Accurate HER2 Testing Essential

HOLLYWOOD, Florida—HER2 testing recommendations and the importance of determining a woman's true menopausal status were the highlights of the updated breast cancer guidelines presented at the National Comprehensive Cancer Network's (NCCN) 12th Annual Conference (see also article on page 40). "It is very important for HER2 testing to be accurate because the ramifications of giving trastuzumab [Herceptin] to someone who is not HER2 positive or depriving someone who is HER2 positive of trastuzumab are high in terms of expense, inconvenience, potential toxicity, and perhaps long-term complications," said John H. Ward, MD, professor of medicine, Huntsman Cancer Institute, University of Utah.

At $2,987.49 for one 440 mg vial, the cost of a year of trastuzumab therapy comes to about $155,349, Dr. Ward said. Cost issues aside, trastuzumab also is associated with cardiac toxicity, with reported incidences of congestive heart failure of 3% and 4%, and lowered ejection fractions by 7%, he added.

A Major Concern

"The accuracy of HER2 assays used in clinical practice is a major concern. Results from several studies have shown that false-positive and false-negative HER2 test results are common," Dr. Ward commented. To address this problem, the NCCN convened a task force to make recommendations about HER2 expression testing in 2006.

The recommendations stipulate that the two methods used to test for HER2 status, immunohistochemistry (IHC) (HercepTest) and fluorescence in situ hybridization (FISH), must be done in laboratories that meet quality assurance standards for HER2 testing methodology, and that all tests must be validated for accuracy. "Only one in four breast cancers express HER2, so this testing is very important," Dr. Ward said.

The panel also gave a conservative nod to gene expression profiling with assays such as the Oncotype DX and MammaPrint that may provide prognostic information and prediction of benefit or lack of benefit from chemotherapy in women with node-negative, hormone-receptor-positive breast cancer treated with tamoxifen. "I think we will evolve toward using these more commonly, but for now, we await the maturation of the clinical trials. The utility of MammaPrint will be prospectively tested in the MINDACT trial, and OncotypeDX is being tested in the TAILORx trial," he said.

Defining Menopause

The NCCN panel spent a good deal of time on the issue of defining menopause, because a woman's menopausal status will determine the utility of aromatase inhibitors, Dr Ward said. Aromatase inhibitors are only effective in postmenopausal women. However, some breast cancer patients become amenorrheic with chemotherapy and may not, in fact, be menopausal.

To address this situation, the guidelines state that it is not possible to assign menopausal status to women who are receiving an LHRH agonist or antagonist. Also, in women who are premenopausal at the beginning of adjuvant chemotherapy, amenorrhea is not a reliable indicator of menopausal status, as ovarian function may still be intact or may resume despite anovulation/amenorrhea after chemotherapy. For these women, oophorectomy or serial measurements of follicle-stimulating hormone (FSH) and/or estradiol are needed to ensure postmenopausal status if the use of aromatase inhibitors is considered as a component of endocrine therapy.

"We were very conservative here, and we think that for these women, strategies that start with tamoxifen and then switch later to an aromatase inhibitor are reasonable. The point is that we wanted to make sure that aromatase inhibitors are appropriately used," Dr. Ward said.