Breast Cancer Update

Genes that protect and new tools that help

by Dr. Barry Starr, Stanford University

Imagine you are a woman and have found a lump. The doctor confirms that it is breast cancer.

Your first thought might be, "Why me?" "Why not all those other women?"

In the first part of this article I'll discuss why some people get cancer and some don't. And why it all seems so random. I'll also talk about some recent findings about a certain DNA change that makes some women less likely to get breast cancer.

Back to your visit with the doctor. After the diagnosis, the doctor does some tests and finds that the cancer didn't spread to the lymph nodes. Thank goodness. Cancer tends to give the most trouble when it spreads.

So the doctor surgically removes all of the cancer. The next step is for you and your doctor to decide whether you should have chemotherapy or not.

But why is this even an issue if the cancer is gone? Because there might be some left.

The cancer was lymph node negative which means the doctor didn't detect that the cancer had spread. But it may have anyway. At very early stages, cancer can be hard to spot.

So it may just be waiting somewhere in the body, ready to bloom. Chemotherapy can destroy these cancers even when the doctor can't detect them.

In the past it was very difficult to tell whether or not a cancer would spread. Which meant a lot of women probably got unnecessary chemotherapy. But if you can't tell whether or not a cancer will spread, it is probably a good idea to have the chemo.

Now there is a better option. In the second section, we'll discuss a new test that can help figure out whether a woman's breast cancer will spread or not. And so help a doctor decide whether chemo is appropriate or not.

Protection against breast cancer

Cancer. What a terrifying diagnosis. Some people get it and others don't. It seems so random.

Lots of things can damage DNA.

In some ways it is. Cancer happens when the DNA in a cell gets damaged so that the cell can now grow uncontrollably. And maybe spread.

Not all DNA damage leads to cancer though. Good thing too since our DNA gets damaged all the time.

Sometimes what we eat causes DNA damage. Or the sunlight. Or second hand smoke. Or it happens from a mistake when our DNA gets copied when a cell divides.

But most of this damage doesn't cause a problem. Our cells can usually fix damaged DNA. And if the damage is too dangerous, the cell will kill itself.

Sometimes, though, the damage isn't fixed and the cell stays alive. That is when the trouble can begin.

Of course, again, not always. Not all of the remaining DNA changes lead to cancer either.

For the DNA change to cause cancer, it has to happen in the right place. This is where the randomness comes in. Some people get the DNA changes in a safe spot. Some people get it in a dangerous spot.

In the cases where there is cancer, often the DNA change happened in the middle of some particular gene. How might this cause a problem?

Remember, a gene is simply a recipe for a protein. The DNA change causes a rogue or wrecked protein to get made. And it is this protein (or lack of the protein) that causes all of the problems.

For example, there is a protein called p16 that keeps a cell from dividing all the time. When there is no p16, cells just keep dividing until they run out of food.

So when the p16 gene is damaged, the cell grows uncontrollably. This kind of DNA change can affect some people more than others though. This is where the process loses some of its randomness. And is why some cancers can run in families. How does this work?

Remember we have two copies of most of our genes, one from mom and one from dad. Often when one copy gets damaged, the other can pick up the slack. So both copies usually need to be changed to get cancer.

Think about our p16 example. Imagine someone has 2 good copies of p16 and another person is born with only one good copy. Who is most likely to get cancer?

Cells usually kill themselves
if they are too damaged.

That's right, the person with only one good copy. It only takes a hit on the other good copy for that person to get cancer. The person with two good copies will need a hit in each copy of the same gene. Which is much less likely.

So that is an example of being born with a bad gene. But some people also have genes that protect them from getting cancer.

Maybe they have genes that are better at fixing damaged DNA before it becomes a problem. And others might have a cell kill itself off faster if it gets a mutation.

Some recent work shows that 13% of women of European descent have a version of a gene that more reliably causes damaged cells to suicide. Who would have thought that a suicide gene would protect a woman from cancer!

This version of a gene was found by a group that was looking over a bunch of other studies. The group looked at 9 different DNA changes in over 33,000 women and found that a certain change in one gene, CASP8, protected women from breast cancer.

CASP8 is a well known gene involved in programmed cell death (or apoptosis). In other words, it is a key player in cell suicide.

Women with a certain version of this gene were 10% less likely to get breast cancer than women with the "normal" version. Presumably this is because damaged cells are eliminated more efficiently in these women.

Of course 10% isn't a lot, but certainly every bit helps. And it is somehow comforting to think that our DNA can have cancer cells suicide for us.

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Baby steps towards personalized medicine

Last week the FDA approved a new weapon in a doctor's arsenal against breast cancer. This genetic test doesn't help doctors find the cancer early. Or figure out who is more likely to get it.

What this test does is help doctors decide whether to prescribe chemotherapy AFTER surgery. Right now doctors often recommend chemo even if all of the tumor has been removed.

If you know anyone who has gone through chemo, you know what a grueling experience it is. And it can sometimes have side effects like permanent damage to organs or even a secondary cancer. Wouldn't it be great if women could get by with less chemo?

This is where the newly approved genetic test can help. The FDA recently approved a genetic test called MammaPrint that is marketed by a Dutch company called Agendia and manufactured by a bay area company, Agilent Technologies, Inc.

A microarray test can help
determine if a cancer will spread.

There is also another competing test made here in the bay area by Genomic Health Inc. called Oncotype DX. Although not FDA approved, the company sold over 14,000 of these tests last year.

Both tests use a technology called microarrays. Microarrays are basically a way to do many genetic tests all at once on a glass slide.

In this case, the tests aren't looking at a person's genes. Instead they look at how the tumor uses its genes.

All the different kinds of cells in our body use their genes a bit differently. This is what makes a lung cell different from a liver cell, for example.

And a tumor uses its genes differently than do the kinds of cells it came from. In other words, a breast cancer cell uses its genes differently than does a normal breast cell. Why is this? Because as we talked about earlier, the cancer cell's DNA is damaged.

This damage can cause a cell to use its other genes differently too. A research group found that the cancers that were most likely to spread used 70 or 80 of their genes similarly. So the microarray test looks at how tumors use these 70 or 80 genes and this helps doctors decide whether chemotherapy is a good option or not.

Now these tests aren't perfect. For MammaPrint, for example, only about one third to one quarter of women whose results indicated they had aggressive cancer actually had their cancer spread.

But as one of many tools that help doctors decide on a treatment, these tests are very powerful. And another step on the road to personalized medicine.

One day doctors may look at a patient's DNA (or the DNA of his or her tumors) and be able to give that patient personalized care. One patient will do well with one form of chemo while another may do better with a different form.

This sort of thing already happens with the drug Herceptin and certain aggressive forms of breast cancer. And with Gleevec and certain forms of leukemia. And now breast cancer has these microarray tests. Maybe personalized medicine is closer than we think.

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Content provided by the Department of Genetics, Stanford University.