Breast cancer treatment

, Assistant Editor(s)-In-Chief: Jack Khouri

Overview
The mainstay of breast cancer treatment is surgery when the tumor is localized, with possible adjuvant hormonal therapy (with tamoxifen or an aromatase inhibitor), chemotherapy, and/or radiotherapy. At present, the treatment recommendations after surgery (adjuvant therapy) follow a pattern. This pattern is subject to change, as every two years, a worldwide conference takes place in St. Gallen, Switzerland, to discuss the actual results of worldwide multi-center studies. Depending on clinical criteria (age, type of cancer, size, metastasis) patients are roughly divided to high risk and low risk cases, with each risk category following different rules for therapy. Treatment possibilities include radiation therapy, chemotherapy, hormone therapy, and immune therapy.

In planning treatment, doctors can also use PCR tests like Oncotype DX or microarray tests like MammaPrint that predict breast cancer recurrence risk based on gene expression. In February 2007, the MammaPrint test became the first breast cancer predictor to win formal approval from the Food and Drug Administration. This is a new gene test to help predict whether men or women with early-stage breast cancer will relapse in 5 or 10 years, this could help influence how aggressively the initial tumor is treated.

Surgery
Depending on the staging and type of the tumor, just a lumpectomy (removal of the lump only) may be all that is necessary, or removal of larger amounts of breast tissue may be necessary. Surgical removal of the entire breast is called mastectomy.

Lumpectomy techniques are increasingly utilized for breast-conservation cancer surgery. However, mastectomy may be the preferred treatment in certain instances:
 * Two or more tumors exist in different areas of the breast (a "multifocal" cancer).
 * The breast has previously received radiation (XRT) treatment.
 * The tumor is large relative to the size of the breast.
 * The patient has had scleroderma or another disease of the connective tissue, which can complicate XRT treatment.
 * The patient lives in an area where XRT is inaccessible.
 * The patient is apprehensive about the risk of local recurrence after lumpectomy.

Standard practice requires the surgeon to establish that the tissue removed in the operation has margins clear of cancer, indicating that the cancer has been completely excised. If the removed tissue does not have clear margins, further operations to remove more tissue may be necessary. This may sometimes require removal of part of the pectoralis major muscle, which is the main muscle of the anterior chest wall.

During the operation, the lymph nodes in the axilla are also considered for removal. In the past, large axillary operations took out 10 to 40 nodes to establish whether cancer had spread. This had the unfortunate side effect of frequently causing lymphedema of the arm on the same side, as the removal of this many lymph nodes affected lymphatic drainage. More recently, the technique of sentinel lymph node (SLN) dissection has become popular, as it requires the removal of far fewer lymph nodes, resulting in fewer side effects. The sentinel lymph node is the first node that drains the tumor, and subsequent SLN mapping can save 65-70% of patients with breast cancer from having a complete lymph node dissection for what could turn out to be a negative nodal basin. Advances in Sentinel Lymph Node mapping over the past decade have increased the accuracy of detecting Sentinel Lymph Node from 80% using blue dye alone to between 92% and 98% using combined modalities. SLN biopsy is indicated for patients with T1 and T2 lesions (<5cm) and carries a number of recommendations for use on patient subgroups.

Radiation therapy
Radiation therapy involves using high-powered X-rays or gamma rays (XRT) that precisely target the area being treated. These X-rays or gamma rays are very effective in destroying the cancer cells that might recur where the tumor was removed. The X-rays are delivered by a machine called a linear Accelerator or LINAC. Alternatively, the use of implanted radioactive catheters (brachytherapy), similar to those used in prostate cancer treatment, is being evaluated. Radiation therapy for breast cancer is usually performed after surgery and is an essential component of breast-conserving therapy. The purpose of radiation is to reduce the chance that the cancer will recur.

