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IRS Proteins and Trastuzumab Resistance

18 Years
70 Years
Open (Enrolling)
Breast Cancer

Thank you

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.

Inclusion Criteria:

1. Women age 18-70 with breast cancer who have signed an IRB approved consent form.

2. Biopsy proven breast cancer with her 2 overexpression by fluorescence in situ
hybridization (FISH).

3. Newly diagnosed patients with Stages 1,2 and 3 breast cancer who will be receiving
neoadjuvant chemotherapy prior to breast surgery

4. Normal Left ventricular ejection fraction, as measured by echocardiogram or MUGA scan

5. Normal bone marrow, kidney and liver function

6. No evidence of distant metastatic disease

Exclusion Criteria:

1. Patients with significant cardiac disease including abnormal LVEF, symptomatic
coronary artery disease, uncontrolled hypertension.

2. Prior treatment with chemotherapy.

3. Any cancer other than previously treated skin cancer.

4. Breast cancer in a previously irradiated breast.

Type of Study:


Study Design:

Observational Model: Case-Only, Time Perspective: Prospective

Outcome Measure:

A tissue acquisition and collection protocol that will analyze potential cellular changes that occur after treatment with trastuzumab to try to elucidate the mechanism of trastuzumab resistance in patients with HER2-positive breast cancer.

Outcome Time Frame:


Safety Issue:


Principal Investigator

Kathryn L Edmiston, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

University of Massachusetts, Worcester


United States: Institutional Review Board

Study ID:




Start Date:

March 2008

Completion Date:

February 2013

Related Keywords:

  • Breast Cancer
  • trastuzumab
  • breast cancer
  • her2 positive breast cancer
  • Breast Neoplasms



University of Mass Medical School Worcester, Massachusetts  01655