Breast Cancer

Breast cancer is the most common type of cancer among women in the United States, accounting for more than a quarter of all cancers in women. Approximately 2.5 million women in this country are breast cancer survivors, and an estimated 192,370 new cases of breast cancer will be diagnosed in women in 2009. Breast cancer can also develop in men, but this is rare; the disease will be diagnosed in approximately 1,900 men in 2009.

The rate of new cases (known as incidence) of breast cancer varies according to race/ethnicity. The incidence is highest among white women and lowest among American Indian/Alaska Native women. However, the death (mortality) rate is highest among black women. This high rate is related to the greater number of black women (compared with white women) who have more advanced cancer at the time of diagnosis. Better use of breast cancer screening by women in minority populations would provide a greater chance for increased survival.

As with all cancers, the development of breast cancer starts from just one genetically abnormal cell. This abnormal cell divides and multiplies rapidly to become a mass of cells, or a tumor. As the tumor grows, it develops a blood supply to help sustain its growth. Cells may break off a large tumor and travel through the blood system to nearby lymph nodes (tiny, bean-shaped organs that are part of the immune system); lymph nodes near the breast are located under the arm, in the neck, and just above the collarbone. Tumor cells can also travel to other parts of the body; this spread of cancer is known as metastasis. The most common sites of breast cancer metastasis are the bones, lungs, and liver.

Breast cancer screening with mammography and routine clinical breast examinations are important for detecting breast cancer early, before the tumor invades a large amount of breast tissue or tumor cells travel beyond the breast. The earlier a breast cancer is found, the greater the chance is for treatment to be effective.

Approximately 90-95% of all breast cancers are sporadic, which means that they occur by chance. The remaining 5-10% of breast cancers are caused by inherited abnormalities in genes, known as genetic mutations. The primary breast cancer-related genetic mutations are BRCA1 and BRCA2 mutations. When breast cancer is diagnosed in a young individual (less than 50 years), or when one or more members of a family have breast cancer or a related hereditary cancer (ovarian, colorectal, or endometrial cancer), other family members may have inherited BRCA1 or BRCA2 mutations, which increases their risk for breast cancer. Genetic counselors can help a woman determine whether genetic testing is appropriate for her or her family members.

There are several different types of breast cancer, depending on the area of the breast tissue in which cancer cells first grow (Table 1). Nearly all breast cancers begin in the milk-carrying ducts or the milk-producing lobes. Breast cancer is defined as either noninvasive or invasive (or infiltrating); noninvasive cancer remains in the place where it originated, while invasive cancer has the potential to extend to other breast tissue and areas beyond the breast (see figure).

Most breast cancers begin in the ducts; these breast cancers are called ductal carcinomas. Ductal carcinoma in situ (DCIS) is cancer that is confined to the duct. Tumors that arise in the lobes are called lobular carcinoma. Lobular carcinoma that is confined to the lobes is known as lobular carcinoma in situ (LCIS), but this condition is not considered to be cancer; it is, however, a risk factor for cancer. When LCIS is diagnosed, close monitoring should be done to check for early signs of breast cancer. Many less common types of breast cancer also exist (Table 1).

The type of breast cancer according to the tissue in which it originates is referred to as its histologic classification. While this classification remains important, the availability of tumor markers and genetic profiling technology has led to the classification of molecular subtypes of cancer according to such tumor markers as estrogen and progesterone receptors (ER and PR) and human epidermal growth factor receptor 2 (HER2). The presence or absence of these tumor markers has become a major factor in selecting treatment and determining prognosis (outcome).

Table: Types of Breast Cancer
 

Screening mammography and clinical breast examinations are done to check for lumps or other signs that may indicate breast cancer. Detection of a lump is just the first step in the diagnosis of breast cancer. Next steps may involve imaging studies and/or a biopsy to determine whether the lump is benign or malignant; if the lump is cancer, a range of subsequent tests are done to identify tumor markers of breast cancer, such as estrogen and progesterone receptors, human epidermal growth factor receptor-2 (HER2), and others. Advances in technology now also enable testing the tumor for its genetic profile, which provides important information about the possibility of recurrence.

