HER2 Heterogeneity and Neoadjuvant Therapy in Breast Cancer

Sara M. Tolaney, MD, MPH: Another challenge we see with HER2 [human epidermal growth factor receptor 2]–positive disease is with regard to HER2 heterogeneity.

We know there are some HER2-positive cancers for which some cells, for example, have either low HER2 positivity or no HER2 positivity. This can be challenging, particularly as we are moving toward treatment that may be solely HER2 directed. I think where this becomes quite clear is in a trial that was conducted by Dr Otto Metzger. He took patients who were getting preoperative T-DM1 [trastuzumab emtansine] and pertuzumab for 6 cycles and looked at patient outcomes based on whether they had a heterogeneous HER2-positive tumor up front.

They defined heterogeneity as having a tumor that had a FISH [fluorescence in situ hybridization] ratio and was positive only in 5% to 50% of this tumor, or was HER2 negative. If you met these criteria, the tumor was considered HER2 heterogeneous. This was the case in about 10% of patients who enrolled in the trial. Interestingly, the majority of patients with HER2 heterogeneity had hormone receptor–positive HER2-positive tumors. About 80% of those heterogeneous tumors were hormone receptor positive.

When they looked to see how those patients did after receiving T-DM1 [trastuzumab emtansine] and pertuzumab, you could see there were no patients who had a pathologic complete response [pCR] if they had a heterogeneous tumor. This was very different from patients who did not have HER2 heterogeneity, where their pCR rate was 55%. Clearly, having HER2 heterogeneity meant that there was less sensitivity to T-DM1 [trastuzumab emtansine] and pertuzumab up front.

This is something that certainly comes to light, especially with data that we saw from the KRISTINE trial where we saw similar challenges with heterogeneous tumors with preoperative T-DM1 [trastuzumab emtansine]–based treatment.

Transcript edited for clarity.