Changes Occur in HER2 Status With Herceptin
CancerWise - October 2008
When treated with Herceptin® (trastuzumab) prior to surgery, 50% of women with HER2-positive breast cancer showed no signs of disease at the time of surgery, according to new study findings. However, of those women who had residual disease, about one-third had tumors that converted from HER2-positive to HER2-negative status — possibly indicating a resistance to the targeted therapy.
M. D. Anderson researchers presented the results Sept. 3, in advance of the American Society for Clinical Oncology Breast Cancer Symposium held Sept 5-7 in Washington, D.C.
Significance of results
It’s known that a percentage of HER2-positive patients develop a resistance to Herceptin during treatment, and there have been several described mechanisms for Herceptin resistance, says Elizabeth Mittendorf, M.D., assistant professor in
M. D. Anderson’s Department of Surgical Oncology.
“The goal of our study was to determine what percentage of patients who started out HER2-positive converted to HER2-negative, suggesting that we’ve possibly identified another mechanism of resistance,” says Mittendorf, the study’s lead author. “Or we could look at it another way. Maybe the findings determine that in this subset of patients, we’ve treated their HER2-positive disease. Now, it’s the HER2-negative disease that’s able to grow.”
Approximately 30% of breast cancer cells have an excess amount of the HER2 protein on their surface, which makes the cancer more aggressive. Herceptin is a monoclonal antibody that latches on to these proteins and slows tumor growth. The drug was approved in 1998 for women whose advanced, metastatic breast cancer is HER2- positive. It was approved in 2006 for use in early stage patients.
Using the M. D. Anderson Breast Medical Oncology database, the retrospective study identified 143 early stage and locally advanced breast cancer patients, all of whom had tumors possessing HER2 at the time of diagnosis. The women were treated with Herceptin in combination with taxane- and anthracycline-based chemotherapies prior to surgery.
At the time of surgery, 50% of the women achieved a pathologic complete response (pCR), or no evidence of breast cancer. Of those who did not achieve pCR, pre- and post-treatment tissue samples were available for 23 patients. The samples were analyzed using FISH, a laboratory technique that uses fluorescent probes to detect specific DNA sequences, in this case, additional copies of the HER2 gene. Seven patients, or 30.4%, were found to be HER2-negative at the time of surgery.
With a median follow-up of 10.2 months, the researchers also found that two patients (2.8%) who had achieved a pCR had a recurrence, compared to eight patients (11.3%) who did not achieve a pCR. Of the second group, tumor samples were available for five patients; three patients had converted to HER2-negative status.
Despite these findings, the clinical applications are limited at this time, and Mittendorf strongly cautions that more research is needed before women who have a change of HER2 status are taken off their scheduled Herceptin treatments following surgery.
“Certainly, the study warrants further investigation of what might be the best adjuvant therapy for this subset of women and suggests that a clinical trial in the adjuvant setting would be appropriate,” says Ana Gonzalez-Angulo, M.D., assistant professor in M. D. Anderson’s Department of Breast Medical Oncology and the study’s senior author.
In the lab, the researchers plan to see if there are any other changes in these tumors that are consistent with what is known about Herceptin resistance, including other mutations and alterations in specific markers, Mittendorf says. If other tumor markers of resistance are found in these patients, it would support the idea that HER2 status conversion promotes Herceptin resistance.
— Adapted by Darcy De Leon from an M. D. Anderson news release
M. D. Anderson resources:
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