Causes of Breast Cancer

Studies continue to uncover lifestyle factors and habits that alter breast cancer risk. Ongoing studies are looking at the effect of exercise, weight gain or loss, and diet on breast cancer risk.

Studies on the best use of genetic testing for BRCA1 and BRCA2 mutations continue at a rapid pace. Other genes that contribute to breast cancer risk are also being identified. This will occur more rapidly now that the human genome has been sequenced.

A large, long-term study funded by the National Institute of Environmental Health Sciences (NIEHS) is now under way to help find the causes of breast cancer. Known as the Sister Study, it will follow 50,000 women for at least 10 years and will collect information about genes, lifestyle, and environmental factors that may cause breast cancer. To be eligible for the study, a woman must:

• live in the United States 
• be between the ages of 35 and 74 
• have a sister (related by blood) who has had breast cancer 
• not have had breast cancer herself

Women who want to find out more about the Sister Study can call 1-877-4-SISTER (1-877-474-7837) or visit the Sister Study Web site (www.sisterstudy.org).

Gene-expression Studies and New Breast Cancer Classifications

One of the mysteries of breast cancer is that doctors cannot always accurately predict which women have a higher risk that their cancer will come back. That is why almost every woman, except for those with small tumors, receives some sort of adjuvant treatment after surgery. To better pick out who will need adjuvant therapy, researchers have looked at many aspects of breast cancers. Scientists have been able to link certain patterns of genes with more aggressive cancers -- those that tend to come back and spread to distant sites. Preliminary studies suggest that some women with favorable patterns might be able to avoid adjuvant therapy after surgery, but most experts feel that more research is needed before this new technology should be used routinely.

Research using sophisticated technology to detect patterns of gene expression has suggested some new ways of classifying breast cancers. The current types of breast cancer are based on appearance of tumors under a microscope. It appears that a new classification, based on molecular features, may be better able than the current classification to predict prognosis and response to several types of breast cancer treatment. The new research suggests there are 4 basic types of breast cancers:

Luminal A and luminal B types: The luminal types are estrogen receptor-positive, usually low grade, and tend to grow slowly. The gene expression patterns of these cancers are similar to normal cells that line the breast ducts and glands (the lining of a duct or glad is called its lumen). Luminal A cancers have the best prognosis. Luminal B cancers generally grow somewhat faster than the luminal A cancers and their prognosis is not quite as good.

HER2 type: These cancers have extra amounts of HER2 DNA, RNA, and protein. They usually have a high-grade appearance under the microscope. These cancers tend to grow rapidly and have a poor prognosis, although they often can be treated successfully with trastuzumab (Herceptin).

Basal type: These cancers lack estrogen or progesterone receptors and have normal amounts of HER2. These are high-grade cancers that grow rapidly and have a poor prognosis. This type is common among women with BRCA gene mutations. For reasons that are not well understood, this cancer is particularly common among young African-American women.

Research continues in this area as scientists look for ways to apply new technology to better understand and improve the treatment of breast cancer.

Chemoprevention

Results of several studies suggest that selective estrogen-receptor modulators (SERMs) such as tamoxifen and raloxifene may lower breast cancer risk in women with certain breast cancer risk factors. But so far, most women are reluctant to take these medications because of concern about possible side effects.

Newer studies are looking at whether or not aromatase inhibitors -- drugs such as anastrozole, letrozole, and exemestane -- can reduce the risk of breast cancer in post-menopausal women. These drugs are already being used as adjuvant hormone therapy to help prevent breast cancer recurrences, but none of them is approved for reducing breast cancer risk at this time. Other drugs are also being studied to reduce the risk of breast cancer. For more information, see the separate American Cancer Society document, Medicines to Reduce Breast Cancer Risk.

Newer Imaging Tests

Several newer imaging methods are now being studied for use in evaluating abnormalities that may be breast cancers.

Scintimammography

In scintimammography, a radioactive tracer (technetium sestamibi) is injected into a vein. The tracer attaches to breast cancer cells and is detected by a special camera. This is a newer technique. Some radiologists believe it is sometimes useful in looking at suspicious areas found by regular mammograms, but its exact role remains unclear. Current research is aimed at improving the technology and evaluating its use in specific situations such as in the dense breasts of younger women.

Tomosynthesis

This technology is an extension of a digital mammogram. Tomosynthesis allows the breast to be viewed as many thin slices and has the possibility of providing a more accurate and earlier diagnosis of breast cancer. This technology is still considered experimental and is not yet commercially available.

Several other newer imaging methods, including thermal imaging (thermography) are discussed in the separate American Cancer Society document, Mammograms and Other Breast Imaging Procedures.

MRI-assisted Breast Biopsy

A new biopsy technique now makes it possible to obtain tissue samples during a vacuum-assisted breast biopsy procedure with magnetic resonance imaging (MRI)-assisted guidance. This method allows many samples to be taken through a single small incision in the skin, using only local anesthesia (numbing of the area). This biopsy technique is being studied in women with a personal or family history of breast cancer, those who have undergone previous breast surgery, and women with dense breast tissue who cannot get accurate screenings with tests such as ultrasound or mammograms.

