Trial Information

IRS Proteins and Trastuzumab Resistance

Twenty percent of invasive breast cancers overexpress Her2 neu. These breast cancers are
more aggressive with a higher relapse rate and shortened overall survival. Trastuzumab is a
humanized monoclonal antibody FDA approved for the treatment of Her2 overexpressing breast
cancer. Trastuzumab is an active single agent for treating metastatic breast cancer and when
combined with chemotherapy improves time to progression and overall survival in women with
metastatic her2 overexpressing breast cancer. In the adjuvant setting recent clinical
trials have demonstrated improved relapse free survival in patients with high risk node
negative and node positive breast cancer. In the neoadjuvant setting in patients with
locally advanced breast cancer the response rates are very high with complete pathologic
responses in 50-60 % of patients. Although trastuzumab is an essential agent for optimal
treatment of Her2 positive breast cancer, not all patients respond and in the metastatic
setting trastuzumab is not curative indicating that resistance develops. The mechanism of
such resistance is unknown.

The fact that not all HER2-expressing breast cancer tumors respond to Herceptin treatment,
and most tumors eventually develop resistance to this drug, underscores the need for
additional research into how HER2 functions to promote aggressive behavior in tumors and why
some tumors become resistant to Herceptin. Recent reports have implicated the IGF-1
signaling pathway in both the mechanism of HER2 action and in resistance to Herceptin. The
IRS proteins are the major downstream effectors of the IGF-1 receptor and they play a
critical role in determining the cellular response to IGF-1 stimulation. Therefore, the IRS
proteins may also be signaling modifiers of the HER2 receptor and may contribute to
Herceptin resistance that results from compensatory signaling through the IGF-1R.