Topoisomerase-IIa as a Predictor of Anthracycline Response

Institution: University of Southern California
Investigator(s): Michael Press, M.D., Ph.D. -
Award Cycle: 2006 (Cycle 12) Grant #: 12IB-0155 Award: $244,499
Award Type: IDEA
Research Priorities
Detection, Prognosis and Treatment>Innovative Treatment Modalities: search for a cure



Initial Award Abstract (2006)
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.


Final Report (2009)
Note: CBCRP funded an IDEA-renewal for this project to continue the research an additional two years.

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 toxicity, particularly in the presence of trastuzumab (Herceptin).

Recently the standard therapy for newly diagnosed HER2-positive breast cancer was dramatically altered to permit the use of trastuzumab in the adjuvant setting. 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 have determined 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 was 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.


Symposium Abstract (2007)
Background. Topoisomerase II-alpha (TOP2A) gene amplification, and not HER2 amplification, may be the predictive marker for responsiveness to anthracycline chemotherapy (AC).

Methods. To address this issue we performed a test set-validation set series of analyses. Amplification of TOP2A and HER2 was evaluated by fluorescence in situ hybridization (FISH) in patients with metastatic breast cancer who participated in a randomized trial (H0648g, n = 469) of anthracycline-based chemotherapy with or without trastuzumab (trade name Herceptin). This group represented the test set. To validate our observations in the H0648g test set we analyzed breast cancers from two other, large, randomized clinical studies of anthracycline-based chemotherapy; one with HER-2 amplification and trastuzumab-based therapy (BCIRG006, n = 3,222) and one without HER-2 amplification and combination-based chemotherapy (BCIRG005, n = 3,298), comparing TOP2A status with clinical outcome. Both of the latter trials were adjuvant trials.

Results. In the H0648g “test set” patients whose breast cancers had TOP2A gene co-amplification and who were treated with doxorubicin (trade name Adriamycin), cyclophosphamide (AC) and trastuzumab had a longer progression-free survival compared to those who were treated with AC alone (p = 0.03). Patients treated solely with AC, whose breast cancers had TOP2A gene co-amplification had a statistically significant improvement in duration of survival compared to those without TOP2A gene amplification (p = 0.004). Among all women entered in the HER2-positive BCIRG 006 clinical trial, as well as among women who were treated with anthracycline-containing chemotherapy alone, women whose breast cancers showed TOP2A gene co-amplification had a significantly longer disease-free (p < 0.001), recurrence-free (p < 0.001) and overall survival (p = 0.01) compared to women whose breast cancers lacked TOP2A amplification. Unexpectedly, the added beneficial effect of trastuzumab was not seen among TOP2A co-amplified breast cancer patients in the larger BCIRG006 trial.

Conclusions. In patients treated with chemotherapy alone the findings demonstrate that TOP2A gene co-amplification is a useful predictive marker of responsiveness to anthracycline-containing chemotherapy.

Use of Trastuzumab in the Adjuvant Treatment of HER2-Positive Breast Cancer: Efficacy and Safety Results from the BCIRG-006 Study
Periodical:New England Journal of Medicine
Index Medicus: N Engl J Med
Authors: Slamon DJ, Eiermann W, Robert N, Pienkowski T, Martin M, Press M, et al.
Yr: 2009 Vol: Nbr: Abs: Pg: