Gene signatures tag breast cancer drug response

Aromatase inhibitors are used to treat breast and ovarian cancer in post-menopausal women, and act by blocking the production of estrogen, the reproductive hormone that can feed the growth of these cancers. They are often used to shrink cancers before surgery, but not everyone's cancer responds, and a team of researchers at Washington University School of Medicine in St. Louis have found genetic mutations that could predict the response to the drugs, as well as how fast the tumors will grow.

The researchers, who published their results in Nature, sequenced pretreatment biopsies from 77 post-menopausal women with stage 2 or 3 estrogen-receptor-positive breast cancer, the most common form of the disease, along with healthy cells. The women then went on to be treated with aromatase inhibitors in two clinical trials.

The researchers compared the DNA sequences from the cancer cells and the healthy cells and used this information to create cancer "signatures." The comparisons found included 18 mutated genes, including some that were known to be involved in breast cancer and others that have been linked with blood disorders, including leukemia. The women who went on to respond to the aromatase inhibitors tended to have only a few mutations, and those who were resistant had more mutations. One mutated gene was seen in 20% of the tumors--TP53, a tumor suppressor gene--and this was linked with a poor response to aromatase inhibitors, fast-growing and metastasizing cancers, and a poor prognosis.

"Rather than give aromatase inhibitors to women with TP53 mutations knowing they are unlikely to be effective, these women may benefit from immediate surgery followed by chemotherapy," says lead author Dr. Matthew Ellis, the Anheuser Busch Professor of Medical Oncology, who treats patients at the Alvin J. Siteman Cancer Center and Barnes-Jewish Hospital.

Not all the genetic mutations were linked with poor outcomes--changes in other genes were associated with a good response to aromatase inhibitors, slow growing cancers and positive outcomes. One of the issues with using genetic mutations as prognostic or predictive biomarkers is that some are relatively rare. Larger studies will be needed to find out whether these are also of importance.

These signatures could help select those patients most likely to respond to this class of drugs, saving non-responders from the side effects (and costs) associated with taking unnecessary treatment. The next step for the cancer signatures is to carry out a trial of patients with estrogen-receptor positive breast cancer, with treatment decisions based on the genomic signatures of tumors, with patients either receiving aromatase inhibitors or other drugs targeted to other mutations.

- read the press release
- see the paper