ERBB2/HER2 Upregulated in MM, Higher Levels Associated With Poor Outcomes

Investigators have identified a biomarker associated with poor outcomes in multiple myeloma (MM) that they say may be a meaningful therapeutic target.

The study, published in International Journal of Molecular Sciences, suggests that high RNA-sequencing–based expression levels of Erb-B2 receptor tyrosine kinase 2 (ERBB2/human epidermal growth factor receptor 2 [HER2]) are associated with shorter progression-free survival and increased mortality.

The authors noted that there are 4 members of the ERBB receptor family. ERBB1, in particular, has been extensively studied in multiple cancer types, and the authors said their own research shows ERBB1 expression is upregulated in MM cells. In the new study, the authors wanted to look specifically at ERBB2/HER2 expression levels in malignant plasma cells of patients with MM. Doing so, they said, might help investigators devise better treatment strategies.

They used an RNA sequencing data set from the Multiple Myeloma Research Foundation to analyze malignant plasma cells from 787 patients with MM who received contemporary standard treatment regimens. Their data show that ERBB2 was expressed at significantly higher levels than both ERBB1 and ERBB3, regardless of disease stage.

The authors then correlated mRNA expression levels of ERBB2 in malignant plasma cells with mRNA expression levels of 14 transcription factors associated with activation of ERBB2 expression. Of 14 genes analyzed, 8 showed significant transcription-level correlation with ERBB2, they said. This is believed to be the first study to show significant correlations between ERBB2 mRNA expression and upregulation of certain transcription factors.

When the authors looked at ERBB2/HER2 expression levels in comparison to patient outcomes, they found significant associations.

“Patients with higher levels of ERBB2 mRNA in their malignant plasma cells experienced significantly increased cancer mortality, shorter progression-free survival, and worse overall survival than other patients,” the authors found.

Those findings held true even after the authors adjusted for the potential influence of other prognostic factors.

The authors said the findings have potential therapeutic implications. They noted that several therapies targeting ERBB/HER2 are approved by the FDA to treat other cancer types, including breast and lung cancer.

“Targeting ERBB2 with FDA-approved small molecule ERBB2 inhibitors as well as monoclonal antibodies could potentially improve the treatment options for high-risk or relapsed/refractory MM patients,” the authors said.

They said their findings make the case for further study of already approved therapies to see if they might also be effective in MM, either as single agents or as part of combination therapies. Potential therapies include the monoclonal antibodies trastuzumab (Herceptin) and pertuzumab (Perjeta), antibody-drug conjugates trastuzumab emtansine (Kadcyla) and trastuzumab deruxtecan (Enhertu), and small molecule tyrosine kinase inhibitor tucatinib (Tukysa), they added.

The authors said their study is subject to several limitations, including that it was focused on bioinformatics-based analyses, and did not include integrated laboratory testing of ERBB2 mRNA levels using other methods. They said their findings need to be validated in a prospective study that includes RNA sequencing and biochemical testing. Such a study will also need to include a multivariate analysis to see how important high expression of ERBB2 is compared with other prognostic factors.

If their findings hold up in such a study, the authors said, the therapy could have a major impact for patients with difficult MM cases.

“Our results encourage further evaluation of the prognostic significance of high-level ERBB2 mRNA expression and the clinical potential of ERBB2-targeting therapeutics as personalized medicines to overcome cancer drug resistance in high-risk as well as relapsed/refractory MM,” they said.

Reference

Uckun FM, Qazi S. Upregulated expression of ERBB2/HER2 in multiple myeloma as a predictor of poor survival outcomes. Int J Mol Sci. Published online June 9, 2023. doi:10.3390/ijms24129943