Topoisomerase-IIa as a Predictor of Anthracycline Response
Creators: name: University Of California Office Of The President
Publisher: name: University of California Office of the President
publisherIdentifier: https://ror.org/00dmfq477
publisherIdentifierScheme: ROR
Year: 2024

description: The human epidermal growth factor receptor type 2 (HER-2) gene is present in an increased copy number, referred to as gene amplification, in 25% of human breast cancers. HER-2 gene amplification is associated with aggressive disease behavior. This gene encodes a membrane receptor protein with a portion extending outside of the cancer cell. This extracellular domain is the target for a therapeutic antibody, known as trastuzumab (Herceptin). This type of treatment is effective in breast cancer patients. In addition, breast cancers with HER-2 gene amplification are reported to be sensitive to chemotherapy agents in the “anthracycline” category, especially adriamycin (also known as doxorubicin). However, the HER-2 gene is located on the long arm of chromosome 17 not far from the location of a second gene, known as topoisomerase II-alpha (TOP2A). The copy number of the TOP2A gene is also increased or co-amplified in 30-40% of HER2-amplified breast cancers. The protein encoded by the TOP2A gene is involved in DNA repair during DNA synthesis. This function of TOP2A is prevented by anthracycline chemotherapy agents such as adriamycin (doxorubicin). TOP2A gene amplification, not HER2 amplification, may be the genetic change that predicts responsiveness to anthracycline chemotherapy. This is an important consideration because anthracyclines have considerable toxic effects, especially cardiac (heart) toxicity, in the presence of trastuzumab (Herceptin).
 
 
 
 
 
 
 
 During the last year the standard therapy for newly diagnosed HER2-positive breast cancer was dramatically altered to permit the use of trastuzumab. This change in treatment is highly problematic because the standard chemotherapy for newly diagnosed HER2-positive breast cancer includes anthracyclines such as adriamycin (doxorubicin). Anthracycline treatment in combination with trastuzumab has been associated with heart toxicity in nearly 20% of women, with 4% experiencing congestive heart failure. It is critically important to determine if this level of risk is necessary for all women with HER2-positive breast cancer. The BCIRG (Breast Cancer International Research Group)-006 clinical trial is uniquely designed to address this important problem.
 
 
 
 
 
 
 
 In this project we will determine TOP2A gene amplification in breast cancers from women who were subjects in a large, randomized clinical trial of chemotherapy with or without trastuzumab (BCIRG006). Clinical outcome will be analyzed to determine how effective three different treatments (adriamycin-containing chemotherapy, adriamycin-containing chemotherapy with trastuzumab and non-adriamycin-containing chemotherapy with trastuzumab) were among women whose breast cancers had HER-2 gene amplification either with or without TOP2A gene amplification. We will determine what relationship exists between the amount of TOP2A protein and various levels of TOP2A gene copy number (amplification). The tissues characterized in this way will be used to validate clinical laboratory methods.