Lab Tests to Help Classify Breast Cancer in Men

Breast cancer is classified in different ways, based on the results of lab tests after biopsy or surgery. Breast cancer is given a type, based on the type of cells it started from; a grade, based on how the cells look and how quickly they grow; and other classifications based on the results of tests for different hormone receptors or genes or proteins in the cancer cells.

Breast cancer type

The tissue removed during the biopsy (or during surgery) is first looked at in the lab 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. 

Breast cancer grade

Cancer cells are given a grade when they are removed from the breast and checked in the lab. The grade is based on how much the cancer cells look like normal breast cells.

For invasive cancers, a lower grade number (1) usually means the cancer is slower-growing, and less likely to spread. A higher number (3) means a faster-growing cancer that’s more likely to spread. The grade is used to help predict your outcome (prognosis) and help figure out what treatments might work best. Sometimes words such as "well differentiated," "moderately differentiated," and "poorly differentiated" are used to describe the grade instead of numbers:

• Grade 1 or well differentiated: The cells are slower-growing, and look more like normal breast tissue.
• Grade 2 or moderately differentiated: The cells are growing at a speed of and look like cells somewhere between grades 1 and 3.
• Grade 3 or poorly differentiated: The cancer cells look very different from normal cells and will probably grow and spread faster.

Our information about pathology reports can help you understand details about your breast cancer.

Ductal carcinoma in situ (DCIS) is also graded, but the grade is based only on how abnormal the cancer cells look. Areas of necrosis (dead or dying cancer cells) are also noted. If there is necrosis, it means the tumor is growing quickly. See Understanding Your Pathology Report: Ductal Carcinoma In Situ for more on how DCIS is described.

Tests to classify breast cancers

Estrogen receptor (ER) and progesterone receptor (PR) status

Receptors are proteins in or on cells that can attach to certain substances in the blood. Normal breast cells and some breast cancer cells have receptors (proteins) that attach to the hormones estrogen and progesterone, and the cells depend on these hormones to grow. Cancers are called hormone receptor-positive or hormone receptor-negative based on if they have these receptors. Knowing the hormone receptor status is important in deciding treatment options. Keeping these receptors from attaching to the hormones can help keep the cancer from growing and spreading. There are drugs that can be used to do this.

Breast cancer cells may have one, both, or neither of these receptors:

• ER-positive (ER+) breast cancers have estrogen receptors.
• PR-positive (PR+) breast cancers have progesterone receptors.

HER2 status

In a small number of breast cancers in men, the cells have too much of a growth-promoting protein called HER2 (also known as HER2/neu). Tumors with increased levels of HER2 are referred to as HER2-positive. Cancer cells become HER2-positive by having too many copies of the HER2 gene (known as gene amplification). Cancer cells with greater than normal amounts of the HER2/neu protein tend to grow and spread more aggressively than other breast cancers.

All newly-diagnosed breast cancers should be tested for HER2 because the outlook for people with HER2-positive cancers is improved if drugs that target the HER2 protein, such as trastuzumab (Herceptin) and lapatinib (Tykerb) are used as part of treatment. See Targeted Therapy for Breast Cancer in Menfor more information on drugs that target this protein.

The 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 it to change color if abnormally high levels are present. 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 think the FISH test gives more accurate results than IHC, but it is more expensive and takes longer to get the results. Often the IHC test is used first.

• If the results are 0, the cancer is considered HER2-negative. These cancers do not respond to treatment with drugs that target HER2.
• If the IHC result is 1+, the cancer is considered HER2-negative. These cancers do not usually respond to treatment with drugs that target HER2, but new research shows that certain HER2 drugs might help in some cases (see below).
• When the result is 2+, the HER2 status of the tumor is not clear and is called “equivocal.” The tumor is then tested with FISH to clarify the result. Some institutions also use FISH to confirm HER2 status that is 3+ by IHC and some perform only FISH.
• If the test comes back 3+, the cancer is HER2-positive. These cancers are usually treated with drugs that target HER2.

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 in men that are hormone receptor-positive can be treated with hormone therapy drugs that lower estrogen levels, block estrogen receptors, or affect androgen (male hormone) levels (see Hormone Therapy for Breast Cancer in Men). 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). Patients 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. About 9 out of 10 male breast cancers are hormone receptor-positive.

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.

HER2 positive: Cancers that have too much HER2 protein or 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.

HER2 low: Some breast cancers that have an IHC result of 1+ or an IHC result of 2+ along with a negative FISH test might be called HER2-low cancers. These breast cancers are still being studied but appear to benefit from certain HER2 targeted drugs.

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 (HER2 negative, ER negative, and PR negative). 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 lab tests

Tests of ploidy and cell proliferation rate

Finding out more information about the DNA in the breast cancer cells can help predict how fast the cancer cells are dividing and growing.

The ploidy of cancer cells refers to how much DNA they contain.

• If there's a normal amount of DNA in the cells, they are said to be diploid. These cancers tend to grow and spread more slowly.
• If the amount is abnormal, then the cells are described as aneuploid. These cancers tend to be more aggressive and grow and spread faster.)

Tests of ploidy may help determine prognosis (outcome), but they rarely change treatment and are considered optional. They are not usually recommended as part of a routine breast cancer work-up.

Cell proliferation is how quickly a cancer cell copies its DNA and divides into 2 cells. If the cancer cells are dividing more rapidly, it means the cancer is faster growing or more aggressive. DNA is copied when the cell is getting ready to divide into 2 new cells. The S-phase fraction is the percentage of cells in a sample that are copying their DNA. The rate of cancer cell division can also be estimated by a Ki-67 test. If the S-phase fraction or Ki-67 test is high, it means that the cancer cells are dividing more rapidly, which can indicate a more aggressive cancer.

Molecular tests for gene changes

In some cases, doctors may test for specific gene changes in the breast cancer cells that could mean certain targeted drugs or immunotherapy drugs might help treat the cancer.

These molecular tests (also known as genomic tests or biomarker tests) can be done on cancer cells from a biopsy or surgery for breast cancer, or on a blood sample.

Some changes that might be tested for include:

• BRCA1 and BRCA2 gene mutations
• PIK3CA, AKT1, and PTEN gene mutations
• ESR1 gene mutations
• Microsatellite instability (MSI) and defects in mismatch repair genes (dMMR) 
• Tumor mutational burden (TMB)
• NTRK fusion gene changes

Gene expression tests

Tests that look at the patterns of certain genes (sometimes referred to as gene expression profiling) can help predict if some early-stage (stage 1 or 2) breast cancer are likely to come back after initial treatment. Doctors can use this information to know who will most likely benefit from chemotherapy after breast surgery.

Oncotype DX and MammaPrint are examples of tests that look at different sets of breast cancer genes. There are more tests in development. Tests like these are part of what’s being called “personalized medicine” – learning more about your cancer to specifically tailor your treatment.

More information is needed to decide how useful this test is for breast cancer in men. But there is enough data that this test can help men with early stage breast cancer make decisions about chemotherapy after surgery. Ask your doctor if these tests might be appropriate.