herceptin and AI synergy? Lani? anyone?

[sarah]

Hello,
I remember reading something about Herceptin and AIs having some synergy and needing to take them together. Here's my question. Could I safely stop taking my AI, Femara, while continuing to take Herceptin??? Most of my annoying side effects - bone loss, etc come from taking the AI.
I'd really appreciate advice
thanks
sarah

[Lani]

there has been a clinical trial showing that adding herceptin to letrozole(femara) improves disease free survival in those with metastatic breast cancer better than letrozole alone. The opposite has never been done.

Theoretically there is cross talk between the ER pathway and the her2 pathway and both should theoretically be blocked to avoid "escape" via the unblocked pathway. Dr. Slamon has stated at several conferences that he believes the best antihormonal treatment for those who are her2+ and treated with herceptin is faslodex, as it works in another way (it causes the estrogen receptors to fall off every cell irreversibly). Now that may be scary in those cells in one's body with estrogen receptors which do not often multiply and thus are unlikely to be replaced with new cells with estrogen receptors. These include the brain. Originally it was thought that faslodex may not cross the blood brain barrier, but a recent article supported that it does.

The absolute answer is not available and that may be because ER+her2+ breast cancer represents about 10% of all breast cancer and because a recent article I posted showed that delay from time of taking the biopsy to placing the specimen formalin may alter the ER, PR and her2 results. So a lot of "conclusions" and even Adjuvant online and results of many clinical trials and stats presented to patients may not be accurate. Lots to think about, but the answer is....we don't know yet.

[Rich66]

http://her2support.org/vbulletin/sho...ncer+treatment

[sarah]

Thanks Lani and Rich for this information. I didn't realize I was in such a minority being ER+. Reading Rich's post elsewhere makes it sound like you had better take them both. bummer, I was hoping to give up the Femara which has the side effects and stay on Herceptin for one more year. A friend suggested Evista/raloxifene which apparently is also good for the bones. Any thoughts or comments?

Here was Rich's post:
Combined ER and HER-targeted therapy in breast cancer treatment
Combined ER and HER-targeted therapy in breast cancer treatment

Citation: THE BREAST, Volume 18, Supplement 1, March 2009, Page S8

K. Osborne1, R. Schiff1

1Breast Center, Baylor College of Medicine, Houston, USA

The estrogen receptor (ER) and HER signaling networks are complex, redundant, evolvable and robust pathways, each with several regulatory controls. Several levels of crosstalk between these two networks act as modulatory circuits that when altered can contribute to resistance to therapies targeting them. Nuclear ER when bound by estrogen increases the expression of ligands binding to HER receptors while at the same time reducing the expression of the receptors themselves. At the same time, the HER signaling pathway reduces expression of ER and progesterone receptor (PR) while it can activate ER functionally through phosphorylation of the receptor and its coactivators. Therefore, blockade of ER signaling by endocrine therapy can increase the cellular content of HER1 and HER2, while blockade of HER signaling can increase the expression of ER and PR. Non-nuclear ER can also activate the HER signaling pathway by several mechanisms at the level of the cell membrane. Although there are several potential mechanisms for resistance to ER and HER-targeted therapy, preclinical data from our group and others, as well as supporting data from recent clinical trials, indicate that upregulation at the HER signaling pathway can cause resistance to ER-targeted therapy and that upregulation of ER signaling can cause resistance to HER-targeted therapy.
These data suggest that optimal treatment in some patients using therapies targeting these two pathways might necessitate simultaneous blockade of both pathways. In preclinical models and, now, data from clinical trials, simultaneous use of endocrine therapy to target ER and therapy targeting the HER receptor network can overcome resistance to endocrine therapy and delay the time to tumor progression. Using a combination of HER inhibitors to completely block the HER pathway together with ER blockade is very potent therapy in preclinical xenograft models of ER+/HER2+ tumors and is able to eradicate tumors even after short term therapy. In ER+ tumors that express initially low levels of HER receptors, the addition of HER receptor blockade to endocrine therapy anticipating upregulation of HER receptors during endocrine therapy delays the emergence of resistance and prolongs time to progression. Combined HER-targeted therapy in this situation does not eradicate these xenograft tumors indicating that other survival pathways still function and that these tumors have not yet become “oncogene addicted” to the HER pathway. There is an urgent need to biopsy patients immediately before embarking on targeted therapy to profile the tumor and to select the optimal patient for this new approach.

[sassy]

Zometa is another option for rebuilding bones with loss due to AI's. I have been on Zometa for three years. After an initial loss, showed an increase after beginning Zometa. (Zoledronic acid)

This article should be helpful.

BTW--welcome to the 10%!

http://www.medpagetoday.com/MeetingC...eeting/tb/7690

[Becky]

Evista and Tamoxifen work in the same way - binding to the ER site while AIs prevent the production of estrogen.

That said, Tamoxifen in Her2+ women is said to promote increased activation of Her2 but not if taken together with Herceptin.

One thought to explore with your medical team is going off the AI but switching to Tamoxifen or Evista during the time you are also on Herceptin therapy. You are blocking both receptors but Evista or Tamoxifen are much kinder to the bones (and can actually make the bones better).

Sassy's idea on adding Zometa is also a good one since not only does it rebuild bone but it also is a chemopreventitive (prevents mets not only in the bones but also in soft tissue).

