How is breast cancer staged?

The stage describes the extent of the cancer in the body. It is based on whether the cancer is invasive
or non-invasive, the size of the tumor, how many lymph nodes are involved, and if it has spread to
other parts of the body. The stage of a cancer is one of the most important factors in determining
prognosis and treatment options.

Staging is the process of finding out how widespread a cancer is when it is diagnosed. Depending on
the results of your physical exam and biopsy, your doctor may want you to have certain imaging tests
such as a chest x-ray, mammograms of both breasts, bone scans, computed tomography (CT) scans,
magnetic resonance imaging (MRI), and/or positron emission tomography (PET) scans. Blood tests
may also be done to evaluate your overall health and sometimes can indicate if the cancer has
spread to certain organs.

The American Joint Committee on Cancer (AJCC) TNM

system
A staging system is a standardized way for the cancer care team to summarize information about how
far a cancer has spread. The most common system used to describe the stages of breast cancer is
the American Joint Committee on Cancer (AJCC) TNM system.

The stage of a breast cancer can be based either on the results of physical exam, biopsy, and
imaging tests (called the clinical stage), or on the results of these tests plus the results of surgery
(called the pathologic stage). The staging described here is the pathologic stage, which includes the
findings after surgery, when the pathologist has looked at the breast mass and nearby lymph nodes.
Pathologic staging is likely to be more accurate than clinical staging, as it allows the doctor to get a
firsthand impression of the extent of the cancer.

The TNM staging system classifies cancers based on their T, N, and M stages:

The letter T followed by a number from 0 to 4 describes the tumor's size and spread to the
skin or to the chest wall under the breast. Higher T numbers mean a larger tumor and/or
wider spread to tissues near the breast.

The letter N followed by a number from 0 to 3 indicates whether the cancer has spread to
lymph nodes near the breast and, if so, how many lymph nodes are affected.

The letter M followed by a 0 or 1 indicates whether the cancer has spread to distant organs --
for example, the lungs or bones.

Primary tumor (T) categories:

TX: Primary tumor cannot be assessed.

T0: No evidence of primary tumor.

Tis: Carcinoma in situ (DCIS, LCIS, or Paget disease of the nipple with no associated tumor mass)

T1 (includes T1a, T1b, and T1c): Tumor is 2 cm (3/4 of an inch) or less across.

T2: Tumor is more than 2 cm but not more than 5 cm (2 inches) across.

T3: Tumor is more than 5 cm across.

T4: Tumor of any size growing into the chest wall or skin. This includes inflammatory breast cancer.

Nearby lymph nodes (N; based on looking at them under a microscope):

Lymph node staging for breast cancer has changed as technology has evolved. Earlier methods were
useful in finding large deposits of cancer cells in the lymph nodes, but could miss microscopic areas
of cancer spread. Newer methods have made it possible to find smaller and smaller deposits of
cancer cells. Experts haven't been sure what to do with the new information. Do tiny deposits of
cancer cells affect outlook the same way that larger deposits do? How much cancer in the lymph
node is needed to see a change in outlook or treatment?

These questions are still being studied, but for now, a deposit of cancer cells must contain at least
200 cells or be at least 0.2 mm across (less than 1/100 of an inch) for it to change the N stage. An
area of cancer spread that is smaller than 0.2 mm (or less than 200 cells) doesn't change the stage,
but is recorded with abbreviations that reflect the way the cancer spread was detected. The
abbreviation "i+" means that a small number of cancer cells (called isolated tumor cells) were seen in
routine stains or when a special type of staining technique, called immunohistochemistry, was used.

The abbreviation "mol+" is used if the cancer could only be found using a technique called RT-PCR.
RT-PCR is a molecular test that can find very small numbers of cells that cannot be seen even using
special stains. However, this test is not often used for finding breast cancer cells in lymph nodes
because the results do not influence treatment decisions.

If the area of cancer spread is at least 0.2 mm (or 200 cells), but still not larger than 2 mm, it is called
a micrometastasis (one mm is about the size of the width of a grain of rice). Micrometastases are
counted only if there aren't any larger areas of cancer spread. Areas of cancer spread larger than 2
mm are known to affect outlook and do change the N stage. These larger areas are sometimes called
macrometastases, but may just be called metastases.

NX: Nearby lymph nodes cannot be assessed (for example, if they were removed previously).

N0: Cancer has not spread to nearby lymph nodes.

N0(i+): Tiny amounts of cancer are found in underarm lymph nodes by using either routine or
special stains. The area of cancer spread contains less than 200 cells and is smaller than
0.2 mm.

N0(mol+): Cancer cells cannot be seen in underarm lymph nodes (even using special stains),
but traces of cancer cells were detected using RT-PCR.
N1: Cancer has spread to 1 to 3 axillary (underarm) lymph node(s), and/or tiny amounts of cancer are
found in internal mammary lymph nodes (those near the breast bone) on sentinel lymph node biopsy.

N1mi: Micrometastases (tiny areas of cancer spread) in 1 to 3 lymph nodes under the arm.
The areas of cancer spread in the lymph nodes are 2 mm or less across (but at least 200
cancer cells or 0.2mm across).

N1a: Cancer has spread to 1 to 3 lymph nodes under the arm with at least one area of cancer
spread greater than 2 mm across.

N1b: Cancer has spread to internal mammary lymph nodes, but this spread could only be
found on sentinel lymph node biopsy (it did not cause the lymph nodes to become
enlarged).

N1c: Both N1a and N1b apply.

N2: Cancer has spread to 4 to 9 lymph nodes under the arm, or cancer has enlarged the internal
mammary lymph nodes (either N2a or N2b, but not both).

N2a: Cancer has spread to 4 to 9 lymph nodes under the arm, with at least one area of
cancer spread larger than 2 mm.

N2b: Cancer has spread to one or more internal mammary lymph nodes, causing them to
become enlarged.

N3: Any of the following:

N3a: either

Cancer has spread to 10 or more axillary lymph nodes, with at least one area of cancer
spread greater than 2mm, OR

Cancer has spread to the lymph nodes under the clavicle (collar bone), with at least one
area of cancer spread greater than 2mm.

N3b: either:

Cancer is found in at least one axillary lymph node (with at least one area of cancer
spread greater than 2 mm) and has enlarged the internal mammary lymph nodes, OR

Cancer involves 4 or more axillary lymph nodes (with at least one area of cancer spread
greater than 2 mm), and tiny amounts of cancer are found in internal mammary lymph
nodes on sentinel lymph node biopsy.

N3c: Cancer has spread to the lymph nodes above the clavicle with at least one area of
cancer spread greater than 2mm.

Metastasis (M):
MX: Presence of distant spread (metastasis) cannot be assessed.

M0: No distant spread is found on x-rays (or other imaging procedures) or by physical exam.

cM0(i +): Small numbers of cancer cells are found in blood or bone marrow (found only by
special tests), or tiny areas of cancer spread (no larger than 0.2 mm) are found in lymph
nodes away from the breast.

M1: Spread to distant organs is present. (The most common sites are bone, lung, brain, and liver.)

Breast cancer stage grouping

Once the T, N, and M categories have been determined, this information is combined in a process
called stage grouping. Cancers with similar stages tend to have a similar outlook and thus are often
treated in a similar way. Stage is expressed in Roman numerals from stage I (the least advanced
stage) to stage IV (the most advanced stage). Non-invasive cancer is listed as stage 0.

