~Breast Cancer, Part 3 - Prognostic and Predictive Factors

PROGNOSTIC AND PREDICTIVE FACTORS

  • Axillary Lymph Nodes
  • The Sentinel Node Biopsy
  • Tumor Size and Lymph Node Status
  • Tumor Grade
  • Hormone Receptors
  • HER2 Gene Overexpression
  • p53 Gene Mutation
  • ras Mutation
  • BRCA1 and BRCA2 Mutations
  • Aggressive Tumors
  • Staging


Once cancer is diagnosed, there are several tests performed on lymph node or tumor tissue that can be useful in determining a woman's prognosis and for assessing the type of treatment that will be most effective for her specific breast cancer. The issue of which factors are the most reliable at determining a woman's prognosis and predicting her outcome to certain treatments is perpetually under study. As research progresses, certain factors will fall in and out of favor. Only when found to be accurate and reliable does a factor become a part of standard practice. Commonly assessed prognostic and predictive factors include lymph node status, tumor size, and tumor grade, type of cancer, hormone receptor status, proliferation rate, and HER2/neu (also known as erbB2 expression).

Axillary Lymph Nodes

Lymph nodes are simply small clumps of immune cells acting as filters for the lymphatic system. Like the circulatory system, the lymphatic system runs throughout the body carrying fluid, cells, and other material. When breast cancer spreads, the first places it usually goes is to the axillary lymph nodes in the armpit. The best prognosis is when the cancer remains localized within the breast. Once the cancer spreads beyond the breast, the prognosis worsens.

There are two ways to determine node status. The first method consists of palpating the axillary lymph nodes during a physical examination. If the nodes are enlarged, it is possible that cancer has spread. This method, while fast and convenient, is not very accurate. It has both a 30% false negative and a 30% false positive rate (Harris et al. 1997).

The second method is removal of the nodes from under the armpit in a procedure called an axillary dissection. The nodes are then examined to determine whether or not they contain cancer. This procedure may be performed at different stages of a woman's treatment. However, a standard axillary dissection is typically performed during removal of the breast tumor, and approximately 10-25 lymph nodes are also removed from tissue layers under the armpit.

When an excisional biopsy serves as definitive surgery, the axillary dissection may be performed at the same time or as a separate procedure. Many surgeons now try to perform both procedures together to eliminate the need for separate surgery, anesthesia, and recovery. However, regardless of when the procedure is performed, the node samples are sent to a pathologist for analysis. If the samples do contain cancer, the pathologist will carefully note the number of cancerous nodes and their order and location, from proximal (closest to the breast) to distal (farthest away from the breast).

The Sentinel Node Biopsy

The sentinel node biopsy is a procedure that finds and removes the first (or sentinel) node from the tumor site and examines it to see if it contains cancer cells. If the sentinel node is cancer free, it's likely that the other axillary nodes are cancer free as well (Turner et al. 1997). However, if the sentinel node is positive for cancer, there is a strong likelihood that other nodes may also be involved, and a standard axillary dissection may be required (Weaver et al. 2000).

In order to locate the sentinel node, a colored dye and/or radioactive-labeled tracer is injected into the breast near the tumor. A device called a scintillation counter determines which lymph node is the first node to take up the dye or tracer. This node is then surgically removed and sent to a pathologist for examination.

The advantages of this procedure are that, when done correctly, it is accurate, less traumatic, and it allows axillary dissections to be done on only those women whose sentinel nodes present positive for cancer.

The disadvantages of the procedure are that it is fairly new, not widely available, and its accuracy depends in large part on the training of the surgeon doing the procedure (Haigh et al. 2000). Several ongoing clinical trials will ultimately determine whether sentinel node biopsy becomes part of the standard diagnostic procedure for breast cancer (Barnwell et al. 1998; Krag et al. 1998; McNeil 1998; Haigh et al. 2000). However, the integration of sentinel node biopsy into contemporary clinical practice is underway (Schwartz et al. 2001).