Treatment

Newer Types of Mastectomy

Newer approaches to mastectomy that attempt to give better cosmetic results are now being studied.

Some studies suggest that a newer procedure known as skin-sparing mastectomy may be as effective as the usual type of modified radical mastectomy for many women. The amount of tissue removed is about the same as with a modified radical mastectomy, but most of the skin over the breast is left intact, with the exception of the nipple and its surrounding areola.

This approach is only used when immediate breast reconstruction is planned. It may not be suitable for larger tumors or those that are close to the skin. Tissues from other parts of the body are used to reconstruct the breast. While this approach is not as well-proven as the more standard type of mastectomy, many women prefer it because it offers the advantage of less scar tissue and a reconstructed breast that seems more natural.

Subcutaneous mastectomy is a newer approach sometimes considered for prophylactic (preventive) mastectomy. In this procedure, the incision is made below the breast. The breast tissue is removed, but the breast skin and nipple are left in place. This procedure leaves less visible scars, but it leaves behind more breast tissue than other forms of mastectomy, so the chances that cancer may develop in the remaining tissue are higher.

An ever newer approach is the nipple-sparing mastectomy. This is similar to the skin-sparing mastectomy in that the nipple and areola are cut away when the breast tissue is removed, but in this approach the nipple and areola are scraped clean of breast tissue and examined by a pathologist. As long as there are no breast cancer cells found close to the nipple and areola, they are then reattached.

Further studies of these techniques are needed to ensure they don't result in an excess risk of cancer developing or returning.

Breast Reconstruction Surgery

Although the number of women with breast cancer choosing breast conservation therapy has been steadily increasing, there are some women who, for medical or personal reasons, choose mastectomy. Some of them also choose to have reconstructive surgery to restore the breast's appearance.

Technical advances in microvascular surgery (reattaching blood vessels) have made free flap procedures an option for breast reconstruction.

For several years, concern over a possible link between breast implants and immune system diseases has discouraged some women from choosing implants as a method of breast reconstruction. Recent studies have found that although implants can cause some side effects (such as firm or hard scar tissue formation), women with implants do not have any greater risk for immune system diseases than women who have not had this surgery.

Similarly, the concern that breast implants increase the risk of breast cancer recurrence or formation of new cancers is not supported by current evidence.

Radiation Therapy

Accelerated partial breast irradiation (APBI): For women who need radiation after lumpectomy, APBI may offer a more convenient way to receive it (as opposed to the standard daily radiation treatments that take several weeks to complete). There are several types of APBI now being studied, including accelerated external radiation schedules, intraoperative radiation therapy (IORT), and intracavitary brachytherapy (MammoSite^®). These are described in more detail in the section "How Is Breast Cancer Treated?" Large studies are under way to determine if these techniques are as effective as standard radiation in helping to prevent cancer recurrences.

Chemotherapy

Dose dense chemotherapy: Some recent research has suggested that giving chemotherapy more often (every 2 weeks) at the usual doses may work better in preventing recurrence than the usual schedule (every 3 weeks). Because of this aggressive schedule, growth factors must be given to prevent low blood counts, a common and serious side effect of chemotherapy. Clinical trials are in progress to define the role of dose density in adjuvant therapy.

New chemotherapy drugs: Because advanced breast cancers are often hard to treat, researchers are looking for newer drugs. One example of a promising experimental drug is ixabepilone. In early studies, this drug has been found to cause a significant percentage of breast tumors to shrink or stop growing, even in some women who have already had several types of chemotherapy.

Targeted Therapies

Targeted therapies are a group of newer drugs that specifically take advantage of gene changes in cells that cause cancer. There are 2 main types of drugs used as targeted therapies – monoclonal antibodies and "small molecule" targeted therapies. Monoclonal antibodies are manmade versions of specific immune system proteins. Trastuzumab (Herceptin) was the first monoclonal antibody drug used to treat women with breast cancer. It works by preventing the HER2/neu protein from promoting excessive growth of breast cancer cells and may also help the immune system fight the cancer. Other monoclonal antibodies that recognize the HER2/neu protein are being tested in clinical trials, as are monoclonal antibodies that block other growth-promoting molecules of breast cancer cells. Lapatinib (Tykerb) is a small molecule targeted therapy taken in pill form, and has recently been FDA approved for use in women with HER2-positive advanced breast cancer whose cancer is growing despite the use of trastuzumab.

Angiogenesis

In order for cancers to grow, blood vessels must develop to nourish the cancer cells. This process is called angiogenesis. Looking at angiogenesis in breast cancer specimens can help predict prognosis. Some studies have found that breast cancers surrounded by many new, small blood vessels are likely to be more aggressive. More research is needed to confirm this.

Bevacizumab (Avastin) is an anti-angiogenesis drug that has shown promise when used in combination with the chemotherapy drug paclitaxel (Taxol) in patients with metastatic breast cancer, although it has not yet been approved for thus use by the FDA.

Other new drugs are also being developed that may be useful preventing new blood vessels from forming. Several of these drugs are now being tested in clinical trials.