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 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 ESR1 and HER3.

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.

TRANSCRIPTION:

0:08 | 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] ESR1 and HER3 are found.

1:19 | 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.