Tumor Size and Lymph Node Status

Based on numerous studies, there appears to be a strong correlation between tumor size and lymph node involvement. Research demonstrates that the larger the breast tumor, the more likely it is that the lymph nodes will be positive for cancer (Carter et al. 1989). One study of 644 women with tumors 2 cm or smaller found that only 11% of the women with tumors 0.1-0.5 cm in size had axillary lymph node involvement. However, when tumors 1.7-2.0 cm were found, more than 40% of the women had axillary lymph node involvement. The prognosis for breast cancer is related to the size of the tumor. Tumor size can be determined by touch during a physical examination, through imaging with an ultrasound or mammography, or most accurately through post-surgical examination of the tumor. In general, the larger the tumor size, the poorer the prognosis.

Tumor Grade

The grade of a tumor is used to determine how fast a cancer may spread to the lymph nodes or other areas of the body. A pathologist microscopically examines biopsied tissue, determining how closely the cancer cells resemble normal tissue. The less the tumor cells resemble normal tissue, the higher the tumor grade. The pathologist will also assess the rate of cancer cell division. Rapidly dividing cells indicate accelerated tumor growth and therefore a higher tumor grade. Tumor grades are determined as Grade I, or low; Grade II, or medium; and Grade III, or high. Tumor grade is considered directly related to prognosis: the higher the grade, the poorer the prognosis.

Hormone Receptors

An important aspect in any reproductive cancer is whether the tumor growth is hormonally driven. Often breast tumors require hormones for growth, i.e., hormonally responsive tumor. The hormones attach to their receptor sites and promote cell proliferation. Hormone receptor-positive tumors consist of cancer cells with receptor sites for estrogen, progesterone, or both. The receptor status of a tumor is determined by testing tissue removed during a biopsy. Breast cancer can be categorized by its receptor status, which can be estrogen receptor-positive (ER+), estrogen receptor-negative (ER -), progesterone receptor-positive (PR+), progesterone receptor-negative (PR-) or any combination thereof. Both estrogen and progesterone are naturally occurring hormones that the body produces in varying amounts throughout one's lifetime. These hormones are essential for many other physiological functions, such as bone integrity, which will be discussed later in this protocol.

Treatment to block the hormones from attaching to the tumor receptor sites may slow or stop the cancer's growth. The drug most often used in this type of treatment is tamoxifen, which is very effective against receptor-positive cancers. Tamoxifen will be discussed extensively later in this protocol.

HER2 Gene Overexpression

HER2 (human epidermal growth factor receptor 2) is a gene found in every cell of the human body, and its purpose is to help a cell divide. The HER2 gene tells a cell to form the HER2 protein on the cell surface. HER2 protein then receives a signal to send a message to the center of the cell, known as the nucleus, that it is time to divide. The HER2 protein is also called the HER2 receptor.

Each healthy breast cell contains two copies of the HER2 gene, which contribute to normal cell function. When a change occurs that causes too many copies of the HER2 gene to appear in a cell, the gene, in turn, causes too many HER2 proteins, or receptors, to appear on the cell surface. This is referred to as HER2 protein overexpression. Patients who are considered HER2-positive have cancer that grows and spreads more rapidly.

HER2 protein overexpression affects about 25% of breast cancer patients and results in a more aggressive form of the disease and earlier disease reappearance; in these cases the disease may not be as responsive to standard therapies. The HER2 status of a tumor is determined by testing tissue removed during a biopsy.

Herceptin may be considered by breast cancer patients whose tumors over-express the HER2 gene (Nihira 2003).

p53 Gene Mutation

The p53 protein is a tumor suppressor encoded by the p53 gene, whose mutation is associated with approximately 50-60% of human cancers. The p53 gene acts as the guardian of DNA and, in the event of DNA damage, it performs several crucial functions. The p53 gene acts as a checkpoint in the cell cycle inducing growth arrest (halting the cell cycle) by increasing the expression of the p21 gene. It initiates DNA repair. If the DNA can be repaired, the p53 gene prevents apoptosis (programmed cell death), or if the DNA cannot be repaired, it initiates apoptosis. The p53 protein also plays a role in the transcription ("reading") of DNA by binding to and initiating the expression of multiple genes.

