Breast Cancer

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Early Detection, Diagnosis, and Staging TOPICS

How is breast cancer classified?

After you have a biopsy, the samples of breast tissue are looked at in the lab to determine whether breast cancer is present and if so, what type it is. Certain lab tests may be done that can help determine how quickly a cancer is likely to grow and (to some extent) what treatments are likely to be effective. Sometimes these tests aren’t done until the entire tumor is removed by either breast-conserving surgery or mastectomy.

If a benign condition is diagnosed, you will need no further treatment. Still, it is important to find out from your doctor if the benign condition puts you at higher risk for breast cancer in the future and what type of follow-up you might need.

If the diagnosis is cancer, there should be time for you to learn about the disease and to discuss treatment options with your cancer care team, friends, and family. It is usually not necessary to rush into treatment. You might want to get a second opinion before deciding what treatment is best for you.

Breast cancer type

The tissue removed during the biopsy (or during surgery) is first looked at under a microscope to see if cancer is present and whether it is a carcinoma or some other type of cancer (like a sarcoma). If there is enough tissue, the pathologist may be able to determine if the cancer is in situ (not invasive) or invasive. The biopsy is also used to determine the cancer's type, such as invasive ductal carcinoma or invasive lobular carcinoma. See "What is breast cancer?" for more about each type.

With an FNA (fine needle aspiration) biopsy, not as many cells are removed and they often become separated from the rest of the breast tissue, so it is often only possible to say that cancer cells are present without being able to say if the cancer is in situ or invasive.

The most common types of breast cancer, invasive ductal and invasive lobular cancer, generally are treated in the same way.

Breast cancer grade

A pathologist also assigns a grade to the cancer, which is based on how closely the biopsy sample looks like normal breast tissue and how rapidly the cancer cells are dividing. The grade can help predict a woman's prognosis. In general, a lower grade number indicates a slower-growing cancer that is less likely to spread, while a higher number indicates a faster-growing cancer that is more likely to spread. The tumor grade is one factor in deciding if further treatment is needed after surgery.

For invasive cancers, the histologic tumor grade is sometimes called the Bloom-Richardson grade, Nottingham grade, Scarff-Bloom-Richardson grade, or Elston-Ellis grade. Sometimes the grade is expressed with words instead of numbers:

  • Grade 1 is the same as well differentiated
  • Grade 2 is the same as moderately differentiated.
  • Grade 3 is the same as poorly differentiated

Grade 3 cancers tend to grow and spread more quickly.

Understanding Your Pathology Report: Breast Cancer has more information about grading invasive cancers.

DCIS is also graded, but the grade is based only on how abnormal the cancer cells appear (nuclear grade). The presence of necrosis (areas of dead or dying cancer cells) is also noted. The term comedocarcinoma is often used to describe DCIS with prominent necrosis. If a breast duct is filled with a plug of dead and dying cells, the term comedonecrosis may be used. The terms comedocarcinoma and comedonecrosis are linked to a higher grade of DCIS.

Understanding Your Pathology Report: Ductal Carcinoma In Situ has more on grading DCIS.

Tests to classify breast cancers

Estrogen receptors (ER) and progesterone receptors (PR)

Receptors are proteins in or on certain cells that can attach to certain substances, such as hormones, that circulate in the blood. Normal breast cells and some breast cancer cells contain receptors that attach to estrogen and progesterone. These 2 hormones often fuel the growth of breast cancer cells.

An important step in evaluating a breast cancer is to test the cancer removed during the biopsy (or surgery) to see if it has estrogen and progesterone receptors. Cancer cells may have neither, one, or both of these receptors. Breast cancers that have estrogen receptors are often referred to as ER-positive (or ER+) cancers, while those containing progesterone receptors are called PR-positive (or PR+) cancers.

All invasive breast cancers should be tested for both of these hormone receptors either on the biopsy sample or when they are removed with surgery. About 2 of 3 breast cancers have at least one of these receptors. This percentage is higher in older women than in younger women. DCIS should be checked for estrogen receptors, as well.

HER2/neu testing

About 1 of 5 breast cancers have too much of a growth-promoting protein called HER2/neu (often just shortened to HER2). The HER2/neu gene instructs the cells to make this protein. Tumors with increased levels of HER2/neu are referred to as HER2-positive.

Cancers that are HER2-positive have too many copies of the HER2/neu gene, resulting in greater than normal amounts of the HER2/neu protein. These cancers tend to grow and spread more aggressively than other breast cancers.

