HER2 Expression Changes Found in Circulating Breast Cancer Cells

Circulating breast tumor cells from patients can convert from HER2-negative to HER2-positive according to a study published  in Nature.

In culture, these circulating HER2-positive breast cancer cells can produce HER2-negative breast cancer cells and vice versa. This ability of tumor cells to switch their molecular identity makes it difficult to use targeted agents for breast cancer treatment.

“The ability of these two populations of tumor cells to convert back and forth highlights the importance of treating tumors with drugs that would simultaneously target both populations,” said study coauthor Shyamala Maheswaran, PhD, of the Massachusetts General Hospital (MGH) Cancer Center and an associate professor of surgery at Harvard Medical School, in a news release. “Now we need to investigate the mechanisms responsible for this interconversion.”

Dr. Maheswaran, Daniel A. Haber, MD, PhD, director of the MGH Cancer Center and professor of oncology at Harvard Medical School, and their colleagues analyzed circulating tumor cell (CTC) samples from 19 women originally diagnosed with estrogen receptor-positive, HER2-negative primary breast cancer tumors. Sixteen of the 19 women (84%) had detectable HER2-positive CTCs.

To identify the interconversation of one molecular tumor cell type to another, the team isolated 22 individual CTCs from several patients and performed single-cell RNA sequencing. They found discrete populations of either HER2-positive or -negative cells and that the HER2-positive cell population tended to increase with disease progression.

Staining breast cancer samples for HER2 showed a similar pattern of increased HER2 expression from the primary to the metastatic tumors.

Yet, unlike HER2-amplified breast cancer, these HER2-positive tumor cells within the metastatic samples did not have evidence of HER2 gene amplification.

“Not only did we observe the acquisition of HER2 positivity in patients with ER-positive/HER2-negative breast tumors, we also found that this population of tumor cells is able to spontaneously oscillate between HER2-positive and HER2-negative states, which contributes to tumor progression and resistance,” said Maheswaran in a statement.

The HER2-positive CTCs were not sensitive to HER2-inhibiting agents such as lapatinib (Tykerb), but the combination of a HER2-targeting agent and an IGFR1 (insulin-like growth factor receptor 1) inhibitor was cytotoxic to the cells. The HER2 expression changed the characteristics of the tumor cells: HER2-positive CTCs proliferated rapidly and were sensitive to chemotherapy agents while HER2-negative CTCs were sensitive to gamma secretase inhibitors, known to inhibit Notch signaling, but were relatively resistant to chemotherapy drugs.

Further testing of combination therapies in mouse models with heterogeneous tumors consisting of HER2-negative and -positive cells suggested that combination therapies may be the best route to target both cell populations. These mouse model studies suggest further combination therapies that, in the future, may be useful to treat patients’ tumors. “The rapid interconversion between proliferative and drug-resistant CTC subpopulations raises the possibility that simultaneous combination therapy may provide a novel strategy for clinical validation,” concluded the study authors.