Breast Cancer

Imaging Techniques

Imaging studies can be an important part of a clinical work-up for breast cancer and are of most benefit when the physical examination, history and symptoms suggest that cancer has spread beyond the breast to lymph nodes or to other parts of the body. These studies can help your doctors better define the size and location of a primary tumor and the extent of disease, essential factors in determining the stage of disease.

Many different imaging techniques can be used to help stage breast cancer, and each has advantages and disadvantages in terms of value in imaging, cost and convenience. Imaging studies are painless, and there are no side effects.

X-rays

Conventional x-rays are typically the first imaging study done because they are a relatively easy, low-cost approach to ruling out metastatic disease. However, if an x-ray shows evidence of metastasis, another imaging study is usually needed to confirm the findings. X-rays are used primarily to rule out evidence of cancer in the lungs, the second most common site of breast cancer metastasis, and may also be used to determine if cancer has spread to the bone, the primary site of metastasis.

Ultrasound

Ultrasound, also known as ultrasonography, of the breast can be useful for evaluating a specific area of suspicion found on mammography and is especially useful for women with very dense breast tissue. Ultrasound of the abdomen may be done to look for cancer in the liver or other abdominal organs.

To perform ultrasound, an ultrasound technician will use a transducer (a small microphone-like instrument) to send sound waves to your body; these sound waves bounce off body tissues and echo into the transducer. The echoes are then converted into images that provide an outline of a part of the body.

Bone Scan

A bone scan is the optimal imaging study to determine whether breast cancer has spread to bone. One advantage of a bone scan compared with x-rays is that a bone scan can provide images of the all the bones in the body at the same time.

Before a bone scan is done, a small amount of a low-level radioactive substance is injected into a vein in your arm. This radioactive substance will collect in areas of metastatic disease in bone. During the scan, you will lie on a table (for about 30 minutes), and a special camera will record images of areas with an increased amount of the radioactive substance. Most of the radioactive substance will be eliminated from your body within 1 day and it will be completely gone within 2 days.

Computerized Tomography (CT)

CT is most often done to verify findings on a chest x-ray or to evaluate the abdominal organs or the brain for signs of breast cancer metastasis.

A CT scan provides three-dimensional, cross-sectional x-ray images, so it can provide more details than a conventional x-ray. A CT scanner takes many pictures of your organs as the table on which you’re laying moves slowly through the scanner. A CT takes longer than a conventional x-ray, and you will need to lie very still while the images are being made. A contrast material may be injected into a vein in your arm before the test to enhance the quality of the images. This contrast material (also referred to as dye) may cause you to feel a brief sense of warmth or flushing in your body. This feeling is normal, but some individuals can allergic to this dye.

Magnetic Resonance Imaging (MRI)

MRI of the breast may be done to look more closely at an area of concern on mammography and/or ultrasound and is especially helpful for women who have dense breast tissue. In addition, the American Cancer Society recommends that breast MRI be used to evaluate the opposite breast after a diagnosis of breast cancer in selected patients. MRI may also be done to look for metastasis in other parts of the body and is especially useful for detecting brain metastasis.

With MRI, images are produced through radiowaves and a powerful magnet linked to a computer. Although MRI is painless, an MRI machine is similar to a large tube, and you will need to lie still on a table within the tube while the MRI machine makes loud, repetitive clicking noises. If you are uncomfortable in closed-in spaces, tell your doctor, as it may be helpful for you to receive medication to decrease anxiety. As with CT scans, contrast material may be used to enhance the images.

Positron Emission Tomography (PET)

PET scans are not usually done as part of the routine work-up for breast cancer for many reasons: the test is expensive, requires special expertise to perform and to interpret the results, and is not available in every medical facility. In addition, PET has limited ability to detect small tumors. However, PET may be done to determine whether breast cancer has spread to the lymph nodes or other parts of the body and is of particular benefit when the findings of other imaging studies are inconclusive.

A PET scan involves the injection of a small amount of a radioactive sugar (or other radioactive substance) into a vein. Breast cancer cells use a high amount of energy and will therefore absorb great amounts of the radioactive sugar. The special camera in a PET scan machine will detect any increased amounts of radioactive sugar and provide an image of an area of metastasis.

A combination of a PET scan and CT scan is increasingly being used in the evaluation of breast cancer. This combination, done in the same testing session, provides a more complete perspective by enabling the radiologist to compare areas of higher radioactivity on the PET scan with the appearance of the same area on the CT scan.

