Treatment of Breast Cancer

Overview of Treatment Options for Breast Cancer

Hormone Therapy for Breast Cancer

Hormone therapy works by blocking the estrogen that causes cell division. It is used for adjuvant therapy and for advanced cancers in patients with hormone receptor positive tumors. Over the past few years, many new anti-estrogen agents have become available. They generally act in one or more of the following ways:

  • Blocking the hormone receptor itself
  • Suppressing estrogen production
  • Destroying the ovaries (which produce estrogen)
Types of Hormone Therapy

  • Selective Estrogen Receptor Modulators (SERMs) - SERMs resemble estrogen in their chemical appearance and trick the breast cancer cells into accepting it in place of estrogen. Unlike estrogen, however, they do not stimulate breast cancer cell growth. Tamoxifen (Nolvadex) has been the standard hormonal agent used for breast cancer. Other SERMs being studied for breast cancer include toremifene, idoxifene, and droloxifene.

    • Tamoxifen may be used for any cancer stage in women of all ages who have hormone receptor-positive cancers. In addition, it is being used protect against cancer in high-risk women. When used as adjuvant therapy for early stage hormone receptor positive breast cancer, tamoxifen is for a total of five years as tolerated. Taking it longer appears to provide no additional advantages. Patients whose tumors are hormone receptor-negative do not benefit from tamoxifen.

    • The most concerning side effect is an increased risk for blood clots, which can, in rare cases, be life-threatening. There also appears to be an increased risk for uterine cancer. Other side effects include hot flashes, vaginal bleeding and discharge, and visual disturbances.

  • Aromatase Inhibitors - These agents block aromatase, an enzyme that is a major source of estrogen in many major body tissues, including the breast, muscle, liver, and fat. These agents are showing great promise for breast cancer and do not have the same risks as tamoxifen (blood clots and uterine cancer). Aromatase inhibitors are classified as either _ nonsteroidal_ or steroidal agents.

    • Nonsteroidal Aromatase Inhibitors - The nonsteroidal aromatase inhibitors include anastrozole (Arimidex) and letrozole (Femara) which are used for patients with advanced breast cancer with hormone-receptor positive tumors. Anastrozole may be used for early breast cancer treatment in postmenopausal women. These agents have fewer side effects, but seem to be as effective as tamoxifen. Another newer nonsteroidal agent, vorozole (Rivisor) is currently being investigated.

    • Steroidal Aromatase Inhibitors - The steroidal aromatase inhibitors include exemestane (Aromasin - given orally) and formestane (Lentaron - given by injection). Exemestane is used in metastatic breast cancer for postmenopausal women who do not respond to tamoxifen.

  • Selective Estrogen Receptor Downregulators (SERDs) - Selective estrogen receptor downregulators (SERDs) block estrogen in all tissues in the body. This class of medications includes fulvestrant (Faslodex) which has showen to be as effective as anastrozole in delaying time to disease progression in women with advanced breast cancer. Side effects are generally gastrointestinal problems and hot flashes.

  • Progestins - Progestins, particularly megestrol (Megace), have been used in the treatment of advanced breast cancer when tamoxifen fails. Side effects include weight gain.

  • Ovarian Ablation - This is the process of shutting down estrogen production by the ovaries. This can be accomplished chemically with medications or it can be done by removing the ovaries surgically or by destroying them with radiation. Risks include the development of osteoporosis, but a number of therapies are available that can help prevent bone loss.

    • Chemical Ovarian Ablation - The primary agents used are luteinizing hormone-releasing hormone (LHRH) agonists, such as goserelin (Zoladex). These drugs block the release of the reproductive hormones LH-RH, which results in the cessation of ovulation and estrogen production. Studies are now suggesting that women with estrogen-positive early stage cancer who take goserelin have similar survival rates to those who are treated with standard chemotherapy and they experience fewer serious side effects.

Chemotherapy for Breast Cancer

Chemotherapy is treatment with cancer-killing drugs that may be given intravenously or orally to reach cancer cells that may have spread beyond the original site of the tumor.

The decision to offer chemotherapy is based on the size of the tumor, grade of the tumor, the presence or absence of lymph node involvement and the risk of developing a spread of the cancer in the future. Chemotherapy can also be used as the primary treatment for women whose cancer has already metastasized (spread outside the breast and underarm area) at the time of diagnosis, or if it spreads after initial treatments.

Adjuvant therapy is the use of chemotherapy following surgery to kill any undetected cancer cells so as to reduce the risk of recurrence and increase the chance of cure.