When a mutation in the p53 gene occurs, one amino acid is substituted for another and p53 loses its ability to block abnormal cell growth. Indeed, some mutations produce a p53 molecule that actually stimulates cell division and promotes cancer. These cancers are more aggressive, more apt to metastasize, and more often fatal.

People inheriting only one functional copy of the p53 gene from their parents are predisposed to cancer in early adulthood. Usually several independent tumors develop in a variety of tissues. This is a rare condition known as Li-Fraumeni syndrome. The p53 gene has been mapped to chromosome 17p13, and mutations in the p53 gene are found in most tumor types and contribute to the molecular events that lead to tumor formation.

Since the hallmark of cancer is the unchecked proliferation of cells, the role of p53 is critical. The question then becomes, if the p53 gene is a built-in tumor suppressor, why does cancer still develop? The answer is that the p53 molecule can be inactivated in several ways. As discussed earlier, in some families p53 mutations are inherited and family members have a high incidence of cancer. More often, the p53 molecule is inactivated by an outside source.

In the cell, p53 protein binds DNA, which in turn stimulates another gene to produce a protein called p21 that interacts with a cell division-stimulating protein (cdk2). When p21 binds with cdk2, the cell cannot pass through to the next stage of cell division. Mutant p53 can no longer bind DNA in an effective way, and as a consequence the p21 protein is not made available to act as the "stop signal" for cell division. Thus, cells divide uncontrollably and form tumors. DNA tumor viruses, such as the human adenovirus and the human papilloma virus can bind to and inactivate the p53 protein function, altering cells and initiating tumor growth. In addition, some sarcomas amplify another gene, called mdm-2, which produces a protein that binds to p53 and inactivates it, much the way the DNA tumor viruses do.

The amount of information that exists on all aspects of p53 normal function and mutant expression in human cancers is vast, reflecting its key role in the pathogenesis of human cancers. It is clear that p53 is just one component of a network of events that culminate in tumor formation.

ras Mutation

The ras oncogenes often governs the regulation of cancer cell growth. The ras family is responsible for modulating the regulatory signals (mitogen activated protein kinase (MAPK) signal transduction cascade) that govern the cancer cell cycle and proliferation. The Ras protein also plays a role in initiating a number of other signal transduction cascades, including phosphoinositide (PI) kinase, and the activation of protein kinase C (PKC). Inhibition of Ras protein action is important because ras induces the expression of the MDM2 gene, whose protein serves to inhibit the activity of the p53 protein. In this way, ras activity reduces the ability of the p53 protein to induce cell death (apoptosis) in cancer cells. Mutations in genes encoding ras proteins have been intimately associated with unregulated cell proliferation of cancer. Further, since ras protein plays an important role in multiple signal transduction pathways and is overexpressed in a large number of cancers, the inhibition of ras is now considered a goal in cancer treatment (Rowinsky et el. 1999).

BRCA1 and BRCA2 Mutations

BRCA1 and BRCA2 are familial (inherited) gene mutations that have been linked to breast cancer. BRCA1 is a tumor suppressor gene located on the long arm of chromosome 17, and BRCA2 is located on chromosome 13. Tumor suppressor genes play a role in regulating cell growth. When one copy of BRCA1 is inherited in a defective (mutant) form, a woman is predisposed to breast and ovarian cancer. However, BRCA1 mutations do not appear critical for the development of the majority of breast and ovarian cancers. Development of cancer in either organ involves a number of additional mutations, at least one of which involves the other copy (allele) of BRCA1. A woman who inherits one mutant allele of BRCA1 from either her mother or father has a greater than 80% risk of developing breast cancer during her life. While it appears that a high number of currently identified high-risk families have mutations in either the BRCA1 or BRCA2 genes, hereditary breast cancer accounts for only about 5% of all cases of breast cancer.