[sarah]

many thanks for your answers and ideas. I really appreciate having all of you to talk to - you are my life line and extended family. let me know if you ever head to southern france.
I am going to take the article about the synergy between AIs and Herceptin (translated into pigin French!) to my chemo doc and ask her what she thinks about zometa and/or Evista.
I've handled the side effects for 5 years, so if all else fails, I can handle them for another year or so. I'm still trying to decide whether or not to stop Hercptin or continue for life. I wish they could believe in Gina's system or getting less and more depending on the serum test (not sure if it's done here).
I once asked about Zometa and they told me it's a monthly injection - is that correct? because that would complicate my life more!!!!
hugs and love to all of you and hope for good health and fun in your lives
sarah

[Becky]

Dear Sarah

Zometa is a monthly infusion IF you have bone mets. For osteopenia or osteoporesis, it is an every 6 months infusion. The first infusion is hard (the next day) with flu like symptoms and bone ache (maybe even a slight fever - I had one of 101). However, even with the next infusion being 6 months later, all the next ones are like nothing happened.

I am pretty sure you will not be permitted to take an AI and Evista as they are both antihormonals. However, even if you switch from the AI to Evista (or Tamoxifen), you can still get biannual Zometa infusions.

Cheers,

[Rich66]

"Dr. Slamon has stated at several conferences that he believes the best antihormonal treatment for those who are her2+ and treated with herceptin is faslodex, as it works in another way (it causes the estrogen receptors to fall off every cell irreversibly). Now that may be scary in those cells in one's body with estrogen receptors which do not often multiply and thus are unlikely to be replaced with new cells with estrogen receptors. These include the brain. Originally it was thought that faslodex may not cross the blood brain barrier, but a recent article supported that it does."

This is interesting. Based on the way it works, I've often wondered why Faslodex/Fulvestrant wasn't the go to endocrine treatment. There is info suggesting it has synergy with chemo other than Herceptin as well. Is there a quote from Slamon on this? Any info on the negative side effects suggested?

[Lani]

faslodex is only approved in stage IV and only after other antihormonals fail.

It is a monthly injection and so far, noone has tried to move it into the adjuvant setting

Haven't seen Dr. Slamon's opinion in print, but if I see a conference recording/video which contains this quote (I have heard him say it at least three times) I will try to remember to post the link.

[Laurel]

Okay, so in the adjuvant setting with our year of Herceptin and our 5 years of hormone therapy are we potentially upregulating the Her2 while trying to down regulate the ER/PR for the four years post-Herceptin that we continue with just the A.I.s? I recently decided to drop Tamoxifen and begin Femara after completion of my year of Herceptin. My understanding of Tamoxifen with Her2 is if you are not a high metabolizer than the metabolized Tamoxifen actually stimulates Her2. Not sure if I have this correct or not.
Feels like us members of the 10% club are flying blind on this one! Disconcerting at best.

[suzan w]

Hi Sarah, you might also check into Forteo (daily injection for 2 years) for bone improvement...worked for me. Once the Forteo is done, then it is a yearly Reclast (zometa) infusion.

[Rich66]

http://her2support.org/vbulletin/showthread.php?t=39563

[sarah]

Thanks everyone. You've offered possible solutions and given me good ideas.
A+ as they say here
sarah

[Rich66]

Bien sur. Avec plasir.

[sarah]

Merci, A+
Sarah
The Canadian living in France with universal health care and the joie de vivre!

[Lani]

this study done in humans, neoadjuvantly, looking realtime at adaptation of tumors to AI treatment.

It seems her2 expression was upregulated as a response to the estrogen deprivation.

Br J Cancer. 2009 Sep 15. [Epub ahead of print]

Nuclear receptor co-activators and HER-2/neu are upregulated in breast cancer patients during neo-adjuvant treatment with aromatase inhibitors.

Flågeng MH, Haugan Moi LL, Dixon JM, Geisler J, Lien EA, Miller WR, Lønning PE, Mellgren G.
[1] Institute of Medicine, University of Bergen, N-5021 Bergen, Norway [2] The Hormone Laboratory, Haukeland University Hospital, N-5021 Bergen, Norway.
Background:Acquired resistance to endocrine therapy in breast cancer is poorly understood. Characterisation of the molecular response to aromatase inhibitors in breast cancer tissue may provide important information regarding development of oestrogen hypersensitivity.Methods:We examined the expression levels of nuclear receptor co-regulators, the orphan nuclear receptor liver receptor homologue-1 and HER-2/neu growth factor receptor using real-time RT-PCR before and after 13-16 weeks of primary medical treatment with the aromatase inhibitors anastrozole or letrozole.Results:mRNA expression of the steroid receptor co-activator 1 (SRC-1) and peroxisome-proliferator-activated receptor gamma co-activator-1alpha (PGC-1alpha) was correlated (P=0.002), and both co-activators increased during treatment in the patient group as a whole (P=0.008 and P=0.032, respectively), as well as in the subgroup of patients achieving an objective treatment response (P=0.002 and P=0.006). Although we recorded no significant change in SRC-3/amplified in breast cancer 1 level, the expression correlated positively to the change of SRC-1 (P=0.002). Notably, we recorded an increase in HER-2/neu levels during therapy in the total patient group (18 out of 26; P=0.016), but in particular among responders (15 out of 21; P=0.008).Conclusion:Our results show an upregulation of co-activator mRNA and HER-2/neu during treatment with aromatase inhibitors. These mechanisms may represent an early adaption of the breast cancer cells to oestrogen deprivation in vivo.British Journal of Cancer advance online publication, 15 September 2009; doi:10.1038/sj.bjc.6605324 www.bjcancer.com.
PMID: 19755984