Locally advanced and inflammatory breast cancer

INTRODUCTION — Breast cancer is the most common female cancer in the United States, the second most common cause of cancer death in women (after lung cancer), and the primary cause of death in women ages 45 to 55. Early detection and treatment can often lead to a cure. Cure is most likely in women whose breast cancers are confined to the breast, while a substantial number of women whose tumors have spread to the local lymph nodes in the armpit (also called the axilla) can also be cured with appropriate therapy.

Occasionally, a breast cancer will not be discovered until it is fairly large or locally advanced. The term locally advanced breast cancer (LABC) is used to describe a breast cancer that has progressed locally but has not yet spread beyond the breast and regional lymph nodes. LABC includes large breast tumors (more than 5 centimeters in diameter), those that involve the skin of the breast or the underlying muscles of the chest wall, and cancers that have extensive involvement of the regional lymph nodes (those located in the axilla or in the soft tissues above and below the collarbone). It also includes inflammatory breast cancer, a rapidly growing type of cancer that makes the breast appear red and swollen (hence the term inflammatory).

Although the likelihood of curing LABC is lower than it would be if the cancer were small and confined to the breast, cure is possible with aggressive treatment. In most cases, this requires a combination of chemotherapy, radiation therapy, and surgery.

This topic review will cover the treatment of locally advanced breast cancer, including inflammatory breast cancer. Breast cancer is a very complex topic. An introduction to breast cancer and an overview of available treatments is available elsewhere. (See "Patient information: Breast cancer guide to diagnosis and treatment").

SIGNS AND SYMPTOMS

Locally advanced breast cancer (LABC) — Most LABCs can be felt (palpated) by both the patient and her doctor; they may also be visible. A careful physical examination of the breasts, skin of the chest, and regional lymph nodes (in the axilla and above the collarbone) is the first step in evaluation.

LABC is suspected if the tumor measures more than 5 cm across, or if it is fixed or attached to the underlying muscles or overlying skin of the chest wall. The finding of skin nodules on the affected breast, lymph nodes above or below the collarbone (called supraclavicular and infraclavicular nodes), or axillary lymph nodes that are non-movable and either attached to the underlying tissues (fixed) or to each other (matted) also suggests LABC.

Inflammatory breast cancer — Inflammatory breast cancer (IBC) is a specific type of LABC which produces a unique set of symptoms. IBC often does not produce a distinct mass or lump that can be felt within the breast. Instead, it causes thickening and swelling of the skin of the breast, which may be reddened and warm to the touch (show picture 1 and show picture 2). The breast is often painful and enlarged, and appears inflamed.

IBC may initially be confused with other inflammatory breast conditions, particularly infections. For example, women who are breastfeeding may develop a breast abscess or mastitis, which can produce symptoms similar to IBC. However, these conditions are usually associated with a fever and other evidence of infection (such as an increase in the number of white blood cells) that distinguish them from IBC.

DIAGNOSIS AND STAGING — Once the diagnosis of a breast cancer is suspected, several procedures must be done to confirm the diagnosis and establish the extent of tumor involvement, both within the breast and elsewhere in the body.

Mammogram — A mammogram of both breasts is needed to visualize the extent of tumor involvement within the breast and to make certain that the opposite breast is unaffected. Other tests such as a breast magnetic resonance imaging (MRI) study or ultrasound may be recommended (show radiograph 1).

Biopsy of the tumor — In order to confirm the diagnosis and type of breast cancer, a biopsy is required. A needle biopsy of the tumor, performed in the office, is usually sufficient to obtain enough tissue for the pathologist to study under the microscope.

The pathologist will also perform other tests to determine if the tumor is making hormone receptors and a protein called Her2 (also called erbB-2). These two factors are important in selecting the best treatment.

Hormone receptors — About 50 to 70 percent of breast cancers require the female hormone estrogen (estradiol) to grow; other breast cancers are able to grow without estrogen. Estrogen-dependent breast cancer cells produce molecules called hormone receptors, which are essential for the cell to use estrogen for growth. These hormone receptors can be estrogen receptors (ER), progesterone receptors (PR), or both.

If hormone receptors are present within a breast cancer, women are significantly more likely to benefit from treatments that lower estrogen levels or block the actions of estrogen, thus depriving the cancer cells of the material that stimulates their growth. These treatments are referred to as endocrine or hormone therapies, and such tumors are referred to as "hormone-responsive". In contrast, women whose tumors do not contain any ER or PR do not benefit from adjuvant hormone therapy.

HER2 expression — HER2 is a protein that is present on about one-third of breast tumors. The finding of HER2 within an individual breast cancer is an important indicator of benefit from a drug called trastuzumab (See "Trastuzumab (Herceptin®)" below).

Staging workup — Once the diagnosis of breast cancer is established, additional studies are performed to stage the cancer (determine how far it has spread). The stage of a breast cancer is based upon tumor size, involvement of the skin, chest wall or regional lymph nodes, and whether the cancer has spread to the bones or other organs (called metastasis).

