Prognostic and Predictive Factors
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.
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.
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.
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.
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.
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.
|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|
|MX:||Distant metastases cannot be assessed|
|M0:||No distant metastases|
|In Situ Cancer|
|Early Stage Invasive Cancer|
|Advanced Stage Invasive Cancer|
|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.