Testing tumors in women with breast cancer for the BRCA1 gene could increase the effectiveness of chemotherapy dramatically. Cancer cells with functional BRCA1 are highly resistant to one type of chemotherapy but extremely sensitive to another. In laboratory tests tumor cells react differently to anti-cancer agents depending on the BRCA1 gene activity. A functioning BRCA1 gene made tumor cells more than 1,000 times more sensitive to drugs such as Taxol and Taxotere, which work by blocking the final stage of cell division. The same cells, however, were between 10 and 1,000 times more resistant to drugs like cisplatin that work by damaging DNA within tumors. Assessing a tumor's BRCA1 status may be invaluable in deciding which type of chemotherapy to use.

The BRCA1 gene plays an important role in stopping the development of cancer, and women who inherit a damaged version of this gene have a high risk of developing breast cancer. BRCA1 may also get "switched off" in as many as 30 percent of tumors, even in patients who inherit a normal version of the gene.

Aggressive Tumors

Certain tumors may be classified as aggressive based on a number of prognostic factors, such as tumor type, size, and grade. Typically, an aggressive tumor is one that under microscopic examination shows signs of fast growth and has a high grade. Because aggressive tumors have a greater chance of spreading to other areas of the body and returning after treatment, they are often treated more intensively. One example of an aggressive tumor is inflammatory breast cancer.

Staging

Cancer is classified into stages, which determine treatment and prognosis. There are a number of methods for staging breast cancer. The most widely used is the TNM classification (Tumor, Nodes, Metastases). TNM takes into account the size of the tumor (T), the number of cancerous lymph nodes (N), and whether or not the cancer has spread to other areas of the body (metastasis) (M). The stage of cancer is usually determined twice. The first is clinical staging, which is based on results from a physician's physical exam and tests such as mammography. The second is pathologic staging based on a direct examination of the lymph nodes and a tumor removed during surgery.

Tumor Size
TX:

 

Tumor size cannot be assessed

T0:

 

No tumor can be found

Tis:

 

Only carcinoma in situ

T1:

 

Tumor is 2 cm or smaller

 

 

Subcategories of T1:

 

 

 

 

T1mic:

 

Very small tumor (0.1 cm or smaller)

 

 

T1a:

 

Tumor is larger than 0.1 cm, but no larger than 0.5 cm

 

 

T1b:

 

Tumor is larger than 0.5 cm, but no larger than 1 cm

 

 

T1c:

 

Tumor is larger than 1 cm, but no larger than 2 cm

T2

 

Tumor is larger than 2 cm, but no larger than 5 cm

T3

 

Tumor is larger than 5 cm

T4

 

Tumor is any size, but has expanded past the breast tissue to the chest wall or skin

 

 

Subcategories of T4:

 

 

 

 

T4a:

 

Tumor has expanded to chest wall

 

 

T4b:

 

Tumor has expanded to skin

 

 

T4c:

 

Tumor has expanded to both chest wall and skin

 

 

T4d:

 

Presence of inflammatory carcinoma


Lymph Node Status
NX:

 

Nodes cannot be evaluated. This can happen if, for
example, they have been removed previously.

N0:

 

Axillary nodes do not have cancer

N1:

 

Axillary nodes have cancer, but can be moved

N2:

 

Axillary nodes have cancer and are fixed to each other or
the chest wall (cannot be moved)

N3:

 

Internal mammary nodes have cancer


Distant Metastases
MX:

 

Distant metastases cannot be assessed

M0:

 

No distant metastases

M1:

 

Distant metastases

   

In Situ Cancer

Stage 0:

 

TisN0M0

    

Early Stage Invasive Cancer

 Stage 1:  

 T1N0M0

Stage 2a*

 

T0N1M0

   

T1N1M0

   

T2N0M0

Stage 2b*  

T2N1M0

   

T3N0M0

   

Advanced Stage Invasive Cancer

Stage 3a:  

T0N2M0

   

T1N2M0

   

T2N2M0

   

T3N1M0

   

T3N2M0

Stage 3b:

 

T4, any N, M0

 

 

Any T, N3, M0

   

Metastatic Breast Cancer

Stage 4:  

Any T, any N, M1

*Though classified here as "early stage," prognosis can be poor for some
stage 2 cancers, particularly those with multiple lymph node involvement.