Radiation therapy eliminates the microscopic cancer cells that may remain near the area where the tumor was surgically removed. The dose of radiation must be strong enough to ensure the elimination of cancer cells. However, radiation affects normal cells and cancer cells alike, causing some damage to the normal tissue around where the tumor was. Healthy tissue can repair itself, while cancer cells do not repair themselves as well as normal cells. For this reason, radiation treatments are given over an extended period, enabling the healthy tissue to heal. Treatments are typically given over a period of five to seven weeks, performed five days a week. Each treatment takes about 15 minutes.

Although radiation therapy can reduce the chance of breast cancer recurrence, it is much less effective in prolonging patient survival. According to a review of six studies by the National Cancer Institute, none of them found a survival benefit for radiation therapy. Patients who are unable to have radiation therapy after lumpectomy should consult with a surgeon who understands this research and who believes that lumpectomy (or partial mastectomy) alone is a reasonable treatment option.

Indications for radiation
Indications for radiation treatment are constantly evolving. Patients treated in Europe have been more likely in the past to be recommended adjuvant radiation after breast cancer surgery. Radiation therapy is usually recommended for all patients who had (lumpectomy, quadrant-resection). Radiation therapy is usually not indicated in patients with advanced (stage IV disease) except for palliation of symptoms like bone pain.

In general recommendations would include:
 * As part of breast conserving therapy when the whole breast is not removed (lumpectomy or wide local excision)
 * After mastectomy: Patients with higher chances of cancer recurring because of conditions such as a large primary tumor or involvement of four or more lymph nodes.

Other factors which may influence adding adjuvant radiation therapy:
 * Tumor close to or involving the margins on pathology specimen
 * Multiple areas of tumor (multicentric disease)
 * Microscopic invasion of lymphatic or vascular tissues
 * Microcopic invasion of the skin, nipple/areola, or underlying pectoralis major muscle
 * Patients with <4 LN involved, but extension out of the substance of a LN
 * Inadequate numbers of axillary LN sampled

Types of radiotherapy
Radiotherapy can be delivered in many ways. The most common delivery method is linear accelerators.

There have been many improvements in the techniques that deliver radiation to the breast. One such new technology is using IMRT (intensity modulated radiation therapy), in which the radiation oncologist can change the shape and intensity of the radiation beam at different points across and inside the breast. This allows for a more focused beam of radiation directed at the tumor cells and leaves most of the healthy tissue unaffected by the radiation.

Another new procedure involves a type of brachytherapy, where a radioactive source is temporarily placed inside the breast in direct contact with the tumor bed (area where tumor was removed). This technique is called a Mammosite and is currently undergoing clinic trials.

New technology has also allowed more precise delivery of radiotherapy in a portable fashion &mdash; for example in the operating theatre. Targeted intraoperative radiotherapy (TARGIT) is a method of delivering therapeutic radiation from within the breast using a portable X-ray generator called Intrabeam. It is undergoing clinical trials in several countries to test whether it can replace the whole course of radiotherapy in selected patients. It may also be able provide a much better boost dose to the tumor bed and appears to provide superior control. This will be tested in a TARGIT-B trial.

Side effects of radiation therapy
The side effects of radiation have decreased considerably over the past decades. Aside from general fatigue caused by the healthy tissue repairing itself, there will probably be no side effects at all. Some patients develop a suntan-like change in skin color in the exact area being treated. As with a suntan, this darkening of the skin will fade with time. Other side effects experienced with radiation include the fact that radiation therapy can and often does cause permanent changes in the color and texture of skin, in addition to:


 * reddening of the skin
 * muscle stiffness
 * mild swelling
 * tenderness in the area
 * long-term shrinking of the irradiated breast

The use of adjuvant radiation has significant potential effects if the patient has to later undergo breast reconstruction surgery. Fibrosis of chest wall skin from radiation negatively affects skin elasticity and makes tissue expansion techniques difficult. Traditionally most patients are advised to defer immediate breast reconstruction when adjuvant radiation is planned and are most often recommended surgery involving autologous tissue reconstruction rather than breast implants.

