become detached from the main breast tumour. These are then usually carried in the lymph to the axillary (armpit) lymph nodes, most likely the sentinel lymph nodes. The cancer cells can grow in the lymph nodes and cause swelling, although not all metastatic lymph nodes are morphologically abnormal. Lymph nodes are often used to stage cancer (measure the extent of the disease) because their function is to monitor lymph and trigger an immune response if a foreign substance is detected, and so they are one of the earliest sites at which the spread of cancer can be detected.
3.5 The treatment of breast cancer can cause many side effects including pain, fatigue, reduced fertility and osteoporosis. A diagnosis of breast cancer and subsequent treatment can cause long-term anxiety, depression and isolation in both the patient and their relatives. Cancer chemotherapy and radiotherapy can cause hair loss, and people with cancer can experience changes to the body that arise from the disease itself or from treatments such as mastectomy. These are associated with social stigma, and can have a significant impact on quality of life and reduce self-esteem.
3.6 One side effect of lymph node surgery is lymphoedema, which is more likely after axillary lymph node dissection than after sentinel lymph node biopsy. The most common symptom is swelling of the arm, hands and fingers on the side of the body that has been operated on, which can persist for months or years. Swelling can also affect the breast, chest and shoulder. Lymphoedema does not affect all people who have lymph node surgery but, in some people, it can develop soon after treatment or years later because of inflammation, infection and scarring.
3.7 Axillary lymph node dissections result in major and minor complications for 80% of women. Major complications include a 22% incidence of seromas (pockets of fluid under the skin), a 21% incidence of arm lymphoedema (general swelling) and a 14% infection rate. Other complications include pain, limited mobility, numbness and sensory loss. Sentinel lymph node biopsy is associated with a 7% incidence of lymphoedema, a 7% incidence of seroma and a 2% infection rate.
3.8 The current breast cancer care pathway is outlined in the NICE guideline on early and locally advanced breast cancer. This guideline recommends that ultrasound evaluation of the axilla (armpit) is done in all patients being investigated for early invasive breast cancer. If morphologically abnormal lymph nodes are identified, ultrasound-guided needle sampling is offered preoperatively.
3.9 For patients who have no evidence of abnormal lymph nodes on ultrasound images or aspiration cytodiagnosis, minimal surgery is performed to stage the axilla during breast surgery to confirm that the cancer has not spread. Sentinel lymph node biopsy, in which the first lymph nodes are removed to see if the cancer has spread from the original site, is the preferred technique. A radioactive solution and a blue dye are injected into the breast before surgery to help identify the sentinel lymph nodes during surgery. However, identifying the nodes during surgery can be difficult and there is a widely recognised learning curve for performing sentinel lymph node biopsy. The Royal College of Surgeons of England, Cardiff University and the Department of Health established a surgical training programme (NEW START) for performing the biopsy and set standards for surgeons to achieve a greater than 90% localisation rate (ability to locate sentinel nodes) and a less than 10% false negative rate. One study reported that the localisation rate achieved for sentinel lymph node biopsy was around 98% (Mansel et al. 2006).
3.10 The fresh biopsy tissue from sentinel lymph node biopsy is currently analysed using postoperative histopathology. This involves slicing the lymph node into very thin sections. These tissue sections are then stained and viewed by a consultant histopathologist to identify any abnormalities in the tissue. There is a small risk that histopathological analysis may miss a metastasis because only a few sections of the lymph node are examined, and metastatic foci are not evenly distributed through a lymph node so may not be present in sections that are examined. It is not clear how many sections from a lymph node are currently analysed in routine NHS practice. Results from histopathology usually take between 5 and 15 working days to be reported in the NHS. If the results are positive, the patient will have a second operation to remove the remaining lymph nodes (axillary dissection). This can be more technically challenging than performing the axillary dissection as part of the initial surgery.
3.11 Two pathological methods that can be used intraoperatively are frozen section and touch imprint cytology. Frozen section involves a section of the lymph node being snap-frozen, stained and sliced before being viewed by a consultant histopathologist. Touch imprint cytology involves the lymph node being sliced and the cut surface of the node imprinted on to a slide, which is then stained and viewed by a consultant histopathologist or cytopathologist. Both intraoperative pathological methods can be used to help determine if axillary lymph node dissection should be done at the same time as the first operation. Postoperative histopathology analysis is usually carried out on the remaining tissue to reduce the risk of a false negative result. However, in practice these intraoperative methods are rarely used because they have low accuracy and pathology resources are limited within the NHS.
3.12 The RD‑100i OSNA system and the Metasin test can be used to analyse either the whole lymph node or half of the lymph node with follow-up histopathology on the remaining half to confirm the results. The decision on whether to analyse the whole lymph node is based on clinical judgement.
3.13 People who have macrometastases or micrometastases detected in their sentinel lymph node are regarded as lymph node-positive, and usually receive axillary lymph node dissection. People who have isolated tumour cells in their sentinel lymph node are regarded as lymph node-negative and will not receive axillary lymph node dissection.
3.14 All information on the sentinel nodes, axillary nodes and primary breast tumour is typically discussed at a multidisciplinary team meeting to determine the appropriate systemic adjuvant therapy. The NICE guideline on early and locally advanced breast cancer recommends that adjuvant chemotherapy and radiotherapy should be started as soon as clinically possible within 31 days of completion of surgery in patients with early breast cancer having these treatments. The use of intraoperative molecular tests and a potential consequent reduction in the number of second operations performed may result in patients starting adjuvant therapy earlier.