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Study Offers New Reason Why Some Cancers Resistant to Hormonal Therapy

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About 70% of breast cancers are hormone-receptor-positive, which means their growth is fueled by the hormones estrogen and/or progesterone. Treatments for hormonal-receptor-positive disease work by lowering the amount of estrogen in the body or blocking estrogen from attaching to the breast cancer cells. There are several types of hormonal therapy medicines, including:

  • aromatase inhibitors
  • selective estrogen receptor modulators (SERMs)
  • estrogen receptor downregulators (ERDs)

Still, about 50% to 60% of early-stage hormone-receptor-positive breast cancers stop responding to hormonal therapy. When this happens, doctors say the cancer has become resistant to hormonal therapy. Almost all advanced-stage, hormone-receptor-positive disease becomes resistant to hormonal therapy at some point.

Right now, doctors are not sure why some breast cancers become resistant to hormonal therapy and some don’t. If the reasons were clear, it might be possible to make resistant cancers start responding to hormonal therapy again.

A very early study suggests that silencing the NOTCH4 pathway in a breast cancer makes the cancer respond to hormonal therapy again.

The study was published on Sept. 29, 2015 by the journal Cell Report. Read “Anti-estrogen Resistance in Human Breast Tumors Is Driven by JAG1-NOTCH4-Dependent Cancer Stem Cell Activity.”

The NOTCH4 pathway plays a role in cell development.

The study was done on cancer tumor cells in a petri dish and in mice.

When the researchers treated the hormone-receptor-positive breast cancer cells with tamoxifen or an ERD, the tumors stopped growing or grew more slowly. But the hormonal therapy also increased the activity of breast cancer stem cells.

Breast cancer stem cells are sometimes called “mother” cells -- they make other breast cancer stem cells and regular breast cancer cells. Breast cancer stem cells make up about 1% of all cells in a breast cancer tumor.

The researchers found that the activity of the breast cancer stem cells was being driven by the NOTCH4 molecule. The NOTCH4 molecule made the breast cancer stem cells resistant to the hormonal therapy and allowed them to keep growing and making new cells.

The researchers then treated the hormone-receptor-positive breast cancer cells with both tamoxifen and a NOTCH inhibitor, a medicine that blocked the signals of the NOTCH4 molecule.

They found that the tamoxifen stopped regular cancer cells from growing and the NOTCH inhibitor decreased the number of breast cancer stem cells, compared to tumors that were treated with tamoxifen alone.

“This showed us that combining standard hormonal therapies with a NOTCH pathway inhibitor, or other drugs targeting breast cancer stem cells, could improve treatment of [hormone-receptor-positive] breast cancer patients by preventing relapse due to therapy resistance,” said Dr. Rob Clarke, of the Breast Cancer Now Research Unit at the University of Manchester in the United Kingdom.

The researchers also tested tissue samples from breast cancers removed from women and found that cancers with high levels of the NOTCH4 molecule before treatment were more likely to have worse outcomes. The researchers said this suggests that testing for the NOTCH4 molecule could help doctors figure out which breast cancers are likely to become resistant to hormonal therapy.

“Validating these findings will take time but general inhibitors of the NOTCH pathway are already being tested in breast cancer clinical trials,” said Dr. Clarke. “The development of resistance to cancer therapies is a huge challenge in the clinic which is why it's vitally important that we continue to find ways to counteract it, taking us closer towards our ambitious goal of stopping women dying from this devastating disease by 2050."

NOTCH4 testing isn’t widely available yet. Still, if you’ve been diagnosed with hormone-receptor-positive breast cancer that has stopped responding to hormonal therapy, you may want to ask your doctor about this study. There may be a clinical trial studying hormonal therapy resistance that might be a good fit for you and your unique situation.

Stayed tuned to Research News for the latest information on NOTCH inhibitors and how they may be used to treat breast cancer.

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