TESTS FOR DISTANT METASTASES

Cancer cells have the ability to leave the original tumor site, travel to distant locations, and metastasize in organs such as the liver, lungs, or bones. The process of metastasis is dynamic and requires an optimal environment in order for a tumor cell to proliferate, invade surrounding tissues, be released into the circulation, adhere to blood vessels in the liver, invade the liver, proliferate, and establish its own blood supply (tumor angiogenesis). This complex process requires interaction of tumor cells with the microenvironment of the liver to the extent that the tumor cell can utilize the growth factors and blood vessels of the liver in order to grow.

In addition to tests for prognostic and predictive factors, women diagnosed with node-positive breast cancer will require a number of tests to confirm that the cancer has not spread to other organs, such as the lungs, liver, and bone. Only about 6% of women when first diagnosed with breast cancer have distant metastases (Ries et al. 2000). Most women found to have metastases have previously been treated for the disease and are experiencing a recurrence.

Symptoms such as shortness of breath, a chronic cough, weight loss, and bone pain may indicate distant metastases. However, only after specific tests can the occurrence of distant metastasis be confirmed or ruled out. The three primary tests performed are blood tests that check for liver and/or bones metastasis, bone scans to test for bone metastasis, and x-ray/CT scans to test for chest, abdomen, and liver metastasis. Based on the results of the primary tests and the symptoms the woman experiences, further testing may be required.

Common Tests for Distant Metastases

X-rays. An x-ray is a test in which an image is created using low doses of radiation reflected on film paper or fluorescent screens providing an image of specific areas. The films created by x-rays show different features of the body in various shades of gray. The darkest images are those areas that do not absorb x-rays well; the lighter images are dense areas (like bones) that absorb more of the x-rays. To enhance visibility, some x-ray exams will use a contrasting solution that can be swallowed, injected intravenously into the circulatory system, or given by an enema to locate or confirm possible metastases.

Computer Axial Tomography (CAT or CT) scan. This procedure combines the use of a digital computer together with a rotating x-ray device to create detailed cross-sectional images, or "slices," of the different organs and body parts. This procedure may or may not involve injecting an intravenous contrasting solution into the circulatory system. It does, however, always involve exposure to ionizing radiation. A CAT scan has the unique ability to image a combination of soft tissue, bone, and blood vessels and can assist in locating possible metastasis.

Magnetic Resonance Imaging (MRI). MRIs involve no ionizing radiation and can be used for precise imaging of any organ suspected of having metastases. This is a special imaging technique used to image internal structures of the body, particularly the soft tissues. An MRI image is often superior to a normal x-ray image. In an MRI exam, the patient passes through a tunnel surrounded by a magnet, which polarizes hydrogen atoms in the tissues and then monitors the summation of the energies within living cells.

A computer tracks the magnetism and produces a clear picture of the tissues, particularly soft tissues. Images are very clear and are particularly good for soft tissue, brain, and spinal cord, joints, and abdomen. These scans may be used for detecting some cancers or for following their progress. Positron Emission Tomography (PET). A highly specialized imaging technique using short lived substances such as simple sugars (glucose), which are labeled with signal emitting tracers (18-fluoro-deoxyglucose (18-FDG)) and injected into the patient. A scanner records the signals these tracers emit as they travel through the body and collect in various organs targeted for examination. Although all cells use glucose, more glucose is used by cells with increased metabolism such as tumor cells, which use more glucose than neighboring cells, and thus, they are easily seen on the PET scan. PET uses a camera that produces powerful images to reveal metastasis that other imaging techniques simply cannot detect. This technique is very sensitive in deciphering and picking up active cancer cells or tumor tissue but does not measure size. PET can follow the course of cancer through the body and accurately show the extent of the disease. PET can differentiate between normal tissue, scar tissue, and malignant cancerous tissue. Ultrasound. Very high frequency sound waves are used to produce an image of many of the internal structures in the body without exposure to ionizing radiation. This is highly operator-dependent and is thought to be useful in diagnosis but not particularly accurate in the assessment of tumor response. For the latter, CT or MRI scans are more accurate. Intraoperative ultrasonography is useful in the detection of liver metastases.

