Overcoming HER2 Inhibitor Resistance in Breast Cancer is the Next Step in Advancing Care

HER2 mutations are a major clinical biomarker in breast cancer. However, overcoming drug resistance remains a key clinical obstacle.

Human epidermal growth factor receptor 2 (HER2) continues to be a major clinical biomarker and drug target in breast cancer treatment. Currently, there are 8 drugs approved by the FDA to target HER2. However, drug resistance remains a common obstacle in the treatment of this disease.

“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,” said Ron Bose, MD, PhD, an associate professor in the Department of Medicine in the Division of Hematology & Oncology at the Washington University School of Medicine in St. Louis, in an interview with Targeted Oncology™.

For the treatment of HER2-positive breast cancer, there are 3 approved monoclonal antibodies, 2 antibody-drug conjugates, and 3 kinase inhibitors.

Efforts are currently underway to overcome drug resistance and improve long-term outcomes in this patient population.

Developing Resistance

There are several different hypotheses as to how HER2 resistance is developed, however, most theories can be placed into 1 of 2 categories: factors associated with receptor-level effects or those associated with downstream signaling components.1

On the receptor level, p95HER2, a HER2-fragment, does not bind to trastuzumab (Herceptin). This is due to the fact it lacks an extracellular binding domain. However, p95HER2 may retain sensitivity to other HER3 targeted therapies that bind intracellularly. Additionally, patients with significant residual disease after neoadjuvant trastuzumab therapy may have a loss of HER2 amplification. This condition is associated with worse recurrence-free survival.

Increased activation of HER3 may also increase HER2 resistance. This may be due to a rise in the number of HER-family activating ligands, which have been detected in cells resistant to trastuzumab.

In terms of downstream signaling, alterations in regulation may lead to aberrant activation of signaling pathways. Crosstalk with HER2 and HER3 or epidermal growth factor receptor may reduce the effectiveness of trastuzumab. Endocrine resistance may also be developed with crosstalk between the estrogen receptor pathway, HER2, and the PI3K/Akt/mTOR pathways.

“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 PI3Kmutations and p53. These can be quite acquired mutations in estrogen receptor ESR1 and HER3,” said Bose

Clinical Trials

While most of the trials evaluating how to overcome HER2 resistance are preclinical, major progress has been made. For example, a study of HER2-mutant breast cancer cell lines found that the combination of neratinib (Nerlynx) and the PI3K alpha inhibitor alpelisib (Piqray) inhibited cancer cell growth, providing support to test this combination in a clinical trial. While a HER3 mutation reduces the binding ability of neratinib, the addition of a PI3K alpha inhibitor can help increase sensitivity and effectiveness in this patient population.2-3

Additionally, this research is supported by the phase 2 SUMMIT trial (NCT01953926) of neratinib in participants with solid tumors harboring somatic HER2 or EGFR exon 18 mutations. The interventional, parallel assignment, basket trial has an estimated enrollment of 650 participants.4

Between July 2013 and January 2019, 47 patients with HER2-mutant, hormone receptor (HR)-positive metastatic breast cancer were enrolled and received a combination of neratinib and fulvestrant. Seventy-nine percent of patients had visceral disease with the median number of prior metastatic therapies being 3 (range, 1-11). The overall response rate (ORR) was 30%, with the median duration, or response in the 14 patients with a confirmed response being 9.2 months. The median progression-free survival was 5.4 months. Over half, 53%, of patients received prior fulvestrant and 43% had received prior CDK4/6 inhibitor therapy. In patients who received prior fulvestrant, the ORR was 16% and 30% for those who received prior CDK4/6 inhibition.5

Another preclinical model of the recombinant enzymatically inactive mutant of human peptidase D, PEPDG278D, found that the molecule is highly active in models of HER2-positive breast cancer that is resistant to HER2 inhibitors. Additionally, it also enhances the therapeutic efficacy of paclitaxel.6

Overcoming Resistance

When it comes to overcoming resistance to HER-targeting agents, promise has been seen using combination therapies. Specifically, when it comes to trastuzumab, resistance is acquired through the enhanced signaling of the insulin-like growth factor-I receptor pathway. Combining trastuzumab with a therapy that targets this pathway can help improve efficacy and overcome resistance.

Additionally, combining trastuzumab with lapatinib may also help in terms of overcoming resistance as it blocks both HER1 and HER2 kinase domains. Lapatinib also stops the activation of phosphorylation and receptor actions, which would have otherwise activated downstream pathways such as MAPK and PI3K/Akt.

Other potential combinations to overcome trastuzumab resistance include afatinib (Gilotrif), tucatinib (Tukysa), pertuzumab (Perjeta, poziotinib, pyrotinib (SHR1258), trastuzumab emtansine (Kadcyla; T-DM1), margetuximab (Margenza), and numerous other experimental agents.7

“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,” said Bose. “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.”

1.Zhang Y, et al. The root cause of drug resistance in HER2-positive breast cancer and the therapeutic approaches to overcoming the resistance. Pharmacol Ther. 2021;128L. doi: 10.1016/j.pharmthera.2020.107677.
2.Bose R, Ma C. Breast cancer, her2 mutations, and overcoming drug resistance. N Engl J Med.2021;385:1241-1243. doi: 10.1056/NEJMcibr2110552
3.Hanker AB, Brown BP, Meiler J, et al. Co-occurring gain-of-function mutations in HER2 and HER3 modulate HER2/HER3 activation, oncogenesis, and HER2 inhibitor sensitivity. Cancer Cell 2021;39(8):1099-1114.e8. doi: 10.1016/j.ccell.2021.06.001
4.Basket study of neratinib in participants with solid tumors harboring somatic HER2 or EGFR exon 18 mutations (SUMMIT). ClinicalTrials.gov. Accessed November 8, 2021. https://bit.ly/3BWImTQ
5.Smyth L, Saura C, Piha-Paul S, et al. Update on the phase II SUMMIT trial: Neratinib 1 fulvestrant for HER2- mutant, HR-positive, metastatic breast cancer. Ann Oncol. 2019;30(3):10-11. doi:10.1093/annonc/mdz09
6.A recombinant human protein targeting HER2 overcomes drug resistance in HER2-positive breast cancer. Sci Transl Med. 2019;11(476). doi: 10.1126/scitranslmed.aav1620
7.Derakhshani A, Rezaei Z, Safarpour H, et al. Overcoming trastuzumab resistance in HER2-positive breast cancer using combination therapy. J Cell Physiol. 2020;235:3142–31562019 doi: 10.1002/jcp.29216