Neoadjuvant therapy is the use of chemotherapy before surgery with the goal of shrinking large tumors so that they are able to be removed by lumpectomy instead of mastectomy. Neoadjuvant chemotherapy also allows the doctors to see how the cancer responds to chemotherapy. If the tumor does not shrink, then different chemotherapy drugs may be substituted.

Chemotherapy drugs are given in cycles, with each period of treatment followed by a recovery period. The usual course of chemotherapy lasts between 3 to 6 months.

In most cases, chemotherapy is most effective, either as an adjuvant or neoadjuvant therapy, when combinations of more than one chemotherapy drug are used together.

The most commonly used combinations of chemotherapeutic agents for the treatment of breast cancer are:

  • CMF - cyclophosphamide (Cytoxan), methotrexate (Amethopterin, Mexate, Folex), and fluorouracil (Fluorouracil, 5-FU, Adrucil)

  • CAF - cyclophosphamide (Cytoxan), doxorubicin (Adriamycin), and fluorouracil (Fluorouracil, 5-FU, Adrucil)

  • AC - doxorubicin (Adriamycin) and cyclophosphamide

  • TAC - docetaxel (Taxotere) concurrent with AC

  • AC -->T - doxorubicin (Adriamycin) and cyclophosphamide (Cytoxan) followed by paclitaxel (Taxol) or docetaxel (Taxotere)

  • Doxorubicin (Adriamycin), followed by CMF

  • CEF - cyclophosphamide (Cytoxan), epirubicin (Ellence), and fluorouracil (with or without docetaxel)

  • TC - cyclophosphamide (Cytoxan) and Docetaxel (Taxotere)

  • GT - gemcitabine (Gemzar) and paclitaxel (Taxol)

Some other chemotherapy drugs used for treating women with breast cancer include carboplatin (Paraplatin), cisplatin (Platinol), vinorelbine (Navelbine), capecitabine (Xeloda), pegylated liposomal doxorubicin (Doxil), and albumin-bound paclitaxel (Abraxane).

In March 2007, the FDA approved a new drug called Tykerb (lapatinib) for women with advanced breast cancer who have failed to respond to treatment with other drugs such as taxanes, anthracyclines, and trastuzumab (Herceptin). Tykerb is a pill that is taken once a day and is used in conjunction with capecitabine (Xeloda). Tykerb, like Herceptin, targets a protein known as HER-2/neu that is overexpressed (overproduced) by about 25% of all breast cancer tumors. Both Tykerb and Herceptin are approved for women with advanced HER-2 positive breast cancer. Tykerb is now considered an option for women whose breast cancer fails to respond to Herceptin after a period of time. Because Tykerb is a newly approved drug, it is not yet known whether women being treated with a combination of Tykerb and Xeloda will survive longer than those receiving Xeloda alone.

Side Effects of Chemotherapy

The side effects of chemotherapy depend on the type of drugs, the amount taken, and the length of treatment. The severity of side effects varies from person to person.

Temporary side effects might include fatigue, nausea and vomiting, loss of appetite, hair loss, and mouth sores, depression and changes in the menstrual cycle. Anemia (low red blood cell count which can cause fatigue), neutropenia (low white blood cell count which can increase risk of infection), and thrombocytopenia (low platelet count which can lead to bruising or bleeding) are the most common side effects due to damage of the blood-producing cells of the bone marrow. Very effective medications are available to help treat or relieve most side effects.

Permanent side effects may include premature menopause and infertility, difficulty in concentration and memory (which may persist for 1-2 years, but then usually resolves).

In rare instances, a life-threatening cancer of the while blood cells called acute myelogenous leukemia may develop 1-2 years after treatment for breast cancer.

Surgery for Breast Cancer

Discussions regarding surgical treatment of breast cancers must take into consideration reproductive issues, psychosocial issues, and body image.

Breast-Conserving Surgery

Breast-conserving surgery approach entails surgery to remove the breast cancer but not the breast itself. Types of breast-conserving surgery include:

  • Lumpectomy - removal of the breast lump
  • Quadrantectomy - removal of one quarter, or quadrant, of the breast
  • Segmental mastectomy - removal of the cancer as well as some of the breast tissue around the tumor and the lining over the chest muscles below the tumor
Mastectomy

  • Simple Mastectomy - (also known as Total Mastectomy) - The entire breast is removed, but the axillary lymph nodes are left intact. No muscles are removed from beneath the breast. Occasionally, lymph nodes may be removed because they are actually located within the breast tissue taken during surgery. A total mastectomy is appropriate for women with ductal carcinoma in situ or DCIS, and for women seeking prophylactic (preventative) mastectomies to prevent any possibility of breast cancer occurring.

