Resistance to HER2 Targeted Agents Remains a Hurdle in Breast Cancer Treatment

Human epidermal growth factor receptor 2 (HER2) is a major drug target and clinical biomarker in patients with breast cancer, with 8 currently approved FDA drugs to target it. However, HER2 drug resistance has emerged as a major barrier to care.

A recent preclinical study identified co-occurring mutations in HER2 and HER3 that increase both HER2 and HER3 activity while also diminishing responsiveness to HER2-targeting agents. Experiments with cell lines and a xenograph found that the combination of neratinib (Nerlynx) plus a PI3K alpha inhibitor could inhibit the growth of cancer cells, supporting a clinical trial.

According to Ron Bose, MD, PhD, an associate professor in the department of Medicine at the Washington University School of Medicine in St. Louis, the fact the preclinical study produced a clinical trial possibility has caused a major impact. Bose says that overcoming HER2 mutations will be a relevant milestone for the clinical trial and drug development arenas.

In an interview with Targeted OncologyTM, Bose discussed the impact HER2 drug resistance has impacted cancer care, promising clinical developments, and what clinicians can do to help manage and overcome drug resistance. 

TARGETED ONCOLOGY: How has drug resistance impacted caring for HER2 mutations in the breast cancer space?

BOSE: Drug resistance has impacted it in many ways. This is a problem with all targeted therapies. And we see this with standard HER2-positive breast cancer, where we've had to use additional drugs to target HER2. And we see this with HER2 mutations, and it can be manifest either as primary drug resistance, lack of response, or acquire drug resistance where the patients initially respond, and then the tumor starts to progress. And we know that HER2 mutations are one of many mutations that occur in patients with breast cancers, so that they're not occurring in isolation. They're not a solitary driver. They may be accompanied by changes in PI3K mutations and in P53. These can be quite acquired mutations in estrogen receptor, ESR1, and HER3. And in the study that we cited that we commented on, it identified a very interesting HER3 kinase domain mutation that enhances HER3's ability to dimerize with HER2 and this results in increased PI3K signaling. And what they proposed was that this can be targeted by a combination of HER2 NPI3 kinase inhibitors. In particular, they tested neratinib

plus alpelisib.

Can you go into the results of that study?

There are 3 clinical trials focusing on HER2 mutations, which motivated this study. One is the SUMMIT trial [NCT01953926], which is a basket trial of neratinib for HER2-mutant cancers. The next is a breast cancer specific trial for HER2 mutations. And third is the British plasmaMATCH trial [NCT03182634], which is a ctDNA based trial which included an arm for HER2-mutated breast cancer. In all of these cases, we're seeing that median progression-free survival, when you're combining neratinib plus fulvestrant, because most of these cancers are ER-possible, is about 5 months. And so, looking at mechanisms of resistance and looking at strategies to try to extend median PFS is going to be very important.

And they identified HER3 kinase domain mutations as a mechanism of drug resistance. They propose that alpelisib [Piqray] would be a good strategy to overcome this drug resistance. And this would be a regimen that can move forward into a clinical trial. So that's the major impact of the study.

There are particular other things that may be of interest to the community. One thing that I found a novel for the study was their use of computer-based simulations for how these mutations affect protein structure and function. And as we're getting into the evaluation and trying to figure out how to target more and more cancer mutations identified by next-generation sequencing, these computer simulations are very powerful because they can rapidly assess what is the consequence of these mutations? Are these mutations functionally silent? Or are these mutations potentially functionally important? And what impact do they have on protein function overall? So, these computer simulations are a very important direction. And as with so many things that are computer based, the field of computer simulations of protein structured functions is really racing ahead, and it's something that oncologist might want to have some appreciation for, because I think we will see it more and more in future studies.

Are there any steps that oncologist can take to help delay or combat drug resistance right now? What can they do to kind of mitigate this factor?

I think that's a certainly a complex question. In the context of HER2 mutations, this is in the clinical trial space right now and in drug development. And so that is something that has to occur within the context of clinical trial protocols. I think with regard to standard of care treatment options, and when we look at drug resistance as emerging on patients on standard regimens, I think that trying to determine when possible, what is the mechanism of drug resistance and what are available drugs that could overcome it is very helpful. So, I make use of ctDNA moderately frequently in those situations. Repeat biopsy whenever clinically feasible also can be very helpful as repeat biopsies can be sent for NGS testing for PD-L1 pathway. Trying to understand the underlying biology and molecular changes in the cancer are one way of approaching the drug resistance. It's still a very challenging area. But it's something that in a large academic medical center, we're trying to make use of more and more.