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.
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.
OncLive: Could you discuss overcoming resistance to HER2-targeted therapies?
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.
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.
Have there been any recent impactful trials in this setting?
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.