One of the most important factors in planning treatment is the extent of disease. Your physician and a pathologist will work together to determine the stage and grade of the tumor. If there are signs that cancer has spread beyond the breast, other imaging studies may be done to determine the location of metastasis.

Taken together, the results of tumor marker testing, the genetic profile, and the stage and grade of disease allow oncologists to practice personalized cancer medicine; that is, to develop a treatment plan that targets the unique characteristics of an individual’s tumor. The patient’s age and general health also contribute to the selection of “best” therapy.

Although mammography can show the presence of a lump or abnormality in the breast tissue, the test cannot distinguish between a benign or malignant lump. Magnetic resonance imaging (MRI) may be done to provide more details about a suspicious area on a mammogram, and an ultrasound can help distinguish between a fluid-filled cyst (benign) and a solid mass (possibly a cancerous tumor).

A biopsy is the only way to confirm that a lump is a breast cancer. With this procedure, the oncologist or a consulting surgeon removes a sample of cells or tissue from the lump or the entire lump itself. A pathologist will examine the biopsy sample under a microscope to see if signs of cancer are present. There are three types of biopsy:

• Fine-needle aspiration: removal of fluid or some cells from the lump using a thin needle
• Cone needle: removal of tissue from the lump using a wider needle or newer instruments
• Surgical: removal of the entire lump (excisional) or only part of it (incisional)

Fine-needle aspiration is the least invasive method for obtaining cells from a suspicious lump in the breast; it is most often done for a lump that was felt during a clinical breast examination. This type of biopsy is best for distinguishing between a fluid-filled cyst and a solid mass. Tissue samples can be obtained with a core needle biopsy, and this method is the one commonly used for biopsy of a lump that was detected on mammography or another imaging study. If the findings on examination of a sample obtained with a needle biopsy are inconclusive, then a surgical biopsy offers the opportunity to obtain the greatest amount of tissue from the lump. If the entire lump and a rim of normal breast cancer tissue around it are removed during surgical biopsy, the procedure is actually a form of breast cancer treatment (lumpectomy).

The type of biopsy actually done depends on several factors, such as the size or location of the lump, and physicians prefer to use the least invasive method possible.

The diagnosis of breast cancer is changing as new ways to examine tumors continue to be discovered. Tumor markers and genetic profiling testing are being used to classify breast cancer according to what is known as the molecular subtype. The distinction between these subtypes is important, as they play a role in selecting the best combination of treatments and because the subtypes differ with regard to outcomes such as the length of time without progression of disease and survival. Estrogen and progesterone receptors (ER and PR) and HER2 are the primary markers currently used in classifying subtypes. The subtypes include:

• Estrogen receptor ER-positive, PR-positive, and HER2-negative
• HER2-positive
• ER-negative, PR-negative, HER2-negative (referred to as triple negative)
• Normal breast-like

Estrogen and Progesterone Receptors

Estrogen and progesterone, female hormones in the body, can affect how a breast cancer grows. These hormones send signals to special receptor cells that are inside normal breast cells and may be present on breast cancer cells as well. The signals prompt the receptor cells to “turn on” the growth of cells. When the level of these receptors is high on breast cancer cells, the breast cancer is said to be sensitive to estrogen or progesterone, meaning that the hormones have helped send signals to the tumor to divide and grow. Breast cancers are classified as ER positive or negative and PR positive or negative based on the presence or absence of receptors on the breast cancer cells. The ER or PR status is further defined with a number from 1-3 to indicate the density of receptors.

About two-thirds of breast cancers have at least one of these receptors. The prognosis for ER-positive and/or PR-positive breast cancers is good because they are more likely to respond to hormone treatment, such as anti-estrogen agents, that suppress the production of hormones in the body. Hormone treatment is used to help prevent recurrence of breast cancer when the tumor is ER-positive and/or PR-positive.

