HER2 THERAPY IN ORDER TO ERADICATE BREAST CANCER STEM CELLS

Therapies targeted at HER2, such as trastuzumab (Herceptin), have revolutionized the treatment of HER2-positive breast cancer in recent years, but this accounts for only 20% of all breast cancers.

However, new research suggests that these drugs may play a role in other breast cancers, because HER2 has been found in cancer stem cells (CSCs), the clump of "mother" cells that drives the disease. Although this small nest of cells accounts for only 1% to 5% of all breast cancer tissue, it is a crucially important driver that fuels its growth and spread.

Even if a breast tumor tissue sample tests negative for HER2, indicating that a patient is not a candidate for HER2-targeted therapies, the drugs could be useful because they would target the HER2 found in the little clump of CSCs.

This theory is supported by experimental data published onlinetoday in Cancer Research.

"If this is confirmed in clinical trials, it could alter our approach to breast cancer treatment," said senior author Max Wicha, MD, distinguished professor of oncology and director of the University of Michigan Comprehensive Cancer Center in Ann Arbor.

The implication of this finding is that a 2-pronged approach to treatment is needed, the researchers suggest. One treatment approach would target the small cluster of CSCs, perhaps with HER2therapy; the other, likely traditional therapy, would target the bulk tumor cells.

"This work has very significant implications," Dr. Wicha said in a statement. "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," he explained. Eliminating the CSCs should prevent tumor recurrence and ultimately result in more cures.

Molecular Explanation for Clinical Findings

In their study, Dr. Wicha and colleagues report findings from laboratory research on breast cancer cell lines, human breast cancer tissue samples, and animal studies using xenograft models. Their results show that HER2 is selectively expressed in the CSC population of luminal estrogen-receptor-positive breast cancers that are negative for HER2 (i.e., show no HER2 gene amplification).

"These observations extend previous studies linking HER2 expression and CSC phenotypes in cell lines," the researchers write.

The findings also "provide a molecular explanation for the surprising finding" that some patients with breast cancer who tested negative for HER2 nevertheless benefited from adjuvant therapy with the targeted drug trastuzumab, Dr. Wicha noted.

He was referring to a "provocative" report that challenges the conventional wisdom that only patients with HER2-amplified breast tumors benefit from trastuzumab (N Engl J Med.2008;358:1409-1411).

That report details a pivotal trial showing the effectiveness of trastuzumab, and notes that 174 cases originally classified as HER2-postitive actually lacked HER2 gene amplification when they were reanalyzed in a central laboratory. Surprisingly, Dr. Wicha explained that the patients who turned out to be HER2-negative benefited from adjuvant trastuzumab to an extent similar to that seen in patients who displayed classic HER2 amplification.

Although there were questions about the reliability of the HER2 analyses in that study, similar results were reported by another group (J Clin Oncol. 2010; 28:4307-4315), which "makes it less likely that these results are due to chance or laboratory error," the researchers write.

"These studies have important implications for the development of clinical trials using HER-targeting agents by suggesting that a much larger group of women with breast cancer may benefit from HER2blockade in the adjuvant setting than currently receive these treatments," Dr. Wicha and colleagues conclude.

The good news is that there are a number of HER2-targeted therapies already available. Trastuzumab, first approved in 1998, has since been joined by lapatinib (Tykerb), pertuzumab (Perjeta), and T-DM1 (Kadcyla), which was approved just last week.

Dr. Wicha reports receiving a commercial research grant from Dompe, having an ownership interest (including patents) in Oncomed Pharmaceuticals, and serving on the consultant/advisory board of Verastem and Paganini. Coauthor Hasan Korkaya, PhD, from the University of Michigan, reports receiving a commercial research grant from MedImmune.

Cancer Res. Published online February 26, 2013. Abstract