relevance of tumor markers discussed at SABC and herceptin

[RobinP]

Okay, if you listened to the 2005 SABC live web cast with Gelbar speaking for the HERA trail, you would have noticed that at the end of that presentation, someone asked the relevance of tumor marker testing in relationship to determine herceptin response/resistane. Specifically, pTEN was mentioned as preclinically the presence of pTEN on one's tumor would indicate a much increased response to Herceptin. Gelbar indicated that they have the tissue specimens from the HERA trail and should be looking into testing for pTEN on those specimens. Wouldn't it be nice if they to see if the pre-clinical data correlates with actual human experience.

One other marker I hope they test for on the HERA trail specimens is TAB250 which tests for the extracellular membrane domain of her2. If you have the extracellar domain in tact with cleavage, Herceptin can bind to it and cellular proliferation events downregulate; thus, Herceptin is effective.Well, we certainly need more markers to test tumors in order to better define therapy and hopefully the HERA trail will deliver some of those results eventually.

Anyway, I had my tumor tested for these markers and had both so I figured it was worthwhile to do very late adjuvant Herceptin.I started it two days ago and it went well other than I hate needle sticks, being the baby I am. Thanks to everybody here that encouraged me along the way. Oh yeh, hopefully insurance will pay the bill for herceptin. We're going to submit it and see what happens. I am her2+ afterall very very strongly at 5.2 HER2-CEP ratio.

See the pasted article concerning pTEN's PRECLINICAL REVELANCE below:



Copyright © 2004 Cell Press.
Cancer Cell, Vol 6, 117-127, August 2004

PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients
Yoichi Nagata,1 (http://www.cancercell.org/content/article/abstract?uid=PIIS1535610804002107&highlight=pTEN and herceptin#aff1),6 (http://www.cancercell.org/content/article/abstract?uid=PIIS1535610804002107&highlight=pTEN and herceptin#fn1) Keng-Hsueh Lan,1 (http://www.cancercell.org/content/article/abstract?uid=PIIS1535610804002107&highlight=pTEN and herceptin#aff1),6 (http://www.cancercell.org/content/article/abstract?uid=PIIS1535610804002107&highlight=pTEN and herceptin#fn1) Xiaoyan Zhou,1 (http://www.cancercell.org/content/article/abstract?uid=PIIS1535610804002107&highlight=pTEN and herceptin#aff1) Ming Tan,1 (http://www.cancercell.org/content/article/abstract?uid=PIIS1535610804002107&highlight=pTEN and herceptin#aff1) Francisco J. Esteva,2 (http://www.cancercell.org/content/article/abstract?uid=PIIS1535610804002107&highlight=pTEN and herceptin#aff2),3 (http://www.cancercell.org/content/article/abstract?uid=PIIS1535610804002107&highlight=pTEN and herceptin#aff3) Aysegul A. Sahin,4 (http://www.cancercell.org/content/article/abstract?uid=PIIS1535610804002107&highlight=pTEN and herceptin#aff4) Kristine S. Klos,1 (http://www.cancercell.org/content/article/abstract?uid=PIIS1535610804002107&highlight=pTEN and herceptin#aff1) Ping Li,1 (http://www.cancercell.org/content/article/abstract?uid=PIIS1535610804002107&highlight=pTEN and herceptin#aff1) Brett P. Monia,5 (http://www.cancercell.org/content/article/abstract?uid=PIIS1535610804002107&highlight=pTEN and herceptin#aff5) Nina T. Nguyen,1 (http://www.cancercell.org/content/article/abstract?uid=PIIS1535610804002107&highlight=pTEN and herceptin#aff1) Gabriel N. Hortobagyi,2 (http://www.cancercell.org/content/article/abstract?uid=PIIS1535610804002107&highlight=pTEN and herceptin#aff2) Mien-Chie Hung,3 (http://www.cancercell.org/content/article/abstract?uid=PIIS1535610804002107&highlight=pTEN and herceptin#aff3) and Dihua Yu1 (http://www.cancercell.org/content/article/abstract?uid=PIIS1535610804002107&highlight=pTEN and herceptin#aff1),3 (http://www.cancercell.org/content/article/abstract?uid=PIIS1535610804002107&highlight=pTEN and herceptin#aff3)

