Brief Exposure to Breast Cancer Drug Could Determine Treatment Success

Findings could eliminate need for weeks of treatments that carry severe side effects.

Findings could eliminate need for weeks of treatments that carry severe side effects.

Researchers at Case Western Reserve have demonstrated that brief exposure to a targeted therapy could let physicians know which HER2-negative breast cancer patients will respond to treatment and which should switch to a different treatment.

If confirmed in clinical trials, the results of the study could provide physicians with further safety and efficacy information regarding the drug bevacizumab (Avastin). Earlier results would spare patients the agony of going through weeks of treatment with medications that have severe side effects and would allow patients to pursue options with greater chances of success.

“What all this means is that we have identified a signature that tells us which patients are likely to respond to bevacizumab and chemotherapy and we can identify those patients within 15 days of the very first dose they receive,” said principal investigator and senior author Lyndsay Harris, MD, professor of medicine at Case Western Reserve.

The research provides yet another example of how targeted therapies can provide more personalized treatment methods. Given that no 2 patients respond the same to the same therapies, scientists are now seeking ways to determine which medication works best and which bring no results or even negative results. Scientists from Case Western Reserve, as well as other universities such as Yale and Brown, came together to determine whether a way could be found to tell if and how patients will respond to bevacizumab.

Bevacizumab inhibits blood vessel formation that supports tumor growth. It is used to treat metastatic HER2-negative breast cancers. However, during long-term follow-up in clinical trials, the drug did not show improvements in overall survival the way other chemotherapy drugs had in the past, leading to the FDA’s retracted approval of the medication for breast cancer in 2011.

Despite this retraction, ongoing tests with bevacizumab revealed that some breast cancer patients achieved significant survival benefits from the drug even if others did not. Researchers were in need of a proper biomarker to determine which patients would benefit from the drug and which patients should avoid it.

Previous studies yielded no possible biomarkers for HER2-negative breast cancer chemotherapy, so researchers pursued an alternative route: observing the molecular responses within the breast tumors after an initial dose of bevacizumab.

Researchers assessed tumor tissue from HER2-negative breast cancer patients at baseline before therapy began. Then patients received a single dose of bevacizumab to disturb the tumor.

After 2 weeks, tumor tissue was recollected to examine what molecular changes occurred within the treatment. Investigators found a decrease in TGF-beta signaling activity, the process responsible for cell proliferation and occurs in tumors that achieve a complete response (no tumor left at surgery). This finding is associated with a more than 90% cure rate for that patient and is likely due to decreases in hypoxia, a state of low oxygen, in the tumor cells that makes them more sensitive to treatment.

The decrease in TGF-beta activity was only observed in those tumors that received treatment with bevacizumab and not in tumors that were treated with alternative targeted therapies, making this a specific biomarker signature for HER2-negative breast cancer treated with the drug.

“The novelty of the study is that for the first time, we show an advantage for a brief-exposure framework to identify molecular and pathologic biomarkers that provide an early readout of the way a HER2-negative tumor responds to a targeted therapeutic agent,” said lead author Vinay Varadan, PhD. “We are among the first groups in the world to show that this approach, which perturbs the tumor with one dose of therapy, allows us to see the changes induced by the therapy that predict how the tumor will respond to the remaining cycles of chemotherapy.”

While bevacizumab is not used to treat breast cancers within the United States, the drug is widely used for this purpose in Europe. There is potential for the drug to make a comeback in the United States, but more importantly, it is used for treating other cancers such as colon cancer. The brief-exposure method could work to bring awareness to a biomarker that is present in other cancers as well, or other chemotherapy agents for that matter, to determine their effectiveness in cancer treatment for individual patients.

“Our finding is not so much about the single drug,” said Harris. “What matters most is we can identify biomarkers to help us select therapy properly. In our study, we have found this signature to be specifically useful in response to bevacizumab, but it may be useful in predicting response to other anti-angiogenic agents as well and should be tested.”