Optimal Tumor Control in HER2-Positive Tumors Requires Complete Blockade

The HER network is robust, complex, redundant, and adaptable. It provides proliferation and survival signals to a subset of breast tumors.

C. Kent Osborne, MD
Photo Courtesy SABCS/Todd Buchanan 2007

To effectively block this all-important and finely tuned system, the therapeutic aim must be to "think beyond HER2," according to C. Kent Osborne, MD, Director of the Dan L. Duncan Cancer Center and the Lester and Sue Smith Breast Cancer Center at Baylor College of Medicine, Houston. "HER2 is the factor driving the HER2-overexpressing tumors to survive and, therefore, is an ideal target. But we have to stop thinking about this system as a HER2 system. It is a complex pathway that requires other receptors and is governed and controlled by many gene products," Dr. Osborne said. "We must identify the key pathway and block it completely using more than one hit. And we need to anticipate the escape mechanisms causing resistance and block these at the same time. This will require combinations of agents." To activate the HER signaling pathway, the four receptors of the network -- HER1, HER2, HER3, and HER4 -- must partner with each other, ie, perform dimerization. This process ultimately results in cell proliferation, migration, differentiation, and apoptosis. HER2 is the favored heterodimer member, though the other receptors are also important and must be blocked for optimal antitumor effect. "Trastuzumab [Herceptin] binds to the external domain of HER2 and somehow blocks this pathway, but it is a weak blocker of signals from other dimer pairs," Dr. Osborne said. While trastuzumab is beneficial in about 50% of patients in the adjuvant setting, de novo resistance is common and acquired resistance is universal. This could be due to activation of some other aspect of the redundant survival pathway or reactivation of the HER pathway, he said.

Resistance to trastuzumab develops by multiple mechanisms:

• activation of downstream pathways
• the presence of mucin, which interferes with the binding of trastuzumab
• mutations in HER2, especially loss of the external binding domain
• overloading of growth factors that cause ligands to flood the system and overcome the block
• activation of a redundant survival pathway, such as the estrogen receptor
• presence in the membrane of other kinases that can bypass the receptor block

Combining receptor inhibitors with each other, or with downstream/alternative signaling inhibitors, may overcome these roadblocks. New agents that may meet this aim include the tyrosine kinase inhibitors lapatinib (Tykerb), gefitinib (Iressa), and erlotinib (Tarceva) and the dimerization inhibitor pertuzumab (investigational). These are not effective by themselves, however, since each leaves a part of the pathway "open," but they are powerful when grouped together in a way that more completely blocks signals from all heterodimer pairs.

Observations in preclinical models have found this approach to have a powerful effect. Cocktails of these agents have been shown to completely eradicate some xenograft models of human breast cancer, Dr. Osborne said. For example, in an MCF7/HER2 (tamoxifen-resistant) mouse model, treatment with tamoxifen and a single agent -- trastuzumab, gefitinib, lapatinib, or pertuzumab -- only partially and temporarily inhibits tumor growth. "Cells survive because this is a robust network that can adapt and be stimulated by another set of receptors other than the one being blocked," he said. "Incomplete blockade of the pathway leaves the rest of the pathway open for the tumor to use." When all are used together, "the tumors disappear and never come back, even when you stop the therapy," Dr. Osborne said. He added that the estrogen receptor must be blocked, either with tamoxifen or ideally with aromatase inhibitors, which completely deprive the tumor of estrogen. There have been no clinical trials yet of such combinations in untreated patients, though they are on the horizon. Upcoming studies will evaluate numerous combinations of lapatinib and trastuzumab with and without paclitaxel in the neoadjuvant and adjuvant settings, and the combination of pertuzumab, trastuzumab, and erlotinib in the metastatic setting.

Disclosures:

The author(s) have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.