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HER2 Testing and Correlation With Efficacy of Trastuzumab Therapy

HER2 Testing and Correlation With Efficacy of Trastuzumab Therapy

The emerging era of targeted
cancer therapies has focused
laboratory scientists and clinicians on the need to define and understand
molecular targets of novel drugs. For breast cancer patients and doctors, this
trend is not news—efforts have been under way for decades to identify the
estrogen and progesterone receptors and define the value of these markers as
predictors of response to hormonal therapy.

With the characterization of the human epidermal growth factor receptor 2
(HER2) and the development of an anti-HER2 therapy—trastuzumab (Herceptin)—which
can improve survival and quality of life in women with HER2-overexpressing
metastatic breast cancer, there is again the imperative to use laboratory assays
to select breast cancer patients for targeted therapy.[1]

HER2 Evaluation

Fornier and colleagues based at Memorial Sloan-Kettering Cancer Center have
written a comprehensive review of current methods of HER2 testing and have also
highlighted important clinical trials of trastuzumab. This review comes at an
important time. HER2 testing is becoming increasingly routine for tumors in
women with both early- and advanced-stage breast cancer.

The need for testing in the setting of advanced disease is apparent—to
select patients for possible trastuzumab therapy. The most compelling rationale
for testing in early-stage disease is the possibility of offering patients
trastuzumab therapy as part of ongoing, national cooperative group randomized
trials that will define the role of the drug in this setting. As a predictable
consequence of widespread testing, however, there is tremendous controversy as
to the optimal way to test tumors for HER2 status.

As Fornier et al describe, there are two widely used strategies for HER2
testing—immunohistochemistry, which measures surface expression of the HER2
protein, and fluorescence in situ hybridization (FISH), which measures the copy
number of the HER2 oncogene. Retrospective studies of the natural history of
operable breast cancer[2] and randomized trials of chemotherapy with or without
trastuzumab[3] suggest that FISH may be a better test for predicting
HER2-related outcomes than immunohistochemistry.

These studies, along with others also performed by large centralized
laboratories,[4] confirm that most of the difference is due to the confounding
presence of "2+" positive tumors identified by immunohistochemistry.
Only a small fraction of these immunohistochemistry 2+ cases have HER2 gene
amplification and increased HER2 mRNA expression; the vast majority are true
false-positives. For this reason, it is standard practice at our institution for
all 2+ tumors identified by immunohistochemistry to be tested by FISH.

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