[Becky]

I am hoping to help explain. Your first question is in regard to those who are resistant to Herceptin from the very beginning. Some reasons for this include that some of us may have the P95 truncated version of the external cellular domain (the receptor on the outside of the cancer cell is misshapen or missing altogether so that Herceptin cannot bind there). Another reason may also be that you may not be FISH positive and may not really be Her2+ at all and another mechanism is driving the cancer. Also, you may be Her1+, ER+, PR+ IGR+ or tons of other positive receptors we know nothing about yet and you are only blocking Her2 (and perhaps the hormonals if hormone positive).


For the second part - acquiring resistance over a long period of time. This may actually have to do with the cancer further mutating (life will find a way) and the cancer may become ER/PR positive (if you started out as negative) or it becomes positive for something else (Her1 or something that is still undiscovered).

Tykerb, since it works on the inside of the cancer cell versus the outside would help with those who have abnormal or missing Her2 receptors on the outside. But like Herceptin resistance over time, I suspect the same would be true with any biological drug (like Tykerb or others) that another mechanism would take over UNLESS the drug actually killed all the cancer cells and this has happened of course. But if it only shrinks the tumor and then creates stable disease, I think resistance will occur at some point. Remember though, resistance does not mean that Herceptin (or Tykerb) does not bind to the intended site but rather, a different mechanism is fueling the cancer to grow.

I hope this helps