One of the most established examples here is the testing of breast cancer patients for the expression of a particular receptor (HER2/neu) on their breast cancer cells. Only patients where this receptor molecule is present can benefit from a particular drug called herceptin®, which relies on this receptor to attack tumor cells. Since the diagnostic test for receptor presence always accompanies respectively precedes the treatment with the particular drug this kind of test is generally called “companion diagnostics”. In the meantime many more drugs have been introduced to the market that come with a mandatory companion diagnostics test.
How Herceptin® works
The HER2/neu molecule is a cell surface receptor on breast (cancer) cells, that transmits growth signals to the cancer cell, perpetuating cell and tutor growth. Cancer cells also have a propensity to display many more of these receptors on their cell surface than healthy treats cells, further amplifying the growth signal. Herceptin® binds to this receptor blocking the growth signal, interrupting tumor growth (see Fig. 6 left half).
Of course presence of this receptor on the cell surface is a prerequisite for Herceptin® to work, otherwise there is nothing the antibody (Herceptin® belongs to the antibody class of biologicals) could bind to and may attach elsewhere unspecifically causing more damage than good.
Therefore, before administering Herceptin® doctors check for presence of the receptor (overexpression) by a molecular test, actually by one of four tests available. If the receptor is detected this patient is called HER2-posiitve and eligible for Herceptin® treatment. Unfortunately that does not guarantee successful healing as not all women who have tumors with too many copies of the HER2 gene and too many HER2 receptors are responding. The following statements are taken from , and edited for this blog.
Figure 8: Perceptions mode of action & four companion tests
Four different tests can be used to test for HER2-positive patients who will likely respond to Herceptin®:
IHC (ImmunoHistoChemistry) (1 in Fig 8)
IHC is the most commonly used test to detect over expression of the HER2 receptor protein on the surface of the cancer cells. The IHC test gives a score of 0 to 3+ that indicates the amount of HER2 receptor protein in tumors. If the tumor scores 0 to 1+, it's called "HER2 negative." If it scores 2+ or 3+, it's called "HER2 positive.” Women with IHC positive scores tend to respond favourably to Herceptin®. The drug is not considered effective for tumors with IHC scores of 0 or 1+. However, als is always the case with quantitative results, these may vary from lab to lab with some labs being more proficient at HER2 testing than others. A second opinion / test lab might be helpful if results are not entirely clear.
The IHC test results are most reliable for fresh or frozen tissue samples. IHC tends to be an unreliable way to test tissue that's preserved in wax or other chemicals. FISH testing is the preferred way to assess preserved tissue samples.
FISH (Fluorescence In Situ Hybridization) (2 in Fig 8)
The FISH test looks for an overall abnormality in the HER2 gene. This test is the most accurate, but less available, way to find out if a breast tumor is likely to respond to Herceptin®. The FISH test shows how many copies of the HER2 gene are in tumor cells. The more copies of the gene, the more HER2 receptors the cells have. With the FISH test, you get a score of either "positive" or "negative" (some hospitals call a negative test "zero"). If the cancer is FISH positive, it will probably respond well to Herceptin®.
SPoT-Light HER2 CISH (Subtraction Probe Technology Chromogenic In Situ Hybridization) (3 in Fig 8)
The SpoT-Light HER2 CISH test looks for HER2 genes in a breast cancer tissue sample. The SpoT-Light test uses a stain that makes HER2/neu genes change color. The stain is applied to the breast cancer tissue sample and looked at with a microscope. This shows how many copies of the HER2 gene are in tumor cells. The SPoT-Light test is less complicated than the FISH or IHC tests. The SPoT-Light test can be used on fresh tissue samples or tissue samples that have been stored in wax or other chemicals, but it doesn't work on frozen tissue samples.
With the SPoT-Light test, you get a score of either "positive" or "negative." If the cancer is SPoT-Light positive, it will probably respond well to Herceptin®.
Inform HER2 Dual ISH (In Situ Hybridization) (4 in Fig 8)
The Inform HER2 Dual ISH test uses a special stain that makes HER2 proteins change color. The stain is applied to the breast cancer tissue sample and viewed under a microscope. The Inform HER2 Dual ISH test can be used on tissue samples that have been stored in wax or other chemicals. This test offers more precise results than the IHC HER test. It is also less expensive and doesn’t need the special microscope of the FISH HER2 test. With the Inform HER2 Dual ISH test, you get a score of either “HER2 positive” or “HER2 negative.”
This example of Herceptin@ companion diagnostics illustrates the principle of this approach: The target molecule of the drug is known and there is a specifically informative biomarker, with which presence of to much or a mutated form can be detected (usually by antbodies). This is used to stratify patients so that non-responders are not treated with the drug but instead with another treatment expected to be more effective in their case.
What’s coming up next?
Next week I will outline the principles of (molecular) risk prediction which is mainly based on DNA tests.