Future Solutions for Drug Resistance in HER2+ Breast Cancer

For the treatment of HER2-positive breast cancer, 8 targeted therapies have been FDA approved and have successfully improved survival and responses rates for these patients, research shows. Drug resistance continues to be an issue, however, limiting the clinical benefit of therapies.

In a recent study that assessed resistance to HER2 tyrosine kinase inhibitors, investigators found utility in obtaining genomic data and using computer simulations ahead of treatment. Additionally, the presence of HER3 was identified as the potential cause of resistance to agents like neratinib (Nerlynx). The findings suggested that other HER2-expressing cancers may benefit from this information as well.

In an interview with Targeted Oncology™, Ron Bose, MD, MPH, associate professor, Department of Medicine, Oncology Division, Molecular Oncology, Department of Cell Biology & Physiology, Washington University School of Medicine in St. Louis, discusses HER2 drug resistance, its impact on treatment, and how new research may help in the future.

TARGETED ONCOLOGY: How has drug resistance impacted the treatment of patients with HER2-positive breast cancer?

Drug resistance has impacted treatment in many ways. This is a problem with all targeted therapies, and we see this with our standard HER2-positive breast cancer where we've had to use additional drugs to target HER2. With HER2 mutations, resistance can manifest either as primary drug resistance, lack of response, or acquired drug resistance where the patients initially respond, and then the tumor starts to progress.

We know that HER2 mutations are one of many mutations that occur in patient with breast cancers, so that they're not occurring in isolation. They're not a solitary driver. They may be accompanied by changes in PI3 kinase mutations in p53, and other mutations. These can be acquired mutations in estrogen receptor. ESR1 and HER3 are found.

Also, in the study that we cited and commented on, investigators identified a HER3 kinase stimming mutation that enhances the ability of HER 3 dimerize with HER2. And this results in increased PI3 kinase signaling. What the investigators proposed was that this can be targeted by a combination of HER2 and PI3 kinase inhibitors. They tested neratinib plus alpelisib [Piqray].

What are the key takeaways from your analysis?

What motivated the study is there's been 3clinical trials focusing on HER2 indications. One is the SUMMIT trial, which is a basket trial of neratinib for HER2-postiive cancers. The next is the MUTER trial, which is a breast cancer-specific trial for HER2 mutations, and third is the British plasma MATCH trial, which is a circulating tumor DNA-based trial which included an arm for HER2-mutated breast cancer. In all of these cases, we're seeing evidence that median progression -free survival, when you're combining neratinib plus fulvestrant, is about five months. And so looking at mechanisms of resistance and looking at strategies to try to extend median PFS is going to be very important. The studies identified HER3 kinase domain mutations as a of drug resistance. They propose that apelisib would be a good strategy to overcome this drug resistance. And this would be a regimen that can move forward into a clinical trial.

Was there anything about this analysis that may be particularly of interest to community oncologists?

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 functionally important? 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 oncologists might want to have some appreciation for, because I think we will see it more and more in future studies.

What is your best advice on how oncologists can delay or stop drug resistance for patients with HER2-positve breast cancer?

It is very complex. In the context of HER2 mutations, that is something that must be research in the clinical trial space right now. I think with regard to standard of care treatment options, 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 frequently in those situations, and do repeat biopsies whenever clinically feasible. Also, it can be very helpful when repeat biopsies are sent for NGS testing for PD-L1 expression. So, trying to understand the underlying biology and molecular changes in the cancer are ways 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.

What are your closing thoughts on this topic?

For clinicians, as they're looking at their patients on standard of care, consider sending ctDNA, consider repeat biopsy when feasible, and try to tie that with literature to make appropriate changes in the patient management.

Also, for the breast cancer and clinical trials communities, I’d like to point out that HER2 mutations in breast cancer are very interesting drug target. There are exciting possibilities for HER2-mutated breast cancer. In particular, we're seeing an association with HER2 mutations and lobular breast cancer, which is a breast cancer for which we have fewer well-defined options. And targeting HER2-mutated lobular breast cancer is I think, going to be an opportunity for the future.

_Reference:

_{Bose R, and Ma C. Breast Cancer, HER2 mutations, and overcoming drug resistance. N Engl J Med. 2021; 385(13):1241-1243. doi: 10.1056/NEJMcibr2110552}