Long-term response to trastuzumab can be predicted by a tumor’s response to a single dose of the drug. Women with the human epidermal growth factor receptor 2 (HER2)-enriched type of HER2-positive breast cancer had the highest rate of immune response to treatment with trastuzumab, with a significant increase after just 1 dose of the drug. The HER2-enriched subtype is negative for both estrogen and progesterone receptors.1

“Our study showed, for the first time, that the immune-cell–activating properties of trastuzumab are likely related to the subtypes of breast cancer,” said Vinay Varadan, PhD, assistant professor at Case Western Reserve University (CWRU) School of Medicine and member of the Case Comprehensive Cancer Center in Cleveland, Ohio. “Knowing this can inform future trials studying the usefulness of adding immunotherapy drugs to trastuzumab.”

Among women with HER2-positive breast cancer, only half of those treated with trastuzumab will have their tumor completely respond to therapy prior to surgical resection of the mass. Even after another drug to target HER2 is added to trastuzumab, such as pertuzumab, only 60% of the women treated will have a complete response. Therefore, this study sought to identify which patients are most likely to respond to this treatment before surgery.

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Varadan and his research team used data from 2 clinical trials to examine if and how the immune system interacted with trastuzumab after a single dose of the drug, and they examined if immune-associated properties of trastuzumab were related to the subtype of HER2-positive breast cancer.

The finding that the HER2-enriched subtype had the highest rate of tumor response led to the development of a molecular signature, Immune Index.

“We found that higher Immune Index evaluated after just one dose of trastuzumab predicted the tumor’s response,” Varadan said.

The response seems to be specific to trastuzumab, as immune activity and breast cancer subtype were not associated after a single dose of another chemotherapy.

When the researchers examined which types of immune cells were associated with the response to the brief exposure to trastuzumab, they found T cell activity. Specifically, PD-1 expression was significantly increased in the HER2-enriched subtype. So, the HER2-subtype may be most effectively treated by the addition of drugs that target PD-1.

“Given that the subtypes of HER2-positive disease and the immune signatures predict response to trastuzumab-based therapy, the next question is whether these signatures can also predict response to dual-HER2 targeted therapy,” Varadan said. “Additionally, we would like to understand why certain breast cancers have a strong immune response when treated with anti-HER2 therapy while others escape immune surveillance. We are poised to answer these questions using both lab-based research as well as an ongoing preoperative clinical trial—CASE14112—being conducted here at CWRU.”


1. Varadan V, Gilmore HL, Miskimen KL, et al. Immune signatures following single dose trastuzumab predict pathologic response to preoperative trastuzumab and chemotherapy in HER2-positive early breast cancer [published online ahead of print February 3, 2016]. Clin Cancer Res. doi:10.1158/1078-0432.CCR-15-2021.