The protein HER2 plays a role even in breast cancers that would traditionally be categorized as HER2-negative. The drug trastuzumab (Herceptin), which targets HER2, may have an even greater role for treating breast cancer and preventing its spread.

Approximately 20% of women with breast cancer have tumors that are categorized as HER2-positive. Trastuzumab has had a tremendous impact on survival for these women, particularly in the adjuvant setting, after surgery to remove the primary cancer. Patients with HER2-negative breast cancer are not advised to take trastuzumab. However, these new findings have potential implications for an additional 65% of women with breast cancer.

A recent study based on new analyses of old data found that some tumors were incorrectly categorized as HER2-positive, which resulted in those women receiving adjuvant trastuzumab. The women benefited from the treatment as much as did those whose cancer actually was HER2-positive.

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“We now provide a molecular explanation for the surprising finding that adjuvant Herceptin benefited some women with HER2-negative breast cancer. If this is confirmed in clinical trials, it could alter our approach to breast cancer treatment,” said study author Max S. Wicha, MD, of the University of Michigan Comprehensive Cancer Center. Results appear online in Cancer Research (2013; doi:10.1158/0008-5472.CAN-12-3349).

The explanation is that HER2 is selectively expressed in the cancer stem cells of many HER2-negative breast tumors. Because the stem cells represent such a small number of cells in a tumor, the amount of HER2 is not high enough to meet the threshold for a HER2-positive cancer.

The researchers had previously shown HER2 plays an important role in cancer stem cells—the small number of cells in a tumor that fuel its growth and spread. These cells represent 1% to 5% of all the cells in a tumor. They are resistant to current chemotherapy and radiation treatments; but because they express HER2, they are effectively targeted by trastuzumab.

Furthermore, the researchers in this new study found that for tumors classified as HER2-negative, HER2 levels were higher in bone metastases compared to the primary breast tumor. Bone is the most frequent site to which breast cancer spreads.

“This work has very significant implications for how we have developed adjuvant therapies. The idea of using drugs that cause tumors to shrink, which has been the accepted paradigm for developing therapies, is flawed. Our work suggests that adjuvant therapies will need to target the cancer stem cell population. Eliminating cancer stem cells by effective adjuvant therapies should prevent tumor recurrence, ultimately resulting in more cures,” Wicha said. A large randomized trial is currently open to address this question, and patients whose tumors are not categorized as HER2-positive should not receive trastuzumab outside of this trial.