About 20 percent of women with breast cancer have tumors labeled HER2-positive. And since the drug Herceptin has come on the scene, it has had a tremendous impact on survival for these women, particularly when it is given in the adjuvant setting, after surgery to remove the primary cancer. The new findings have potential implications for an additional 65 percent of women with breast cancer.

A recent study based on new analyses of old data found some tumors were incorrectly categorized as HER2-positive and as a result those women received adjuvant Herceptin. It turns out, they benefited as much from the treatment as woman with actual HER2-positive cancer.

"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," says study author Max S. Wicha, M.D., distinguished professor of oncology and director of the U-M Comprehensive Cancer Center.

At this point, patients with HER2-negative breast cancer are not advised to take Herceptin.

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. Results appear online in Cancer Research.

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 percent to 5 percent of all the cells in a tumor. They are resistant to current chemotherapy and radiation treatments -- but since they express HER2, they are effectively targeted by Herceptin.

Further, 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.

The researchers administered Herceptin to mice with these bone lesions and found that it was most effective when given early, when tumors were small or mere "micrometastases." In these cases, Herceptin almost completely blocked the tumors from growing. When the drug was given later, after tumors were established, it had little effect.

"We have shown that the bone microenvironment induces HER2 expression in these tumors. If Herceptin can target bone micrometastases, then administering it to patients before metastases develop could help reduce tumor recurrence," says study author Hasan Korkaya, Ph.D., research assistant professor of internal medicine at the U-M Medical School.

The implications of this finding are that we need cancer treatments that target the small number of cancer stem cells in addition to traditional chemotherapies that eliminate the bulk tumor cells. This means that merely looking at whether a tumor shrinks is not good enough to determine whether the treatment will have long term benefit.

"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 says.

A large randomized clinical trial sponsored by the National Institutes of Health is currently open at U-M and other sites across the country to address this question. Patients whose tumors are not considered HER2-positive by classic testing should not receive Herceptin outside of this trial. For information about the trial, call the U-M Cancer AnswerLine at 800-865-1125.

Additional authors: Suthinee Ithimakin, Kathleen C. Day, Fayaz Malik, Qin Zen, Scott J. Dawsey, Tom F. Bersano-Begey, Ahmed A. Quraishi, Kathleen Woods Ignatoski, Stephanie Daignault, April Davis, Christopher L. Hall, Nallasivam Palanisamy, Amber N. Heath, Nader Tawakkol, Tahra K. Luther, Shawn G. Clouthier, Whitney A. Chadwick, Mark L. Day, Celina G. Kleer, Dafydd G. Thomas, Daniel F. Hayes

Funding: National Cancer Institute grants CA129765 and CA101860; Breast Cancer Research Foundation; Komen for the Cure; Taubman Institute at the University of Michigan; Fashion Footwear Charitable Foundation of New York/QVC Presents Shoes-On-Sale; Stand Up to Cancer grant SU2C-AACR DT0409

Disclosure: Max Wicha has financial holdings in OncoMed Pharmaceuticals, receives support from Dompe and MedImmune and serves on the scientific advisory board of Veristem; Hasan Korkaya receives research support from MedImmune; Daniel Hayes has received research support from Pfizer, Novartis and Veridex and holds stock options for his role on the scientific advisory board for OncImmune.