HER2 Support Group Forums - View Single Post - Lani

Lani · 12-19-2007, 02:47 PM

Please note that the study you are interested is by the group including CKent Osbourne and Rachel Schiff that I believe to be doing some of the most interesting work on the understanding of the pathways involved in her2+ breast cancer. They have written a lot on how it is influenced by/influences the ER pathway--they along with Graciela Arpino published the original work on how/why the ER+PR- subset of tumors might benefit more from AIs than tamoxifen.

ER status is notoriously inexact unfortunately. And it looks like the results one gets with other methods one looking at ER and PR content differ markedly from that obtained using the traditional Allred method.

This paper shows that they are trying to dissect out the cherries vs the peaches vs the grapes in the fruit=salad that is called breast cancer, which so many other researchers lump together when trying to figure out cause, prognosis and best treatment.

I believe it is only by dividing and then subdividing out these types that we will find the cause (could be different for each), prognosis (we know these vary widely by subtype) and best treatment for (which 3 or 4 pathways are most important to the survival of any one breast cancer tumor, but some subgroups may share these).

That said, it is probably the molecular pathways which drive the tumor, rather than how they look on microscopy or how the inexact "art" of staining (and then reading the results) which can be modified by multiple factors (%ER+ can vary with stage of the menstrual cycle, %ER+ can be obscured if methylene blue was used at the time of the sentinel node biopsy, etc).

Why tumors do or do not respond to AIS, tamoxifen and/or chemo appears to be multifactorial and there is de novo (immediate) resistance AND acquired (developed) resistance to contend with.

Drs. Osbourne and Schiff have done some interesting work on the fact that there are two kinds of ERalpha--one which sits in the nucleus and works slowly and one which sits on the cytoplasmic (outside) membrane of the cell and works quickly and there is ERbeta and there are two types of PR, PR1
and PR2 involved to complicate the picture further. Drs. Schiff and Osbourne have studied the crosstalk mechanisms between her2 and ER and these are multifactorial as well.

It is only with enough tissue samples and highly powered computers and a lot of brainpower, will, passion and "propeller grease" (Tom used to call me propeller head!) that this puzzle will be worked out. I have gone to lectures at Stanford by mathematical modellers of networks trying to simplify the way the computer structures its analysis of this complicated web that.

At SABCS Dr. Yigel Yarden, who performed some of the seminal work on her2, spoke about this network analysis very eloquently.

From the abstract it seems they believe their work points toward classifying patient's tumors by assessing ER and PR by methods other than the Allred method and that it may be necessary to subclassify them as well.

I have a suspicion from my readings that much of the effect of antihormonals may be via their effect on cyclooxygenase (see the paper I posted today by a researcher at Ohio State who has published a lot of great papers on making a tissue specific drug which works as an antiaromatase only in the breast (bypassing lots of sideeffects hopefully) by modifying celecoxib (celebrex). My suspicion is likely to be entirely wrong, but I would suggest you read the papers by Bruggemeister (sp?) from OSU and see what you think.

Estrogen seems to have effects besides stimulating growth of breast cancer cells-- including angiogenic effects, whether directly or indirectly.

Similary NSAIDs have both antiangiogenic and antiaromatase effects. Those two facts may be relate, they may not.

The point is we only have insight into a tiny corner of an enormous puzzle.

That is what makes donating the specimens to help speed things up so important. Many poster presenters based their results on 20-60 tumors and felt lucky they had so many. Of those very few were ER+PR+ or ER+PR-. Since this group thinks there are at least 3 subgroups of her2+ER+PR-, how are we ever going to tease out the answer without more data?

Hope I answered your question...off my soapbox for now!

12-19-2007, 02:47 PM	#4
Lani Senior Member Join Date: Mar 2006 Posts: 4,783	still trying to get things organized and still answer some questions as best I can Please note that the study you are interested is by the group including CKent Osbourne and Rachel Schiff that I believe to be doing some of the most interesting work on the understanding of the pathways involved in her2+ breast cancer. They have written a lot on how it is influenced by/influences the ER pathway--they along with Graciela Arpino published the original work on how/why the ER+PR- subset of tumors might benefit more from AIs than tamoxifen. ER status is notoriously inexact unfortunately. And it looks like the results one gets with other methods one looking at ER and PR content differ markedly from that obtained using the traditional Allred method. This paper shows that they are trying to dissect out the cherries vs the peaches vs the grapes in the fruit=salad that is called breast cancer, which so many other researchers lump together when trying to figure out cause, prognosis and best treatment. I believe it is only by dividing and then subdividing out these types that we will find the cause (could be different for each), prognosis (we know these vary widely by subtype) and best treatment for (which 3 or 4 pathways are most important to the survival of any one breast cancer tumor, but some subgroups may share these). That said, it is probably the molecular pathways which drive the tumor, rather than how they look on microscopy or how the inexact "art" of staining (and then reading the results) which can be modified by multiple factors (%ER+ can vary with stage of the menstrual cycle, %ER+ can be obscured if methylene blue was used at the time of the sentinel node biopsy, etc). Why tumors do or do not respond to AIS, tamoxifen and/or chemo appears to be multifactorial and there is de novo (immediate) resistance AND acquired (developed) resistance to contend with. Drs. Osbourne and Schiff have done some interesting work on the fact that there are two kinds of ERalpha--one which sits in the nucleus and works slowly and one which sits on the cytoplasmic (outside) membrane of the cell and works quickly and there is ERbeta and there are two types of PR, PR1 and PR2 involved to complicate the picture further. Drs. Schiff and Osbourne have studied the crosstalk mechanisms between her2 and ER and these are multifactorial as well. It is only with enough tissue samples and highly powered computers and a lot of brainpower, will, passion and "propeller grease" (Tom used to call me propeller head!) that this puzzle will be worked out. I have gone to lectures at Stanford by mathematical modellers of networks trying to simplify the way the computer structures its analysis of this complicated web that. At SABCS Dr. Yigel Yarden, who performed some of the seminal work on her2, spoke about this network analysis very eloquently. From the abstract it seems they believe their work points toward classifying patient's tumors by assessing ER and PR by methods other than the Allred method and that it may be necessary to subclassify them as well. I have a suspicion from my readings that much of the effect of antihormonals may be via their effect on cyclooxygenase (see the paper I posted today by a researcher at Ohio State who has published a lot of great papers on making a tissue specific drug which works as an antiaromatase only in the breast (bypassing lots of sideeffects hopefully) by modifying celecoxib (celebrex). My suspicion is likely to be entirely wrong, but I would suggest you read the papers by Bruggemeister (sp?) from OSU and see what you think. Estrogen seems to have effects besides stimulating growth of breast cancer cells-- including angiogenic effects, whether directly or indirectly. Similary NSAIDs have both antiangiogenic and antiaromatase effects. Those two facts may be relate, they may not. The point is we only have insight into a tiny corner of an enormous puzzle. That is what makes donating the specimens to help speed things up so important. Many poster presenters based their results on 20-60 tumors and felt lucky they had so many. Of those very few were ER+PR+ or ER+PR-. Since this group thinks there are at least 3 subgroups of her2+ER+PR-, how are we ever going to tease out the answer without more data? Hope I answered your question...off my soapbox for now!