The following studies may be recommended to search for evidence of spread to other organs: Blood tests, including a complete blood count and liver function tests Bone scan Chest X-ray or CT scan CT scan of the abdomen and pelvis CT scan or magnetic resonance imaging (MRI) of the brain A PET scan

After a complete evaluation, the size and extent of the breast tumor, type and extent of lymph node involvement, and the presence or absence of spread to other organs are grouped together to form the stage grouping of a breast cancer, which ranges from stage I to IV. A description of each stage is provided in table 1 (show table 1) Locally advanced breast cancer is stage III disease, and the presence of IBC makes the cancer a stage IIIB cancer

In contrast, women who have stage I or II breast cancer are referred to as having early stage disease, while stage IV means that spread to other organs has taken place.

Staging the axilla — The majority of patients with LABC have lymph nodes or glands that can be felt or palpated in the axilla by their physician. For the minority who do not have palpable axillary nodes, formal assessment of these nodes is often considered before beginning therapy. Knowing if the lymph nodes in the axilla are involved with the cancer can influence the choice of therapy. Surgery to remove some or all of these lymph nodes is the only accurate way to determine if the cancer has spread to the axillary lymph nodes.

Complete removal of the axillary lymph nodes (called axillary lymph node dissection or ALND), has traditionally been a routine component of the management of breast cancer. However, one of the most feared complications of ALND is swelling of the arm (called arm edema), the severity of which depends on the extent of the ALND and the use radiation therapy of the axilla. Thee need to accurately identify women who have involved lymph nodes while minimizing the chance of arm swelling led to the development of the sentinel node biopsy technique. (See "Patient information: Lymphedema after breast cancer surgery").

Sentinel node biopsy — The sentinel lymph node (SLN) concept is based on the premise that tumor cells that have broken off from a breast tumor first involve one or a few lymph nodes before involving other nodes or spreading elsewhere. To identify this node, the surgeon injects dye, a radioactive material, or a combination of both into the area surrounding the tumor, where it enters lymphatic channels and then flows to lymph nodes. If an SLN is identified, it is removed and examined under the microscope. If this node is negative, the chance of the other axillary nodes being also negative is good, and such women may not need a full axillary lymph node dissection. In contrast, if the SLN is positive, there is a good chance that other nodes will contain tumor cells, and a full ALND is usually performed.

Sentinel node biopsy is only appropriate for women who do not have evidence or suspicion of involved lymph nodes on physical examination. In such cases, a full axillary dissection is needed.

Guidelines from the American Society of Clinical Oncology recommend against the routine use of sentinel node biopsy for large breast cancers (>5 cm), tumors that are fixed or attached to the skin or chest wall, and inflammatory breast cancers [1]. This recommendation was largely based upon the lack of published studies in these groups of women. However, many clinicians feel that SLN biopsy is an acceptable way of assessing the status of the axillary lymph nodes in patients with a large breast cancer (> 5 cm) who do not have enlarged axillary lymph nodes on physical examination, as long as the tumor is not fixed to the skin or underlying chest wall and there is no inflammatory component.

For patients who undergo a sentinel node biopsy for LABC, the timing of the procedure is also controversial; there is no consensus as to the best approach. Most clinicians (including the authors) perform SLN biopsy prior to beginning therapy for the LABC in order to guide later management of the axillary nodes. If the SLN is negative, a full ALND is not performed at the time of surgery, and instead the axilla is radiated. If the SLN is positive, a full ALND is done at the time of surgery.

TREATMENT OF LOCALLY ADVANCED BREAST CANCER — LABC is most often treated with combined chemotherapy, surgery, and radiation therapy. Another term for combination treatment such as this is multimodality therapy. Studies suggest that when a combined approach is used, approximately 50 percent of women with LABC will be long-term survivors and possibly cured of their breast cancer.

Chemotherapy — Chemotherapy refers to the use of medicines to stop or slow the growth of cancer cells. Chemotherapy works by interfering with the ability of rapidly growing cells (like cancer cells) to divide or reproduce themselves. Because most of an adult's normal cells are not actively growing, they are not affected by chemotherapy, with the exception of bone marrow (where the blood cells are produced), the hair, and the lining of the gastrointestinal tract. Temporary effects of chemotherapy on these and other normal tissues cause the majority of side effects during treatment.

In most cases, chemotherapy includes a combination of two or more drugs, most often given intravenously (IV). These combinations are referred to as regimens. The drugs themselves are usually not administered daily but periodically, in cycles. A cycle of chemotherapy refers to the time it takes to administer the individual drug components of each regimen and then allow the body to recover from the effects of the medicines. A cycle of chemotherapy typically ranges from two to four weeks.

Preoperative chemotherapy — For most women with LABC, chemotherapy is the first component of the treatment. It is given before surgery is performed to remove the breast tumor. Preoperative (also called neoadjuvant) chemotherapy can successfully shrink the breast tumor, and in as many as one-third of cases, it completely removes all traces of the cancer from the breast and lymph nodes. This is termed a complete clinical response. Successful shrinkage of a large breast tumor can increase a woman's options for subsequent surgery. As an example, it might allow selected women to consider breast conserving surgery in which only the tumor is removed (lumpectomy) rather than total removal of the breast (mastectomy). (See "Surgery and radiation therapy" below).

