Max S. Wicha, MD
Professor, Department of Internal Medicine
Director, University of Michigan Comprehensive Cancer Center
Ann Arbor, MI
Max S. Wicha, MD, a founding director of the University of Michigan Comprehensive Cancer Center, is an internationally renowned research expert in the field of breast oncology. His lab was part of the first team to discover stem cells in breast cancer, and he is among the most highly cited investigators in the field of cancer stem cells (CSCs). Wicha is a study author on the Cancer Research
report that trastuzumab may help women with HER2-negative tumors as a result of its role in regulating CSCs (2013;73(5):1635-1645).
What does the emerging research regarding HER2-negative breast cancer patients mean for the use of HER2-targeted agents in the clinic?
There are two broad types of breast cancer: the 20% that show HER2 gene amplification and the remaining 80% that don’t. Until now, the thinking has been that only the 20% that show gene amplification would benefit in the clinic from HER2-targeted therapy. Our research in preclinical mouse models suggests that a much larger number of breast cancers, in which HER2 is not amplified, but in which HER2 may still play a very important role, may also benefit from HER2 therapy.
We found that in luminal breast cancers without HER2 amplification, HER2 is expressed but at a lower level than in HER2-amplified tumors. It is selectively expressed within a population of cells that have stem cell propertiesâŽ¯the cancer stem cellsâŽ¯that represent usually between 1% and 5% of the cells. That’s why this was missed before, because when you look at the tumor as a whole, you only see HER2 expression in a tiny subset of cells below the level that would be classified as HER2-positive. Most importantly, HER2 seems to play an important role in regulating these cells, meaning HER2-targeted therapies are able to affect stem cells even in tumors that don’t have HER2 gene amplification.
The foundation for our study was several retrospective analyses of previously performed adjuvant trials that were supposedly done only in patients who were HER2-positive. Controversy arose when a significant number of these patients were actually found to be HER2-negative when reanalyzed in a central laboratory. They really shouldn’t have received trastuzumab at all, but interestingly, these patients were found to benefit at least as much, maybe even more, than patients whose tumors were confirmed HER2-positive.
HER2 therapies were developed with the aim of achieving tumor shrinkage or regression in advanced cancers. What we’ve learned from this research is that when you shrink advanced tumors, you are measuring the effect on the bulk population of cells in the tumor, but not necessarily the stem cells. In contrast, when developing a therapy for adjuvant disease you want to target tiny foci of metastasis. Only stem cells have the capacity to form metastases from these foci. That’s why we think that although HER2-targeted therapies don’t cause tumor shrinkage in tumors that don’t have HER2 amplification, these therapies may be effective in the adjuvant setting because they can knock out the stem cells.
Another key finding of the study was that if you inject tumor cells that are HER2-negative into the tibia of a mouse, the bone microenvironment stimulates the cells to express more HER2. We took a series of breast cancer patients from whom we could get matched samples of primary tumor and the bone metastasis and demonstrated that, just like in the animal model, women who had HER2-negative breast cancer had bone metastases in which the cells expressed HER2. We did fluorescence in situ hybridization analysis on the bone and confirmed that HER2 expression was not due to gene amplification.