All newly diagnosed invasive breast cancers should be tested for HER2/neu because HER2-positive cancers are much more likely to benefit from treatment with drugs that target the HER2/neu protein, such as trastuzumab (Herceptin®) and lapatinib (Tykerb®). DCIS is not tested for HER2 because it is not treated with these drugs.

A biopsy or surgery sample is usually tested in 1 of 2 ways:

  • Immunohistochemistry (IHC): In this test, special antibodies that identify the HER2/neu protein are applied to the sample, which cause cells to change color if many copies are present. This color change can be seen under a microscope. The test results are reported as 0, 1+, 2+, or 3+.
  • Fluorescent in situ hybridization (FISH): This test uses fluorescent pieces of DNA that specifically stick to copies of the HER2/neu gene in cells, which can then be counted under a special microscope.

Many breast cancer specialists feel the FISH test is more accurate than IHC. However, it is more expensive and takes longer to get the results. Often the IHC test is used first. If the results are 1+ (or 0), the cancer is considered HER2-negative. People with HER2-negative tumors are not treated with drugs (like trastuzumab) that target HER2. If the test comes back 3+, the cancer is HER2-positive. Patients with HER2-positive tumors may be treated with drugs like trastuzumab. When the result is 2+, the HER2 status of the tumor is not clear. This usually leads to testing the tumor with FISH. Some institutions also use FISH to confirm HER2 status that is 3+ by IHC and some perform only FISH.

A newer type of test, known as chromogenic in situ hybridization (CISH), works similarly to FISH, by using small DNA probes to count the number of HER2 genes in breast cancer cells. But this test looks for color changes (not fluorescence) and doesn't require a special microscope, which could make it less expensive. Right now, it is not being used as much as IHC or FISH.

Classifying breast cancer based on hormone receptors and HER2 status

Doctors often divide invasive breast cancers into groups based on the presence of hormone receptors (ER and PR) and whether or not the cancer has too much HER2.

Hormone receptor-positive: If the breast cancer cells contain either estrogen or progesterone receptors, they can be called hormone receptor-positive (or just hormone-positive). Breast cancers that are hormone receptor-positive can be treated with hormone therapy drugs that lower estrogen levels or block estrogen receptors. This includes cancers that are ER-negative but PR-positive. Hormone receptor-positive cancers tend to grow more slowly than those that are hormone receptor-negative (and don’t have either estrogen or progesterone receptors). Women with these cancers tend to have a better outlook in the short-term, but cancers that are hormone receptor-positive can sometimes come back many years after treatment. Hormone receptor-positive cancers are more common in women after menopause.

Hormone receptor-negative: If the breast cancer cells don’t have either estrogen or progesterone receptors, they are said to be hormone receptor-negative (or just hormone-negative). Treatment with hormone therapy drugs is not helpful for these cancers. These cancers tend to grow more quickly than hormone receptor-positive cancers. If they return after treatment, it is more often in the first few years. Hormone receptor- negative cancers are more common in women who have not yet gone through menopause.

HER2 positive: Cancers that have too much HER2 protein or extra copies of the HER2 gene are called HER2 positive. These cancers can be treated with drugs that target HER2.

HER2 negative: Cancers that don’t have excess HER2 are called HER2 negative. These cancers do not respond to treatment with drugs that target HER2.

Triple-negative: If the breast cancer cells don’t have estrogen or progesterone receptors and don’t have too much HER2, they are called triple-negative. These cancers tend to occur more often in younger women and in women who are African-American or Hispanic/Latina. Triple-negative breast cancers tend to grow and spread more quickly than most other types of breast cancer. Because the tumor cells don’t have hormone receptors, hormone therapy is not helpful in treating these cancers. Because they don’t have too much HER2, drugs that target HER2 aren’t helpful, either. Chemotherapy can still be useful, though.

Triple-positive: This term is used to describe cancers that are ER-positive, PR-positive, and have too much HER2. These cancers can be treated with hormone drugs as well as drugs that target HER2.

Other tests of breast cancers

Tests of ploidy and cell proliferation rate

The ploidy of cancer cells refers to the amount of DNA they contain. If there's a normal amount of DNA in the cells, they are said to be diploid. If the amount is abnormal, then the cells are described as aneuploid. Tests of ploidy may help determine prognosis, but they rarely change treatment and are considered optional. They are not usually recommended as part of a routine breast cancer work-up.

