Expert Weighs in on Future of HER2-Positive Breast Cancer Treatment

C. Kent Osborne, MD

The treatment paradigm for HER2-positive breast cancer continues to focus on minimizing the role of chemotherapy and determining the optimal combination of HER2-targeted agents for specific patient subsets, says C. Kent Osborne, MD.

OncLive: Could you discuss overcoming resistance to HER2-targeted therapies?

In an interview with OncLive, Osborne, director, Dan Duncan Comprehensive Cancer Center, Baylor College of Medicine, sheds light on the current and future treatment of HER2-positive breast cancer.Osborne: There is a premise that HER2-amplified tumors are addicted to that oncogenic pathway. If you agree with that premise, then blocking that pathway completely ought to be really good therapy. Meaning, we might be able to get away with using only therapy that blocks HER2 and avoid chemotherapy, which, of course, is a lot more toxic.

First, in the laboratory a number of years ago, my group published some papers on using combinations of HER2-targeted drugs to more completely block the HER2 pathway. HER2 is part of a family of 4 receptors, and all of those receptors can work together to stimulate the growth signal downstream. Trastuzumab, the drug we started using 15 years ago, blocks 1 of those members—but does not block the others. So, we hypothesized that it would be more effective if you used more drugs to block the entire pathway. And we showed that it was the case, which lead to clinical trials which also showed that it was the case, for the most part.

We eventually did 2 studies in the Translational Breast Cancer Research Consortium. Other studies were done elsewhere, such as in Europe with the PAMELA trial, where we gave dual HER2-targeted therapy and no chemotherapy in a neoadjuvant situation. We showed a pathologic complete remission rate ranging between 20% and 40%, depending on different characteristics of the tumor, suggesting that there may be a substantial group of patients with HER2 overexpressing tumors that do not need chemotherapy.

This group can be treated with simpler, much less toxic forms of HER2-targeted therapy, such as trastuzumab and lapatinib (Tykerb) or maybe trastuzumab and pertuzumab. If 30% or 40% of those patients have eradication of tumor in the breast—and these were large tumors at an average of 6 cm—what about the others? Even though they are HER2-amplified, why do they not respond?

We started to profile those tumors through a baseline biopsy done on all of the patients to see we could identify factors that would predict resistance to the HER2-targeted therapy. And we found a couple tumors, but a ratio of 2 has been set as the cutoff criteria. The normal cutoff that we use for the FISH assay, a ratio of the number of HER2 copies versus the number of normal copies in the cell, is 2 or more. We did not see a single pathologic complete remission, unless the ratio was 4 or more, suggesting that maybe the ratio that has been identified so far and we've been using is not the right one. So, we did not see any tumors with a complete response when the amplification ratio was less than four.

We also did some genomic assays on the tumors, and we found that if the tumor had mutations in PIK3CA, or if that tumor had downregulated a tumor suppressor gene called PTEN so that the protein was not as expressed as it is in normal cells, that activated the PI3 kinase pathway inside of the cell and caused resistance to blocking the receptors—which is what the HER2-targeted therapy does. In fact, in the tumors that were [high] HER2 and should have responded, but did not, almost all of them had dysregulation of the PI3 kinase pathway, either in the form of a mutation in PIK3CA or in the form of lower levels of PTEN.

Have there been any recent impactful trials in this setting?

So, now we have to validate that data, and if we do validate it then I think that [those two] biomarkers could be used in future trials to select patients that are most likely to respond to HER2-targeted therapy alone without chemotherapy. Basically, we are de-escalating treatment, because not everyone needs such aggressive treatment. De-escalation in the HER2 space requires knowledge of our biomarkers to select the right patients.Trials of dual targeted therapy have shown that multiple agents are better than trastuzumab by itself, for the most part. When you block the entire receptor layer—all of the receptors that can trigger downstream signaling and growth of the tumor—it is much more effective than using trastuzumab alone. So, there are 8 or 9 of those trials now, some of them with chemotherapy and some without, that demonstrate the concept of dual targeted therapy that we reported in animal models years ago is correct.

Now, in the adjuvant situation, this has not always proved to be the case, which is possibly because those trials used very aggressive chemotherapy. We know that HER2-positive tumors are very sensitive to chemotherapy; it is a very effective therapy without any trastuzumab. When you add HER2-targeted therapy though, it helps a little bit. So, I think the chemotherapy is destroying cells that the dual targeted therapy will also destroy. If you have a tumor and you add chemotherapy plus dual targeted therapy you do not see much added benefit from the dual targeted therapy because the chemotherapy is doing that job.

Do you see the role of pertuzumab expanding within the next 5 to 10 years?

Using 2 drugs is much better than using 1 drug to block HER2 in the HER2 pathway. So, I think dual targeted drug studies will drive the future, in terms of how can we learn to better treat HER2-positive breast cancer. Some will only need to be treated with HER2-targeted therapy, others will need to be treated with something else—either chemotherapy or therapy that blocks the PI3 kinase pathway and those tumors that are mutated for that. So, I think that is where the future is headed for HER2-positive breast cancer.In the studies that have been conducted, particularly the NEOSPHERE study, adding pertuzumab to trastuzumab doubled the complete pathologic response rate in the neoadjuvant setting when it was combined with the single chemotherapy drug docetaxel. We will have to wait and see.

What are your thoughts on the future of chemotherapy?

It was then used in APHINITY adjuvant trial, and the [results] are said to be positive, but we don't know how positive. We do not know the details of that study yet, but it suggests that adding pertuzumab to trastuzumab provides some additional benefit in the adjuvant situation.I think we are in the era of genomic medicine, or targeted therapies, where we identify a specific abnormality in a patient's tumor and have a drug that would target that abnormality. Once we get that right, and once we know not only the target and block it, but the escape pathways that a tumor has, I think that targeted therapy will be the only therapy that we need. Think of it this way, a tumor has 5 or 6 little factories to stay alive, if we blow up 1 of the factories, there are several others that can take over and start driving the tumor. We've got to figure out not only what the driver is—the major factory—but what will take over if you block or destroy the main one.

Is there anything else you'd like to add?

We may not need nonspecific poison like chemotherapy, at least for certain tumors. There are other tumors that chemotherapy is still very effective for and will be hard to get rid of. But I think there will be many patients that can be treated with targeted therapies alone—not only in breast cancer, but in other tumors as well.The only other thing that I might say is that in the tumors that are both HER2-positive and ER-positive, [ER signaling also] needs to be blocked, because it provides an immediate escape pathway. There is an inverse relationship between ER and HER2; when you block HER2, ER signaling and levels go up, and when you block ER, HER2 signaling and levels go up. So, in tumors that have both, we think you need to block both of those pathways, with endocrine therapy for ER and HER2-targeted therapy.