Question for RobinP

[Barbara]

Robin:

Many of us on the board do not have the knowledge that you do about cancer markers. You had said you had six tests run. Do you have a recommendation for PR- ER- Her2 positive women as far as appropriate tests? I did look at TMD's site and their list of tests and did not see the TAB250 test listed. Is there another name for it? The DNA Ploidy and S-phase fraction was run with the specimen right after my surgery in January 2004 along with the hormone receptors.

I would appreciate any advice you can offer.

Barbara

[RobinP]

Hi Barbara,
Thanks for the compliment. I have tried to learn my best about molecular markers to determine Herceptin's response or resistance pre-clinically as this was a great area of interest to me to help me decide if I had a good reason to start late Herceptin. I must admit that I had the help of one of the speakers from the SABC to determine what markers I needed. He actually referred me to Dr. Bacus at TMD lab who defined that list even further and more specifically. I shall list each test for you that she recommended with a description as to why.

1. Her2 by FISH with overexpression ratio. A her2-CEP ratio of over 4 is truly OVEREXPRESSION and not just amplification. As you know, those with overexpression of her2 usually respond more to Herceptin.
2. TAB250 tests for the extracellular domain of her2 to see if you have an intact extracellular surface with cleavage where the Herceptin fits into like a lock and key. If you are missing this extracellular domain, Herceptin can not bind to its target site. I believe via of my research that about 25% of early stage her2+ breast cancer do not have this extracellular domain and have p95 or truncated form of her2 rather than the elonagated form, p185.
3. pTen-test for the presence of pTEN in your tumor. If you have pTEN, Herceptin well activate it. It is the activation of pTEN by Herceptin that causes decreased proliferation events almost immediately after receiving Herceptin, even before downreguation of her2 by herceptin. So if you have pTEN,you probably will be a good responder to Herceptin particularly early on via of Herceptin exposure.
4. Her1 test to see if you have EGFR or her1. If you do, you may not only respond to herceptin but you may be a good candidate for Lapatinib which acts on her1 and her2.
5. Her3. The overexpression of her3 may cause Herceptin resistence. However, if you only have moderate to low over- expression of her3, you will probably respond to Herceptin. Unfortunately, TMD did not give me a quantitative result on her3, I only know that I do have it but not aware of how much expression. Hopefully, I am a low expressor.
6. Her4 is not so much a marker to determine Herceptin response but having her4 is thought to be favorable prognostic characteristic.
7. IGF-suggest that the IGF-IR/HER-2 heterodimer contributes to trastuzumab resistance and justify the need for further studies examining this complex as a potential therapeutic target in breast cancers that have progressed while on trastuzumab.


One thing you must understand, is that her2 does not work in and by itself. Interestingly, this forum is focused on one Epidermal Growth Factor, Her2. However, Her2 can only carry out its cancerous proliferation events with other infidel family members, her1 or her3 as her2 has no known ligands to bind with. Her2 heterodimers with her1 or 3 to form strong cellular signaling to set off a cascade of proliferation events. I wonder if being her2 would be a problem if you did not have her1 and her3. Funny, how her1 and her3 just are not spoken here on these forums when they play such a pivotal role in her2's jaded character.

PS. PLEASE REMEMBER THAT ALL THESE MARKERS ARE PRE-CLINICAL INDICATORS OF HERCEPTIN RESPONSE AND THIS MAY NOT TURN OUT TO BE INDICATORS IN THE HUMAN RESPONSE OR IN VIVO EXPERIENCE. I BELIEVE AS TIME GOES ON, MORE CLINICAL TRAILS WILL FIND THAT THE PRE-CLINICAL EXPERIENCE WILL CORRELATE WITH THE IN VIVO EXPERIENCE. HOWEVER, UNTIL CLINCIAL TRAILS PROVE THESE MARKERS HAVE EFFICACY , THERE IS NO MEDICAL BASED EVIDENCE FOR THEM, AT LEAST AT THIS MOMENT IN TIME. NONETHELESS, IF YOU WANT TO DRAW YOUR OWN LOGICAL CONCLUSIONS AS I HAVE, YOU CAN.

I CAN'T WAIT TO SEE IF THEY LOOK BACK ON THE SPECIMENS FROM THE HERA TRAIL FOR THESE MARKERS TO FIND OUT WHICH INDIVIDUALS RESPONDED AND NOT TO HERCEPTIN.

[Barbara]

Robin:

Thank you very much for your post. It will help me when I meet with my oncologist on Wednesday. I am stage 2B and in my second year of Herceptin. My cancer was HER2 neu amplified 6.9%. If I can have the additional tests run I may feel better about whether I may be benefiting from Herceptin. I know nothing is absolute but it still could help booster my spirits. Thanks again.


Barbara

[al from Canada]

Robin, that is very comprehensive and obviously know what you are doing or you wouldn't be requesting tests. I would like your opinion on a few more that I think should be run as our repetoir of targetted drugs increase; especially on new diagnoses:

p53: the gene responsible for apoptosis,

TOPO2, the expression that will tell you if you will respond to adriamycin. If you don't have this expression then there is no sense in taking adriamycin thus, potentially sparing future cardio problems resulting from the combination with herceptin.

VEGF: (let's see if I can get this right): vascular epithelial growth factor; this will determine response to anti-angiogenic drugs such as avastin

c-myc: closely associated to HER2 overexpression, if overexpressed will increase genetic transcription errors resulting in proliferation

PI3K: also closely associated with HER2 over-expression and, when inhibited, down-regulates HER2 and increases the effacy of herceptin.

