[Becky]

I cannot comment on the 60% of Her2+ women have measureable Her2 serum but I will comment on the rest of your post (taking an approach that uses many of the presentations at SABCS and some of the nighttime sessions we were invited to and attended).


There is about 20% of Her2+ cancers that have a missing or truncated extra cellular domain. On Sat night (12/16), Dr. Mark Pegram spoke that some of the truncated versions still have enough of a structure for Herceptin to bind to but most do not. Therefore, they are always stuck in the on position (hence, the usefulness of lapatinib or other small molecule inhibitors since they work in the intracellular domain). Dr. Pegram and others did mention that the truncated and/or different types of Her2+ extra cellular domains may not be able to be measured by testing. Likewise, those with low tumor burden or non shedders (this WAS NOT explained at all) would test low (or the serum test would not work).

It is obvious that drugs like Herceptin will work for some and drugs like Tykerb will work for others however, it was Dr. Pegram's opinion, that Herceptin's response rate is higher than Tykerb's and the benefit may come from combining the two drugs in clinical practice (and it does make sense to attack both the extra and inter cellular domains simultaneously). All the "greats" (ie: Pegram, Rugo, Winer, Slamon) reported (some in a round about way but Pegram directly) that antibody technology (ie: Herceptin types) are better and will outperform small molecule inhibitors (ie: Tykerb types) - especially if used alone.
The reason that Tykerb does not cause shedding of the extracellular domain is that ligand binding still occurs there and there is no cell surface immuno response occuring. Tykerb binds to the phosphorylation sites within the cell and prevents it. Therefore, the extracellular domain remains intact on the cell membrane (and no Herceptin to attract an immuno response to cleave it).

That's it for now. Hopefully we can have a hardy discussion on this.