  • Modified Radical Mastectomy - This is the most common type of mastectomy - The entire breast is removed in addition to some of the axillary lymph nodes in the underarm area (axillary dissection)

  • Radical Mastectomy - This procedure includes removal of the entire breast, all of the axillary lymph nodes, and the chest wall muscles under the breast. These days, radical mastectomy is usually only performed when cancer has spread to the chest muscles under the breast.

  • Skin-Sparing Mastectomy - This procedure removes the nipple and areola and most of the breast tissue, but leaves the majority of the skin of the breast intact to accommodate reconstruction

  • Nipple-Sparing Mastectomy - This is a type of skin-sparing mastectomy that leaves the natural nipples intact (only if they are free of cancer cells).

Ovariectomy

An overiectomy is the surgical removal of the ovaries which produce the estrogen that is needed for breast cancers to grow. Its use has resulted in some improvement in breast cancer survival rates in some premenopausal women whose tumors are hormone receptor-positive. In these women, combining this procedure with tamoxifen may improve results beyond those of standard chemotherapies. Ovariectomy does not benefit women after menopause, and its advantages can be reduced in women who have already received adjuvant chemotherapy. The procedure causes sterility and may not be an optimal choice in younger women.

Side Effects of Surgery

Possible side effects of mastectomy and lumpectomy include wound infection, hematoma (accumulation of blood in the wound), and seroma (accumulation of clear fluid in the wound).

If axillary lymph nodes are removed, a condition called lymphedema may develop which involves swelling and tightness of the arm on the affected side. This condition occurs in 25% to 30% of women who undergo removal of the lymph nodes in this area. Sometimes the swelling is temporary lasting only a few weeks. Sometimes, however, the swelling persists.

Other side effects may include temporary or permanent limitations in arm and shoulder movement, and numbness of the skin on the upper, inner arm (resulting from damage to the nerve that controls sensation in this area).

Breast Reconstruction

Some women are comfortable wearing a prosthetic to achieve a more natural appearance under clothing following removal of a breast. However, some prefer to undergo reconstruction of the breast which is a surgical procedure to rebuild the breast contour and if desired, the nipple and the areola.

Generally, breast reconstruction is completed in 3 stages over 6-8 months. This initial surgery forms the breast mound without a nipple. Further surgery refines the shape and size and creates nipples. Tattooing is used to create the appearance of the areola.

Breast reconstruction may be performed immediately after mastectomy (which may result in better cosmetic results) or can be delayed months or even years.

In general, there are two methods for performing breast reconstruction:

  • Implants - Implants filled with saline or silicone are placed under the skin to provide shape and volume. The first step involves placement of a tissue expander under the chest muscles which are gradually inflated with saline over a period of weeks to gently stretch the skin and muscles. A later surgical procedure in performed to replace the expanders with implants. Implants are not permanent and must eventually be removed or replaced anywhere from 1 to 15 years after reconstruction.

  • Muscle Flap - This procedure entails using skin and fatty tissue from the back, buttocks or abdomen to surgically recreate the breast. Because the procedure uses the person's own tissue, it feels and moves more naturally, however, the surgery is complex and requires significant recovery time. Additional surgery refines the breast shape and creates the nipple.

Radiation Therapy

Radiation therapy is treatment with high-energy rays that destroy cancer cells. This treatment may be used to destroy cancer cells that remain in the breast, chest wall, or underarm area after surgery. In some cases, the area treated by radiation therapy may also include supraclavicular lymph nodes (nodes above the collarbone) and internal mammary lymph nodes (nodes beneath the sternum or breast bone in the center of the chest).

Radiation therapy is usually recommended after mastectomy if:

  • The tumor is larger than 5 centimeters
  • The area around the tissue that is removed (margin) is positive for cancer
  • Four or more lymph nodes are involved
  • The cancer is present in more than one location within the breast

When given after surgery, radiation is usually delayed for several weeks to allow time for healing of the incision and surrounding tissues. Radiation therapy is usually delayed until chemotherapy is complete.

Radiation therapy may also be used to treat areas of metastatic disease (such as lung, liver, brain or bone) for palliation (relief of symptoms) such as pain.

In general, there are two major types of radiation therapy:

  • External beam radiation - the source of the radiation comes from outside the body and is produced by a special machine
  • Brachytherapy - a radiactive source is placed inside the body
External Beam Radiation Therapy

External beam radiation treatments are generally given five days a week for about six to eight weeks on an outpatient basis. The initial appointment may take up to 2 hours to allow for treatment planning and placement of markings where the radiation beam is to be directed. After that, each treatment appointment takes about 15 minutes.

