Sara A. Hurvitz, MD: Although there have been tremendous successes in the management of HER2-positive metastatic breast cancer with a clear improvement in overall survival now for a patient diagnosed today compared with 1 diagnosed even 5 or 10 years ago, there is a huge unmet need because virtually all patients will have their disease progress. Strong, durable remissions are rare with HER2-positive metastatic breast cancer. We need to have new agents that target pathways of resistance to try to manage resistant disease and hopefully someday to reduce the incidence of metastatic disease.

A number of pathways have been implicated in the development of resistance to HER2-targeted therapy. The truncated HER2 receptor that would not then be amenable to targeting by an antibody is 1 of the earliest pathways of resistance that was identified. We’re now identifying intracellular signaling pathways that take over when we’re blocking HER2 and allow the cancer cell to survive and grow, such as the PI3 kinase AKT/mTOR pathway. In fact, 30% to 40% of metastatic breast cancer that’s HER2 positive has a mutation in PI3 kinase that makes it constitutively active, so drugs to target PI3 kinase are in development to look at dealing with that pathway.

The hormone receptor pathway itself can be a mechanism of resistance. And then we have this issue that is not as rare as we once thought of HER2 heterogeneity, in which some tumor clones within a tumor that have lower expression of HER2 are allowed to survive the targeting that we use of the HER2 receptor. I do think it’s a very exciting time for us to be evaluating agents that don’t target only HER2 but are hitting these other pathways.

Another area of unmet need that we are focusing a lot on today is the development of central nervous system metastases in this subtype of breast cancer. Around 50% of patients diagnosed with HER2-positive metastatic breast cancer will develop central nervous system metastases in their life. The challenge is that most of our agents, especially bulky antibodies and antibody-drug conjugates, do not traverse the intact blood-brain barrier. Our most effective therapies in yielding a response have been surgery, radiation, Gamma Knife surgery, etc. And we haven’t really had agents that reliably cross and act and induce responses that are systemically delivered to help us with this problem.

Transcript Edited for Clarity