Source: DGNews  |  Posted 3 years ago

By Lisa M. Cockrell, PhD

WASHINGTON, DC -- September 10, 2008 -- Nearly one-third of cases of incomplete response to neoadjuvant trastuzumab therapy may be due to a change in HER2 status following treatment, according to a study presented here at the American Society of Clinical Oncology's Annual Breast Cancer Symposium (ASCO-Breast).

This finding may provide a possible explanation for why some HER2-positive breast cancers do not achieve a complete response to the HER2-directed monoclonal antibody trastuzumab.

Elizabeth A. Mittendorf, MD, University of Texas M. D. Anderson Cancer Center, Houston, Texas, and colleagues presented their findings here on September 6.

Their retrospective study included 143 patients with HER2-positive breast cancer who were treated with neoadjuvant therapy comprised of a taxane, anthracycline, and concurrent trastuzumab.

Approximately half of the patients (50.3%) achieved a pathological complete response (pCR). The remaining patients experienced a partial response (42.7%), stable disease (4.9%), or disease progression (2.1%).

The researchers performed fluorescence in situ hybridisation (FISH) analysis on tissue samples from 23 of the patients who did not achieve a pCR. They found that samples from 7 (30.4%) of the women were HER2-negative at the time of surgery, even though their HER2-positive status prior to neoadjuvant therapy had been confirmed.

Additionally, after a median follow-up of 10.2 months, 2 (2.8%) patients who had originally achieved a pCR experienced disease recurrence, compared with 8 (11.3%) patients in the group that did not achieve a pCR who experienced disease recurrence (P = .05). Tissue samples were available from 5 patients in this second group; 3 of these were found to have converted to a HER2-negative status.

When Dr. Mittendorf and colleagues compared their results with those of 2 previous, smaller clinical studies, they found that they were consistent and showed evidence that some patients who did not achieve a pCR after taking trastuzumab converted to a HER2-negative status.

One mechanistic explanation for this apparent conversion is that the tumour cells change their HER2 status as a mechanism of resistance to trastuzumab therapy, according to Dr. Mittendorf, but "we don't yet know, on a molecular level, what causes tumours to change [their HER2 status]," she said.

Dr. Mittendorf also stated that there were no apparent differences in the clinical or pathological factors between patients who responded to trastuzumab and those that did not, such as histology, grade, or oestrogen-receptor status. Current research is ongoing to determine if molecular factors may be linked to this HER2 conversion, she said.

According to Eric Winer, MD, Department of Medicine, Harvard Medical School, Boston, Massachusetts, this study raises several questions regarding the mechanism of nonresponse to trastuzumab therapy.

"The big question is," Dr. Winer said, "were these tumours heterogeneous to begin with, with some HER2-positive and some HER2-negative cell populations?" If this were true, it is possible that trastuzumab therapy eradicated the HER2-postive disease, allowing the HER2-negative disease to grow. Otherwise, there may have been some "fundamental conversion" in HER2 status, he said.

Although Dr. Mittendorf asserted that the clinical significance of these findings may be currently unclear, the results indicate the HER2 status of nonresponding patients should be reassessed.

She added that further studies are needed to determine the most appropriate adjuvant therapy for patients exhibiting a HER2 conversion and less than pCR to trastuzumab.

[Presentation title: Determination of HER2 Status in Patients Achieving Less Than a Pathologic Complete Response Following Neoadjuvant Therapy With Combination Chemotherapy Plus Trastuzumab. Abstract 150]