Sep. 8, 2008 Researchers at The University of Texas M. D. Anderson Cancer Center have discovered that when treated with Herceptin prior to surgery, 50 percent of HER2 positive, breast cancer patients showed no signs of disease at the time of surgery. However, of those women who had residual disease, about one-third had tumors that converted from HER2 positive to HER 2 negative status —possibly indicating a resistance to the targeted therapy.
The study will be presented today in advance of the American Society for Clinical Oncology Breast Cancer Symposium.
Approximately 30 percent of breast cancer cells have an excess amount of the HER2 protein on their surface, which makes the cancer more aggressive. Herceptin, also known as trastuzumab, is a monoclonal antibody that latches on to these proteins and inhibits tumor growth. It was approved in 1998 for women whose advanced, metastatic breast cancer is HER2-positive; it was approved in 2006 for use in the early setting.
It's known that a small percentage of HER2 positive patients develop a resistance to Herceptin during treatment, and there have been several described mechanisms for Herceptin resistance, said 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 convert to HER 2 negative, suggesting that we've possibly identified another mechanism of resistance," said 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."
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 expressed 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 percent 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 percent, 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 percent) who had achieved a pCR had recurred, compared to eight patients (11.3 percent) who did not achieve a pCR. Of the second group, tumor samples were available for five; three had converted to Herceptin negative status.
Despite these findings, at this time, the clinical applications are limited, said Mittendorf, and she strongly cautions that more research is needed before women who have a change of HER2 status not receive their scheduled Herceptin following surgery.
"At this stage, I think the findings advocate for reassessing HER2 status at the time of surgery," said Ana Gonzalez-Angulo, M.D., assistant professor in M. D. Anderson's Department of Breast Medical Oncology and the study's senior author. "However, it would be inappropriate for clinicians to conclude from our study that women with a change in HER2 status should not receive their full course of Herceptin therapy. Certainly, the study warrants further investigation of what might be the best adjuvant therapy for this sub-set of women and suggests that a clinical trial in the adjuvant setting would be appropriate."
In the lab, the researchers plan to see if there are any other changes in these tumors that are consistent with what we know about Herceptin resistance, including other mutations, alterations in specific markers. If other tumor markers of resistance are found in these patients, explains Mittendorf, then it would support the idea that HER2 status conversion promotes Herceptin resistance.
In addition to Mittendorf and Gonzalez-Angulo, other authors on the all-M. D. Anderson study include: Gabriel N. Hortobagyi, M.D., professor and chair of the Department of Breast Medical Oncology; Francisco Esteva, M.D., Ph.D., associate professor in the Department of Breast Medical Oncology; Aman Buzdar, M.D., professor in the Department of Breast Medical Oncology; Funda Meric-Bernstam, M.D., associate professor in the Department of Surgical Oncology; Kelly Hunt, M.D., professor in the Department of Surgical Oncology; and Shaheena Dawood, M.D., now with Dubai Hospital.
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