The phase II PERTAIN study is exploring the combination of pertuzumab, trastuzumab, and an aromatase inhibitor for postmenopausal women with hormone receptor-positive, HER2-positive metastatic breast cancer. This study, and others looking at HER2 therapies, raises the questions of whether there is an optimal strategy for HER2 testing, suggests Adam M. Brufsky, MD, PhD.

IHC 3+, a HER2/CEP17 ratio above 2, or a HER2 copy number greater than 6 is considered HER2-positive, according to the ASCO guidelines. Adding confusion is the fact that positive results may return negative following central review, Eleftherios P. Mamounas, MD, notes. Heterogeneity within tumors may also confound results, if only a small portion of the tumor is HER2-positive. Additionally, studies have not looked at outcomes for patients with discordant FISH results, such as a high copy number but a negative or normal ratio, Mamounas states.

The B-47 phase III adjuvant therapy study is exploring whether the level of HER2 expression impacts efficacy, Mamounas points out. This study is randomizing patients with HER2-low tumors (IHC 1+, 2+) to either chemotherapy or chemotherapy with trastuzumab. In general, if a patient is positive by IHC or FISH, they deserve treatment with a HER2-targeted therapy, the panel agrees.

Borderline test results represent an area of confusion, Hope S. Rugo, MD, suggests. If a copy ratio is 2.01 or a copy number is less than 4 but the ratio is 2.1, it can often be difficult to ascertain whether the tumor is HER2-positive or not. Studies have indicated that the efficacy of T-DM1 is based on the level of HER2 expression, notes Sara Hurvitz, MD. It is unclear whether T-DM1 will be as effective in patients with lower expression of HER2.