Truncated HER2 in Blood Associated With Poor Outcome in Breast Cancer

The presence of the truncated form of human epidermal growth factor receptor 2 (p95HER2) in circulating tumor cells (CTCs) is associated with poor survival in breast cancer patients, according to a new study. These cells are detectable in both early and metastatic patients, though their incidence is higher in the metastatic setting.

“CTCs have been proposed as a powerful prognostic factor in patients with breast cancer,” wrote study authors led by Galatea Kallergi, MSc, PhD, of the University of Crete in Greece. “We, among others, have shown that HER2 is expressed on CTCs of early and metastatic breast cancer patients irrespective of the HER2 status of the primary tumor.” The presence of p95HER2 has been associated with resistance to trastuzumab and poor outcome, though there was no prior data on p95HER2 in breast cancer CTCs.

In the new study, researchers used triple-staining immunofluorescence on peripheral blood mononuclear cells from 24 patients with early breast cancer and from 37 patients with metastatic breast cancer. Results of the study were published online ahead of print in Breast Cancer Research.

CTCs that were positive for HER2 were found in 55.6% of early breast cancer patients, and in 65.2% of metastatic patients. Among those patients with confirmed HER2-positive tumors, HER2-positive CTCs were found in 50% of early patients and in 70% of metastatic patients. CTCs positive for p95HER2 were found in 11.1% of early patients and in 39.1% of metastatic patients (P = .047).

The investigators also compared CTCs in 14 patients with metastatic HER2-positive breast cancer before and after treatment with trastuzumab. Treatment reduced the number of patients who had full-length HER2-positive CTCs from 7 of 14 to 4 of 14 (P = .035), but increased the number of those with truncated HER2-positive CTCs, from 4 patients to 5. Further, the median expression of p95HER2-positive CTCs per patient was 0% before treatment, and 22.92% after treatment.

Clinical outcome was worse in those expressing p95HER2-positive CTCs. The median overall survival of those with detectable p95HER2-expressing CTCs was 11.5 months, compared with 29 months in those without (P = .03).

“It could be of interest to investigate whether dual inhibition of HER2 with trastuzumab and lapatinib is associated with a more effective eradication of both HER2-positive and p95HER2-positive CTCs, in order to provide an explanation for the increased clinical efficacy of this combination in HER2-positive breast cancer patients,” the authors wrote. They also noted that the clinical correlation between outcome and p95HER2 should be confirmed in larger groups of patients.