important new article by Dr. Slamon et al

[Lani]

http://breast-cancer-research.com/content/10/1/R3

please see the sections on effect of her2 on 5 yr DFS, and effect of pAKT on 5 yr survival

Study on 141 tumors --patients all of Afro-American and Hispanic descent

If there was a tumor registry, they could quickly examine this in larger numbers of patients and perhaps it could become an acknowledged biomarker earlier, if warranted

[Lani]

Good news though. Stats were almost entirely pre-herceptin. Remember that before getting in a panic...

http://breast-cancer-research.com/co...df/bcr1844.pdf (now better formatted w less typos)

Found prognosis (5 year survival)depends on combination of her2/ER status AND Akt status, with worst prognosis in those with

triple negative + high Akt(suprisingly triple negative w low Akt patients fared much better)

her2+ ER- w high Akt patients, could be separated out into two groups, 20% 5 yrs DFS vs 60% 5yrs survival w her2_er- with low Akt

Her2+ ER+ --among these patients, 5 yrs survival was poor with our without elevated Akt , but those patients w elevated pAkt 5 yr DFS was worse:

high her2 neu combined w high Akt had the worst outcome--10-15% 5 yr DFS

her2 +patients had an average DFS of 2.8 years whether er+ or er- vs 3.9 year DFS in her2 negative patients.

More than 70% of patients with HER2/neu positive tumors had overexpression of pAkt, and the high pAkt tumors were associated with positive lymph nodes

luminal B patients (her2+ ER+) had pAkt levels of 42.3 compared to her2+er- patient's Akt levels of 56.3, and triple negative Akt levels averaged 35

her2+er- had 20% dfs w hi akt 60% w low Akt

The above stats were a bit hard to summarize as the provisional pdf does not include any charts , tables or graphs yet

all patients in this study got surgery and chemo a few got herceptin (toward the end of the study period)

They were primarily black and Hispanic as the study took place in an East LA County Hospital (Martin Luther King-Drew)



These tests could be done simply on normal paraffin embedded original breast biopsy specimens using only IHC (or FISH).

This is the kind of information one can get from a set of tumor specimens combined with patients medical histories ...hint , hint! WHEN I LAST LOOKED ONLY ABOUT 46 OF OVER 946 VIEWERS HAD OFFERED ACCESS TO THEIR SPECIMENS. We sure aren't going to be able to get researchers, cancer centers, etc excited about that, I am afraid. That's about one out of 22 persons offering. I originally made the suggestion in a thread started by, I believe, Alaska Angel who was grieving her friend as a way to both honor those lost and try to speed up research to prevent us from losing more. I will stop proselytizing here and let you know where I think this paper may lead...

If this pans out with larger numbers of patients of all ethnic groups, races
a newly diagnosed patient could be put into one of 8 different risk categories , the lowest being ER+her2-Akt- ...and, for example, the her2+er- person could know they were in the group with 20% 5 year survival or the group with 60% 5 year survival if no herceptin is given. With additional tumors and prognoses to analyze they may find that if they separate those with respect to, say her3+ status, as well, or PTEN high/ low status as well-- these patients may need, let's say the triple combo of Dr. Osbourne (herceptin, pertuzumab, iressa) or to herceptin+ avastin or other combined targetted therapy on an adjuvant bases to see if starting with "the big guns" ie combination targetted treatments can make the difference.

If separating these patients out by tissue microarray is necessary, that will take much more time to do clinical trials as they are much more expensive and require fresh frozen specimens. Luckily of the two trials I outlined above one drug company makes both drugs in one case (herceptin+ avastin) and two of the 3 drugs in the other (herceptin, pertuzumab) in the other. That company is Genentech and they also make a drug similar to Iressa called Tarceva, although I don't know if the Osbourne team tried it to see if it works the same, worse or better than Iressa. I would expect that years would get added on if one has to wait until drug companies agree to combine their efforts and funds in a clinical trial together rather than funding one of their own.

This type of study, where patients already were treated similarly, where one only has to retrieve specimens and do relatively inexpensive and simple tests
has a lot of merits (as well as pitfalls). But this one was done so well (under the guidance and supervision and with critiquing by Dr Slamon) that it is already the highlighted article on the website and one of the most highly accessed articles on the Breast cancer research site.

