ER+her2+ breast cancer may be fundamentally different in its response...

[Lani]

more likely some of them may be:

European Society for Medical Oncology
Estrogen receptor status of HER2+ breast cancer correlates with response to anti-HER therapies

Brussels, 6 May 2010 -- An international team of researchers has discovered molecular evidence that may explain why some women with HER2 over-expressing breast cancer do not respond to drugs designed to target this important molecule.

The research, presented at the IMPAKT Breast Cancer Conference in Brussels, Belgium, could have an important impact on future clinical trial design and treatment strategies in HER2 over-expressing breast cancer.

The over-expression of HER2 --a molecule found on the surface of cells-- is an important marker in breast cancer. It had been associated with a poor outcome for women, but with the advent of anti-HER2 targeted agents, the prognosis for these women has improved.

But oncologists have known for some time that some HER2 over-expressing (HER2+) breast cancers do not respond to trastuzumab, currently the most commonly prescribed anti-HER2 agent.

Belgian and US researchers led by Dr Sherene Loi from the Institute Jules Bordet in Brussels set out to determine whether estrogen receptor status, another major biological variable in breast cancer, was involved.

"We looked at HER2+ breast cancer using gene expression data, array comparative genomic hybridization, cell lines and clinical data from nealry 2000 patients to determine if estrogen-receptor status plays a significant part in the biology of HER2+ breast cancer and response to anti-HER2 therapies," said Dr Loi.

"We found that estrogen receptor status of HER2+ breast cancer seems to be correlated with different responses to anti-HER therapies. Currently, the biological differences in the group of breast cancers that overexpress HER2 are largely unknown."

The results show that patients with ER+/HER2+ compared with ER-/HER2+ breast cancers may actually benefit more from drugs that inhibit the PI3K/AKT molecular pathway, as this could be the dominant biological pathway for tumor growth and progression, the researchers say.

"In contrast, our data suggest that inhibition of estrogen receptor --alone and in combination with such an inhibitor—could actually result in a worse outcome for the patient," Dr Loi adds. "This may help explain why researchers saw such a poor outcome in clinical trials where women with HER2+ cancer were given hormonal therapy alone."

[Rich66]

Perhaps related to ER/Her2 crosstalk (http://her2support.org/vbulletin/showthread.php?t=38998).

[michka]

Lani and Rich first let me thank you both for your precious contributions and the time you spend to share your findings. Do you know what drugs, if any, are "drugs that inhibit the PI3K/AKT molecular pathway" as written in the article? Michka

[Becky]

And also, what if Herceptin and an AI or Tamoxifen were given concurrently?

[Rich66]

There's conflicting/ongoing research on this..might depend on combinations tried. Some is HERE (http://her2support.org/vbulletin/showthread.php?t=43403) if you scroll down. I have contacted one researcher/clinician who combines Fulvestrant with Aromatas inhibs.

[Westcoastgirl]

Could someone please explain in layman's terms, what this means for we Her2+/E+ women. So much appreciated.

[Lani]

I prefaced the posting of the abstract with my opinion that its conclusions do not, in my humble opinion, hold.

I think there are several types of er+her2+ breast cancer not just one, so drawing conclusions based on separating her2+ breast cancer into er+ and er- may be misleading.

In this paper, they found that er+ breast cancers may not respond equally well to her2 targeted agents (despite the fact that neither the North American nor the HERA adjuvant herceptin trials came to that conclusion) and that they may respond to agents targeting PI3K/AKT (there are several in development, but none near FDA approval as far as I can tell from having attended the AACR annual meeting in mid-April).

They noted that adding an "estrogen receptor inhibitor" to a PI3K/AKT inhibitor may even worsen the outcome, as would using an "estrogen receptor inhibitor" alone. I can only guess that they mean tamoxifen as an estrogen receptor inhibitor as AIs work in a different way ie, inhibiting formation of the ligand for the estrogen receptor ie, estrogen. Fulvestrant is not an estrogen receptor inhibitor either as it degrades (destroys) the estrogen receptor.

I hesitated to post this as it is a summary of a paper given, so no way to check out the details and I knew those who were treated only with tamoxifen without herceptin might panic.

However, in light of the recently discussed problems with her2 testing and the retrospective nature of this study (vs. the prospective nature of HERA and the North American study), I would take this study with a grain of salt and utilize it as a spring-board to motivate one to look up other studies on the behavior differences between er+ and er- her2+ breast cancer and subtypes being found within er+ breast cancer.

This paper raises all kinds of questions, but answers none.

Why did I post it?

