JOE at SABCS: question regarding HER2 vaccine

[heblaj01]

Joe,
could you find out from the experts at SABCS if the preventative vaccine in this article below is delaying reccurrence in one of the two groups of patients patients.
Also is this vaccine (or any other one presented at SABCS) likely to be usefull as a treatment.
Thanks in advance.

http://patient.cancerconsultants.com/news.aspx?id=38786

[Becky]

Hi

I am here at SABCS with the group. The E75 vaccine trial prevented recurrence by 50 percent vs the contol group over 58 months. This was a phase 2 trial with 120 women. They will begin the process of getting a phase 3 together. You cannot be stage4for this but you can be node negative. You cannot be HLA-A positive. If so, you will be in the control group who only receives the CM-CSF (aka - Leukine). I will report more when I return home tomorrow.

[heblaj01]

Thanks Becky for your comment. Then I will fire an other question regarding an other presentation at SABCS:

Presentation title: Lapatinib Plus Capecitabine Shows Superior Efficacy Compared to Capecitabine Alone in Patients With Erbb2 Positive Advanced or Metastatic Breast Cancer Initial Biomarker Data. Abstract 2

In a brief summary of the priesentation it is stated that Lapatinib when added to Xeloda is effective in improving progression free survival regardless of the extracellular domain levels which I assume means independant of serum levels of HER-2 protein shed by cancer cells.
Does this mean that the Bayer serum test for HER-2 is not meaningfull for selecting Lapatinib treatment? How about Herceptin?
By the way, the summary states that only 60% of HER-2 cancers cause measurable levels of serum HER-2 a fact I did not know. Is this a recent finding?

[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.

[Dace]

Hi Becky,

Just want to make sure I am understanding you. The reason Herceptin did not work for me is because My her2 had less of a structure than others? And that they think that even though it didn't work, it can and possibly dhould be combined with the tykerb? I am currently on tykerb/xeloda.

Thank you!
Dace

[Becky]

Dear Dace


A missing or truncated version of the extra cellular domain is not the only reason Herceptin resistance (either that it doesn't work or fails to continue working). It could be a reason but other resistance pathways can be involved (such as other receptors being positive that we don't know about - even in the case of Tykerb, one could be strongly Her1+ as well and it is well documented at SABCS this year that Tykerb is a very weak Her1 inhibitor. There are no documented cases of even a partial response with Tykerb if one is only Her1+. One must be Her2+ for it to work).

Therefore, in answer to your specific question - no, it does not mean you have a missing or different extra cellular domain of Her2 (as the only reason Herceptin did not work in your case).

[Sandy H]

Becky, having been in San Antonio with you I think you did a good job answering these questions! Will look for more from you. It was nice meeting you and now I know who I can go to for questions!!! I hope you had a nice trip home. I could write a book on my return trip. It took me 18 hours!! I am so tired but I can honestly say it was worth it. hugs, Sandy

[heblaj01]

Becky,

Can you (& your partners who attended SABCS) summarize which presentations impressed you most regarding metastatic breast cancer in terms of improved overall survival as opposed to improved progression free survival.

[alw]

To those who attended the conference,

Did anyone hear from the Seattle Vaccine Group regarding an update from their Phase I/II vaccine trials? Most of the news seems to be about the E75 vaccine at Walter Reed.

Thanks,

Amy

[Becky]

Hebla01 - I will review everything and write something up within a week so I get all the high points.


Vaccine trials - there were posters that I have copies of that I will review and compare to E75