Genes in breast cancer cells affect how the cancer grows and how it responds to certain treatments. The study reviewed here found that HER2-negative breast cancers are usually topo II-negative. This means that the cancers don't have an abnormal topoisomerase II alpha gene (called topo II or TOP2A for short).
Cancers that are HER2-positive and topo II-positive respond better to chemotherapy therapy regimens that include an anthracycline such as Adriamycin (chemical name: doxorubicin). Cancers that are HER2-negative and topo II-negative don't seem to respond to anthracyclines, which means they could be treated with other chemotherapy medicines that have fewer severe side effects.
Anthracyclines work by damaging cancer cell genes, which causes the cells to weaken or die. Other anthracyclines are daunorubicin (brand names: Cerubidine, DaunoXome), Doxil (chemical name: doxorubicin) and Ellence (chemical name: epirubicin). CEF, which uses Ellence, Cytoxan (chemical name: cyclophosphamide) and flourouracil (also known as 5FU), is a common chemotherapy regimen containing an anthracycline.
In this study, the researchers compared the results of treatments for women diagnosed with topo II-negative and topo II-positive breast cancer:
Right now, testing for an abnormal topo II gene isn't common. But almost all breast cancers are tested for HER2 status. This research found that breast cancers that are topo II-positive are usually HER2-positive and cancers that are topo II-negative are usually HER2-negative. So HER2 status is a good way to figure out topo II status.
This research is important because anthracyclines tend to cause more serious side effects (including possible heart damage) than some other chemotherapy medicines. So using anthracycline-based chemotherapy only makes sense for women who will benefit from it. This and other studies suggest that anthracycline-based chemotherapy should be used to treat only HER2-positive breast cancers.
If you've been diagnosed with breast cancer and chemotherapy will be part of your treatment plan, talk to your doctor about the HER2 status of the cancer and ask about the type of chemotherapy medicines being considered for you. You may want to mention that this and other studies suggest that the risks of treatment with an anthracycline make sense only if the cancer is HER2-positive. Together you and your doctor can decide on a chemotherapy treatment plan that makes the most sense for you and your unique situation.
RIDGEWOOD, N.J., April 29 (MedPage Today) -- Women whose breast cancers were characterized by alterations in the TOP2A gene experienced better survival with anthracycline-based adjuvant chemotherapy than with other regimens, researchers found.
Patients with tumors having either amplifications or deletions in TOP2A who were treated with a regimen containing epirubicin showed statistically significant improvements in relapse-free survival (adjusted HR 0.35, 95% CI, 0.17 to 0.73, P=0.005) compared with patients whose tumors do not have these alterations, Kathleen I. Pritchard, M.D., of Sunnybrook Odette Cancer Centre, in Toronto, and colleagues reported online in the Journal of the National Cancer Institute.
They also had improved overall survival (adjusted HR 0.33, 95% CI 0.15 to 0.75, P=0.008), the researchers said.
Patients whose tumors did not have TOP2A alterations had corresponding adjusted hazard ratios for relapse-free survival and overall survival of 0.90 (95% CI 0.66 to 1.23, P=0.49) and 1.09 (95% CI 0.77 to 1.56, P=0.62), the researchers said.
This improved responsiveness to the anthracycline-based therapy among patients with TOP2A alterations is similar to that seen in patients whose tumors carry an amplification of the HER2 gene.
HER2 amplification and overexpression "may simply be markers for changes in topoisomerase II alpha, an enzyme that is integrally associated with the cytotoxic action of anthracyclines and whose gene, TOP2A, is close to HER2 on the long arm of chromosome 17," the investigators explained.
To determine whether the difference in treatment response among patients could be traced to TOP2A alterations, the researchers conducted an analysis of data from the randomized Canadian Mammary 5 trial, which compared adjuvant cyclophosphamide, epirubicin, and 5-fluorouracil (CEF) with cyclophosphamide, methotrexate, and 5-fluorouracil (CMF).
Tumor samples, available for 438 of the 710 participants, were evaluated for TOP2A and HER2 amplification by fluorescence in situ hybridization on tissue microarrays, and the association of treatment type with survival was analyzed.
Analysis of the association of TOP2A status with CEF versus CMF, after adjustment for primary covariates including age, node status, and tumor grade and size, revealed a hazard ratio of 0.53 for relapse-free survival (95% CI 0.26 to 1.10, P=0.09) and 0.38 for overall survival (95% CI 0.17 to 0.85, P=0.02).
Analysis of the association of HER2 status with CEF versus CMF found a hazard ratio of 0.40 (95% CI 0.21 to 0.79, P=0.008) for relapse-free survival and 0.44 (95% CI 0.22 to 0.90, P=0.02) for overall survival.
The authors concluded that patients with both TOP2A alteration and HER2 amplification may derive a greater benefit from CEF than from CMF. Those whose tumors lacked these features appeared to receive "virtually no benefit" from CEF and could potentially be treated with the less toxic CMF regimen.
In an accompanying editorial, Dennis J. Slamon, M.D., Ph.D., of UCLA, and Michael F. Press, M.D., Ph.D., of the University of Southern California, wrote that the Canadian investigators reported "important, critical, and compelling new evidence" for the association between alterations in HER2 and sensitivity to anthracycline-based adjuvant therapy for breast cancer.
The editorialists stated that the widespread use of adjuvant anthracyclines is largely based on a meta-analysis by the Early Breast Cancer Trialists' Collaborative Group, which found that women given these agents had a 3% to 4.5% absolute point improvement in relapse-free and overall survival, but they noted that many studies have now clearly demonstrated incremental benefits only in HER2-positive women.
Despite data demonstrating that 75% to 80% of breast cancer patients are HER2 negative, they pointed out that "the vast majority of currently used adjuvant regimens for almost all breast cancer patients worldwide . . . are anthracycline based."
Increased understanding of the molecular diversity of breast cancers in the postgenomic era has revealed the complexity and dissimilarity of many of these cancers, they said, supporting the concept that molecular subtyping of disease can be used to guide not only targeted therapies such as trastuzumab and lapatinib, but also conventional cytotoxic agents.
The question remains as to whether these therapies that target HER2 alteration directly will supplant the anthracyclines -- the answer will require analysis of recently completed and ongoing studies -- but with regard to anthracycline-based therapy, "the 'verdict' is in for HER2-normal breast cancers: they should not receive anthracyclines as part of their adjuvant treatment," the editorialists wrote.
The study was supported by the National Cancer Institute of Canada, the Canadian Cancer Society, and the Canadian Breast Cancer Research Alliance.
Primary source: Journal of the National Cancer Institute Source reference: O'Malley FP, et al "Topoisomerase II alpha and responsiveness of breast cancer to adjuvant chemotherapy" J Natl Cancer Inst 2009; DOI: 10.1093/jnci/djp067.
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