[MJo]

This is interesting to me because I got a painful rash on my hands with each dose of adriamycin. When I showed it to my oncologist he said "But you're not supposed to ...." I didn't ask him to finish the sentence because I was sick and spaced out from the AC. In my support group, an african american woman who was taking AC mentioned that black people often get a rash on their hands from adriamycin. Since my father's side lived on the Adriatic coast of Italy, I wouldn't be surprised if an African or two is in my gene pool, but what does the mean for my cancer? Should my doctor take into consideration that I might have African genes? I'm going to get my genes tested by one of these family tree gene sites to see Africa shows up. Should I mention it to my oncologist if it does?

[BonnieR]

What is Akt??? I am slow this morning....

[Lani]

the first page of the article itself, after the page with the names of the authors
starts with the word abstract, then it says background.

two sentences in that paragraph describe what Akt is

[Lani]

the first page of the article itself, after the page with the names of the authors
starts with the word abstract, then it says background.

two sentences in that paragraph describe what Akt is

[Lani]

what AKt is, how it works:
the first page of the article itself, after the page with the names of the authors
starts with the word abstract, then it says background.

two sentences in that paragraph describe what Akt is

[Lani]

the first page of the article itself, after the page with the names of the authors
starts with the word abstract, then it says background.

two sentences in that paragraph describe what Akt is

the first starts with The

[Lani]

two sentences in that paragraph describe what Akt is--I won't even refer to the first word in each sentence as it seems the CENSORS are at work

You will just have to guess the two sentences!

expression is a word they use too describe the output of a protein which is a product of a gene (amplification is the word they use for too mamy copies of the gene, rather than the protein (its product), by the way)

Many proteins are enzymes which are like machines that make the body work by building things they make up, or breaking bigger things down (to the building blocks the cells need) or to stop something from working when there is already enough of it.

A common plan in the body is the use of adding or subtracting a phosphate group (phosphyrylation) to activate (turn on) or deactivate(turn off) function of a protein, especially an enzyme.

One of the deadliest pathways leading to cell proliferation (the source of uncontrolled growth of breast cancer) and there definitely can be more than one, and usually many..is the PI3K pathway which involves Akt. This pathway can be turned on by her2neu (but also by IGFR1) activation among others, but can also be turned on separately further down the pathway (sort of like a diagram by Rube Goldberg-- who showing how letting a marble go down a path could in turn make a lever launch a rubber ducky which ended up in a tub that overflowed which caused a spring to shoot an arrow in the air which ended up hitting a bulls eye) independently of her2neu, which would potentially be a reason for a patient doing poorly even if herceptin worked for them. So if Akt itself is overexpressed and activated whether by her2 neu having passed on the phosphorylation batton to it via the PI3K pathway like a relay rase, or having received the baton from elsewhere, the proliferation rate tends to become out of control . When her2 is negative and Akt is not activated or in low amounts, the proliferation rate is the least and these are least likely to metastasize and be aggressive. If her2+ER-
the difference in 5 yr survival (because of differences in proliferation rate and the propensity to metastasize, it is assumed) was found to be 20% if AKt was high vs 20% if it was low. In those her2+er+ prognosis was not good with or without high Akt, but was worse with high Akt at 10-15% 5 year survival.

Now these patients were from poor backgrounds, so it is unsure if they really took their tamoxifen, AIs (don't know if they were on medicaid, how hard it is to get prescriptions filled) and it doesn't say which got radiation therapy (although their metastatic rate far exceeded their rate of local recurrence, so that probably was not a major factor in their decreased 5 year survival). They did get their chemotherapy and surgery (and in the latter days of the study a few got herceptin, but perhaps late)

Again, I recommend the lecture of Dr. Osbourne whose link I posted in a thread around the holidays. It has great cartoons of the cascade from her2 on the cell surface through all the intermediate cascades to the nucleus and shows which ones have more to do with proliferation and which ones more to do with other functions of cancer cells (mobility, etc)

[Becky]

Also, survival rate was so low for all categories - far lower than anywhere I have ever seen.

Secondly, Her2+, ER+ disease, from the literature, the Hera trial studies etc has always had a better prognosis than ER negative disease. Is that why you are alluding that Tamoxifen/AIs might not have been taken or taken consistently?