Stage 0: Tis, N0, M0: This is ductal carcinoma in situ (DCIS), the earliest form of breast cancer. In
DCIS, cancer cells are still within a duct and have not invaded deeper into the surrounding fatty breast
tissue. Lobular carcinoma in situ (LCIS) is sometimes also classified as stage 0 breast cancer, but
most oncologists believe it is not a true breast cancer. Paget disease of the nipple (without an
underlying tumor mass) is also stage 0. In all cases the cancer has not spread to lymph nodes or
distant sites.

Stage IA: T1, N0, M0: The tumor is 2 cm (about 3/4 of an inch) or less across (T1) and has not
spread to lymph nodes (N0) or distant sites (M0).

Stage IB: T0 or T1, N1mi, M0: The tumor is 2 cm or less across (or is not found) (T0 or T1) with
micrometastases in 1 to 3 axillary lymph nodes (the cancer in the lymph nodes is greater than 0.2mm
across and/or more than 200 cells but is not larger than 2 mm)(N1mi). The cancer has not spread to
distant sites (M0).

Stage IIA: One of the following applies:

T0 or T1, N1 (but not N1mi), M0: The tumor is 2 cm or less across (or is not found) (T1 or T0) and
either:

It has spread to 1 to 3 axillary lymph nodes, with the cancer in the lymph nodes larger than 2
mm across (N1a), OR

Tiny amounts of cancer are found in internal mammary lymph nodes on sentinel lymph node
biopsy (N1b), OR

It has spread to 1 to 3 lymph nodes under the arm and to internal mammary lymph nodes
(found on sentinel lymph node biopsy) (N1c).

OR
T2, N0, M0: The tumor is larger than 2 cm across and less than 5 cm (T2) but hasn't spread to the
lymph nodes (N0).

The cancer hasn't spread to distant sites (M0).

Stage IIB: One of the following applies:

T2, N1, M0: The tumor is larger than 2 cm and less than 5 cm across (T2). It has spread to 1 to 3
axillary lymph nodes and/or tiny amounts of cancer are found in internal mammary lymph nodes on
sentinel lymph node biopsy (N1). The cancer hasn't spread to distant sites (M0).

OR

T3, N0, M0: The tumor is larger than 5 cm across but does not grow into the chest wall or skin and
has not spread to lymph nodes (T3, N0). The cancer hasn't spread to distant sites (M0).

Stage IIIA: One of the following applies:

T0 to T2, N2, M0: The tumor is not more than 5 cm across (or cannot be found) (T0 to T2). It has
spread to 4 to 9 axillary lymph nodes, or it has enlarged the internal mammary lymph nodes (N2). The
cancer hasn't spread to distant sites (M0).

OR

T3, N1 or N2, M0: The tumor is larger than 5 cm across but does not grow into the chest wall or skin
(T3). It has spread to 1 to 9 axillary nodes, or to internal mammary nodes (N1 or N2). The cancer
hasn't spread to distant sites (M0).

Stage IIIB: T4, N0 to N2, M0: The tumor has grown into the chest wall or skin (T4), and one of the
following applies:

It has not spread to the lymph nodes (N0).

It has spread to 1 to 3 axillary lymph nodes and/or tiny amounts of cancer are found in
internal mammary lymph nodes on sentinel lymph node biopsy (N1).

It has spread to 4 to 9 axillary lymph nodes, or it has enlarged the internal mammary lymph
nodes (N2).

The cancer hasn't spread to distant sites (M0).

Inflammatory breast cancer is classified as T4 and is at least stage IIIB. If it has spread to many
nearby lymph nodes (N3) it could be stage IIIC, and if it has spread to distant lymph nodes or organs
(M1) it would be stage IV.

Stage IIIC: any T, N3, M0: The tumor is any size (or can't be found), and one of the following applies:
 Cancer has spread to 10 or more axillary lymph nodes (N3).

Cancer has spread to the lymph nodes under the clavicle (collar bone) (N3).

Cancer has spread to the lymph nodes above the clavicle (N3).

Cancer involves axillary lymph nodes and has enlarged the internal mammary lymph nodes
(N3).

Cancer has spread to 4 or more axillary lymph nodes, and tiny amounts of cancer are found
in internal mammary lymph nodes on sentinel lymph node biopsy (N3).

The cancer hasn't spread to distant sites (M0).

Stage IV: any T, any N, M1: The cancer can be any size (any T) and may or may not have spread to
nearby lymph nodes (any N). It has spread to distant organs or to lymph nodes far from the breast
(M1). The most common sites of spread are the bone, liver, brain, or lung,

If you have any questions about the stage of your cancer and what it might mean in your case, be
sure to ask your doctor.

Treatment Options by Stage

Ductal Carcinoma In Situ (DCIS)
Lobular Carcinoma In Situ (LCIS)
Stage I, Stage II, Stage IIIA, and Operable Stage IIIC Breast Cancer
Stage IIIB, Inoperable Stage IIIC, Stage IV, and Metastatic Breast Cancer
Stage IIIB and inoperable stage IIIC breast cancer
Stage IV and metastatic breast cancer

A link to a list of current clinical trials is included for each treatment section. For some types
or stages of cancer, there may not be any trials listed. Check with your doctor for clinical
trials that are not listed here but may be right for you.

Ductal Carcinoma In Situ (DCIS)

Treatment of ductal carcinoma in situ (DCIS) may include the following:

Breast-conserving surgery and radiation therapy with or without tamoxifen.

Total mastectomy with or without tamoxifen.
Breast-conserving surgery without radiation therapy.
Clinical trials testing breast-conserving surgery and tamoxifen with or without radiation
therapy.

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting
patients with ductal breast carcinoma in situ. For more specific results, refine the search by
using other search features, such as the location of the trial, the type of treatment, or the name
of the drug. General information about clinical trials is available from the NCI Web site.

Lobular Carcinoma In Situ (LCIS)

Treatment of lobular carcinoma in situ (LCIS) may include the following:

Biopsy to diagnose the LCIS followed by regular examinations and regular mammograms to
find any changes as early as possible. This is called observation.
Tamoxifen to reduce the risk of developing breast cancer.
Bilateral prophylactic mastectomy. This treatment choice is sometimes used in women who
have a high risk of getting breast cancer. Most surgeons believe that this is a more
aggressive treatment than is needed.
Clinical trials testing cancer prevention drugs.

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting
patients with lobular breast carcinoma in situ. For more specific results, refine the search by
using other search features, such as the location of the trial, the type of treatment, or the name
of the drug. General information about clinical trials is available from the NCI Web site.

Stage I, Stage II, Stage IIIA, and Operable Stage IIIC Breast Cancer

Treatment of stage I, stage II, stage IIIA, and operable stage IIIC breast cancer may include
the following:

Breast-conserving surgery to remove only the cancer and some surrounding breast tissue,
followed by lymph node dissection and radiation therapy.
Modified radical mastectomy with or without breast reconstruction surgery.
Sentinel lymph node biopsy followed by surgery.

Adjuvant therapy (treatment given after surgery to lower the risk that cancer will come back)
may include the following:

Radiation therapy to the lymph nodes near the breast and to the chest wall after a modified
radical mastectomy.
Chemotherapy with or without hormone therapy.
Hormone therapy.
Monoclonal antibody therapy with trastuzumab combined with chemotherapy.
A clinical trial of new targeted therapies.