The type of chemotherapy and the duration of treatment before surgery is variable. No one particular chemotherapy regimen has been shown to be best for treatment of LABC. A typical treatment course might include four cycles of a chemotherapy combination containing an anthracycline (eg, doxorubicin) followed by four cycles of a regimen containing taxanes (eg, paclitaxel or docetaxel). Although the entire course of chemotherapy is often administered prior to surgery, it may be divided between the preoperative and postoperative periods.

Hormone therapy — As noted above, breast cancers that produce hormone receptors are responsive to hormone therapy. In some cases, hormone therapy may be used instead of chemotherapy as the initial treatment for a LABC.

Preoperative hormone therapy — The preoperative (neoadjuvant) use of hormone therapy can successfully shrink breast cancers that are hormone-responsive. However, the likelihood of achieving a complete clinical response seems to be lower than that found with chemotherapy. Because hormone therapy is generally better tolerated than chemotherapy (and can be given by mouth rather than intravenously), it may be recommended for elderly women whose organ function is impaired, patients who want to avoid chemotherapy-related toxicity, or those who are physically debilitated.

Postoperative (adjuvant) hormone therapy — For most women with hormone-responsive LABC, hormone therapy is usually recommended after surgery for five or more years. When hormone therapy (or chemotherapy) is given after surgery, it is referred to as adjuvant therapy, and its purpose is to eliminate any tumor cells that remain in the body (often termed micrometastases) following surgery.

Adjuvant hormone therapy is usually started after the entire course of chemotherapy is finished because of concerns that the two treatments will counteract each other if given together. However, hormone therapy can be started during the radiation treatment.

Trastuzumab (Herceptin®) — Trastuzumab (Herceptin) is a unique drug that works by a different mechanism than chemotherapy. It is an antibody that specifically targets a protein called HER2, which is present on the cells of some breast cancers. About 20 percent of breast cancers express very high levels of this marker, and trastuzumab appears to be effective only in this group of women (see "HER2 expression" above).

Interest in using trastuzumab in women with LABC has increased because of information that suggests that adding trastuzumab to chemotherapy in women with earlier stage (stage II) breast cancers that produce high levels of the protein HER2 improves their chances of surviving their breast cancer. (See "Patient information: Adjuvant chemotherapy and trastuzumab (Herceptin) for early stage breast cancer").

Initial reports of neoadjuvant trastuzumab treatment are encouraging [6]. However, this approach is still considered investigational since data on long-term outcome and safety are lacking. In addition, the best way to incorporate trastuzumab into neoadjuvant chemotherapy for women with LABC is unknown.

Surgery and radiation therapy — Following chemotherapy, tests are performed to assess how the tumor responded to treatment. A physical examination and repeat imaging studies (using mammography, breast ultrasound, or MRI) are conducted to measure the extent of disease that remains in the breast and regional lymph nodes. Breast surgery may then be performed.

Breast-conserving surgery (such as a lumpectomy) is an option for many women with LABC, as long as they do not have inflammatory breast cancer (see "Inflammatory breast cancer" belowsee "Inflammatory breast cancer" below). Mastectomy (total removal of the breast) is necessary if skin involvement has not regressed following chemotherapy or if the tumor is still fixed to the underlying chest wall (show figure 1).

After surgery, radiation therapy to the remaining breast tissue (on the side where the tumor was located) is necessary for women who have undergone breast conserving therapy. This substantially decreases the chance that the tumor will return or recur in the remaining breast tissue.

In addition, chest wall radiation therapy may be recommended to women who have undergone a mastectomy, particularly if they have a large number of involved axillary lymph nodes or inflammatory breast cancer. Studies show that using both surgery and radiation therapy decreases the chance that the breast cancer will return (recur) locally in the breast or the chest wall.

INFLAMMATORY BREAST CANCER — The treatment of inflammatory breast cancer is similar to that of other types of LABC. Multimodality therapy involving chemotherapy, surgery, and radiation therapy is generally recommended as it is associated with the best outcomes. As with other forms of LABC, two types of chemotherapy agents (anthracyclines and a taxane) are usually used.

One difference in the treatment of IBC is that mastectomy is usually recommended, rather than breast-conserving surgery, even if there was a good response to neoadjuvant chemotherapy. Following mastectomy, chest wall and regional lymph node radiation therapy is strongly recommended as a part of postoperative management.

WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.

This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.

A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. National Cancer Institute

1-800-4-CANCER
(www.nci.nih.gov)
People Living With Cancer: The official patient information

website of the American Society of Clinical Oncology
(http://breastca.asco.org)
National Comprehensive Cancer Network

(www.nccn.org/patients/patient_gls.asp)
American Cancer Society

1-800-ACS-2345
(www.cancer.org)
National Library of Medicine

(www.nlm.nih.gov/medlineplus)
Susan G. Komen Breast Cancer Foundation

(www.komen.org)


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