Biomarker May Predict Prognosis for Targeted Therapy in Patients With HER2-Negative Breast Cancer

Brief exposure to a targeted therapy can tell doctors which patients with HER2-negative breast cancer will respond and which should switch to another kind of treatment. These findings were published in the International Journal of Cancer (2015; doi:10.1002/ijc.29808).

If confirmed in clinical trials, the discovery would provide physicians invaluable information regarding the effectiveness of bevacizumab (Avastin). Such early results would spare patients weeks of the medication's sometimes severe side effects, allowing them to pursue options with greater chances for 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," said principal Investigator and senior author Lyndsay Harris, MD, professor of Medicine at Case Western Reserve in Cleveland, Ohio. "We can identify those patients within 15 days of the very first dose they receive."

Harris and a team of scientists and physicians came together to determine how to tell early whether bevacizumab might work or whether the medication's significant toxicity would cause much harm without commensurate success in stemming breast cancer.

Bevacizumab emerged in the early 2000s as a therapeutic agent known for inhibiting formation of blood vessels that nourish tumors. Based on early reports of improved efficacy of this agent in advanced disease, the Food and Drug Administration approved bevacizumab in February 2008 for use in metastatic HER2-negative breast cancers. However, longer-term follow-up in clinical trials did not show improvements in overall survival compared with other chemotherapy drugs, and thus the FDA retracted approval of bevacizumab for breast cancer in 2011.

Despite this setback, ongoing experience with bevacizumab revealed that some breast cancer patients achieved significant survival benefit from bevacizumab even if others did not. What the researchers needed were biomarkers that could show which patients would benefit most from the drug to justify the toxicity in those patients and avoid it in those who would not benefit.

Researchers assessed tumor tissue from HER2-negative breast cancer patients at baseline before therapy began. Then patients received a single dose of bevacizumab to perturb the tumor. After 10 to 14 days, tumor tissue was collected again to examine what molecular changes occurred with bevacizumab treatment.

What investigators found was a decrease in TGF-beta signaling activity, a process that affects cell proliferation, occurs exclusively in tumors that achieve a complete response, which is 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 in the tumor cells that makes them more sensitive to treatment.

Furthermore, this decrease in TGF-beta activity in responders was only seen when tumors were perturbed by bevacizumab and not observed by other targeted therapies, making this a specific biomarker signature for HER2-negative breast cancer treated with bevacizumab.

"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, assistant professor of General Medicine and a member of the Case Comprehensive Cancer Center.

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