To remind people that unfortunately herceptin alone doesn't work for all so research is necessary to find out why (and how we can remedy that), to remind people that
there is oversimplification as to how many types of her2+ breast cancer there are and how each behave, to point out to people that there are pathways besides er and her2 which may become the driving force in a particular breast cancer and need blocking, and to remind people that the 5 subtypes of breast cancer (normal type, her2 type, luminal A type and luminal B type and basal type)
classification we now have is not all inclusive and leaves a lot of questions about er+her2+ breast cancer.
THe good news--just around the corner is a method to look at INDIVIDUAL circulating tumor cells (or those in bone marrow) and determine which pathways are active. With that knowledge, treating early by blocking the
three or so most active pathways simultaneously with agents effective against cancer stem cells, may allow shorter courses of more effective treatment and prevent dormant stem cells from launching a recurrence later or subclones of resistant cells from benefiting from lack of competition for resources.

[Rich66]

"a method to look at INDIVIDUAL circulating tumor cells (or those in bone marrow) and determine which pathways are active."

Well that could be a game changer as opposed to blocking pathways without knowing whether they are active. Considering te hnumber of pathways possible, very curious as to which/how many they could/would check. If you have a name or other info on it, do tell.
I'm still hoping they drill down to find fewer, but more fundamental approaches..like thwarting glycolysis and angiogenesis.

[sarah]

Hello,
It seems to me that most anti-estrogen tests are still on tamoxifen when AIs seem to be be given more frequently. Why aren't more tests including AIs?
Again Lani, many thanks for another interesting and informative post.
thanks
sarah

[Ellie F]

The debate rages on! I think Lani's comment about oversimplification of sub types of her 2 is certainly very relevant and as research continue I believe will bear this out.

Having recently had a bone marrow aspirate I am still CONFUSED about these sneaky cancer cell. Is the theory that csc just float around the blood stream forever, never dying just waiting for the opportunity to attach and grow? or are there csc produced in the bone marrow and then released into the bloodstream?If as a recent paper suggests they die after 3 days without signals does this mean there is a source in the bone marrow which harbours them and is never truly killed by any treatment? And what about women that never have a recurrence, does this mean that treatment has killed all the stem cells as well as circulating cancer cells?
Ellie

[Hopeful]

there is oversimplification as to how many types of her2+ breast cancer there are and how each behave, to point out to people that there are pathways besides er and her2 which may become the driving force in a particular breast cancer and need blocking, and to remind people that the 5 subtypes of breast cancer (normal type, her2 type, luminal A type and luminal B type and basal type) classification we now have is not all inclusive and leaves a lot of questions about er+her2+ breast cancer.

To this end, I invite you to give a look to the papers I posted in the articles forum yesterday:

http://her2support.org/vbulletin/showthread.php?t=45050&referrerid=1173

The first, in particular, is a little tough going, so you might want to start with the second to give a frame of reference. Here is a salient paragraph from the first paper that speaks to Lani's observation about Her2+ER+ bc, above:

"Of the 200 Her2+ tumors analyzed . . . 87 had concurrent gene expression data and were classified according to the gene expression subtypes. . . Strikingly, 83% of the Her2+ER- cases with available gene expression data were classified into either the basal-like or ERBB2 subtype, while only 30% of HER2+ER+ tumors were classified to any of the two luminal subtypes." (emphasis added).

HER2+ER+, while less common than HER2+ER- bc, is apparently far more heterogenerous in terms of gene alterations and pathways.

Hopeful

[Becky]

And that classification via genetic expression is why Herceptin works on some but not others (genetically they behave like Her2 negative cancers).

This is very much like the presentation Jean and I saw on ER+PRneg cancer (not taking Her2 into consideration). Some ER+PRneg cancers genetic expression is really like ER+PR+, some like ER-PR- and others are truly different and are, in reality, ER+PR-. But the group that is really ER+PR- is quite small.

Also interesting is that some ER+PR+ cancers look like ER-PR- and vice versa. This may be why progression occurs and why some do well on Tamox/AI and some don't and why some ER-PR- women might respond to an AI.

They really need to come up with new and better pathology testing that does things on a genetic expression scale.

[1rarebird]

I've read all these posts with great interest for obvious reasons. I am still uncertain as to the answer of Michka's orginal question:

"Do you know what drugs, if any, are "drugs that inhibit the PI3K/AKT molecular pathway" as written in the article?"

I think the answer may be that there are no drugs currently used for this approach to the PI3k/AKT molecular pathway, but there are some that are under development. Am I getting this right?

bird

[Rich66]

Possibilities:
Tamoxifen (http://her2support.org/vbulletin/showthread.php?t=41711) itself, Zoledronate acid (http://her2support.org/vbulletin/showthread.php?t=39563), green tea (http://her2support.org/vbulletin/showthread.php?t=44079), artemesinin (http://her2support.org/vbulletin/showthread.php?t=43153&highlight=Artemesinin), IP-6 (http://her2support.org/vbulletin/showthread.php?t=36019), Honokiol