  • Whole Breast Irradiation - This is the standard approach for radiation therapy for breast cancer. Additional "Boost Irradiation" doses may be administered to the tumor site ("bed") to reduce the risk of local recurrence after surgery, such as lumpectomy.

  • Electron Intraperative Therapy (ELIOT) is the application of high dose radiation during surgery following removal of the tumor. Advantages to this approach include the fact that it does not irradiate the skin and other breast, and radiation exposure to the lungs and heart is greatly reduced.

Brachytherapy

Brachytherapy, also known as internal or interstitial radiation, is another way to deliver radiation therapy. Radioactive "seeds" are placed directly into the breast tissue next to the cancer. Often this is used to add an extra "boost" of radiation to the tumor site. This method is also being studied in clinical trials as the only source of radiation for women who have had lumpectomy. This is not yet considered a standard treatment, but studies thus far have been promising.

Mammosite is a method of brachytherapy where a balloon that is attached to a thin tube is inserted into the lumpectomy space and is filled with saline solution. Radioactive material is inserted through the tube into the balloon for a brief time and is then removed. This is done twice daily for 5 days. Once treatment is completed, the balloon is deflated and removed.

Partial Breast Irradiation is a new, experimental approach which may be administered via external beam or brachytherapy. It allows treatment over a much shorter period of time (5 days total) and to only the part of the breast with the cancer. It is hoped that partial breast irradiation will prove to be equal to the current, standard whole breast irradiation. However, this technique is still experimental.

Side Effects of Radiation Therapy

The main side effects of external beam radiation therapy are swelling and heaviness in the breast, sunburn-like skin changes in the treated area, and fatigue. These changes to the breast tissue and skin usually abate in 6 to 12 months. There may also be some aching in the breast and, rarely, a rib fracture due to weakening of the bone.

Radiation therapy of axillary lymph nodes can cause lymphedema (swelling of the arm on the affected side). A rare complication is the development of another cancer called angiosarcoma. It is treated with mastectomy but can be life-threatening.

Transplantation Procedures

A transplantation procedure may be used as adjuvant therapy in some women with a high risk of breast cancer recurrence or for treatment of advanced disease.

  • Peripheral Blood Stem Cell Transplantation - Before chemotherapy is initiated, a sample of immature blood cells are collected and frozen for later transplantation back into the person. These stem cells are then re-injected after treatment is complete to help the bone marrow recover and continue producing healthy blood cells.

  • Bone Marrow Transplantation (BMT) - This technique entails removal of a sample of bone marrow which is then frozen. Following treatment with chemotherapy and/or radiation, the marrow is thawed and re-injected intravenously to help with recovery of healthy blood cells.

Immunotherapy for Breast Cancer

Immunotherapy stimulates the body's own immune system to help fight the caner. Monoclonal antibody (MAb) therapy is a form of passive immunotherapy because it uses antibodies made in the lab rather than by a person's own immune system. Although only monoclonal antibodies have been approved for immunotherapy against breast cancer so far, many other forms of treatment are under study.

  • Trastuzumab (Herceptin) is a monoclonal antibody that attaches to a growth-promoting protein known as HER2/nue. Too much of this protein can cause cancer to grow and spread faster. Herceptin can stop the protein from causing this growth as well as help the immune system to attack the cancer more effectively. Trastuzumab is used to treat breast cancer that is HER2-positive and has spread after treatment with other drugs. It is also used with other anticancer drugs to treat HER2-positive breast cancer after surgery.

Bevacizumab (Avastin) is a monoclonal antibody that slows blood vessel growth in tumors and has been shown to be helpful when used along with chemotherapy in some women with advanced breast cancer.

Other forms of immunotherapy under investigation include:

  • Interferons and interleukins, usually in conjunction with tumor vaccines or immunotoxins.

  • Autologous vaccine therapy has been shown to lengthen remission and survival times of some women with early breast cancer.

  • A HER2/neu peptide (a small part of the protein made by the HER2/neu gene), used as the antigen in a vaccine, has been shown to cause an increased immune response against the HER2/neu receptor on cancer cells.

Bisphosphonates

These medications may be used to help prevent fractures and reduce pain in persons whose disease has spread to the bone. Examples of commonly used biphosphonates include:

  • Clodronate (Bonefos; Ostac; Clasteon)
  • Pamidronate (Aredia)

There have been reports of a few serious side effect from bisphosphonates, including deterioration and pain in the jaw bone. The reason for this is unknown, however, it seems to occur in patients who have had dental work done while on the drugs. Therefore, dental work should be done before starting treatment with biphosphonates.