Imagine two women sitting in an oncologist's office. Both have been diagnosed with a type of breast cancer called hormone-receptor positive, and both will receive the same chemotherapy drug.

For all intents, this type of cancer looks the same on the outside. What puzzles cancer doctors, though, is that tumors in women with this type of breast cancer don't respond to the treatment in the same way. Research presented last week at the San Antonio Breast Cancer Symposium by Dr. Matthew Ellis, a professor at Washington University School of Medicine, is helping explain why.

In some women with this type of breast cancer, the tumor will shrink and the cancer will stay gone after surgery. In other women, the tumor won't respond to the treatment, leaving them with a chance that the breast cancer will return.

That's the challenge oncologists face: People are different genetically, and so are tumors. These differences may explain why some cancers respond to treatment and some don't.

Ellis is leading several research projects to unravel the genetic differences between breast cancer and normal cells.

In one of those projects, he is studying the type of breast cancer called hormone-receptor positive. It is so named because cells in the tumor sprout receptors on their surface, like microscopic hands, that grab onto estrogen molecules and convert the hormone to fuel.

To prevent that from happening, doctors treat women with this type of breast cancer with aromatase inhibitors, which keep those tiny "hands" from latching onto estrogen or progesterone, shrinking the tumor. Aromatese inhibitors are not chemotherapy. They are endocrine, or hormone, therapy.

"If you use these inhibitors frequently, as I do, you will find that the response to them is highly variable," Ellis said. He is working with Elaine Mardis, co-director of The Genome Institute and a team of genetic researchers, all from Washington U. The work is funded by the Susan Komen foundation and the National Institutes of Health.

In the mid-2000s, Ellis started a clinical trial to study a basic feature of aromatase inhibitor therapy. He wanted to know whether giving the chemo before surgery to remove the tumor, would shrink the tumors enough that the women could have less extensive surgery, perhaps a lumpectomy rather than a mastectomy. He delayed surgery in one group of women and gave another group of women the aromatase inhibitor for four weeks or so, right after diagnosis.

Ellis and his colleagues found that giving aromatase inhibitors for four weeks or so before removing the breast tumor, will, in some cases, shrink the tumor enough to allow a lumpectomy rather than a mastectomy. The results were published in 2009.

TAKING SAMPLES

At the start of the clinical trial, Ellis knew that he wanted to examine these breast tumors on a genetic level, so he got permission from some of the women to do studies on their tumors. For these genetic studies, he took samples of the tumors twice — once at diagnosis and again four weeks later when the tumors were surgically removed.

Those tumor samples are valuable, says Mardis, because she and the team can compare genetic changes in the breast tumors before and after the women took aromatase inhibitors.

Ellis and his team will continue to follow the women in the clinical trial for five years, during which they will take the aromatase inhibitors. They know which women are responding to the therapy and which aren't. They have also found some mutations that happen again and again in individual tumors. These mutations will either switch genes on or turn them off, so researchers are trying to match the mutations to the women who are not responding to the therapy to get at the fundamental question of why some tumors don't respond to treatment.

The team expects the early results of this study will be published soon. In results that Ellis presented in San Antonio, the team discovered three groups of mutations in tumors that may point out which tumors will keep responding to the hormone therapy and which won't. Ellis says that the only way to find these mutations is to look for them in every tumor gene before and after women are treated with aromatase inhibitors.

"This is like saying, 'I'm looking at the night sky and I see stars and those stars look like little points of light so I can't tell the difference between them,' " he said. "And then you get on the Hubble telescope and you see dramatically there are billions of stars and different constellations."

The long-term goal of the study, Ellis and Mardis said, is to develop a test that will predict which tumors will shrink with aromatase inhibitors. Then, doctors can analyze DNA in each patient before and after hormone therapy to figure out which women will respond and which won't.

'GAME CHANGER'

Now, everyone with this type of breast cancer is getting aromatase inhibitor therapy, whether they are responders or nonresponders, said Ellis. If doctors know ahead of time that a woman responds to the inhibitors, then doctors might be able to give a lower dose and lessen the side effects, Ellis said. By identifying genetic weak spots in the tumors, he wants to find the "game changer" for hormone receptor positive breast cancer, so he can match the mutations with chemotherapy drugs already on the market and find a better way to treat these breast cancers that don't respond to aromatase inhibitors.

Researchers are already identifying mutations common to breast and colon cancers and to melanoma, so drugs that target mutations in melanoma, are already being tested in colon cancers.

Later this month, Ellis and a colleague at the University of North Carolina at Chapel Hill will announce results of an analysis of 500 breast cancer tumors, part of the Cancer Genome Atlas, a large project sponsored by the National Institutes of Health.

"Within the next couple of years, we're going to see a brand new map of the breast cancer universe emerging," Ellis said.

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Editor's note - Corrected the name of the Genome Sequencing Center to The Genome Institute at Washington University.