Systemic therapy
Systemic therapy uses medications to treat cancer cells throughout the body. Any combination of systemic treatments may be used to treat breast cancer. Systemic treatments include chemotherapy, immune therapy, and hormonal therapy.

Chemotherapy
Chemotherapy (drug treatment for cancer) may be used before surgery, after surgery, or instead of surgery in those patients who are unsuitable for surgery.

See breast cancer chemotherapy.

Hormonal treatment
Patients with estrogen receptor positive tumors will typically receive hormonal therapy after chemotherapy is completed. Typical hormonal treatments include:


 * Tamoxifen is typically given to premenopausal women to inhibit the estrogen receptors
 * Aromatase inhibitors are typically given to postmenopausal women to lower the amount of estrogen in their systems
 * GnRH-analogues
 * ovarian ablation or suppression is used in premenopausal women

Targeted therapy
In patients whose cancer expresses an over-abundance of the HER2 protein, a monoclonal antibody known as trastuzumab (Herceptin ®) is used to block the activity of the HER2 protein in breast cancer cells, slowing their growth. In the advanced cancer setting, trastuzumab use in combination with chemotherapy can both delay cancer growth as well as improve the recipient's survival. More recently, several clinical trials have also confirmed that in the adjuvant setting i.e. postoperative following breast cancer surgery, the use of trastuzumab for up to one year also delays the recurrence of breast cancer and improves survival.

Antiangiogenic therapy
A commercially available monoclonal antibody that blocks the activation of the VEGF receptor, bevacizumab, underwent testing in a randomized clinical trial whose preliminary results were announced by the National Cancer Institute in 2005. The preliminary data indicated that bevacizumab delays disease progression for up to five months over conventional chemotherapy, but survival was no better. Genentech, manufacturer of bevacizumab, has filed a supplemental biological application with the FDA for approval of bevacizumab in the setting of metastatic breast cancer, on the strength of the improvement in progression-free survival.

Protein tyrosine phosphatase 1B (PTP1B)
In the March 2007, edition of the scientific journal, Nature Genetics, researchers from Canada's McGill University reported that they have developed a potential drug target for treating up to 40 percent of breast cancers by blocking an enzyme called protein tyrosine phosphatase 1B (PTP1B), which has been implicated in the onset of breast cancer in mouse models of the disease. Elevated levels of PTP1B have also been found in diabetes and obesity. A drug to block the activity of PTP1B is under development by Merck, and was found to delay the development of breast tumors and prevent lung cancer up to two months from the administration of the drug. The researchers hope to continue further research in mouse models which are also HER-2 positive (responsive to Herceptin) so that the drug could benefit a significant population of women.

Flax seeds
Preliminary research into flax seeds indicate that flax can significantly change breast cancer growth and metastasis, and enhance the inhibitory effect of tamoxifen on estrogen-dependent tumors.

Traditional Chinese medicine
The use of traditional Chinese medicine to treat breast cancer has been claimed, but no successful clinical trials have yet been reported.

Personalization with gene expression profiling
Recently, the acceleration of gene expression profiling research has made available additional markers to predict disease recurrence. Beyond conventional TNM staging, doctors can now order a gene expression profile on tumors to predict whether a breast cancer patient will have a high chance of developing breast cancer again. There are currently 2 commercial tests on the market, MammaPrint and Oncotype DX. Oncotype DX is not used in every clinical setting; for example, in a patient with positive lymph nodes who is a candidate for chemotherapy, the test would not change therapy decisions. The most useful setting for Oncotype DX testing is where there are negative lymph nodes, and the benefit of chemotherapy is felt to be small. In up to 10% of patients, there will be disease recurrences, but treating every patient with chemotherapy is overkill. In this setting, a high-risk score on the Oncotype DX can help doctors decide whether to recommend chemotherapy.