M. Elizabeth Hammond, MD
University of Utah School of Medicine, Chair, Department of Pathology, LDS Hospital and Urban Central Region, Intermountain Health Care, Salt Lake City, UT
Oncologists know the power of trastuzumab (Herceptin) in treating patients with breast cancer that overexpresses human epidermal growth factor receptor 2 (HER2). But many have been frustrated by a common barrier to using the drug effectively: test results that incorrectly label tumors as positive or negative for HER2 expression, according to M. Elizabeth Hammond, MD, a pathologist who has helped set the standards for improved assessment of patients’ status.
Although progress has been made on improving the accuracy and understanding of HER2 testing, pitfalls remain, Hammond noted during a presentation at the 11th International Congress on the Future of Breast Cancer, held in Coronado, California, in July 2012. Efforts to improve guidelines continue, not only for HER2 testing but also in evaluating whether patients’ tumors are estrogen receptor (ER)-positive and progesterone receptor (PR)-positive. Hammond said a variety of issues could lead to inaccuracies in specimen handling, analytical testing, interpretation, and reporting of results.
The first guidelines for HER2 testing1
were published in 2007 by the National Comprehensive Cancer Network in collaboration with the American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP); guidelines for ER/PR testing followed in 2010.2
Due out in 2013, updated HER2 guidelines will offer more information about what to do when a test doesn’t work as expected, or when two labs generate divergent findings for the same patient, with a goal of keeping the nation’s false-negative and false-positive results below 5% each, Hammond said.
While tests are now done by immunohistochemistry or fluorescence in situ hybridization (FISH), the 2013 guidelines will also list bright-field in situ hybridization as an acceptable method, she said.
“I have only one motivation, and that is that I want people to improve this testing,” the pathologist told OncologyLive
in an interview. “I want the tests to be right. Herceptin is a very effective drug. It’s the most effective drug for breast cancer we have, but the only way it can be applied properly is if the test is done right, and so I want the test to be right every time.”
According to three large clinical trials whose results were released around 2002, immunohistochemistry tests for HER2- positive breast cancer were associated with a 20% false-positive rate and a 10% false-negative rate, while FISH testing garnered a 15% rate of false-negative results, Hammond said. Similar pitfalls can occur when testing for ER-positive and PR-positive cancers, she said.
As an example of these inconsistencies in test results, Hammond cited a retrospective study by Intermountain Healthcare that looked at 5044 test results for ER activity conducted between 1997 and 2005.3
The tissue was collected at seven hospitals and then tested in a central lab using standard processes and interpretation.
After controlling for age, stage, and grade, the study found that the rates of ER-negative diagnoses were different for each of the hospitals where tissue had been collected, with 28.6% being the highest rate and 16.5% the lowest.
Investigators proposed that the differences were due to varied specimen-handling practices, and considered whether the day of the week on which tissue was collected made a difference. They found that if a specimen was removed Monday through Thursday, it had a statistically significantly lower chance of being diagnosed as ER-negative than if it was removed on Friday or Saturday, Hammond said.
Research toward understanding such inconsistencies, which led to the establishment of the first guidelines for HER2 testing, revealed that enzymatic processes begin degrading breast tissue as soon as it is removed from a patient, making it extremely important to put samples into a fixative such as formalin within one hour, Hammond said.
Samples should remain in the fixative solution for at least six hours, but not for longer than 72 hours, and then should be promptly examined, she said. Especially when a sample is going to be analyzed at a facility other than where it was collected, she added, time points should be recorded so that the pathologist who examines the tissue knows it was handled properly.