IRS Proteins and Trastuzumab Resistance
Condition: Breast Cancer
MeSH terms: Breast Neoplasms
Study type: Observational

Summary: 
      Significant progress has been made in the treatment of women with Her2 positive breast cancer
      who are treated with trastuzumab, a humanized monoclonal antibody that inhibits Her2. Despite
      this progress not all patients with Her2 positive metastatic breast cancer respond to
      trastuzumab and patients with metastatic disease who do respond usually develop progressive
      disease during treatment with trastuzumab. The mechanism of such resistance is unknown. We
      propose to investigate the mechanism of trastuzumab resistance in Her2 positive breast
      cancer. The hypothesis to be examined in the basic science section of this study is that
      IRS-1 and IRS-2 are modifiers of HER2 signaling and that these adapter proteins could be
      predictive indicators of treatment response to Herceptin in patients that are candidates for
      this targeted therapy. The connection between IRS-1 and IRS-2 expression and Herceptin
      response and clinical outcome in HER2 positive human breast tumors will be evaluated to
      determine if IRS expression correlates with resistance to Herceptin therapy and with the
      aggressive behavior of these tumors. This study will establish if the IRS proteins influence
      HER2 function in tumors and if they are predictive markers for evaluating treatment options
      for HER2 positive patients.
    

Detailed description: 
      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.
    

Observational model: Case-Only
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Women age 18-70 with breast cancer
      
Keywords: trastuzumab; breast cancer; her2 positive breast cancer