M. D. Anderson study finds change in HER2 status after treatment with Herceptin

September 04, 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.

University of Texas M. D. Anderson Cancer Center

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Citation Details
Title: Herceptin Linked to Serious Side Effects, Deaths.(Brief Article)(Statistical Data Included)
Author: Elizabeth Mechcatie
Publication: Family Practice News (Magazine/Journal)
Date: June 15, 2000
Publisher: International Medical News Group
Volume: 30 Issue: 12 Page: 42

Article Type: Brief Article, Statistical Data Included

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Citation Details
Title: Two-Year Follow-Up Shows Herceptin Ups Survival.(Brief Article)(Statistical Data Included)
Author: Mitchel L. Zoler
Publication: Family Practice News (Magazine/Journal)
Date: June 15, 1999
Publisher: International Medical News Group
Volume: 29 Issue: 12 Page: 39

Article Type: Brief Article, Statistical Data Included

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Citation Details
Title: Early Herceptin use cuts breast Ca recurrence in half: 'stunning' results when used as adjuvant tx.(News)
Author: Jane Salodof MacNeil
Publication: OB GYN News (Magazine/Journal)
Date: June 15, 2005
Publisher: Thomson Gale
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by Jane Salodof MacNeil (Author)

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Citation Details
Title: HERA trial shows better overall survival with trastuzumab.(Women's Health)(herceptin adjuvant)
Author: Jane Salodof MacNeil
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Citation Details
Title: Nine weeks only for Herceptin funding.(NEWS AND EVENTS)
Author: Gale Reference Team
Publication: Kai Tiaki: Nursing New Zealand (Magazine/Journal)
Date: September 1, 2008
Publisher: New Zealand Nurses' Organisation
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Citation Details
Title: The hype over Herceptin.(LETTERS)(Letter to the editor)
Author: Jo Fitzpatrick
Publication: Kai Tiaki: Nursing New Zealand (Magazine/Journal)
Date: March 1, 2009
Publisher: New Zealand Nurses' Organisation
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Article Type: Letter to the editor

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Optimising the Role of Herceptin in Breast Cancer (Supplement Issue: Oncology 2001, 2)
by D. Khayat (Editor)

The humanised monoclonal antibody Herceptin[registered] targets human epidermal growth factor receptor-2 (HER2) positive cells, i.e. cells in which HER2 is overexpressed, a feature associated with many tumour characteristics. Approximately 20-30 per cent of breast cancers are HER2 positive and are known to be particularly aggressive. Thus, HER2-positive clinical trials of Herceptin[registered] have clearly demonstrated that it provides significant clinical benefit in HER2-positive metastatic dis-ease, most importantly increased survival when administered first line in combination with chemotherapy. The articles in this supplement review our knowledge of the activity of HER2 and how to test for HER2 status, and describe the clinical trials of Herceptin[registered] that have been performed...