Is topoisomerase II alpha a valid biomarker for taxane sensitivity?
The story on topoisomerase II alpha is unfolding. Using the conventionally available tool, which was a FISH probe, it looked like a pretty good marker, but, and this is important, there are counter-examples out there that are not getting the press the positive examples get.
For example, a prospective, randomized clinical trial of epirubicin and then CMF compared with CMF alone showed an advantage for the epirubicin-containing arm. A specific drill-down looking at HER2, HER1, HER3, FISH, IHC and topo failed to find that association, and in some instances went in the opposite direction.
There may be genes in the neighborhood of TOP2 and, to be fair, they may be represented when a FISH probe is positive, but it may not be the topoisomerase II alpha thats ultimately controlling this. It may be the genes in the neighborhood.
This is a gene that is, in genetic terms, proximate to HER2; and about one-third of the time when HER2 is amplified, topoisomerase II alpha is also amplified. The point here is that although that is a) interesting and b) a target of doxorubicin and epirubicin, it is not necessarily the only target. The focus of that as the sole arbiter of anthracycline benefit is perhaps a little too strict.
Clifford Hudis, MD, is Chief of the Breast Cancer Medicine Service at Memorial Sloan-Kettering Cancer Center.
No. First of all, there are several ways of measuring topoisomerase II alpha and Im not sure we know the best method.
With respect to the biology, anthracyclines do work through topoisomerase II, but they have other functions as well. There are interesting data relating HER2-amplification to anthracycline activity, as well as topoisomerase II-amplification to anthracycline activity. Several studies have found that topoisomerase II-amplification occurs almost solely in HER2-amplified tumors, which has led to the hypothesis that topoisomerase II-amplification is responsible for the apparent increased activity of anthracyclines in HER2-amplified breast cancers.
On the other hand, there are negative trials that contradict that position. Investigators in the NEAT trial compared CMF with epirubicin followed by CMF and did not demonstrate that either HER2- or topoisomerase II-amplification predicted response to anthracyclines. In their study, chromosome 17 polysomy seemed to predict response.
Recently, an article by Lindsey Harris showed there was a dose response to CAF chemotherapy with respect to HER2-amplification. Among patients treated on CALGB 8541, those with HER2-amplification seemed to benefit from higher doses of anthracycline-based chemotherapy. This relationship was not seen for patients with the topoisomerase II-amplification, suggesting that topoisomerase was not responsible.
There was a meta analysis of the topoisomerase II data presented as a poster at the San Antonio Breast Cancer Conference last year, which concluded that the researchers could not prove a relationship existed. However, the authors admitted they were not able to obtain all the original specimens and run all the assays in the same way, so the study was flawed.
For all of these reasons, I am not entirely convinced that we can make treatment decisions based on topoisomerase II.
G. Thomas Budd, MD, is a Professor of Medicine with the Cleveland Clinic Lerner College of Medicine at Case Western Reserve University.