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IRS Proteins and Trastuzumab Resistance

NCT ID: NCT00657345

Last Updated: 2013-11-05

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

COMPLETED

Total Enrollment

9 participants

Study Classification

OBSERVATIONAL

Study Start Date

2008-03-31

Study Completion Date

2013-02-28

Brief Summary

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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

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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.

Conditions

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Breast Cancer

Keywords

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trastuzumab breast cancer her2 positive breast cancer

Study Design

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Observational Model Type

CASE_ONLY

Study Time Perspective

PROSPECTIVE

Study Groups

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1

This is a tissue acquisition and collection protocol that will analyze potential cellular changes that occur after treatment with trastuzumab.

No interventions assigned to this group

Eligibility Criteria

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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.
Minimum Eligible Age

18 Years

Maximum Eligible Age

70 Years

Eligible Sex

FEMALE

Accepts Healthy Volunteers

No

Sponsors

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University of Massachusetts, Worcester

OTHER

Sponsor Role lead

Responsible Party

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Kathryn Edmiston

Principal Investigator

Responsibility Role PRINCIPAL_INVESTIGATOR

Principal Investigators

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Kathryn L Edmiston, MD

Role: PRINCIPAL_INVESTIGATOR

University of Massachusetts, Worcester

Locations

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University of Mass Medical School

Worcester, Massachusetts, United States

Site Status

Countries

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United States

References

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Mohsin SK, Weiss HL, Gutierrez MC, Chamness GC, Schiff R, Digiovanna MP, Wang CX, Hilsenbeck SG, Osborne CK, Allred DC, Elledge R, Chang JC. Neoadjuvant trastuzumab induces apoptosis in primary breast cancers. J Clin Oncol. 2005 Apr 10;23(11):2460-8. doi: 10.1200/JCO.2005.00.661. Epub 2005 Feb 14.

Reference Type BACKGROUND
PMID: 15710948 (View on PubMed)

Hurley J, Doliny P, Reis I, Silva O, Gomez-Fernandez C, Velez P, Pauletti G, Powell JE, Pegram MD, Slamon DJ. Docetaxel, cisplatin, and trastuzumab as primary systemic therapy for human epidermal growth factor receptor 2-positive locally advanced breast cancer. J Clin Oncol. 2006 Apr 20;24(12):1831-8. doi: 10.1200/JCO.2005.02.8886. Epub 2006 Mar 20.

Reference Type BACKGROUND
PMID: 16549824 (View on PubMed)

Coudert BP, Largillier R, Arnould L, Chollet P, Campone M, Coeffic D, Priou F, Gligorov J, Martin X, Trillet-Lenoir V, Weber B, Bleuse JP, Vasseur B, Serin D, Namer M. Multicenter phase II trial of neoadjuvant therapy with trastuzumab, docetaxel, and carboplatin for human epidermal growth factor receptor-2-overexpressing stage II or III breast cancer: results of the GETN(A)-1 trial. J Clin Oncol. 2007 Jul 1;25(19):2678-84. doi: 10.1200/JCO.2006.09.9994. Epub 2007 May 21.

Reference Type BACKGROUND
PMID: 17515572 (View on PubMed)

Other Identifiers

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UM200801

Identifier Type: -

Identifier Source: org_study_id