False Negative Results Found in Prognostic Testing for Breast Cancer

A recent study evaluating HER2 testing in a large cohort of women with breast cancer found important limitations in the conventional way HER2 testing is performed in the U.S. and internationally.

Peter Kaufman
Peter Kaufman, MD

Led by Peter Kaufman, MD, a physician and researcher at Dartmouth-Hitchcock Norris Cotton Cancer Center, the research team retested tumor samples from 552 women, all of whom had tumors that had been classified as HER2 negative. They found that, in 22 of the women, the tumor type had been incorrectly classified. They reported their findings in the article “Assessing the Discordance Rate Between Local and Central HER2 Testing in Women with Locally Determined HER2-Negative Breast Cancer,” which was published in Cancer on June 13.

Breast cancer is categorized into several subtypes based on conventional laboratory and newer molecular tests. This study looked at the accuracy of breast cancer classifications in one particular subtype: those that are positive for human epidermal growth factor receptor 2 (HER2). There are specific treatments proven extremely effective in improving outcomes and preventing recurrence of cancer for HER2-positive tumors, making it important to accurately classify tumors.

“We, and other groups, have previously shown that a certain percentage of cases found to be HER2 positive in local laboratories are in fact HER2 negative when tested in more experienced central labs,” said Kaufman. “There has, however, been almost no research evaluating the accuracy of a negative HER2 result. This is the first large study to look at this. What is comforting is that we found that retesting in experienced larger labs confirmed the original local lab results in the majority of cases.”

Kaufman noted that they did find about four percent of cases that were originally determined to be HER2 negative were in fact HER2 positive on repeat testing. Many of these cases were detected as being positive by testing for HER2 using both of two different and complementary tests (IHC and FISH, as described below).

The repercussions of incorrectly identifying a cancer’s subtype are considerable. “While it is comforting that only four percent of these women were misclassified initially, this is an enormous issue for those who fall into this group," said Kaufman. “This is because HER2-targeted therapies are critically important for women with HER2-positive breast cancer.”

The variance in accuracy may be related to how tests are conducted in smaller versus larger pathology laboratories. Two different tests are approved for and widely used for HER2: immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH). Either test may be used to determine a woman’s HER2 status. Frequently, based on recommendations by leading oncology groups, one or the other is used. In this case, using both tests allowed researchers to uncover errors resulting from reliance on a single test. Of the 22 samples incorrectly categorized, 18 had been processed by a local laboratory using only one testing method.

The analysis was based on the VIRGO study, a large, disease-based, observational cohort study of 1,267 women with HER2-negative metastatic breast cancer from June 2008 through January 2011. Out of the 1,267 patients enrolled in VIRGO, 776 submitted samples for this study of which 552 were suitable for centralized testing using IHC and FISH assays. The study was funded by Roche-Genentech, Inc.