Ron Bose, MD, PhD

Ron Bose, MD, PhD, associate professor in the department of medicine and the department of cell biology and physiology at the Washington University School of Medicine in St. Louis, discusses the rationale for a trial of neratinib (Nerlynx) plus alpelisib (Piqray) for patients with HER2-positive breast cancer.

Resistance to HER2-targeted inhibitors has led to research into mutations associated with drug resistance. There have been several trials of HER2-mutation cancers, including the SUMMIT basket trial (NCT01953926) of patients with solid tumors harboring HER2 or 

 exon 18 mutations, the MutHER trial (NCT0167087) of neratinib plus fulvestrant (Faslodex) for HER2-positive breast cancer, and the plasmaMatch trial (NCT03182634) of circulating tumor DNA (ctDNA) screening for therapeutic targets in advanced breast cancer.

Median progression-free survival (PFS) for patients receiving neratinib and fulvestrant was around 5 months. This makes overcoming resistance to neratinib to improve PFS a major priority in this setting, according to Bose.

These studies identified HER3 kinase domain mutations as a source of drug resistance, leading to the design of a new clinical trial of the combination of neratinib plus alpelisib. A HER3 mutation led to increased PI3K signaling, which could be inhibited by alpelisib.

What motivated the study is there's been 3 clinical trials focusing on HER2 mutations. One is the SUMMIT trial, which is a basket trial of neratinib for HER2-mutant cancers. The next is the MutHER trial, which is a breast cancer-specific trial for HER2 mutations, and third is the British plasmaMATCH trial, which is a ctDNA-based trial which included an arm for HER2-mutated breast cancer. In all of these cases, we're seeing evidence that median PFS, when you're combining neratinib plus fulvestrant, because most of these cancers are [estrogen receptor]–positive also, is about 5 months. 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 proposed that alpelisib would be a good strategy to overcome this drug resistance. And this would be a regimen that can move forward into a clinical trial.

Videos

Ron Bose, MD, PhD, discusses the rationale for a trial of neratinib plus alpelisib for patients with HER2-positive breast cancer.

Exploring Resistance to HER2-Targeted Therapy for Breast Cancer

Ron Bose, MD, PhD, associate professor in the department of medicine at the Washington University School of Medicine in St. Louis, discusses the challenge of drug resistance due to mutations for patients with HER2-positive breast cancer.

According to Bose, drug resistance can manifest as primary drug resistance leading to lack of response to targeted therapies, or as acquired drug resistance where there is an initial response followed by disease progression.

In HER2-positive breast cancer, HER2 mutations lead to drug resistance to HER2-targeted therapies such as trastuzumab (Herceptin), making additional combination therapies necessary. Bose says that HER2 mutations are accompanied by other mutations in breast cancer, including changes to phosphoinositide 3-kinase (PI3K) pathways that are activated by HER2. Other mutations can impact the estrogen receptor such as 

A recent paper by Ariella B. Hanker, PhD, and Carlos L. Arteaga, MD, identified a mutation in the HER3 kinase domain that led to reduced efficacy of neratinib (Nerlynx) in inhibiting HER2. This mutation led to increased PI3K signaling, which suggested that combining neratinib with alpelisib (Piqray), which targets PIK3CA, would improve HER2 targeting, according to Bose.

 Drug resistance has impacted [treating patients with HER2 mutations] 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, and we see this with HER2 mutations. It can be 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 1 of many mutations that occur in patients’ 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 [where] 

 In the study that we cited that we commented on, Arteaga and colleagues identified a very interesting HER3 kinase domain mutation that enhances HER3’s ability to dimerize with HER2. And this results in increased PI3 kinase signaling. What they proposed was that this can be targeted by a combination of HER2 and PI3 kinase inhibitors. In particular, they tested neratinib and alpelisib.

Ron Bose, MD, PhD, discusses the challenge of drug resistance due to mutations for patients with HER2-positive breast cancer.

Addressing Drug Resistance Due to Mutations in HER2+ Breast Cancer

Ron Bose, MD, PhD, associate professor in the department of medicine at the Washington University School of Medicine in St. Louis, discusses the importance of computer simulations to develop treatments for patients with HER2-positive breast cancer.

Bose highlights the methods and results of a recent study by Ariella B. Hanker, PhD, et al, which explored solutions to drug resistance against various approved treatments for HER2-positive breast cancer.

According to Bose, computer simulation of protein function played a crucial role in identifying molecular-targeted therapies related to 

 mutations. Using these simulations of protein structure, Hanker and fellow investigators were able to predict that co-occurring mutations in 

 genes would enhance PI3K-AKT activation, identifying a potential combination of neratinib (Nerlynx) and a PI3K alpha inhibitor, alpelisib (Piqray) to inhibit the growth of cancer cells.

Protein structure simulations can quickly determine whether mutations will play a role in drug resistance, helping oncologists predict the outcomes of existing and new treatments, Bose says. With the rising usage of next-generation sequencing (NGS) in identifying mutations that are biomarkers or oncogenic drivers, increasingly detailed simulations of protein interactions identify areas of investigation for new treatments and provide more options for targeted therapies.

 One thing that I found novel for the study was their use of computer-based simulations for how these mutations affect protein structure and function. As we're getting into the evaluation, and trying to figure out how to target more and more cancer mutations identified by NGS, 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 structure and 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.

Ron Bose, MD, PhD, discusses the importance of computer simulations to develop treatments for patients with HER2-positive breast cancer as established by a recent study. 

Ron Bose, MD, PhD | Authors

Articles

Exploring Resistance to HER2-Targeted Therapy for Breast Cancer

Addressing Drug Resistance Due to Mutations in HER2+ Breast Cancer

Computer Simulations Predict Treatment for HER2-Mutated Breast Cancer