A Closer Look at HER2-Targeted Therapies

Today we are discussing dual HER2-targeting therapies in the neoadjuvant and adjuvant breast cancer setting with Dr. Adam Brufsky, MD, PhD, the associate chief of the division of hematology/oncology and the co-director of the comprehensive breast cancer center at the University of Pittsburgh. Brufsky specializes in the treatment of patients with breast cancer and also takes part in clinical trials.

-Interviewed by Anna Azvolinsky

Cancer Network: What are the HER2-targeted therapies that are now available, for any patients with HER2-positive breast cancer?

Dr. Brufsky: We're very fortunate that we have trastuzumab which has been around for about 20 years. When combined with chemotherapy, it can dramatically reduce the risk of recurrence in early-stage breast cancer. In women with advanced breast cancer, it can prolong their survival. This drug binds to the HER2 protein.

There is another drug called pertuzumab that binds to another part of the HER2 protein and prevents HER2 from interacting with another protein called HER3. It turns out that when we give trastuzumab and pertuzumab together, they are synergistic and women with metastatic HER2-positive breast cancer who take both tend to live quite a long time, 5 years or more.

In terms of early-stage therapy of pertuzumab and trastuzumab before surgery, the number of women who have a complete pathological response is about 80%, [which] is quite dramatic. There are other HER2 targeted therapies including TDM-1 (trastuzumab emtansine), a trastuzumab antibody molecule with a chemotherapy linked to it. When used to treat those who have progressed on standard therapy for metastatic breast cancer, it also improves their survival.

The other kind of targeted agent category are called HER2 tyrosine kinases, which are small molecules that bind to the internal part of the HER2 molecule and work really well in several different types of breast cancers. We think that these drugs can actually go into the brain [and] if a patient has HER2-positive breast cancer brain metastases, these drugs might be able to treat them.

Cancer Network: What are the dual HER2-targeted therapies that are available for the neoadjuvant or adjuvant settings and for which patients are these appropriate?

Dr. Brufsky: When we talk about dual HER2-targeted agents we are giving two separate HER2-targeted agents. For example, trastuzumab plus pertuzumab, [which] is available for women with early-stage breast cancer to shrink their cancers down dramatically as well as for women with metastatic breast cancer that has spread beyond the breast and lymph nodes. This dual therapy improves the patients' survival as well as their response rate. When we talk about dual HER2 targeted therapy, we mean that we are giving more than one HER2-targeted therapy.

Cancer Network: Are there biomarkers beyond HER2 overexpression that can help guide clinicians on whether a dual HER2 therapy might be best for a breast cancer patient?

Dr. Brufsky: We don’t really have anything else at this point in time. We thought that HER3 expression could help but it doesn’t. The only thing that guides these therapies is the level of HER2 protein expression as well as the copy number of HER2 per cell. If a patient has more than six copies of HER2 per cell, they are likely to respond well. If the HER2 protein expression is more than three they will also respond well. Unfortunately, we have not found any other biomarkers that will help.

Cancer Network: Are there additional dual HER2 therapies that are currently in clinical trials that you could highlight?

Dr. Brufsky: I think the ones that are really important are those I mentioned, the HER2 tyrosine kinase inhibitors, and drugs like tucatinib, neratinib and epertinib that actually bind to the internal portion of the HER2 protein. These are fairly active molecules in clinical trials. Other drugs that are really interesting are new monoclonal antibodies. There is a drug called SYD985 which is a trastuzumab molecule with a protein called MNE that is bound to it. Then there is DS-8201, [which is] also a HER2 molecule attached to a chemotherapy.

Cancer Network: What are the important outstanding questions about HER2 targeted therapy and where it should fit in the treatment paradigm in breast cancer?

Dr. Brufsky: I think one of them is do we continue the dual targeted HER2 approach after progression in the first-line? In the first-line, the combination of docetaxel, trastuzumab and pertuzumab, do we simply switch to chemotherapy if a patient progresses? Do we include pertuzumab, or another one of these monoclonal antibodies? Do we give trastuzumab plus pertuzumab or one of these tyrosine kinase inhibitors? These are some of the outstanding questions. The nice thing is that most people do well on these therapies and the median survival is upwards of 5 years. With these dual HER2 targeted agents, I think we will increase that survival.

Cancer Network: Thank you so much for joining us today.

Dr. Brufsky: You are more than welcome.