ER and PR testing must be accurate to ensure that a woman receives hormone treatment only when it will be effective. The American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN)—two organizations of oncology specialists—have established guidelines in which it is recommended that ER and PR testing be done on all invasive breast cancers. The NCCN guideline also recommends that the ER and PR status be determined for ductal carcinoma in situ (DCIS), but the ASCO guideline states that there is insufficient evidence to recommend the routine determination of ER/PR status in cases of DCIS. Both ASCO and NCCN recommend that ER and PR testing be done only by approved methods at accredited facilities. You should talk to your doctor about the accuracy of your ER and PR testing results and whether testing should be repeated for verification.

HER2

HER2 is a specialized protein that is present on the surface of breast cells and breast cancer cells. The gene related to this protein is the HER2/neu gene. A breast cancer is said to be HER2-positive when the protein or copies of the gene is present at high levels. High levels are associated with tumors that grow and spread faster and with an increased likelihood that cancer will recur after treatment. About one in five breast cancers has increased levels of the HER2 protein or gene.

ASCO and the College of American Pathologists (CAP) established a joint clinical practice guideline about HER2 testing, recommending that the HER2 status be determined for all invasive breast cancers; the NCCN also recommends that this testing be done on all invasive breast cancers. Again, ASCO/CAP and the NCCN recommend that testing be done only by approved methods at accredited facilities. You should talk to your doctor about the accuracy of your HER2 results and whether testing should be repeated for verification.

Other Tumor Markers

Several other tumor markers have been investigated for their potential to provide information that will help guide treatment for breast cancer. Currently, the only other two that have been found to offer consistent information are urokinase-type plasminogen activator (uPa) and plasminogen activator inhibitor 1 (PAI-1). These markers can help predict recurrence of breast cancers that are positive for ER and/or PR and that have not spread to lymph nodes. Low levels of uPa and PAI-1 indicate a low risk of recurrence, which means that more treatment to prevent recurrence may not be needed.

The routine use of these markers has not yet been recommended, but the ASCO guideline suggests that they may be of benefit.

Two new tests take advantage of a technology known as gene expression profiling, which allows for several genes in a tumor specimen to be studied at the same time. This type of analysis provides information on the expression (activity) of genes that activate and suppress the development of cancer cells. Researchers have found that the genetic profile of a tumor is related to its behavior; that is, the activity of specific genes can indicate whether the tumor will recur or metastasize. The test is currently valid only for early-stage, ER-positive breast cancers.

One test, Oncotype DX®, evaluates the activity of 21 genes (16 cancer genes and 5 control genes) in a tissue specimen and the activity is calculated as a Recurrence Score® of 0 to 100 points. ER, PR, and HER2 are included in these 21 genes. A low score indicates low risk and a high score indicates high risk of recurrence within 10 years after diagnosis. The Oncotype DX assay has been recommended by both ASCO and the NCCN to predict the risk of recurrence for women with newly diagnosed ER-positive breast cancer that had not spread to the lymph nodes (node-negative). It is performed in paraffin blocks of the tumor, readily available in all hospitals.

The other test, MammaPrint®, is an assay of 70 genes that research has found to be related to distant recurrence of breast cancer. With this test, a tissue specimen from the breast cancer is analyzed for the activity of these 70 genes, and the results indicate either a high or low risk of the cancer recurring within 10 years after diagnosis. Several studies have demonstrated that MammaPrint is a reliable predictor of disease-free survival, and in 2007, the US Food and Drug Administration cleared the test for use in the United States (not a requirement for use). This assay requires fresh tumor tissue or tissue that is frozen shortly after it has been removed from the body.

Oncotype DX® assay had been recommended by both ASCO and NCCN (which publishes treatment guidelines for all types of cancer) as a way to predict the risk of recurrence for women with newly diagnosed ER-positive, node-negative breast cancer. The ASCO statement also notes that the test can be used to identify patients who may be successfully treated with hormone therapy and therefore may safely avoid adjuvant chemotherapy.

The benefit of both MammaPrint and Oncotype DX is that treatment can be tailored—or customized —to the specific risk and needs of each individual woman. In determining the optimum treatment plan, the oncologist will consider the likelihood of recurrence (as identified by either test) as well as traditional factors, such as the size or grade of the tumor. In general, women with a low risk of recurrence can avoid the side effects of chemotherapy and be treated safely with hormone therapy alone. Women with a high risk of recurrence can be treated with adjuvant chemotherapy to help reduce that risk and can be monitored closely to help ensure early intervention if cancer does recur.