Bone Scan. A bone scan is a nuclear medicine study of the body skeleton used to look for cancer, stress fractures, and other bone or joint problems. It does not measure bone density and is not used to diagnose osteoporosis. This procedure uses a radioisotope tracer (Technetium-99m MDP or HDP) injected intravenously into the circulatory system. This radioactive compound localizes in the bone and the distribution of the radioactivity in the body is recorded by the radionuclide scanner (better known as a gamma or scintillation camera), producing an image of the tracer's distribution in the skeletal system. This recording can reveal the presence of bone metastases.

Bone Density. Since excessive bone breakdown releases tumor growth factors into the bloodstream that can fuel cancer growth, a bone density scan and a test that can be used to assess bone resorption rates should be regularly performed for cancer patients. All bone density scan measurements with the exception of ultrasound use small doses of radiation to determine the amount of bone present.

DPD. The deoxypyridinoline (DPD) cross-links urine test (Pyrilinks-D) can be used to assess bone resorption rates; this test should be done every 60-90 days to detect bone loss in patients with cancer that has a proclivity to spread to bone. A QCT bone density scan should be done annually. Every cancer patient should take a bone-protecting supplement to protect against excess bone breakdown. For information regarding maintaining bone integrity refer to the protocol Cancer Treatment: The Critical Factors.

QCT. Quantitative Computed Tomography, or QCT Densitometry (often referred to as a QCT bone density scan) is a method used to measure bone mass. The principle underlying QCT densitometry and other bone mass measurements (such as DXA) is that calcified tissue will absorb more x-rays than surrounding tissue so that the CT density measurement can be used to measure total bone mass within a sample of tissue. With proper technique, precision for the conventional (2D) method is 2-3%, and about 1% for 3D QCT, so monitoring patients at yearly intervals yields clinically useful results. Only QCT isolates the metabolically active bone for analysis. The QCT examination is performed on any modern CT scanner and takes approximately 10 minutes. Insurance companies and Medicare may reimburse for QCT examinations.

DXA. DXA stands for dual x-ray absorptiometry. It was previously known as DEXA, dual energy x-ray absorptiometry. Low dose x-rays of two different energies are used to distinguish between bone and soft tissue, giving an accurate measurement of bone density at these sites. However, DXA also includes aortic calcification and osteophytes in the calculation of bone mineral. Lateral DXA, has been shown to have a sensitivity intermediate between the high sensitivity of QCT and the somewhat lower one of conventional DXA (used for detection of osteoporosis), but it uses 4-10 times the radiation exposure, is less precise, and the study time is increased compared to conventional DXA/QDR.

Blood Tests. A variety of blood tests can assess the health of different organs and systems in your body. "Cancer marker" tests can detect possible cancer activity in the body. If cancer is present, it can produce specific protein in the blood that can serve as a "marker" for the cancer. CA 15.3 is the name of a protein used to find breast and ovarian cancers, although it is important to note that there may be insufficient quantities of this protein present in the blood to ensure early stage breast cancer detection. Creatine-kinase-BB serves as a marker for breast, ovarian, colon, and prostate cancers. CEA (carcinoembryonic antigen) is a marker for the presence of colon, lung, and liver cancers and a marker for secondary breast and ovarian cancer sites. CA125 may signal ovarian cancer and secondary breast and colorectal cancer sites. TRU-QUANT and CA 27.29 are other examples of proteins associated with the recurrence of breast cancer (more information on tumor markers will follow). Blood tests should evaluate for the presence of anemia or hepatic dysfunction, both of which can be consequences of the patient抯 underlying cancer.

Continued . . .


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