HER2 Support Group Forums - View Single Post - of that subpopulation of her2+ bc patients who have brain mets

Lani · 12-19-2007, 11:39 AM

the answer is it is unknown

there are several possibilities (and more I haven't thought or read about):
1)the arimidex is small enough to get past the blood brain barrier but the herceptin isn't and if there are bc cells in the brain which are not dormant
their ER pathway is "downregulated" by estrogen deprivation, but since their her2 pathway may not be blocked (Herceptin not crossing the blood-brain barrier) while ER is relatively blocked the cancer may increase the her2 pathway activity via crosstalk

2) the arimidex gets in but the crosstalk story is too simplfied and her2 does not get increased ( but IGFR, AKT, and other downstream pathways could still provide a "backdoor for the puppy wanting to get out" if the cells awake from dormancy and divide) This also may not happen--all those pathways and their positive and negative feedback loops haven't been figured out yet

3) Arimidex, its metabolites, or other entities it might complex with may not get through the blood-brain barrier. I have not looked up how many Daltons it is (measurement of size --molecules over a certain number of Daltons don't cross the blood-brain barrier) The fact that brain mets of ER+ her2+ tumors are not as agressive may relate to the antiestrogen treatment patients are receiving. It would be interesting to see if any of the patients did not receive antiestrogens (doubt), which took tamoxifen (felt to be less effective in those on her2 WHEN NOT on herceptin) vs AIs vs Faslodex

4) I have asked oncologists and drug company reps at SABCS last year whether faslodex crosses the blood brain barrier and they did not know.

It makes estrogen receptors fall off every cell in the body irreversibly--OK for nonbrain cells as they are constantly replaced throughout life and will come back on cells when treatment ends. Brain cells rarely get replaced so IF faslodex crosses the bloodbrain barrier, those brain cells will be deprived of what makes women smarter than men (sorry for the infusion of humor, but I couldn't control myself). Seriously, estrogen has an important role in the central nervous system.

Perhaps I am too cautious/pessimistic in painting my scenarios and armidex keeps the micrometastases in the brain at bay or creates an inhospitable environment for them, but the speed with which brain mets occurs in her2+ER+ patients (less than the 66 months or so before antihormonals might first be stopped)
makes me think they do not provide 100% protection--but then, perhaps those people are innately antihormonal resistant or it took just that long for acquired resistance to occur, or perhaps the time to recurrence was determined by the "angiogenic switch" and only then did the dormant cells start to multiply and before that presence/absence of estrogen wou;dn't have made a difference.

The experiments to tell which of these scenarios (or some other) applies are ongoing. We must do what we can to support that research!

4)

12-19-2007, 11:39 AM	#5
Lani Senior Member Join Date: Mar 2006 Posts: 4,783	MJo the answer is it is unknown there are several possibilities (and more I haven't thought or read about): 1)the arimidex is small enough to get past the blood brain barrier but the herceptin isn't and if there are bc cells in the brain which are not dormant their ER pathway is "downregulated" by estrogen deprivation, but since their her2 pathway may not be blocked (Herceptin not crossing the blood-brain barrier) while ER is relatively blocked the cancer may increase the her2 pathway activity via crosstalk 2) the arimidex gets in but the crosstalk story is too simplfied and her2 does not get increased ( but IGFR, AKT, and other downstream pathways could still provide a "backdoor for the puppy wanting to get out" if the cells awake from dormancy and divide) This also may not happen--all those pathways and their positive and negative feedback loops haven't been figured out yet 3) Arimidex, its metabolites, or other entities it might complex with may not get through the blood-brain barrier. I have not looked up how many Daltons it is (measurement of size --molecules over a certain number of Daltons don't cross the blood-brain barrier) The fact that brain mets of ER+ her2+ tumors are not as agressive may relate to the antiestrogen treatment patients are receiving. It would be interesting to see if any of the patients did not receive antiestrogens (doubt), which took tamoxifen (felt to be less effective in those on her2 WHEN NOT on herceptin) vs AIs vs Faslodex 4) I have asked oncologists and drug company reps at SABCS last year whether faslodex crosses the blood brain barrier and they did not know. It makes estrogen receptors fall off every cell in the body irreversibly--OK for nonbrain cells as they are constantly replaced throughout life and will come back on cells when treatment ends. Brain cells rarely get replaced so IF faslodex crosses the bloodbrain barrier, those brain cells will be deprived of what makes women smarter than men (sorry for the infusion of humor, but I couldn't control myself). Seriously, estrogen has an important role in the central nervous system. Perhaps I am too cautious/pessimistic in painting my scenarios and armidex keeps the micrometastases in the brain at bay or creates an inhospitable environment for them, but the speed with which brain mets occurs in her2+ER+ patients (less than the 66 months or so before antihormonals might first be stopped) makes me think they do not provide 100% protection--but then, perhaps those people are innately antihormonal resistant or it took just that long for acquired resistance to occur, or perhaps the time to recurrence was determined by the "angiogenic switch" and only then did the dormant cells start to multiply and before that presence/absence of estrogen wou;dn't have made a difference. The experiments to tell which of these scenarios (or some other) applies are ongoing. We must do what we can to support that research! 4)