[Debbie L.]

There is nothing decided about the significance of topo 2a expression/amplification. You can find respected oncologists on either side of this argument, which tells me that the jury is still out, and in addition - that the difference/significance, if any, is probably not huge. There are all kinds of arguments - whether the assays are looking at the right thing (is it overexpression, amplification, or something else altogether that is a marker for additional anthracylcline benefit), whether topoIIa+'s can be HER2 negative, etc.

Dennis Slamon, who is respected especially in the HER2 community for his amazing work in studying HER2+ cancer and in developing Herceptin, believes that there is no place for anthracyclines in current adjuvant treatment for breast cancer. This is especially interesting because he's been one of the most interested people in the investigation of topoIIa r/t anthracyline response. He supports his anti-anthracycline stance by citing evidence to support the idea that anthracycline chemos offer an additional advantage over other chemos only to those who are topoIIa positive. BTW, it is NOT that anthracyclines do not "work" for topo2a negative cancer - it is that (according to this theory) topo2a negative cancers do not receive an ADDITIONAL benefit from anthracyclines, over other chemos. TopoIIa negative cancers do respond to anthracyclines, just as they do to other chemos. But if there is no additional benefit to an anthracycline and there is an addition to the side effect profile (mainly heart damage but also leukemia) when anthracylines are used - who would choose that?

So, again - continuing with Slamon et al's theory: He thinks that only HER2+ cancers (about 1/4 of them?) are topoIIa+. He says that if Herceptin is available, it trumps the anthracycline and so there is no place for an anthracyline when Herceptin is available, even for topoIIa cancers.

So, if you subscribe to Slamon's theory about topoIIa - you can only be topoIIa+ if you are also HER2+ and if you are HER2+, you'll get Herceptin and so there is no reason to know the topoIIa status because with Herceptin in the picture, an anthracycline offers no additional benefit to topoIIA+ cancers.

OTOH, other respected experts say that there is not enough evidence to support Slamon et al's claims. They say that there are reliable studies that show that it's possible to be topoIIa + and HER2-, in which case an anthracycline could (perhaps) offer additional benefit. They say that for high risk cancer, all evidence still points to an additional benefit from an anthracycline-based chemo, and they are not ready to deny this possible increased benefit to their high-risk patients, whether HER2+ or HER2- and whether topo2a + or - . They don't say that Slamon is wrong necessarily, but they do say that there's not enough evidence to say that he is right, and they do not want to deny their patients possible benefit until they know for sure.

Slamon's argument sounds plausible to me, when I hear him argue it. But then - so does the opposition's argument. I guess I'm gullible. Frustratingly, Slamon has not published his results even though he has been talking about this for years.

I don't know the answer. I've given myself brain fatigue just trying to write this semi-intelligibly. But when the argument among the big guns and the brilliant minds goes on this long, it makes me think that the answer is not going to show a very big difference either way, especially in the presence of Herceptin.

DL