Medicare and private health insurance policies generally cover such testing for ER-positive, node-negative breast cancer, but you may want to check with your individual provider.

Stage

The cancer stage defines the extent of disease; there are two types of stage: clinical and pathologic. Your oncologist determines the clinical stage of disease on the basis of your physical examination and the findings on mammography and other imaging studies. The pathologic stage is assigned by the pathologist who examines the biopsy specimen. Sometimes, a final pathologic stage cannot be determined until surgery has been done to remove the breast cancer and nearby lymph nodes.

As with other cancers, breast cancer is classified in stages according to the system developed by the American Joint Committee on Cancer (AJCC). This classification describes the tumor (T) in terms of size and the tissue it has invaded, whether cancer has spread to nearby lymph nodes (N), and whether cancer has metastasized (M) to other parts of the body (Tables 1 and 2). This TNM classification is then used as a foundation for an overall stage of breast cancer.

Breast cancer is described as node-negative if it has not spread to lymph nodes and as node-positive if cancer has spread to lymph nodes. When breast cancer has spread to lymph nodes, it is important to note the number and location of involved nodes, as disease is more extensive the farther away the involved nodes are from the breast. Thus, the categories of N2 and N3 are subclassified according to the location and number of positive lymph nodes.

Table 1: American Joint Committee on Cancer System (AJCC) for Classifying a Breast Cancer Tumor (T)

 *The T1 category is broken down into subcategories (mic, a, b, and c) according to sizes between 0.1 cm and 2 cm. T1mic (microinvasion) is assigned when there is a limited number of cancer cells in the breast tissue. The T4 category is broken down into four subcategories (a-d) because researchers have found that some characteristics correspond to different prognoses (predictions of outcome).

Table 2: American Joint Committee on Cancer System (AJCC) for Classifying Breast Cancer Spread to Lymph Nodes (N)

 The M category indicates whether there is evidence of distant metastasis. This category consists of the following:

• Mx: metastasis cannot be measured or found
• M0:no distant metastasis
• M1: distant metastasis

The presence of metastasis is confirmed by imaging studies. Because the most common sites of metastasis are the lungs, bone, and the liver, a chest x-ray, bone scan, and computed tomography (CT) or MRI of the abdomen may be done to check for signs of cancer spread. A positron emission tomography (PET) scan can help detect metastasis when the physician suspects that cancer has spread but is not sure to which areas of the body.

The overall stage of breast cancer ranges from 0 to IV. Stage 0 breast cancer is noninvasive; that is, cancer cells are found only in the ducts or lobules in the breast (Tis), such as DCIS or lobular carcinoma in situ (LCIS). A breast cancer that is small (T1) and has not spread to the lymph nodes (N0) is classified as stage I disease. Stage II breast cancer is subclassified as either stage IIA or IIB. Stage IIA breast cancer describes one of several situations. The tumor may be small (T1) with spread to the axillary (underarm) lymph nodes (N1), the tumor may be larger (T2) but with no spread to the lymph nodes (N0), or there may be no evidence of a tumor in the breast (T0) but there are cancer cells in the axillary lymph nodes (N1). Stage 0, I, or IIA represent early stage breast cancer.

Later stage disease is defined as stage IIB and stage III disease. Stage IIB describes a medium-size tumor (T2) that has spread to no more than three axillary lymph nodes (N1). Stage IIB also indicates a large tumor (T3) that has not spread to lymph nodes (N0).

Stage III breast cancer is also subclassified. Stage IIIA breast cancer is defined as a tumor that is either smaller than 5 cm (T1 or T2) and has spread to the axillary lymph nodes (N2) or that is larger than 5 cm (T3) and has spread to nearby lymph nodes (N1 or N2). Stage IIIB breast cancer includes locally advanced tumors in the breast with extension to the chest wall, swelling, and ulceration or inflammatory breast cancer (T4), which may or may not have spread to nearby lymph nodes (N0, N1, or N2). Stage IIIC is characterized by extensive spread to lymph nodes (N3); the tumor can be of any size and extension (any T).