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting
patients with stage I breast cancer, stage II breast cancer, stage IIIA breast cancer and stage
IIIC breast cancer. For more specific results, refine the search by using other search features,
such as the location of the trial, the type of treatment, or the name of the drug. General
information about clinical trials is available from the NCI Web site.

Stage IIIB, Inoperable Stage IIIC, Stage IV, and Metastatic Breast Cancer

Stage IIIB and inoperable stage IIIC breast cancer

Treatment of stage IIIB and inoperable stage IIIC breast cancer may include the following:

Chemotherapy.
 Chemotherapy followed by surgery (breast-conserving surgery or total mastectomy), with
lymph node dissection followed by radiation therapy. Additional therapy (chemotherapy,
hormone therapy, or both) may be given.
Clinical trials testing new anticancer drugs, new drug combinations, and new ways of giving
treatment.

Stage IV and metastatic breast cancer

Treatment of stage IV or metastatic breast cancer may include the following:

Hormone therapy and/or chemotherapy with or without trastuzumab.

Monoclonal antibody therapy with trastuzumab and pertuzumab combined with
chemotherapy.
Tyrosine kinase inhibitor therapy with lapatinib combined with capecitabine.
Radiation therapy and/or surgery for relief of pain and other symptoms.
Bisphosphonate drugs to reduce bone disease and pain when cancer has spread to the bone.
Clinical trials testing new chemotherapy and/or hormone therapy.
Clinical trials of new combinations of treatments, including targeted therapy, hormone
therapy, and chemotherapy.
Clinical trials testing other approaches, including high-dose chemotherapy with stem cell
transplant.

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting
patients with stage IIIB breast cancer, stage IIIC breast cancer and stage IV breast cancer. For
more specific results, refine the search by using other search features, such as the location of
the trial, the type of treatment, or the name of the drug. General information about clinical
trials is available from the NCI Web site.

There are different types of treatment for patients with breast cancer.

Different types of treatment are available for patients with breast cancer. Some treatments are
standard (the currently used treatment), and some are being tested in clinical trials. A
treatment clinical trial is a research study meant to help improve current treatments or obtain
information on new treatments for patients with cancer. When clinical trials show that a new
treatment is better than the standard treatment, the new treatment may become the standard
treatment. Patients may want to think about taking part in a clinical trial. Some clinical trials
are open only to patients who have not started treatment.

Six types of standard treatment are used:

Surgery

Most patients with breast cancer have surgery to remove the cancer from the breast. Some of
the lymph nodes under the arm are usually taken out and looked at under a microscope to see
if they contain cancer cells.

Breast-conserving surgery, an operation to remove the cancer but not the breast itself,
includes the following:

Lumpectomy: Surgery to remove a tumor (lump) and a small amount of normal tissue
around it.
 Partial mastectomy: Surgery to remove the part of the breast that has cancer and some
normal tissue around it. The lining over the chest muscles below the cancer may also
be removed. This procedure is also called a segmental mastectomy.

Enlarge

Breast-conserving surgery. Dotted lines show the area containing the tumor that is removed
and some of the lymph nodes that may be removed.

Patients who are treated with breast-conserving surgery may also have some of the lymph
nodes under the arm removed for biopsy. This procedure is called lymph node dissection. It
may be done at the same time as the breast-conserving surgery or after. Lymph node
dissection is done through a separate incision.

Other types of surgery include the following:

Total mastectomy: Surgery to remove the whole breast that has cancer. This
procedure is also called a simple mastectomy. Some of the lymph nodes under the
arm may be removed for biopsy at the same time as the breast surgery or after. This is
done through a separate incision.
 Enlarge

Total (simple) mastectomy. The dotted line shows where the entire breast is removed.
Some lymph nodes under the arm may also be removed.

Modified radical mastectomy: Surgery to remove the whole breast that has cancer,
many of the lymph nodes under the arm, the lining over the chest muscles, and
sometimes, part of the chest wall muscles.
 Enlarge

Modified radical mastectomy. The dotted line shows where the entire breast and some
lymph nodes are removed. Part of the chest wall muscle may also be removed.

Chemotherapy may be given before surgery to remove the tumor. When given before surgery,
chemotherapy will shrink the tumor and reduce the amount of tissue that needs to be removed
during surgery. Treatment given before surgery is called neoadjuvant therapy.

Even if the doctor removes all the cancer that can be seen at the time of the surgery, some
patients may be given radiation therapy, chemotherapy, or hormone therapy after surgery to
kill any cancer cells that are left. Treatment given after the surgery, to lower the risk that the
cancer will come back, is called adjuvant therapy.

If a patient is going to have a mastectomy, breast reconstruction (surgery to rebuild a breasts

shape after a mastectomy) may be considered. Breast reconstruction may be done at the time
of the mastectomy or at a future time. The reconstructed breast may be made with the
patients own (nonbreast) tissue or by using implants filled with saline or silicone gel. Before
the decision to get an implant is made, patients can call the Food and Drug Administration's
(FDA) Center for Devices and Radiologic Health at 1-888-INFO-FDA (1-888-463-6332) or
visit the FDA's Web site for more information on breast implants.

Sentinel lymph node biopsy followed by surgery

Sentinel lymph node biopsy is the removal of the sentinel lymph node during surgery. The
sentinel lymph node is the first lymph node to receive lymphatic drainage from a tumor. It is
the first lymph node the cancer is likely to spread to from the tumor. A radioactive substance
and/or blue dye is injected near the tumor. The substance or dye flows through the lymph
ducts to the lymph nodes. The first lymph node to receive the substance or dye is removed. A
pathologist views the tissue under a microscope to look for cancer cells. If cancer cells are
not found, it may not be necessary to remove more lymph nodes. After the sentinel lymph
node biopsy, the surgeon removes the tumor (breast-conserving surgery or mastectomy).

Enlarge

Sentinel lymph node biopsy of the breast. A radioactive substance and/or blue dye is injected
near the tumor (first panel). The injected material is detected visually and/or with a probe that
detects radioactivity (middle panel). The sentinel nodes (the first lymph nodes to take up the
material) are removed and checked for cancer cells (last panel).

Radiation therapy

Radiation therapy is a cancer treatment that uses high-energy x-rays or other types of
radiation to kill cancer cells or keep them from growing. There are two types of radiation
therapy. External radiation therapy uses a machine outside the body to send radiation toward
the cancer. Internal radiation therapy uses a radioactive substance sealed in needles, seeds,
wires, or catheters that are placed directly into or near the cancer. The way the radiation
therapy is given depends on the type and stage of the cancer being treated.

Chemotherapy

Chemotherapy is a cancer treatment that uses drugs to stop the growth of cancer cells, either
by killing the cells or by stopping them from dividing. When chemotherapy is taken by
mouth or injected into a vein or muscle, the drugs enter the bloodstream and can reach cancer
cells throughout the body (systemic chemotherapy). When chemotherapy is placed directly
into the cerebrospinal fluid, an organ, or a body cavity such as the abdomen, the drugs mainly
affect cancer cells in those areas (regional chemotherapy). The way the chemotherapy is
given depends on the type and stage of the cancer being treated.

See Drugs Approved for Breast Cancer for more information.