COX2: so easily inhibited with drugs such as celebrex, over-expressed in many cancers, especially with HER2.

Regards,
Al

[sherri]

Al,
How do they do these tests? From Blood work? Do we have these tests in Canada? Because I asked for Serum HER2 and it seems we don't have it here yet.

[michele u]

Robin,

You never said. Does the lab core have the TAB250 test?

Sherri,
The biomarkers are better is off the original tumor block. The serum Her2 is a blood test.

[RobinP]

Al, I did have Dr. Bacus, a pathologist from TMD lab, help me select my tests after I told her what I was looking for, that is whether I would respond to Herceptin or Lapatinib or both. I agree with your repetoir of markers to be tested for targetted drugs and chemotherapy and suspect it will be standard of care in the future. P53 mutations often confers to chemotherapy resistance and Taxol is the most effective chemotherapy in this case.Cmyc is often resistent to chemotherapies as well; however, I haven't seen much research on Cmyc. I agree that TOPO2 expression correlates with anthracycline use. And PI3k levels correlates with pTEN levels, and IGF levels and perhaps with partial decreases in Herceptin responsiveness as Herceptin's impact on PI3K is only one of its pathways for decreased proliferation, the other being downreguation of her2 itself. As for VEGF and COx2, I think they are going to be ignored as markers for as Avastin never met its primarily endpoint, disease reduction in mets bc. unless detected early enough and Cox2 inhibitors, at least in theory may decrease angiogensis but I haven't seen many studies on it, particularly in the mets population.

Michelle, I haven't commented on lab core because I don't know a thing about it. I used TMD lab.

[Lolly]

Gosh you guys, this is really interesting information and it's very helpful to me that you are able to condense your conclusions from all the reading you've done into a more understandable format. Most of the time when I attempt to read the medical literature my eyes just glaze over. So thanks for "putting it all together" for us. It really helps!

<3 Lolly

[al from Canada]

Robin,

Avastin never met it's primary end-point in the general BC population but there is a revitalization of studies in HER2 because it far exceeded that endpoints in a few small trials, and as a result of molecular profiling along the HER2 / VEGF axis. VEGF testing makes sense as avastin is a very expensive drug and you wouldn't want to try it on everyone (like they did in that trial). I would like to see COX2 markers being checked because it is over-expressed in so many cancers and it is so easy to block. All this profiling has three basic purposes:
1. the obvious, so we know what drugs to throw at patients,
2. so we don't give drugs needlessly...the best example I can think of is anthracylins and,
3. a cost benefit analysis...a lot of countries medical budgets are over-stressed and this profiling actually cuts down the cost of health care

Lolly...your welcome

Al

[StephN]

"P53 mutations often confers to chemotherapy resistance and Taxol is the most effective chemotherapy in this case"

This quote interested me. Maybe the reason I was given a trial with Taxol for my raging mets 4 years ago before they had all the sophisticated testing.
I did talk to my med onc about p53 as I had come across something on this out of one of conferences back then. He said he hoped I had a good level of p53! (And I must had to have a complete response.)

Do you have some new trials bookmarked that I could take a look at??
Thanks

[Rupali]

Hi Robin and Al,

One thing which is confusing is that are all these tests done on blood samples or on actual tumor tissue sample.
Can I still get these tests done while I am on Herceptin and 1 year after my mastectomy.
Regards,
Rupali

[RobinP]

Al, thanks for the information regarding small studies and Avastin. I am ever hopeful that it newer and larger clinical trails will give Avastin a thumbs up. I certainly do see it as a potential drug in breast cancer treatment, particularly in syngery with other bc targeted regimens and chemotherapy.

I must say that you are very up on everything concerning her2 and treatments Al and I commend you for your knowledge and input on this site. I also believe that the day and age of emphirically administering various medications without known rationales is coming to an end, considering the proven benifit of targeted therapies. For example, Herceptin never would have been effective in the adjuvant trails if her2 was not screened for first. Lets hope for the long term success of other targeted bc drugs that are in trails now, like Lapatinib. Thanks God that pharmaceutical companies today are studying the histological make up of tumors and developing targeted drugs for those markers.

Steph, I am sorry to say that I do not have any book marks for p53, I know I read it recently but not sure where.

PS. To everybody who has asked, you must test your invasive tumor for these markers, not your blood.

[al from Canada]

Dear Robin,
Just to continue this train of thought just 1 more step:

There is a future in anti-angiogenic drugs but I feel that this can be maximized through multi-targetting with different drugs. For example: it is well know that herceptin resistant cells can be resensitized to herceptin with HER1 or multi-HER drugs such as lapatinib, pertuzumab and iressa. As well, the sum of taking these drugs together seems to be greater than the parts in terms of effacy. Likewise, per-clinical trial studies have shown that combining a macular degeneration drug such as lucentis (which is also made by genetech) augments the effect of avastin because it targets VEGF in a different way. I can see lucentis combined with avastin being used in cancer very soon just as avastin has crossed-over into macular degeneration treatment.

I think the way this works is because of the transcription between the different HER targets and likewise between VEGF targets.

Regards,
Al

PS more on anti-angiogenic drugs here: http://www.mdsupport.org/library/anti-angio.html

[RobinP]

Al,
Pharmaceutical companies have everything to gain from marketing drugs in novel ways, such as in drug combinations, to make them both more effective and profitable. Genetech is already combining Avastin and Herceptin in trails and I wouldn't be surprised either if future clinical trails will combine Avastin and Locentis