1Department of Surgical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030 USA
2Department of Breast Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030 USA
3Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030 USA
4Department of Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030 USA
5ISIS Pharmaceuticals, Carlsbad, CA 92008 USA http://www.cancercell.org/webfiles/images/ccell/pixel.gif Correspondence:

http://www.cancercell.org/webfiles/images/ccell/pixel.gif http://www.cancercell.org/webfiles/images/ccell/pixel.gifThe ErbB2-targeting antibody, trastuzumab (Herceptin), has remarkable therapeutic efficacy in certain patients with ErbB2-overexpressing tumors. The overall trastuzumab response rate, however, is limited and what determines trastuzumab response is poorly understood. Here we report that PTEN activation contributes to trastuzumab's antitumor activity. Trastuzumab treatment quickly increased PTEN membrane localization and phosphatase activity by reducing PTEN tyrosine phosphorylation via Src inhibition. Reducing PTEN in breast cancer cells by antisense oligonucleotides conferred trastuzumab resistance in vitro and in vivo. Patients with PTEN-deficient breast cancers had significantly poorer responses to trastuzumab-based therapy than those with normal PTEN. Thus, PTEN deficiency is a powerful predictor for trastuzumab resistance. Additionally, PI3K inhibitors rescued PTEN loss-induced trastuzumab resistance, suggesting that PI3K-targeting therapies could overcome this resistance.

[Becky]

Good job on getting the Herceptin and a Dr. who would give it to you.


You didn't let us know (or I missed it).

Best regards

Becky

[RobinP]

Yes, I did finally get someone who really knows the erbB pathways to recommend late adjuvant herceptin. I think it only made his decision easier knowing I was pTEN positive and TAB250+. Since I was in the GRAY zone, where the benefits are unknown, he recommended the 9 week regimen, like the FinHer trail, to be certain that I take on no cardiac risks when the benefits are uncertain. Besides, he really is convinced that adjuvant Herceptin efficacy is in the first several infusions. In time, we will know timing issues more clearly as they are going to do more and larger trails with the shorter 9 week regimen, I think,and compare with the longer runs.

[Becky]

My new onco and one of his partners agree that in the future, far less Herceptin will be used with the same good results as the one year regime. I guess we will see how the 1 yr versus 2 yr Hera arm works out to be (if there is a significant difference or not) and then there will be the trials that test one year vs 6 months versus 3 months (you can kind of see that coming).


I am very,very happy for you Robin. You worked hard and are a real asset to this site.

Warmest regards

Becky

[Barbara]

Robin:

Did you have the pTEN and TAB250+ testing done on a lab stored tissue specimen some time after your original surgery? Was the testing done by a speciality lab or at a university center? I am on my second year of Herceptin and have always wondered if I might be pTEN positive as that would improve my prognosis.

Barb

[michele u]

Robin, i spoke with a guy at Lab Core today. Very very nice guy. We are going to get my slides and send them in for the PTEN testing. Is TAB250 another biomarker they do at Lab core with the same specimens? The tests were only 190per biomarker, which i thought was very cheap. What exactly is that TAB250? Is is just another marker like PTEN?

[RobinP]

If you have pTEN present, Herceptin activates it and in vitro proliferation events decrease. So you might say that pTEN presence may enhance the effectiveness of Herceptin. Again, Herceptin only acts to bind her2 only if you are truely positive and have an extrcellular domain for Herceptin to bind to. TAB250 tests for the presence of the extracellular domain-ECD of her2. Again, if you have the ECD present, you probably will respond to Herceptin. Herceptin binds to the cleaved her2 ECD to downregulate it. And if you don't have an ECD on her2 which is possible if you have the truncated form, p85, then Herceptin has nothing to bind to. Perhaps, Lapatinib, a small molecule then might be indicated since it works inside the her1 and her2 cell as oppposed to on the her2's ECD .

I used the following lab and had 6 biomarkers tested for on my stored tissue block from 3 years ago . But Michele used lab core.

Targeted Molecular Diagnostics
610 Oakmont Lane
Westmont, IL 60559
1-866-897-7350
http://www.tmdlab.com/
LOOk at this; it's interesting, really! http://www.wallstreetreporter.com/linked/TargetedMolecularDiagnostics.html

[Gina]

You really did well and made the right decision about getting the Herceptin for yourself...I LOVE YOUR RESEARCH!!! Keep it coming,

Gina

[Barb]

Robin, whereever do you get your research from. I'm feeling like a true country bumpkin as to knowledge. Before I looked at this site, I thought I knew as much as I needed to know, but now, I'm not sure anymore.
Cheers
Barb

[Christine MH-UK]

This is a very interesting thread.

I know that the charity Cancer Research UK was doing a trial paralleling HERA to see if it could match the tumour characteristics of HERA participants with outcomes. I would imagine that they would be looking at the kinds of things that you have mentioned. It would be great if they could find out who doesn't respond because then they might be able to find out how to get the recurrence rate down even further.

My oncologist felt that Finher was significant, but needed more followup.

[Barbara]

Robin:

Your information has been very helpful. I did bring up TMD's website and looked at the Bio-marker menu. However, I could not figure out which of the tests is the one you called TAB250. What six biomarkers did you have run? Are they the ones you would recommend for woman who are ER- PR- and HER2 positive? I tested HER2 positive 6.9%. I thank you for any advice you might offer.

Barbara