Hormone therapy

Hormone therapy is a cancer treatment that removes hormones or blocks their action and
stops cancer cells from growing. Hormones are substances made by glands in the body and
circulated in the bloodstream. Some hormones can cause certain cancers to grow. If tests
show that the cancer cells have places where hormones can attach (receptors), drugs, surgery,
or radiation therapy is used to reduce the production of hormones or block them from
working. The hormone estrogen, which makes some breast cancers grow, is made mainly by
the ovaries. Treatment to stop the ovaries from making estrogen is called ovarian ablation.

Hormone therapy with tamoxifen is often given to patients with early stages of breast cancer
and those with metastatic breast cancer (cancer that has spread to other parts of the body).
Hormone therapy with tamoxifen or estrogens can act on cells all over the body and may
increase the chance of developing endometrial cancer. Women taking tamoxifen should have
a pelvic exam every year to look for any signs of cancer. Any vaginal bleeding, other than
menstrual bleeding, should be reported to a doctor as soon as possible.

Hormone therapy with an aromatase inhibitor is given to some postmenopausal women who
have hormone-dependent breast cancer. Hormone-dependent breast cancer needs the
hormone estrogen to grow. Aromatase inhibitors decrease the body's estrogen by blocking an
enzyme called aromatase from turning androgen into estrogen.

For the treatment of early stage breast cancer, certain aromatase inhibitors may be used as
adjuvant therapy instead of tamoxifen or after 2 or more years of tamoxifen. For the treatment
of metastatic breast cancer, aromatase inhibitors are being tested in clinical trials to compare
them to hormone therapy with tamoxifen.

See Drugs Approved for Breast Cancer for more information.

Targeted therapy

Targeted therapy is a type of treatment that uses drugs or other substances to identify and
attack specific cancer cells without harming normal cells. Monoclonal antibodies and tyrosine
kinase inhibitors are two types of targeted therapies used in the treatment of breast cancer.
PARP inhibitors are a type of targeted therapy being studied for the treatment of triple-
negative breast cancer.

Monoclonal antibody therapy is a cancer treatment that uses antibodies made in the
laboratory, from a single type of immune system cell. These antibodies can identify
substances on cancer cells or normal substances that may help cancer cells grow. The
antibodies attach to the substances and kill the cancer cells, block their growth, or keep them
from spreading. Monoclonal antibodies are given by infusion. They may be used alone or to
carry drugs, toxins, or radioactive material directly to cancer cells. Monoclonal antibodies
may be used in combination with chemotherapy as adjuvant therapy.

Trastuzumab is a monoclonal antibody that blocks the effects of the growth factor protein
HER2, which sends growth signals to breast cancer cells. About one-fourth of patients with
breast cancer have tumors that may be treated with trastuzumab combined with chemotherapy.

Pertuzumab is a monoclonal antibody that may be combined with trastuzumab and

chemotherapy to treat breast cancer. It may be used to treat certain patients with HER2-
positive breast cancer that has metastasized (spread to other parts of the body).
Tyrosine kinase inhibitors are targeted therapy drugs that block signals needed for tumors to
grow. Tyrosine kinase inhibitors may be used with other anticancer drugs as adjuvant therapy.

Lapatinib is a tyrosine kinase inhibitor that blocks the effects of the HER2 protein and other
proteins inside tumor cells. It may be used with other drugs to treat patients with HER2-
positive breast cancer that has progressed after treatment with trastuzumab.

PARP inhibitors are a type of targeted therapy that block DNA repair and may cause cancer
cells to die. PARP inhibitor therapy is being studied for the treatment of triple-negative breast
cancer.

See Drugs Approved for Breast Cancer for more information.

New types of treatment are being tested in clinical trials.

This summary section describes treatments that are being studied in clinical trials. It may not
mention every new treatment being studied. Information about clinical trials is available from
the NCI Web site.

High-dose chemotherapy with stem cell transplant

High-dose chemotherapy with stem cell transplant is a way of giving high doses of
chemotherapy and replacing blood -forming cells destroyed by the cancer treatment. Stem
cells (immature blood cells) are removed from the blood or bone marrow of the patient or a
donor and are frozen and stored. After the chemotherapy is completed, the stored stem cells
are thawed and given back to the patient through an infusion. These reinfused stem cells grow
into (and restore) the bodys blood cells.

Studies have shown that high-dose chemotherapy followed by stem cell transplant does not
work better than standard chemotherapy in the treatment of breast cancer. Doctors have
decided that, for now, high-dose chemotherapy should be tested only in clinical trials. Before
taking part in such a trial, women should talk with their doctors about the serious side effects,
including death, that may be caused by high-dose chemotherapy.

Patients may want to think about taking part in a clinical trial.

For some patients, taking part in a clinical trial may be the best treatment choice. Clinical
trials are part of the cancer research process. Clinical trials are done to find out if new cancer
treatments are safe and effective or better than the standard treatment.

Many of today's standard treatments for cancer are based on earlier clinical trials. Patients
who take part in a clinical trial may receive the standard treatment or be among the first to
receive a new treatment.

Patients who take part in clinical trials also help improve the way cancer will be treated in the
future. Even when clinical trials do not lead to effective new treatments, they often answer
important questions and help move research forward.

Patients can enter clinical trials before, during, or after starting their cancer treatment.
Some clinical trials only include patients who have not yet received treatment. Other trials
test treatments for patients whose cancer has not gotten better. There are also clinical trials
that test new ways to stop cancer from recurring (coming back) or reduce the side effects of
cancer treatment.

Clinical trials are taking place in many parts of the country. See the Treatment Options
section that follows for links to current treatment clinical trials. These have been retrieved
from NCI's listing of clinical trials.

Follow-up tests may be needed.

Some of the tests that were done to diagnose the cancer or to find out the stage of the cancer
may be repeated. Some tests will be repeated in order to see how well the treatment is
working. Decisions about whether to continue, change, or stop treatment may be based on the
results of these tests. This is sometimes called re-staging.

Some of the tests will continue to be done from time to time after treatment has ended. The
results of these tests can show if your condition has changed or if the cancer has recurred
(come back). These tests are sometimes called follow-up tests or check-ups.

Surgery is usually the first line of attack against breast cancer. This section explains the
different types of breast cancer surgery.

Decisions about surgery depend on many factors. You and your doctor will determine the
kind of surgery thats most appropriate for you based on the stage of the cancer, the
"personality" of the cancer, and what is acceptable to you in terms of your long-term peace of
mind.

The following pages will help you explore your surgery options:

In our What to Expect with Any Surgery section, you can learn the basic steps
common to all breast cancer surgeries.
If you need to choose between surgeries, Mastectomy vs. Lumpectomy explains the
pros and cons of each.
Lumpectomy, also known as breast-conserving surgery, is the removal of only the
tumor and a small amount of surrounding tissue.
Mastectomy is the removal of all of the breast tissue. Mastectomy is more refined
and less intrusive than it used to be because in most cases, the muscles under the
breast are no longer removed.
Lymph node removal, or axillary lymph node dissection, can take place during
lumpectomy and mastectomy if the biopsy shows that breast cancer has spread outside
the milk duct. Some people qualify for the less-invasive sentinel lymph node
dissection.
Breast reconstruction is the rebuilding of the breast after mastectomy and sometimes
lumpectomy. Reconstruction can take place at the same time as cancer-removing
surgery, or months to years later. Some women decide not to have reconstruction and
opt for a prosthesis instead.
Prophylactic mastectomy is preventive removal of the breast to lower the risk of
breast cancer in high-risk people.
 Prophylactic ovary removal is a preventive surgery that lowers the amount of
estrogen in the body, making it harder for estrogen to stimulate the development of
breast cancer.
Cryotherapy, also called cryosurgery, uses extreme cold to freeze and kill cancer
cells. Right now, cryotherapy is an experimental treatment for breast cancer.

