For patients with HER2-positive breast cancer undergoing treatment with anti-HER2 therapy, resistance to the therapy may be prevented or delayed by adding a phosphatidylinositol-3 kinase (PI3K) inhibitor to their treatment regimens. Failure of the anti-HER2 antibody trastuzumab to block HER2 from activating the PI3K signaling pathway can lead to resistance to treatment. Therefore, dual simultaneous inhibition of both HER2 and PI3K may prolong the use of anti-HER2 therapies in women with breast cancer.

“HER2 breast cancer is a subtype of breast cancer for which we have an increasing number of effective treatments, including trastuzumab, an antibody that targets HER2,” said Carlos L. Arteaga, MD, of Vanderbilt-Ingram Cancer Center in Nashville, TN. “Unfortunately, many breast cancer tumors learn how to resist this therapy.”

This study explored the possibility that aberrant signaling through the PI3K pathway was a mechanism of resistance to trastuzumab. Breast cancer models of trastuzumab resistance with different modes of aberrant PI3K pathway activation were studied. The cells were treated with a PI3K inhibitor with or without trastuzumab.

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When PI3K was inhibited, the cancer cells had reduced ability to proliferate and the death of trastuzumab-resistant cells was induced. Additionally, combining PI3K inhibitors with trastuzumab resulted in superior anti-tumor effects against trastuzumab-resistant, HER2-positive cells in xenografts compared with the PI3K inhibitor alone. This study was published in Cancer Research (2012; doi: 10.1158/1078-0432.CCR-12-2024).

When the investigators conducted analyses to determine how the drug combination decreased resistance to trastuzumab, “We found that the trastuzumab-resistant cells in which the PI3K pathway was activated had high levels of an anti-death protein called survivin,” said Arteaga. “This implied that if we could get levels of survivin to decrease, these cells would become sensitive to treatment.”

They also measured pretreatment levels of survivin in HER2-positive breast cancer tumors and found that higher pretreatment levels of the protein correlated with a poor response to therapy.

“This suggests that we could measure levels of survivin in tumors, and if they are high or do not decrease with treatment, we could predict that the tumor is resistant to anti-HER2 therapy and try to find alternative treatments,” Arteaga said.

Arteaga and colleagues plan to continue testing PI3K inhibitors, which are already in early clinical development, in combination with other HER2 drugs in breast cancer. They also plan to measure survivin levels in HER2-overexpressing breast cancer tumors to determine if levels can predict tumors that will benefit from combination treatment.