The S-phase fraction is the percentage of cells in a sample that are replicating (copying) their DNA. DNA replication means that the cell is getting ready to divide into 2 new cells. The rate of cancer cell division can also be estimated by a Ki-67 test. If the S-phase fraction or Ki-67 labeling index is high, it means that the cancer cells are dividing more rapidly, which indicates a more aggressive cancer.

Tests of gene patterns

Researchers have found that looking at the patterns of a number of different genes at the same time (sometimes referred to as gene expression profiling) can help predict whether or not an early-stage breast cancer is likely to come back after initial treatment. Two such tests, which look at different sets of genes, are now available: the Oncotype DX® and the MammaPrint®

Oncotype DX®: The Oncotype DX test can be helpful when deciding whether additional (adjuvant) treatment with chemotherapy (after surgery) might be useful in women with early-stage breast cancers that are hormone receptor-positive. This test is most often used for tumors that are small (1 cm or less) and have not spread to lymph nodes, but it can be used for more advanced tumors.

The test looks at a set of 21 genes in cells from tumor samples to determine a “recurrence score,” which is a number between 0 and 100:

  • Cancers with a recurrence score of 17 or below have a low risk of recurrence (cancer coming back after treatment) if they are treated with hormone therapy. Women with these cancers would probably not benefit from chemotherapy.
  • Cancers with a score of 18 to 30 are at intermediate risk of recurrence. Some women with these cancers might benefit from chemotherapy.
  • Cancers with a score of 31 or more are at high risk of recurrence. Women with these cancers are likely to benefit from chemotherapy in addition to hormone therapy.

The test estimates risk and helps predict who would be likely to benefit from chemotherapy. Still, it cannot tell for certain if any particular woman will have a recurrence with or without chemotherapy. It is a tool that can be used, along with other factors, to help guide women and their doctors when deciding whether more treatment might be useful.

MammaPrint®: This test can be used to help determine how likely breast cancers are to recur in a distant part of the body after initial treatment.

The test looks at the activity of 70 different genes to determine if the cancer is low risk or high risk. So far though, it hasn’t been studied to see if the results are useful in guiding treatment.

Usefulness of these tests: Many doctors use these tests (along with other information) to help make decisions about offering chemotherapy, but they aren’t needed in all cases. These tests are now being looked at further in large clinical trials. In the meantime, women might want to ask their doctors if these tests might be useful for them.

Classifying breast cancer based on gene expression

Research on patterns of gene expression has also suggested some newer ways to classify breast cancers. The current types of breast cancer are based largely on how tumors look under a microscope. A newer classification, based on molecular features, divides breast cancers into 4 groups. This testing, called the PAM50, is currently available but it isn’t clear that it is any more helpful in guiding treatment than tests of hormone receptors and HER2:

Luminal A and luminal B types: The luminal types are estrogen receptor (ER)–positive. The gene expression patterns of these cancers are similar to normal cells that line the breast ducts and glands (the inside of a duct or gland is called its lumen). Luminal A cancers are low grade, tend to grow fairly slowly, and have the best prognosis. Luminal B cancers generally grow somewhat faster than luminal A cancers and their outlook is not as good.

HER2 type: These cancers have extra copies of the HER2 gene and sometimes some others. They usually have a high-grade appearance under the microscope. These cancers tend to grow more quickly and have a worse prognosis, although they often can be treated successfully with targeted therapies aimed at HER2 which are often given along with chemotherapy.

Basal type: Most of these cancers are of the so-called triple-negative type, that is, they lack estrogen or progesterone receptors and have normal amounts of HER2. The gene expression patterns of these cancers are similar to cells in the deeper basal layers of breast ducts and glands. This type is more common among women with BRCA1 gene mutations. For reasons that are not well understood, this cancer is also more common among younger and African-American women.

These are high-grade cancers that tend to grow quickly and have a poor outlook. Hormone therapy and anti-HER2 therapies like trastuzumab and lapatinib are not effective against these cancers, although chemotherapy can be helpful. A great deal of research is being done to find better ways to treat these cancers.

It is hoped that these new breast cancer classifications might someday allow doctors to better tailor breast cancer treatments, but more research is needed in this area before this will be possible.

More on testing biopsy tissue to classify cancer

For more information on how biopsy tissue is looked at and tested by pathologists, see Testing Biopsy and Cytology Specimens for Cancer.

Last Medical Review: 06/01/2016
Last Revised: 09/13/2016