Chemotherapy for early-stage disease

Early-stage breast cancer generally means cancer that is classified as:

stage 0
stage I
stages IIA and IIB
some stage III

(For more information on the specific characteristics of each cancer stage, visit the
Breastcancer.org Stages of Breast Cancer page.)

Chemotherapy is used after surgery to remove the breast cancer to get rid of any cancer cells
that may be left behind and to reduce the risk of the cancer coming back. In some cases,
chemotherapy may be used before surgery to shrink the tumor so less tissue needs to be
removed.

Each person's treatment plan will be different, but there are some general guidelines about
who would benefit from chemotherapy:

Chemotherapy is almost always recommended if there is cancer in the lymph nodes,

regardless of tumor size or menopausal status.
Doctors recommend more aggressive treatments for premenopausal women diagnosed with
invasive breast cancer. Breast cancer in premenopausal women tends to be more aggressive,
so chemotherapy is often part of the treatment plan.
Chemotherapy may be recommended for some women diagnosed with early-stage breast
cancer if the cancer is hormone-receptor-negative and HER2-positive. Both of these
characteristics are associated with cancer that is more aggressive.
The Oncotype DX test may help some women diagnosed with estrogen-receptor-positive
breast cancer and their doctors decide if the cancer is likely to come back and if
chemotherapy would offer benefits.
Chemotherapy usually is NOT recommended for non-invasive, in situ cancers such as DCIS
because they have very little risk of spreading to other parts of the body.

Chemotherapy for advanced-stage/metastatic disease

Advanced-stage breast cancer generally means cancer that is classified as:

some stage III

stage IV

Metastatic disease is breast cancer that has spread beyond the breast area and nearby lymph
nodes to other parts of the body. Metastatic cancer is considered stage IV.
Chemotherapy is used to treat advanced-stage breast cancer by destroying or damaging the
cancer cells as much as possible. Because chemotherapy medicines affect the entire body,
chemotherapy is commonly used to treat advanced-stage breast cancer. Research has shown
that newer chemotherapy medicines, such as:

Taxol (chemical name: paclitaxel)

Abraxane (chemical name: albumin-bound paclitaxel)
Taxotere (chemical name: docetaxel)
Adriamycin (chemical name: doxorubicin)
Ellence (chemical name: epirubicin)

are helping women diagnosed with advanced-stage breast cancer live longer. Other
chemotherapies used in metastatic breast cancer include Gemzar (chemical name:
gemcitabine), Xeloda (chemical name: capecitabine), Navelbine (chemical name:
vinorelbine), and Ixempra (chemical name: ixabepilone).

Each person's treatment plan will be different, but there are some general guidelines that
doctors follow when using chemotherapy to treat advanced-stage breast cancer:

If you've had chemotherapy before, your doctor may recommend using only one
chemotherapy medicine at a time to treat advanced-stage disease. This way you get benefits
with fewer possible side effects.
In general, most chemotherapy medicines can be used until side effects become a problem
or the medicine stops being effective.
Some chemotherapy medicines seem to work better against cancer tumors when used in
combination. So your doctor may recommend a combination of medicines for you because
research has shown that combining treatments has contributed to a better overall prognosis
for some advanced-stage cancers.
If you've had chemotherapy before and the cancer came back or didn't respond, your doctor
will likely recommend a different combination of medicines. There are many chemotherapy
medicines and if one medicine or combination of medicines doesn't seem to be working,
there is almost always something else you can try.

If the cancer is hormone-receptor-positive, your doctor may choose to use hormonal therapy
before or after initiating chemotherapy.

If you have metastatic breast cancer and chemotherapy is part of your treatment plan, your
doctor may use different tests to determine how well the chemotherapy is working and how
you're handling the chemotherapy:

Blood cell counts

Blood tumor marker tests
Bone scans
Chest X-rays, or X-rays of other parts of the body
MRI
CT (CAT) scans
PET scans

Chemotherapy medications for breast cancer include:

 Abraxane (chemical name: paclitaxel)
Adriamycin (chemical name: doxorubicin)
carboplatin (brand name: Paraplatin)
Cytoxan (chemical name: cyclophosphamide)
daunorubicin (brand names: Cerubidine, DaunoXome)
Doxil (chemical name: doxorubicin)
Ellence (chemical name: epirubicin)
fluorouracil (also called 5-fluorouracil or 5-FU; brand name: Adrucil)
Gemzar (chemical name: gemcitabine)
Halaven (chemical name: eribulin)
Ixempra (chemical name: ixabepilone)
methotrexate (brand names: Amethopterin, Mexate, Folex)
Mitomycin (chemical name: mutamycin)
mitoxantrone (brand name: Novantrone)
Navelbine (chemical name: vinorelbine)
Taxol (chemical name: paclitaxel)
Taxotere (chemical name: docetaxel)
thiotepa (brand name: Thioplex)
vincristine (brand names: Oncovin, Vincasar PES, Vincrex)
Xeloda (chemical name: capecitabine)

In many cases, chemotherapy medicines are given in combination, which means you get two
or three different medicines at the same time. These combinations are known as
chemotherapy regimens. In early stage breast cancer, standard chemotherapy regimens lower
the risk of the cancer coming back. In advanced breast cancer, chemotherapy regimens make
the cancer shrink or disappear in about 30-60% of people treated. Keep in mind that every
cancer responds differently to chemotherapy.

Standard chemotherapy regimens include:

AT: Adriamycin and Taxotere

AC T: Adriamycin and Cytoxan, with or without Taxol or Taxotere
CMF: Cytoxan, methotrexate, and fluorouracil
CEF: Cytoxan, Ellence, and fluorouracil
FAC: fluorouracil, Adriamycin, and Cytoxan
CAF: Cytoxan, Adriamycin, and fluorouracil
(The FAC and CAF regimens use the same medicines but use different doses and
frequencies)
TAC: Taxotere, Adriamycin, and Cytoxan
GET: Gemzar, Ellence, and Taxol

Depending on the characteristics of the cancer, a targeted therapy medicine, such as

Herceptin (chemical name: trastuzumab), may be used in combination with some
chemotherapy regimens. For example, the TCH regimen includes Taxotere, Herceptin, and
carboplatin.

Your doctor may talk about certain groups of chemotherapy medicines:

 Anthracyclines are chemically similar to an antibiotic. Anthracyclines damage the
genetic material of cancer cells, which makes the cells die. Adriamycin, Ellence, and
daunorubicin are anthracyclines.
Taxanes interfere with the way cancer cells divide. Taxol, Taxotere, and Abraxane
are taxanes.

Most standard chemotherapy regimens include a medicine from one or both of these groups.

How Herceptin Works

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Cancer cells grow in an uncontrolled fashion. Herceptin works on the surface of the cancer
cell by blocking the chemical signals that can stimulate this uncontrolled growth.