The Importance of Tumor Markers in the Diagnosis & Treatment of Breast Cancer

Tumor markers are substances (usually proteins) that are abnormally expressed in the body when cancer is present. These substances are either produced by cancer cells themselves or by other cells in response to cancer and can be found in the blood, urine or tumor tissue. Tumor markers can serve a variety of purposes; in the breast cancer setting, they are used primarily to help guide treatment decisions and monitor response to treatment. Thus, tumor markers play an important role in personalized treatment, as they enable doctors to classify breast cancer tumors according to what is referred to as a molecular subtype. The distinction between these subtypes is important, as different subtypes are associated with different outcomes such as the length of time without progression of disease, survival and different responses to therapy. Knowing the molecular subtype of your breast cancer tumor allows your doctor to provide a prognosis (prediction of the outcome) and to select treatments that are most likely to be effective.

Primary Tumor Markers

Estrogen and progesterone receptors and HER2 are the primary markers currently used in defining breast cancer according to molecular subtype. Molecular subtypes are still being studied in clinical trials and there is insufficient data to plan according to these subtypes. However, treatment can be planned according to the tumor marker status that is generally associated with each subtype, which include:

• Estrogen receptor-positive (ER+), and/or progesterone receptor-positive (PR+), and HER2-negative (HER2-) (molecular subtype, luminal A)
• ER+, PR+, HER2+ (molecular subtype, luminal B)
• ER-negative (ER-), PR-negative (PR-), HER2- (molecular subtype, triple negative)
• ER-, PR-, HER2+ (molecular subtype, HER2+)

ER and PR

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 in increased amounts in 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 circulating estrogen or progesterone hormones in the body, meaning that the hormones have helped send signals to the tumor to divide and grow. Breast cancers are classified as ER+ or ER- and PR+ or PR- on the basis of the presence or absence of these receptors on the breast cancer cells.

About two-thirds of breast cancers have at least one of these receptors. The prognosis for ER+ and/or PR+ breast cancers is better than that for ER- and PR- tumors because they are more likely to respond to hormone (endocrine) treatment, such as anti- estrogen agents, that inhibit female hormone stimulation of the growth of breast cancer cells.

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.

ASCO, the College of American Pathologists (CAP), 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+ 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 even after chemotherapy. About one in five breast cancers has increased levels of the HER2 protein or gene.

Breast cancers with high expression of HER2 are likely to respond to treatment with an anti-HER2 agent (such as trastuzumab or lapatinib) that prevents HER2 from sending signals to promote the growth of cancer cells.

ASCO and 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. Testing for HER2 status can be done to determine either expression of the protein (by immunohistochemical [IHC] analysis) or by amplification of the gene (by fluorescent in situ hybridization [FISH]). Both are equally reliable, but studies have shown significant variations in the results of HER2 testing in local laboratories. Because of this, 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 (Table 1). Although some tumor markers offer substantial benefits, many have limitations.

Among the other tumor markers used in the breast cancer setting are urokinase-type plasminogen activator (uPa) and plasminogen activator inhibitor 1 (PAI-1), Ki-67, cancer antigen (CA) 15-3 and CA 27.29 and carcinoembryonic antigen (CEA). Currently, only uPa and PAI-1 have been found to offer consistent information. These markers, found in the breast cancer tissue, 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 additional 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. Talk to your doctor about the possibility of testing with these markers.

Ki-67, also known as the Ki-67 proliferation index, is a measure of proliferation, or the percentage of cancer cells that are actively dividing. The Ki-67 index and other markers of proliferation (such as cyclin D, cyclin E, p27, p21, mitotic index, MIB-1, thymidine labeling index, and topoisomerase II) are increasingly being used, in association with ER status, to identify certain subtypes of breast cancer. However, these markers have not been properly standardized and are not consistently reliable as an indicator of prognosis. For this reason, the ASCO guideline notes that the data are insufficient to recommend the use of these markers to assign prognosis.

CA 15-3, CA 27.29, and CEA, found in the bloodstream, are used to monitor response to treatment. If the levels of these markers increase, it may be an indication that the cancer is not responding to treatment. In that case, your doctor may want to change the treatment regimen. However, the results of testing of these markers are not definitive; low levels may not correspond with response, and high levels may be a sign of a condition other than cancer. Because of this, ASCO recommends that these tumor markers should not be used alone to monitor response; rather, they should be used in conjunction with diagnostic imaging, history and physical examination. Used in this way, these tumor markers can help provide a more complete picture of how the cancer is responding.

The levels of these tumor markers are determined before treatment begins, so that your doctor has a baseline against which to compare future levels. Monitoring response usually begins 3-4 months after treatment has begun because levels may be falsely elevated in the first several weeks after the start of treatment. Tumor marker testing is done on a small sample of blood drawn from a vein (usually in the arm).

Table 1. Tumor Markers Used for Breast Cancer

* The National Comprehensive Cancer Network (NCCN) recommends determining the ER/PR status for ductal carcinoma in situ (DCIS), but the American Society of Clinical Oncology (ASCO) guidelines state that there is insufficient evidence to recommend routine determination of ER/PR status to guide treatment decisions for women with DCIS.