HER2 Guidelines for Breast Cancer Could Misclassify Some Patients

The 2013/2014 American Society of Clinical Oncology-College of American Pathologists (ASCO-CAP) guidelines for HER2 gene amplification testing leave some patients at risk for misclassification and inappropriate treatment. These results were presented at the 34th Annual Miami Breast Cancer Conference, held March 9–12 in Miami Beach, Florida, and were published in the Journal of Clinical Oncology.

“Implementation of the new ASCO-CAP guidelines for HER2 fluorescent in situ hybridization [FISH] testing results in no changes for approximately 90% to 95% of cases,” said Michael F. Press, MD, PhD, professor of pathology and Harold E. Lee Chair for Cancer Research at the Norris Comprehensive Cancer Center, Keck School of Medicine of the University of Southern California in Los Angeles. But changes in ASCO-CAP guidelines “will result in potential disagreements for approximately 5% of cases.”

Up to a quarter of breast cancers harbor HER2 gene amplifications, with tumor cells frequently having 20 gene copies or more. Despite more than 2 decades of research, however, HER2 testing to identify candidates for targeted therapies remains controversial, Press said.

With colleagues, Press sought to assess new guidelines in a retrospective analysis of data from three Breast Cancer International Research Group (BCIRG) clinical trials (BCIRG-005, -006, and -007), for which patient outcomes were available. They reevaluated 10,468 patients’ samples using HER2 immunohistochemistry (IHC) and FISH assessments from the trials, whose authors had classified tumors using earlier US Food and Drug Administration–approved guidelines.

The ASCO-CAP guidelines define five separate status categories, based on HER2 FISH ratios and average HER2 gene copy numbers per tumor cell:

Group 1 (ISH positive; 40.8% of the 10,468 patients): average HER2 copy number ≥ 2.0 per tumor cell;

Group 2 (ISH positive; 0.7% of patients): average HER2 copy number < 4.0 per tumor cell;

Group 3 (ISH positive; 0.5% of patients): average HER2 copy number ≥ 6.0 per tumor cell;

Group 4 (ISH equivocal; 4.1% of patients): average HER2 copy number < 6.0 per tumor cell;

Group 5 (ISH negative; 53.9% of patients): average HER2 copy number < 4.0 per tumor cell.

The new ASCO-CAP guidelines included changes in HER2 gene amplification evaluation, creating ambiguities in HER2 amplification status in a minority of patients. Group 1 breast cancers were strongly associated with IHC HER2 protein group 3+ status, but that was not the case for the other groups. Groups 2, 4, and 5 were strongly associated with IHC 0/1+ status but group 3 was not.

When HER2 gene amplification status was compared with IHC HER2 protein expression in ASCO-CAP Group 3 patients, there were significant differences among these cases, with IHC staining scores of 2+/3+ in 83% of tumors deemed “amplified” using the BCIRG trial’s HER2 FISH status classification, vs 89% in BCIRG HER2 FISH nonamplified tumors (P = .002).

“Development of companion diagnostics for clinical trials and patient management is a complex regulatory, as well as research, issue,” Press concluded.