		Professor, Department of Internal Medicine

		Director, University of Michigan Comprehensive Cancer Center

	What does the emerging research regarding HER2-negative breast cancer patients mean for the use of HER2-targeted agents in the clinic?

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 

 report that trastuzumab may help women with HER2-negative tumors as a result of its role in regulating CSCs (2013;73(5):1635-1645).

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.

	What clinical trials are under way in HER2- negative patients as a result of these findings, and how far are we from changing the approved indications of HER2-targeted therapies currently on the market?

	Are these results affecting the development of new HER2-targeted agents, or just the way we use existing ones?

	What are the implications for the design of targeted therapies in general?

	What are the most significant unanswered questions regarding HER2 biology?

What that means is that when a woman has a HER2- negative breast tumor, she may get a bone metastasis in which HER2 is expressed and stimulates the stem cells in the bone. We think these women may benefit from trastuzumab in the adjuvant setting because it knocks out the stem cells in the bone. Hopefully, if these results are confirmed in clinical trials, it could completely change our whole approach to breast cancer, because most breast cancer patients might benefit from trastuzumab in the adjuvant setting.

As a result of the initial controversial findings, a large, randomized clinical trial was initiated (NSABP B47) in which women with HER2-negative tumors (no gene amplification) are randomized to receive chemotherapy alone or in combination with trastuzumab. A number of oncologists didn’t understand the rationale for this trial; there was no real biological explanation for why trastuzumab should work in these patients. We think that our research provides a potential explanation for why women with HER2-negative breast cancer may benefit from adjuvant trastuzumabâŽ¯because their stem cells are driven by HER2 and trastuzumab will therefore knock out the stem cells. As I understand it, the trial is recruiting well now and is about halfway to its goal, so, given another couple of years, we could have definitive answers that may guide changes in approved indications.

Yes, according to our model, since HER2 is driving stem cells, the newer agents like T-DM1 may be even more effective than trastuzumab. We are actually studying this now in mouse models. One could imagine in the future that many women may be able to completely avoid chemotherapy in the adjuvant setting and just receive something like T-DM1 plus hormone therapy (if they have hormone-positive cancer), with the potential to cure many more patients. Although this approach needs to be proven with a clinical trial, we are encouraged by the fact that it seems as though T-DM1 is even more effective than trastuzumab at targeting HER2- expressing cells.

I think one very important implication of our work is that in the future we may need two different kinds of targeted therapy. Right now, we are trying to develop targeted therapies that target the bulk population of tumor cells in advanced disease. Since we are now finding that some of the pathways that regulate cancer stem cells may not be the same as the pathways that regulate bulk tumor cells, we may need to independently target the stem cells. I think the therapies of the future will be combinations of agents that can target stem cells and bulk tumor cells, kind of a combined targeted therapy.

5 What are the most significant unanswered questions regarding HER2 biology? I think the crucial question is: What is HER2 doing in stem cells? How does it regulate them? Because of our previous assumption that HER2 was only important if the gene was amplified, we may have greatly underestimated the role of HER2 in many other tumor types, like stomach cancer, bladder cancer, and ovarian cancer, to name a few. A percentage of patients with these types of cancer seem to have elevated HER2 expression in at least some tumor cells. In the past, it was thought that unless HER2 was amplified, even if it was expressed in some cells, it didn’t have much importance in those tumor cells. I think we need to re-examine this now. It may be that HER2 is regulating stem cells in other cancers, and that HER2- targeted therapy could be of benefit there, too.

Articles

Max S. Wicha, MD, 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. 

Max S. Wicha, MD

Articles

Wicha Sees Potential for Significant Expansion of Anti-HER2 Therapy