Everolimus May Help Those With HER2-positive Breast Cancer That No Longer Responds Well to Trastuzumab

Breast Cancer News
September 9, 2014
Erin Rowley, Writer and Content Coordinator
Reviewed By: 
Gini Fleming, MD

Adding everolimus could make trastuzumab work better in women who aren’t seeing the same benefits this medicine once gave them. But everolimus isn’t without risk – it has the potential to lower the user’s quality of life.

Background and Goals

When breast cancer tumors grow because of a protein called human epidermal growth factor receptor-2, the cancer is considered HER2-positive. This could represent as much as 25 percent of breast cancers. It is usually treated with trastuzumab (Herceptin), a medicine that targets HER2-positive cells and tries to stop them from growing.

Eventually, trastuzumab may stop working as well as it once did. Researchers behind the BOLERO-3 study wanted to see if they could reverse this. They looked at everolimus (Afinitor), an mTOR inhibitor that works by slowing or stopping the function of mTOR protein kinase, which encourages cell growth.

Everolimus is FDA-approved for postmenopausal women with metastatic, or late stage, breast cancer that is hormone receptor-positive, meaning it grows in response to estrogen. These researchers wanted to see if everolimus would also help women with HER2-positive breast cancer that was no longer responding well to trastuzumab.


The BOLERO-3 trial’s 569 participants had HER2-positive, metastatic breast cancer that had stopped responding to trastuzumab. They all had previously received chemotherapy, including a taxane, which blocks cell growth by stopping cell division.

Participants were randomly assigned to one of two groups. Both groups received weekly trastuzumab and vinorelbine (Navelbine), a chemotherapy medicine used to treat metastatic disease. But the treatment group also received a daily dose of the study medicine, while the placebo group received an inactive treatment instead.

The trial measured progression-free survival, or PFS, the length of time after starting treatment in which the disease does not get worse.

The treatments continued until the disease got worse, side effects became unacceptable or the woman decided she didn’t want to participate anymore. Women could have the medicine dose adjusted to ease some effects.


The study found median PFS to be 7 months with everolimus and 5.78 months with the placebo. This suggests that adding everolimus to trastuzumab and vinorelbine somewhat lengthened the time without disease growth in women with HER2-positive, metastatic breast cancer that had been pre-treated with chemotherapy and stopped responding to trastuzumab.

Certain factors, such as having cancer that was not hormone receptor-positive, may be linked to greater benefit from everolimus.

Everolimus caused more than twice as many reports of serious side effects in the treatment group, including mouth sores, low white blood cell counts and fatigue.

What This Means for You

If you have HER2-positive, metastatic breast cancer that stopped responding to trastuzumab and you had chemotherapy in the past, you may find this study encouraging. These results show it may be possible for other medicines, such as everolimus, to improve your benefit from trastuzumab. The results were especially encouraging in people whose tumors were not also hormone receptor-positive.

It’s important to keep in mind that everolimus was associated with some serious side effects. When choosing treatments that are right for you, you and your doctors should discuss how you can keep your quality of life high while you manage the disease.

More research is being done in this area. If you’re interested in participating in current trials, talk to your doctor and visit ClinicalTrials.gov to see what studies are happening now and if you may be eligible.

André, Fabrice, O'Regan, Ruth, Ozguroglu, Mustafa et al.  Everolimus for women with trastuzumab-resistant, HER2-positive, advanced breast cancer (BOLERO-3): a randomised, double-blind, placebo-controlled phase 3 trial. The Lancet Oncology, Volume 15, Issue 6. Pages 580 - 591, May 2014.

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