Examining the HER2 Testing Puzzle: Fresh Research Explores Nagging Questions

Anita T. Shaffer @Shaffer1
Published: Tuesday, Mar 27, 2012
Breast Tumor
In the more than 30 years since the human epidermal growth factor receptor 2 (HER2) gene was first successfully explored, HER2 status in patients with breast cancer has emerged as a durable and effective marker for evaluating tumors and selecting therapies.1

The FDA has approved several methods of assessing whether the gene is promoting tumor growth, and HER2 gene amplification and/or protein overexpression has been variously estimated to be at work in 10% to 34% of invasive breast cancers, with the frequency associated with tumor grade and carcinoma status.1-3
Established agents have proved effective in inhibiting HER2-positive forms of the disease, and now the treatment of such cancers is poised to enter a new era as strategies for dual inhibitors have emerged.

Yet key aspects of HER2 status in breast tumors remain a source of debate–and sometimes frustration– among researchers, despite the volumes of research that has been conducted and the hundreds of thousands of women worldwide4 who have been treated with HER2-targeted therapies, particularly trastuzumab (Herceptin).

Giuseppe Viale, MD, FRCPath, a professor in the Department of Pathology in the European Institute of Oncology and the University of Milan in Italy, wrote in a paper presented at the American Society of Clinical Oncology annual meeting in June 2011 that the oncology community should revisit some basic assumptions about HER2 status.5

He said outstanding issues include the accuracy and reproducibility of HER2 testing, scoring systems for HER2-positive disease, and the impact of tumor heterogeneity on HER2 status.

“Many oncologists seem to believe that pathologists are now infallible in assessing HER2 status of breast cancer, and that a very accurate identification of patients who are candidates for HER2-targeted therapies may be informed by the pathologic report,” he said. “Accordingly, oncologists are now already asking the next clinical question: whether it is possible to identify among the patients who are candidates those who will actually respond to the different anti- HER2 interventions.”

Viale, however, said tumors continue to behave in ways that “challenge our assumptions and dogmas.”

Edith A. Perez, MD

Edith A. Perez, MD

“This should prompt a renovated willingness to try and unveil peculiar aspects of HER2-positive breast cancer that have been apparently overlooked or misinterpreted until now,” he said.

Indeed, prominent researchers have been exploring HER2 controversies, with findings presented in recent months in journal papers and medical conferences that shed new light on testing issues.

The issues at stake are vital not only to patients with breast cancer but also to those with other tumor types, noted Edith A. Perez, MD, deputy director of the Mayo Clinic Cancer Center and a professor of Medicine at Mayo Medical School in Jacksonville, Florida.

“In this era of individualized medicine—the era of targeted therapies for patients with breast cancer and other malignancies—one of the most important aspects is to test for the target,” Perez said in an interview. “HER2 serves as an example of the management of patients today, and also the challenges that we will encounter in the future.”

Defining Criteria for HER2-Positivity

Perez has tackled one of the critical questions involved with HER2-targeted therapies: which criteria should be used to define the threshold of HER2 positivity.

“We don’t want to use therapies that have a low chance of working,” she said. “But I tell you it’s as important not to miss a single patient who may benefit from potentially lifesaving treatment.”

FISH testing compared to IHC

Breast cancer tissue assessed by fluorescence in situ hybridization, left, and immunohistochemistry, in samples tested at Clarient, Inc.
Photos courtesy of Clarient/GE Healthcare

Perez fears patients who could benefit from trastuzumab and other HER2-targeted therapies may not receive the drug because of confusion over what constitutes HER2-positive disease.


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