Mechanisms Behind Drug-Resistant Estrogen-Driven Breast Cancer Discovered

A new study shows why certain types of breast cancer drugs stop working. These drug-resistant tumors begin to make their own supply of nutrients, which leaves the disease unscathed by treatment, according to a study published by Nature Genetics.

The investigators hope these findings can be used to develop novel treatment options for patients with recurrent disease.

Approximately 70% of breast cancers are ER-positive, which is a subtype of cancer driven by estrogen. Patients with ER-positive breast cancer are typically treated with a choice of 2 drugs after surgery to prevent recurrence, according to the study.

The drug tamoxifen prevents estrogen from binding to cancer cell DNA, and aromatase inhibitors block estrogen production in other tissues. The aromatase inhibitors are typically used to treat patients who already underwent menopause.

During menopause, a woman’s ovaries stop producing estrogen. However, the hormone is still made in other tissues through the aromatase enzyme. Inhibitors of this enzyme block the production of estrogen, and are thought to prevent recurrent ER-positive breast cancer.

Unfortunately, 1 in 3 patients develop resistance to both drugs. Previously, it was believed that tumors developed resistance, but the process was unknown.

Included in the study were 150 women with recurrent breast cancer that had metastasized upon return.

In the new study, researchers have found that 1 in 4 patients receiving treatment with aromatase inhibitors had increased production of aromatase within the cancer cells. The cancer cells appear to do this through amplification of aromatase, according to the study.

An increased level of aromatase allows cancer cells to create their own estrogen, without relying on alternative sources of the hormone. This makes treatment with aromatase inhibitors ineffective.

“For the first time we have seen how breast cancer tumours [sic] become resistant to aromatase inhibitors,” said co-lead author of the study Luca Magnani, PhD. “The treatments work by cutting off the tumour’s [sic] fuel supply — oestrogen [sic] – but the cancer adapts to this by making its own fuel supply.”

The investigators also discovered that tumors develop resistance based on whether tamoxifen or aromatase inhibitors are administered. Very few patients receiving treatment with tamoxifen had increased levels of aromatase to increase estrogen.

The authors next plan to conduct additional studies to determine how cancer cells develop resistance to tamoxifen. They are also working to create a test that can identify whether a tumor has begun to increase aromatase production, according to the study.

Currently, when aromatase inhibitors stop working, physicians will prescribe another type of aromatase inhibitor. The current findings suggest that if the patient develops resistance due to increased estrogen production, another aromatase inhibitor would not be effective.

Until the researchers are able to conduct clinical trials, they suggest that physicians biopsy the recurrent tumor. Since patients typically only have 1 biopsy, information regarding the recurrent disease is being lost.

The authors hope that their findings may provide patients with recurrent or metastatic cancer additional treatment options in the future.