Genes are like instruction manuals that tell each cell of our body how to grow, what kind of
cell to become, and how to behave. Genes do this by ordering the cell to make special
proteins that cause a certain activity -- like cell growth, rest, or repair.

Some cancer cells have abnormalities in genes that tell the cell how much and how fast to
grow. Sometimes the cancer cells have too many copies of these genes with abnormalities.
When there are too many copies of these genes, doctors refer to it as "overexpression." With
some forms of gene overexpression, cancer cells will make too many of the proteins that
control cell growth and division, causing the cancer to grow and spread.

Some breast cancer cells make (overexpress) too many copies of a particular gene known as
HER2. The HER2 gene makes a protein known as a HER2 receptor. HER2 receptors are like
ears, or antennae, on the surface of all cells. These HER2 receptors receive signals that
stimulate the cell to grow and multiply. But breast cancer cells with too many HER2
receptors can pick up too many growth signals and so start growing and multiplying too
much and too fast. Breast cancer cells that overexpress the HER2 gene are said to be HER2-
positive.

Herceptin works by attaching itself to the HER2 receptors on the surface of breast cancer
cells and blocking them from receiving growth signals. By blocking the signals, Herceptin
can slow or stop the growth of the breast cancer. Herceptin is an example of an immune
targeted therapy. In addition to blocking HER2 receptors, Herceptin can also help fight breast
cancer by alerting the immune system to destroy cancer cells onto which it is attached.

A video animation that illustrates how Herceptin attaches itself to the HER2 receptors on the
surface of breast cancer cells and blocks them from receiving growth signals. This video was
created by Genentech BioOncology

Herceptin can only be given intravenously, which means it is dripped into your body through
a needle inserted into a vein. The first dose of Herceptin takes about 90 minutes. After that, it
only takes about 30 minutes to get the other doses of Herceptin, which are usually given
weekly in a doctor's office. Sometimes Herceptin can be given on a 3 week schedule -- you
can talk to your doctor about your treatment schedule options.

If you have early stage breast cancer (stage I, II or III) that is HER2-positive, you may take
Herceptin alone or together with a chemotherapy regimen. You will receive it for a specific
amount of time, either during your course of chemotherapy or after your chemotherapy is
complete.

If you have metastatic breast cancer that is HER2-positive, Herceptin can be taken
indefinitely in order to keep the cancer under control. Herceptin has not been used long
enough to know yet if you can stop taking it after you appear to be free of breast cancer for a
certain period of time. So if you have metastatic disease and start taking Herceptin, you
continue to take it, unless your doctor recommends you stop taking the medication because it
is no longer working or you are unable to tolerate the side effects. The following
chemotherapy medications can be given together with, before, or after Herceptin:

Taxotere (chemical name: docetaxel)

Taxol (chemical name: paclitaxel)
5-fluorouracil (5-FU)
Xeloda (chemical name: capecitabine)
Navelbine (chemical name: vinorelbine)
Gemzar (chemical name: gemcitabine)
Cytoxan (chemical name: cyclophosphamide)

Adriamycin (chemical name: doxorubicin) and Ellence (chemical name: epirubicin) are given
before or after, but not together with Herceptin.

There are currently five targeted therapies doctors use to treat breast cancer:

Herceptin
Herceptin (chemical name: trastuzumab) works against HER2-positive breast cancers
by blocking the ability of the cancer cells to receive chemical signals that tell the cells
to grow.
Tykerb
Tykerb (chemical name: lapatinib) works against HER2-positive breast cancers by
blocking certain proteins that can cause uncontrolled cell growth.
Avastin
Avastin (chemical name: bevacizumab) works by blocking the growth of new blood
vessels that cancer cells depend on to grow and function. On Nov. 18, 2011, the U.S.
Food and Drug Administration announced that it had removed the breast cancer
indication from Avastin because the drug has not been shown to be safe and effective
for that use. The medicine itself is not being removed from the market and doctors can
choose to use Avastin to treat metastatic breast cancer whether or not that particular
use is officially approved by the FDA.
Perjeta
Like Herceptin, Perjeta (chemical name: pertuzumab) works against HER2-positive
breast cancers by blocking the cancer cells ability to receive growth signals.
Afinitor
 Afinitor (chemical name: everolimus) is an mTOR (mammalian target of rapamycin)
inhibitor. Afinitor works against hormone-receptor-positive breast cancers that have
stopped responding to Arimidex or Femara by stopping the cancer cells from getting
the energy they need.

Stage 5-year
Survival Rate

0 93%

I 88%

IIA 81%

IIB 74%

IIIA 67%

IIIB 41%*

IIIC 49%*

IV 15%

*These numbers are correct as written (stage IIIB shows worse survival than stage IIIC).

Last Medical Review: 08/23/2012

Last Revised: 10/31/2012

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Stage TNM Description 5-year Survival
0 Tis N0 M0 Carcinoma in situ. No tumor is regional lymph 99%
nodes, No distant metastases

I T1 N0 M0 Tumor is less than or equal to 2 centimeters, No 92%

tumor is regional lymph nodes, No distant
metastases

IIA T0 N1 M0 No evidence of primary tumor, 82%

T1 N1 M0
T2 N0 M0 metastases to movable ipsilateral nodes,
No distant metastases.
Tumor is less than or equal to 2
centimeters, metastases to movable
ipsilateral nodes, No distant metastases.
 Tumor is between 2 and 5 centimeters,
No tumor is regional lymph nodes, No
distant metastases
IIB T2 N1 M0 Tumor is between 2 and 5 centimeters, 65%
T3 N0 M0
metastases to movable ipsilateral nodes,
No distant metastases.
Tumor is over 5 centimeters, No tumor is
regional lymph nodes, No distant
metastases.
IIIA T0 N2 M0 No evidence of primary tumor, 47%
T1 N2 M0
T2 N2 M0 metastases to fixed ipsilateral nodes, no
T3 N1, N2 M0 distant metastases.
Tumor is less than or equal to 2
centimeters, metastases to fixed
ipsilateral nodes, No distant metastases.
Tumor is between 2 and 5 centimeters,
metastases to fixed ipsilateral nodes, no
distant metastases.
Tumor is over 5 centimeters, metastases
to movable or fixed ipsilateral nodes, no
distant metastases.
IIIB T4 Any N M0 Tumor extends to chest wall, any nodal 44%
Any T N3 M0
involvement, no distant metastases.
Any primary tumor involvement,
metastases to ipsilateral internal
mammary nodes, no distant metastases.
IV Any T Any N M1 Any primary tumor involvement, any nodal 14%
involvement, distant metastases.

