Gene amplification could guide treatment for high-risk breast cancer

May 11 2006

A new study shows that breast cancer patients with an "amplification," or greater number of copies, of the TOP2A gene are 45% more likely than women who do not have this amplification to benefit from a longer course of anthracycline-based adjuvant chemotherapy.

The study - which is published online in the Journal of Clinical Oncology - suggests that TOP2A amplification could help oncologists further refine breast cancer therapy by identifying patients most likely to benefit from a more sustained duration of anthracyclines after surgery.

The TOP2A gene is associated with increased production of topoisomerase - a protein that accelerates cell division and is thought to encourage cancer growth and proliferation. Anthracyclines work by inhibiting the TOP2A gene. Previous research has shown that amplification of TOP2A occurs almost exclusively in patients who also have amplification of HER2/neu, another genetic biomarker currently used to guide breast cancer treatment.

"Increasingly, breast cancer treatment is being personalized based on the presence of molecular markers, such as HER2, and estrogen and progesterone receptors," said Jorma Isola, PhD, Professor of Cancer Biology at Tampere University, Finland and lead author of the study. "These findings indicate that the TOP2A gene could one day serve as an additional biomarker for breast cancer, helping to further refine adjuvant therapy for this disease."

Researchers performed an analysis of stored tissue samples obtained from 391 patients who had undergone treatment for breast cancer and were at highest risk for disease recurrence. Of the 391 tissue samples, 32.7% had amplification of HER2/neu, and 37% of those also had TOP2A amplification. All patients received initial adjuvant anthracycline-based chemotherapy and then were randomized to either continue on anthracycline-based chemotherapy or to undergo high-dose, non-anthracycline-based chemotherapy and stem-cell transplantation.

After six years, among patients who only had HER2/neu amplification, researchers found no significant difference in outcome between women in the two treatment arms. However, when looking specifically at women with TOP2A amplification, those who received additional rounds of personalized anthracycline-based chemotherapy were 45% more likely to be relapse-free than those who underwent non-anthracycline-based chemotherapy.

Researchers noted that the tissue samples used for this study were obtained from a database compiled before newer targeted therapies had been developed. Today, all patients with tumors with HER2/neu amplification would receive adjuvant therapy with a chemotherapy agent and the targeted therapy trastuzumab (Herceptin). Additional research is underway to determine how HER2/neu-positive tumors, both with and without TOP2A amplification, respond to anthracyline- and trastuzumab-based adjuvant therapies.

"Topoisomerase IIagene amplification predicts favorable treatment response to tailored and dose-escalated anthracycline-based adjuvant chemotherapy in HER-2/neu amplified breast cancer. Results from the randomized trial SBG 9401." Minna Tanner, Tampere University and Tampere University Hospital, Tampere, Finland.