Stage IV breast cancer is considered to be advanced disease. The characteristic of this stage is metastasis (any T, any N, M1).

Grade

When examining tissue from an invasive breast cancer, the pathologist will evaluate several features of the breast cancer cells, such as how closely they resemble normal breast cells and how they are arranged in relation to each other, as well as other characteristics. Based on this evaluation, the pathologist will assign a grade of 1, 2, or 3. In general, a tumor of a lower grade is slow growing and less likely to spread, while a tumor of a higher grade is faster growing and more likely to spread. The grade of the tumor is most important when the tumor is small and cancer has not spread to the lymph nodes; in such cases, a low grade is an indicator that additional treatment (other than removal of the tumor) may not be necessary.

Diagnosing breast cancer and identifying all of the characteristics of the tumor are challenging tasks and require the expertise of physician specialists. The accuracy of testing and interpretation of results is essential, as treatment is planned according to the final results. Getting a second opinion from another pathologist with extensive expertise in interpreting breast cancers can be of benefit, especially if there was difficulty or controversy in interpreting the findings. You should be sure to seek the opinion of another pathologist if the pathology report does not contain a definite diagnosis, if you have a rare type of cancer, or if the cancer has already metastasized. Another pathologist’s interpretation can confirm your diagnosis or may suggest an alternative diagnosis. Selecting the best treatment possible for your particular breast cancer depends on accuracy in the pathology diagnosis and staging.

• Agendia: www.agendia.com, MammaPrint (for patients and caregivers)
• American Cancer Society: www.cancer.org, Learn about Breast Cancer, Call 1-800-227-2345 to learn about low-cost mammograms in your area
• Artemis Monthly Breast Cancer Journal: available at www.hopkinsbreastcenter.org/artemis/
• ASCO's patient Web site: www.cancer.net, Breast Cancer: Breast Cancer, Hereditary Breast and Ovarian Cancer, Diagnosis, What to Know: ASCO's Guideline on HER2 Testing for Breast Cancer, What to Know: ASCO's Guideline on Tumor Markers for Breast Cancer
• Book: Be a Survivor – Your Guide to Breast Cancer Treatment, available at www.beasurvivor.com
• Book:  Bigger Than Pink, available at www.biggerthanpink.org
• Book: Navigating Breast Cancer: A Guide for the Newly Diagnosed, available at www.jbpub.com
• Book: Stealing Second Base: A Breast Cancer Survivor’s Experience and Breast Cancer Expert’s Story, available at www.jbpub.com
• Book: The Handbook of Humor, Survivor Stories, Support, and Hope for People with Inflammatory Breast Cancer, available at www.outskirtspress.com/handbookforwomen
• Breastcancer.org: www.breastcancer.org, Your Pathology Report, Oncotype DX Test Helps Make Chemo Decisions for Women with ER-Positive Cancer
• Centers for Disease Control and Prevention: www.www.cdc.gov/cancer/NBCCEDP, National Breast and Cervical Cancer Early Detection Program (provides access to breast cancer screening for underserved women
• College of American Pathologists' Web site for consumers: www.mybiopsy.org
• Facing Our Risk of Cancer Empowered: www.www.facingourrisk.org, Hereditary Cancer
• Genomic Health: www.genomichealth.com, Oncotype DX Breast Cancer Assay
• Living Beyond Breast Cancer: www.lbbc.org, The State of Breast Cancer
• National Breast Cancer Coalition: www.stopbreastcancer.org
• National Cancer Institute: www.cancer.gov, What you Need to Know About Breast Cancer; Breast Cancer: Prevention, Genetics, Causes; Inflammatory Breast Cancer: Questions and Answers
• National Society of Genetic Counselors: www.nsgc.org/resourcelink.cfm, Search for counselors in your area
• Susan G. Komen for the Cure: www.komen.org or Komen Breast Care Helpline: 1-877-465-6636

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• Inflammatory Breast Cancer: The Silent Killer
• Mammography Guidelines Debate: To Change or Not to Change
• Methods of Breast Cancer Diagnosis
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• Sheryl Crow Talks About Her Experience with Breast Cancer
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