T= Status of Primary tumor; N = Regional lymph nodes; M = Distant Metastases

HER-2/neu (also called erbB-2) is the gene that encodes for the human epidermal growth factor receptor type 2.
This receptor is found in moderate levels on some normal cells and as the gene's name implies, it is involved in
cellular responses to growth factors. As shown below, binding of the factor under the right conditions can
stimulate cell division.
The HER-2/neu gene is amplified in up to 30% of human breast cancers. The increase in the number of copies of
the HER-2/neu gene leads to an increase in the expression of the HER2 protein on the cell surface, and is
thought to lead to an increase in cell proliferation (shown below).(1) The gene amplification is also thought to
affect the response of the tumors to treatment and as well as the ability of the tumor to grow and spread.
Overexpression of this gene may make a tumor more aggressive, but may also make the cancer more sensitive
to some chemotherapy agents.(2)

HER-2/Neu and Cancer Treatments

HER-2/neu and Chemotherapy

The effect of HER-2/neu overexpression on the effectiveness of chemotherapy drugs has not been fully
elucidated. Several studies have been conducted to ascertain the effects of the HER2 protein on responses to
chemotherapy. One recent study exposed the cells of 140 primary breast tumors to various concentrations of two
different chemotherapy combinations. The study showed that cells with strong HER-2/neu overexpression
exhibited greater growth inhibition with the chemotherapy treatments than those with lower expression levels.
The HER-2/neu amplification seemed to impart chemotherapy sensitivity to the tumor cells rather than making
them more drug resistant. Chemotherapy attacks cells that are replicating, and HER-2/neu amplification causes
faster replication. One possible conclusion would be that due to their high rate of cell division, the HER2
overexpressing cancer cells are killed off more effectively. The actual effects of HER-2/neu amplification is still in
question because there have been some contradictory results showing a lack of effect on chemotherapy.(1)
Other work has shown HER-2/neu overexpression to be associated with estrogen receptor negativity, poor tumor
cell differentiation, and decreased patient survival.(2) It is clear that this proto-oncogene is important in the
development of several forms of cancer but the story is far from complete.

Antibody treatment and HER2

Cancer treatments have been designed to combat cancers overexpressing the HER2 protein. Trastuzumab
(Herceptin), from Genentech, is a humanized monoclonal antibody that binds to the HER2 protein and blocks
its activity, preventing excessive cell proliferation. This process is shown in the animation below. Herceptin has
been used recently in conjunction with chemotherapy for HER-2/neu amplified cancers.(2) (3) More on

Oncogenes: Ras
Ras gene products are involved in kinase signaling pathways that control the transcription of genes, which then
regulate cell growth and differentiation. To turn "on" the pathway, the ras protein must bind to a particular
molecule (GTP) in the cell. To turn the pathway "off," the ras protein must break up the GTP molecule. Alterations
in the ras gene can change the ras protein so that it is no longer able to break up and release the GTP. These
changes can cause the the pathway to be stuck in the "on" position.(1) The "on" signal leads to cell growth and
proliferation. Therefore, ras overexpression and amplification can lead to continuous cell proliferation, which is a
major step in the development of cancer.(2) Cell division is regulated by a balance of positive and negative signals.
When ras transcription is increased, an excess of the gene's protein is in the cell, and the positive signals for cell
division begin to outweigh the negative signals.
The conversion of ras from a proto-oncogene into an oncogene usually occurs through a point mutation in the
gene. The altered function can affect the cell in different ways because ras is involved in many signaling
pathways that control cell division and cell death. Anti-cancer drugs are now being developed that target ras
dependent pathways. Much remains to be discovered before these drugs can be put into use. (3)
Mutant ras has been identified in cancers of many different origins, including: pancreas (90%), colon (50%), lung
(30%), thyroid (50%), bladder (6%), ovarian (15%), breast, skin, liver, kidney, and some leukemias.(1) It is also
possible that in the future, ras may be used to detect certain cancers. Historically, pancreatic cancer has been
difficult to diagnose. The identification of ras mutations in the DNA of pancreatic cells shed into feces may enable
clinicians to differentiate between chronic pancreatitis and pancreatic cancer. (1)

Oncogenes: Myc
The myc protein acts as a transcription factor and it controls the expression of several genes. Mutations in the
myc gene have been found in many different cancers, including Burkitt's lymphoma, B-cell leukemia, and lung
cancer. The myc family of oncogenes may become activated by gene rearrangement or amplification. Gene
rearrangements involve the breakage and reunion of chromosomes. This process can involve large amounts of
DNA and can affect many genes. The movement of a gene or group of genes to a different location within the
same chromosome or to a different chromosome often leads to altered gene expression and cell function.

Translocation is one type of gene rearrangement, and a translocation between chromosomes 8 and 14 has been
shown to result in overexpression of myc and ultimately B-cell lymphoma. The animation below shows what a
translocation between two different chromosomes looks like.

The amount of myc protein present in the cell is important because the activity of myc is balanced by another
protein that opposes myc activity. Therefore, an increase in either protein will offset the balance and affect cell
division.(1)>

Oncogenes: Src
Src is the first oncogene ever discovered. It was identified as the transforming (cancer causing) agent of the
Rous sarcoma virus (RSV), which infects chickens and other animals. RSV is a retrovirus. It infects cells and then
inserts its own genes into the cellular DNA. This quickly results in the development of cancer. The virus is
therefore called an acutely transforming virus. When infected, chickens develop large tumors within two weeks.
Researchers discovered that the protein from a particular gene in RSV causes cells to grow in an abnormal
manner. A corresponding proto-oncogene was found in the human genome. The human gene, when activated
into an oncogene, functions in a similar manner.

The Src protein is a tyrosine kinase. Kinases are enzymes that transfer phosphate groups onto target molecules.
The important aspect of this process is that the removal/addition of phosphates changes biomolecules and is a
key way by which the activities of cells are regulated. The phosphate addition/removal process acts like an on/off
switch to control the activity of the target molecules. The src proteins alter several target molecules, resulting in
the transmission of signals to the nucleus that help regulate the cell.(1)
There are at least nine different known src genes. Due to different processing of the mRNA produced by these
genes, at least 14 different proteins may be produced. C-src is normally found in most cells at a low level, but
have been found to be overexpressed in certain cancer types, including human neuroblastoma, small-cell lung,
colon, and breast carcinomas, and rhabdomyosarcoma.(2)

Due to the nature of the DNA replication process the ends (telomeres) of our chromosomes become shortened
during each cell division. The shortening of the chromosomes serves to limit the number of times any given cell
can undergo division. When telomeres shorten to a critical length the cell is unable to replicate its DNA without
losing vital genetic material. At this point normal cells enter cellular senescence, or growth arrest, after which no
further cell division takes place.
Cancer cells have the ability to replicate without reaching a state of senescence. In many cancers the ability to
divide without limit is achieved by the production of an enzyme called telomerase. Telomerase maintains the
ends of chromosomes so that they do not shorten. Telomerase is a normal protein that is present in cells during
fetal development. In most cells of an adult human, telomerase is not present as the gene for the enzyme is not
being expressed (transcribed and translated). However, in some cancer cells the necessary task of achieving
unlimited replication is made possible by the reactivation of the gene that codes for telomerase.

The animation on the right below depicts the lengths of chromosomes both with (right) and without (left) active
telomerase.

In cancer cells that do not possess telomerase activity, shortening of chromosomes is thought to be prevented by
other mechanisms. The maintenance of telomere length allows for unlimited cell division. The gene that codes for
the active component of the telomerase enzyme, hTERT, is considered a proto-oncogene because abnormal
expression contributes to unregulated cell growth.

Oncogenes: Bcl-2
Bcl-2 (for B cell lymphoma gene-2) proteins are associated with membranes and membrane activity. The Bcl-2
protein is a part of a complex system of signaling that controls apoptosis. Apoptosis (cell death) may be induced
by a variety of signals including irreparable DNA damage. This form of cellular suicide prevents the expansion of
damaged cells. Bcl-2 works to prevent apoptosis.(1) Therefore, its overexpression can prevent apoptosis in cells
that are damaged. This can lead to the continued division of the mutated cells lines and eventually cancer. Also,
overexpression of Bcl-2 can contribute to metastasis in certain cancers.(2)
If apoptosis controls are disrupted, then drugs that work by inducing apoptosis will not work as efficiently.
Therefore, drugs are being developed that will down-regulate Bcl-2 and allow other anti-cancer drugs to work
more efficiently (and at lower doses). One such drug is the antisense nucleotide Genasense", which has shown
in phase I trials to reduce Bcl-2 production and is currently in phase II and III trials as a supplementary treatment
for various cancers.(3) More on antisense drugs.

Also, there are drugs that indirectly reduce the amount of Bcl-2 protein, such as all-trans retinoic acid, paclitaxel,
vincristine, and docetaxel. These drugs are are often combined with other chemotherapy agents during treatment.
New methods, not yet tested in humans, include Bcl-2 binding peptides that inactivate the protein and antimycin
A that binds to Bcl-2 related proteins. (4)

Since Bcl-2 overexpression can affect the success of cancer treatment, knowing if it is functioning normally may
prove to be a valuable diagnostic tool. This proto-oncogene can become activated into an oncogene by a
translocation that causes overexpression of the gene, and an increased amount of Bcl-2 protein has been
discovered in many different types of cancers.(5)

Section Summary: Oncogenes

Oncogenes

Oncogenes are the mutated forms of normal cellular genes (proto-oncogenes).

The protein products of proto-oncogenes stimulate cell division and/or inhibit cell death.
Proto-oncogenes can be likened to the gas pedal in a car.
Normally, internal and external signals strictly regulate the activity of the proto-oncogenes, but
oncogenes are defective and are 'on' even when they do not receive appropriate signals.
Oncogenes also help cells to ignore negative signals that would prevent a healthy cell from dividing.
Oncogenes can cause cells to divide continuously even in the absence of any pro-growth signals.
The following list describes different cellular roles for a few of the many known oncogenes:

HER-2/neu

o
HER-2/neu encodes for a cell surface receptor that can stimulate cell division
The HER-2/neu gene is amplified in up to 30% of human breast cancers

RAS

o
The Ras gene products are involved in kinase signaling pathways that ultimately
control transcription of genes, regulating cell growth and differentiation.
Overexpression and amplification of RAS can lead to continuous cell proliferation.

MYC

o
The Myc protein is a transcription factor and controls expression of several genes.
Myc is thought to be involved in avoiding the cell death mechanism.
MYC oncogenes may be activated by gene rearrangement or amplification.

SRC

o
SRC was the first oncogene ever discovered.
The Src protein is a tyrosine kinase which regulates cell activity.

hTERT

o
hTERT codes for an enzyme (telomerase) that maintains chromosome ends.
 In most normal cells telomerase is only present during fetal development.
Activation of hTERT in adult cells gives them the ability to divide indefinitely.

BCL-2

o
The Bcl-2 protein works to prevent cell death (apoptosis).
Overexpression of BCL-2 allows continued division of mutated cells.

BRCA Function
Mutations in the BRCA-1 and BRCA-2 genes are associated with a subset of breast and ovarian cancers. These
two genes have different functions within cells. Like the other tumor suppressors discussed so far, mutations can
arise spontaneously or they may be inherited. Individuals who inherit a BRCA-1 or BRCA-2 mutation are known
to be more susceptible to developing breast cancer. Individuals carrying a BRCA mutation have a lifetime risk (if
they live to the age of 85) of 80% for developing breast cancer. The lifetime risks for developing ovarian cancer is
10-20% for BRCA-2 mutations and 40-60% for BRCA-1 mutations. The presence of these mutations may also
increase the risk of prostate, pancreatic, colon, and other cancers.The total risk for any person depends on the
individual genetic and environmental risk factors to which they are exposed. BRCA-1 and BRCA-2 mutations are
thought to be associated with 5-10% of all breast cancers.

The BRCA Genes and Estrogen

Mutation of the BRCA genes has been associated with cancers of certain tissues, including the breast and
ovaries. This suggests that estrogen may play a role in the development of cancer in these tissues. Estrogen
fluctuations, such as those seen during puberty, menstruation, pregnancy, and menopause are associated with
cancer development. Increases in estrogen, especially at puberty and during pregnancy, cause an increase in
breast epithelial cell proliferation, which in turn places increased demands on the DNA repair capabilities of the
cells. Reproduction (cell division) of cells with lowered DNA repair efficiency may lead to the formation of cancer.
In the animation below, estrogen (shown in pink) stimulates cells to divide, producing a cancerous cell. (1)

If one BRCA gene is already mutated, a mutation that removes the only functioning copy will cause DNA repair
defects. When both copies of the repair gene are non-functional, there is an increased likelihood of a cell
acquiring mutations that lead to tumor development. In an individual who has inherited a defective copy of the
BRCA gene, ALL of their cells carry the defect. A mutation of the second copy in any cell can trigger DNA repair
difficulties. Two independent mutation events are required for cancer development in individuals who have not
inherited a defective BRCA allele. Both of these sporadic mutations must occur in the same cell. The occurrence
of two mutations in the same cell is rare; this explains why these cancers tend to appear later in life. (1)

More information on this topic may be found in Chapters 3,4,7, and 9 of The Biology of Cancer by Robert A.
Weinberg.
A Closer Look at BRCA's Affects on Survival
There have been several studies designed to determine the differences in survival between BRCA mutation
carriers with cancer and those who developed cancer sporadically. The results are somehwhat contradictory,
probably due to differing study designs and factors such as the degree of matching between controls (sporadic)
and carriers. However, though the BRCA mutation carriers have a poorer prognosis based on the characteristics
of their cancer, they seem to have an equal or higher survival rate when compared with sporadic cancer patients.
This is thought to be due to the responsiveness of the tumors to chemotherapy. The increased susceptibility may
be due, in part, to their high proliferation( )rates. The tumors are also more susceptible to cancer treatments such
as gamma radiation, cisplatin, and mitomycin C because those treatments cause DNA damage that would
normally be repaired by functioning BRCA gene products. If the BRCA genes are inactive the cell can not repair
DNA damage as efficiently and cell death results. The non-cancerous cells in a BRCA mutation carrier retain one
functional BRCA gene and can therefore repair their DNA.(2)

Section Summary: Tumor Suppressors

Tumor Suppressors

The protein products of tumor suppressor genes can directly or indirectly prevent cell division or lead to
cell death.
Tumor suppressors can be likened to the brake system in a car.
Loss of function of tumor suppressors leads to abnormal cellular behavior.
The following describes the function of some key tumor suppressor genes:

p53

A transcription factor that regulates genes controlling cell division and cell death.
Important in the cellular response to DNA damage.
Aids in decision between repair and induction of cell death.

Rb

Functions by altering transcription factor activity.

Contributes to the control of cellular division by acting as an inhibitor.

APC

The APC protein binds and stimulates the degradation of a transcription factor.
Absence of functional APC protein leads to increased cell division.

BRCA

BRCA proteins have multiple functions including repairing DNA damage and
regulation of gene expression.
Non-functional BRCA leads to compromised DNA repair and gene regulation.